The primary immunodeficiency disorders(PID) are associated with elevated risks for recurrent infections, autoimmunity, and types of cancer. The degree of tumor pre-disposition and underlying mechanisms involved are diverse among different categories of PID. The aim of this study is to evaluate the malignancies that develop particularly in clinical course of PIDs.
In this cross-sectional retrospective study, we evaluated the PID patients who developed malignancy followed at the departments of Immunology and Oncology between 2008-2018. We searched for the type of PID and malignancy, epidemiological data, clinical and laboratory findings, histopathological characteristics, treatment and outcomes of patients through their hospital records.
There were five cases of malignancies (3 males/2 females) associated with PIDs. The mean age at first admission, PID diagnosis and occurrence of malignancy were 7.2±2.7, 8.2±2.1 and 10.6±2.4 years respectively. Two patients diagnosed with autosomal recessive hyper-IgE syndrome developed stage IV gastrointestinal stromal tumor and human papillomavirus-associated squamous cell carcinoma, other two sisters with ataxia-telangiectasia developed stage IIIA nodular sclerosis classical Hodgkin lymphoma and hepatocellular carcinoma in the clinical course. Stage IA EBV-associated classical Hodgkin lymphoma was defined on another patient genetically diagnosed with CD137 deficiency recently. Three of these patients were died within the first year after cancer diagnosis.
Deep study of these situations may lead to the earlier diagnosis of disease, choosing the best treatment modalities available and development of novel therapeutic strategies to decrease morbidity and mortality. The clinicians must be vigilant about the association between immunodeficiency and tumor susceptibility which are two closely intertwined concepts.
In national PID registries, the incidence of malignancies in X-linked agammaglobulinemia (XLA) seems lower than in other primitive immune deficiencies.
We describe a teenager with XLA who developed a fulminant gastric adenocarcinoma.
A boy was diagnosed from birth with XLA (mutation of BTK exon 9) and received from early infancy adapted immunoglobulin replacement. He suffered of recurrent Campylobacter colitis, megaloblastic anemia and B12 deficiency. From the age of 8, he presented a recurrent Helicobacter pylori (Hp) gastritis finally eradicated at the age of 14 (mutation for macrolide resistance, repeated courses of high doses proton pump inhibitor, clarithromycin, amoxicillin, metronidazole, and finally bismuth). At the age of 16, he consulted with abdominal pain, weight loss and abundant ascitis. Tomodensitometry identified a voluminous gastric tumor, peritoneal carcinomatosis, liver and bone metastatic spread. Gastroduodenoscopy confirmed a muco-secretant adenocarcinoma HER2/Neu+++. Absence of CDH1 mutation. The tumor rapidly progressed and the patient died 2 months after the diagnosis. Retrospectively, the gastric biopsies showed atrophic gastritis of fundus, intestinal metaplasia and focal dysplasia for at least 5 years.
Genetic causes may be responsible of rare cancers in young patients. In humoral deficiencies, chronic Hp infection is the main factor involved in gastric carcinogenesis, and in case of symptoms, it should be early detected and eradicated. The improvement of outcome for those cancers is based on pathologic and molecular survey of any potentially precancerous lesion. Another major challenge is the multidisciplinary follow-up of those rare patients with a special attention for the transition period.
CVID, represents the most common symptomatic PID in adults in Costa Rica. It is characterized by hypogammaglobulinemia causing an heterogenous clinical phenotype including infectious, autoimmune, atopic and malignant complications.
We present a 37 years old male presenting CVID since his was 35 years old. The diagnostic of his PID was in contex of an episode of cryptococcal meningitis. At that moment, he showed low IgG (150 mg/dL), low IgM (16 mg/dL) and normal IgA, absent isohemagglutinins, poor response to vaccines and slight low B cells count (80 uL). He was succesfully treated.
Two years after, the patient consulted for subacute right upper quadrant pain and jaundice. The blood test revealed cholestasic and liver enzyme alteration. A thoracoabdominal CT was performed. At least 16 liver suggesting tumors images were found. Also CT manifested enlarged retroperitoneal and mediastinal lymph nodes.
The patient was admitted to the internal medicine service. A liver biopsy and an endobronchial ultrasound with transbronchial aspiration needle of a lymph node were performed. A flow citometry of the extracted lymph node requested.
The liver biopsy revealed germinal center DLBCL. Immunochemestry (IHC) was positive for HANS algorithm (Bcl-6, MUM1, CD10+).
Lymph node flow citometry reported the presence of 6.7% of mature monoclonal B lymphocytes (KAPPA +, LAMBDA-), in the absence of normal B cells.
Bone marrow biopsy resulted with DLBCL infiltration.
R-CHOP chemotherapy regimen was started.
PID is not only about infectious diseases. Unfortunately, we do not have the possibility of genetic squencing for PID diagnostic.
About 5% of patients with CVID develop lymphoma during follow-up. We hypothesized that lymphoma could be the revealing symptom of PID, challenging the current exclusion criteria for CVID diagnosis.
This French unicentric retrospective study analyzed adult patients presenting both a CVID-like phenotype and a lymphoma. For patients without a previous genetic diagnosis or extensive genetic investigation, a targeted Next Generation Sequencing of 301 PID-associated genes was performed.
Fifty-two lymphomas developed in 46 patients: non-Hodgkin B-cell lymphoma (65%), Hodgkin lymphoma (27%), and T-cell lymphoma (8%). EBV association was found in 15/33. In 25 patients, lymphoma developed before or within 6 months of the diagnosis of hypogammaglobulinemia. Compared to the 21 patients in whom lymphoma occurred during the follow-up of PID, Hodgkin lymphoma was overrepresented (48% versus 10%) whereas MALT lymphoma was absent (0 versus 33%). However, both groups presented with similar clinical and immunological characteristics, including age at hypogammaglobulinemia diagnosis (33.1 versus 31.4 years), consanguinity rate (20% versus 14%) or severe T-cell defect (LOCID, 44% versus 57%). Genetic analyses identified a probable molecular diagnosis in 9 patients, without peculiar gene recurrence. Possibly damaging variants of uncertain imputability were found in 10 additional patients.
Overall, a genetic cause for PID was identified in 20% of patients. Patients with lymphoma before or at diagnosis of hypogammaglobulinemia had similar characteristics than patients who developed lymphoma after a CVID diagnosis, and a high molecular diagnosis yield in the LOCID subgroup. Thus, a diagnosis of CVID-like PID should not be systematically ruled out in those patients.
Background and Aims:Tight regulation of IL-7Rα expression is essential for normal T-cell development and IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of T-ALL patients display very high IL7RmRNA levels and cases with IL7Rgains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear.
Methods: Overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7Rknock-in mice.
Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7Rknock-in mice drives thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia. The tumors mimic key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of PI3K/Akt pathway that is paralleled by downregulation of p27Kip1and upregulation of Bcl-2, and gene expression signatures evidencing JAK/STAT, PI3K/Akt/mTOR and Notch signaling activation. Notably, we also find that established tumors no longer require high levels of IL-7R expression upon secondary transplantation and can progress even in the absence of IL-7, but remain sensitive to the Bcl-2 inhibitor Venetoclax. The relevance of these findings for human disease are highlighted by the fact that T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases.
Conclusion: Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.
Malignancies are extremely rare complications of severe combined immunodeficiencies (SCID). We report 2 patients with X-linked SCID, who developed lymphomas.
P1 and P2 were diagnosed with X-SCID at the age of 2,5 and 7 months, respectively.
In P1 a lesion (34х37х38mm) of upper posterior mediastinum was detected via CT scan. Histologic examination confirmed EBV-positive Hodgkin-like lymphoprolipherative disorder. P1 received dexamethasone 6mg/m2/d for 15 days and rituximab 375mg/m2/week twice.
In P2 multiple small hypodensive foci in liver and single large focus (24х18х30mm) in spleen were found by ultrasound investigation. Complex anti-infectious therapy was not effective. After splenectomy the histological examination revealed EBV negative lymphoma unclassifiable with features intermediate between Hodgkin and large B-cell lymphomas. P2 received 2 courses of prednisolone 60mg/m2/d 15 days each with 15 days pause in between, rituximab 375mg/m2/week 4 times, brentuximab vedotin 1,8 mg/kg once in 3 weeks 3 times.
After the reduction of lymphoma foci in both patients allogenic hematopoietic stem cell transplantation (HSCT) from haploidentical donors with treosulfan/fludarabine based conditioning was performed. Patients are currently 20 and 4 months after HSCT, with full donor chimerism and no signs of active lymphoma.
We report 2 cases of lymphoma in SCID. Due to high risks of infectious complications in SCID, the use of chemotherapy may lead to intolerable toxicity. Both of our patients were successfully treated with short courses of steroids and targeted immunotherapy, followed by conditioned HSCT.
CVID courses with infections, autoimmunity, benign lymphoproliferations, and increased incidence of malignancies such as lymphomas and carcinomas. The most prevalent neoplasm is lymphoma followed by gastric cancer. Our objective was to evaluate the prevalence of malignancies in CVID patients from 1981 to 2019, followed at Division of Clinical Immunology and Allergy, HCFMUSP, São Paulo/Brazil.
Review of medical records of adult CVID patients.
We evaluated 180 CVID patients (55% women). Mean age at onset was 13.2y, mean age at diagnosis, 33.6y. Time between onset and diagnosis was 20.3y and time of IVIG replacement was 21.4y. Thirty-five patients developed cancer: 13 gastric tumor; 6 non-Hodgkin and 1 Hodgkin lymphoma; 7 skin; 2 colorectal; 2 thyroid; 2 breast; 1 gallbladder; 1 adrenal cancer. Average disease time of patients was 36y, and mean age at cancer diagnosis 45.2y, being their mean ID diagnosis before cancer 30.8y. Regarding gastric cancer, 12 patients presented adenocarcinoma and one well differentiated neuroendocrine tumor. Five died, mean time of fatal evolution, 48.6mo. There was no age difference between gastric patients’ survivors and non-survivors. Ten patients presented gastric atrophy, autoimmunity and lymphocyte number alterations, 11 intestinal metaplasia, 7 H. pylori (+) and all had chronic diarrhea and IgA deficiency. We observed an increase in gastric tumors’ prevalence in the last 5 years, being before 2013, 0.23 new cases/year and after, 1.20 new cases/year.
Unlike reported in literature, the most frequent malignancy observed in our cohort was gastric cancer. We observed a striking increase in incidence in the last five years.
Primary immunodeficiencies(PIDs) are characterized by susceptibility to infections, autoimmunity but also cancer. Chromosome instability, chronic antigenic stimulation, tissue inflammation, impaired cell development and impaired immune surveillance may play a crucial role in the appearance of cancer in PIDs.
The aims of this study are to establish the frequency and evolution of the lymphoproliferative diseases in PIDs, in comparison with that of lymphoproliferative diseases without PIDs.
We analyzed 220 patients aged 0-18 years, diagnosed with PID in the period 1990 – 2018.
18 patients (8,1%) developed lymphoproliferation (8 females and 10 males): 1 case with acute myeloblastic leukemia, 9 cases with non-Hodgkin lymphoma and 8 cases with lymphoproliferative disorders. The types of PID were: congenital neutropenia-1 case, ataxia-telangiectasia-1 case, hyperIgM syndrome-1 case, IgA deficiency-1 case, LRBA deficiency-1 case, TACI deficiency – 1 case, APDS- 1 case, CVID- 2 cases, combined immunodeficiency-2 cases, ALPS-2 cases and 5 cases with Nijmegen breakage syndrome. In 10 patients (55,5%) the onset of lymphoproliferative disorder preceded PID diagnosis. Treatment consisted in IVIg-11 patients, chimiotherapy-12 patients, G-CSF-2 patients and BMT-1 patient. 10 patients (55,5%) deceased. Mortality rate in patients with malignant lymphoproliferation was 70%. Mortality rate in 649 patients diagnosed (in the same clinic) with malignant hemopathies (AIDS patients were excluded) but without PIDs was 40,6%.
PIDs show a significantly higher incidence of lymphoproliferation. All patients with lymphoproliferation should be investigated for PID. The mortality rate was significant higher in patients with PIDs and malignant hemopathies in comparison with the patients with malignant hemopathies and without PIDs.
Patients with immunodeficiencies especially the severe-combined(SCID) and common-variable(CVID) types have an increased risk of developing malignancy due to a defective immunity towards cancer cells. Thus, we herein report the importance of targeted multigene panels via next-generation sequencing(NGS) via cases based review to clarify the genetic background of susceptibility to neoplasms and SCID diagnosis.
The major focus of this study is on malignancies that develop in SCID patients whom the customized multigene panel testing (QiaSeq, Qiagen) including ABL1, ASXL1, ATRX, BCOR, BCORL1, CBL, CBLB, DAXX, DNMT3A, EED, ETV6, EZH2, FLT3, GATA1, GNAS, IDH1, IDH2, IKZF1, JAK1, JAK2, JAK3, KAT6A, KIT, KMT2A, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PRPF40B, PTPN11, RAD21, RB1, RUNX1, SETBP1, SF1, SF3A1, SF3B1, SH2B3, SMC1A, SMC3, STAG2, SUZ12, TET2, TP53, U2AF1, U2AF2, WT1 and ZRSR2 genes related to myeloid and lymphoid malignancies was performed via NGS (MiSeq Platform, İllumina).
Bioinformatic analysis were performed using QCI-Analyze and QCI-Interpret tools. The data was then reviewed on alterations and those reported in different variant/mutation databases. The clinically relevant alterations were classified due to ACMG criteria. Overall, pathogenic/likely-pathogenic variants in DAXX, ABL1, ZRSR2, NF1 and JAK1 genes were detected due to databases or in-silico analysis.
In most PIDs when the molecular defect is known, the molecular mechanism leading to malignancy can be determined by NGS technologies. It seems, however that diagnosing the SCID patients with NGS multigene panels resulting the treatment strategies effectively, also using more targeted multigene panels influence both the lifespan of these patients and the treatments might have changed.
Common variable immunodeficiency (CVID) is one of the clinically most important primary immunodeficiencies. Clinical picture of untreated patients usually includes complicated recurrent respiratory tract infections. Patients with CVID are in higher risk of lymphoreticular malignancies and gastric cancer. On the other hand, haematological malignancies and their therapy can lead to hypogammaglobulinemia development.
We present a case of 59-year-old female patient with the history of recurrent lower respiratory tract infections and bronchopneumonias since early childhood. The frequency and course of infections became worse after the diagnosis and the therapy of B-cell Non-Hodgkin Lymphoma. Laboratory tests revealed three-isotype hypogammaglobulinemia, but results could have been influenced by recent anti-CD20+ targeted therapy (rituximab).
Since laboratory examinations performed in the past before lymphoma diagnosis and therapy have also shown hypogammaglobulinemia, and B cell depletion persists more than one year after the last administration of rituximab, we suspect primary immunodeficiency (CVID) to be the cause of antibody deficiency and later development of lymphoma. Moreover, detailed patient's history analysis (bronchiectasis since early childhood, heterotaxy) lead to suspicion of primary ciliary dyskinesia (PCD), which was confirmed by the analysis of ciliary kinematics.
We would like to point out that some of patients with lymphoreticular malignancy may represent undiagnosed CVID patients. The documentation of these patients from the period before manifestation of lymphoreticular malignancy has to be carefully analysed to discover possible clinical signs and laboratory findings typical for immunodeficiency. Moreover, we would like to raise the awareness about primary ciliary diskinesia as a cause of early bronchiectasis development.
Nijmegen breakage syndrome (NBS) is a syndromic disorder of DNA repair resulting in microcephaly, growth retardation, immunodeficiency, and cancer predisposition.
We performed clinical, immunological, and genetic analysis.
Two sisters of 7 and 16 years presented to us with failure to thrive, microcephaly, bird-like face, and chronic lung disease. Immunological work-up revealed hypogammaglobulinemia, low switched-memory B cells, and loss of T-cell naivety. Additionally, the younger sister had T-cell acute lymphoblastic leukaemia treated with conventional chemotherapy three years ago. We found the known Slavic homozygous NBN nonsense variants (c.657_661del5) confirming NBS. PCP prophylaxis and immunoglobulin replacement were started. Two months later, the index patient developed aggressive, diffuse large B-cell lymphoma stage III with infiltration of the kidneys, liver, spleen, pancreas and thyroid gland. Modified chemotherapy according to the B-NHL 2013 protocol was initiated and led to partial remission. Due to the high relapse risk and to cure the associated immunodeficiency, the patient and her family opted for allogeneic hematopoietic stem cell transplantation (HSCT). After reduced intensity conditioning, the patient underwent allogeneic HSCT from an HLA compatible (9/10) matched unrelated donor. Her post-transplant course was complicated by transient kidney dysfunction and the development of acute GvHD °IV involving skin (°II) and gut (°IV). After intensive treatment with methylprednisolone, infliximab and ruxolitinib the patient’s condition stabilized.
NBS is associated with a very high risk of variable hematopoietic malignancies. Apart from conventional treatment individualized allogeneic HSCT approaches are feasible and can correct the immunodeficiency and reduce the risk of recurring hematopoietic malignancies.
Primary immunodeficiencies (PIDs) are often associated with malignancies due to lack of immune response to cancerous cells. Next-generation-sequencing (NGS) is a great success of genetic testing to identify specific genes that, when altered, confer clinically recognized traits such as cancer susceptibility. Thus, it becomes a clinically useful tools to test a patient for both PID diagnosis and enables predictive genetic testing. In this our case-based review, a multi-gene panel NGS based testing offers significant benefits even though a benign variant in relation to PID might be related to susceptibility for malignancies.
We performed next-generation-sequencing (MiSeq, Illumina) via a customized multi-gene panel including 18 genes related to SCID (severe combined immunodeficiency) (IL7R,LIG4,RAG1,AK2,FOXN1,JAK3,CTPS1,CORO1A,PTPRC,PRKDC,RAG2,DCLRE1C,CD3D,IL2R, ADA,NHEJ1,CD247,PNP) from peripheral blood samples of clinically SCID diagnosed patients.
As a result of our multi-gene panel NGS testing we detect heterozygous p.T414M and p.V138I variants in IL7R gene which is classified as benign according to ACMG (American Collage of Medical Genetics) criteria for SCID phenotype. However, these under specified variants are also related to lynch syndrome and myeloid neoplasms.
Multi-gene panels via NGS offer significant benefits however, with complications of main three uncertainties (1) the penetrance of cancer risk (2) the scope of cancer risk (3) the clinical relevance of variants which the spectrum of normalcy is not well defined. To sum up, skilled genetic testing laboratory for both molecular diagnostics and immunodeficiencies are crucial to design and to determine the clinical and society value of multi-gene panel testing via NGS technologies.
Germline heterozygous GATA2 mutations causing GATA2 deficiency are characterized by a broad phenotypic spectrum including cytopenias, severe bacterial, viral and nontuberculous mycobacterial infections, myelodysplasia and myeloid leukemias, pulmonary alveolar proteinosis, and lymphedema. The only curative treatment is allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Based on our experience with three cases, we address the difficulties often faced by clinicians in this extraordinary syndrome that was only identified in 2011.
Hematological, immunological and genetic analyses were performed.
Three GATA2-deficient patients were diagnosed in our center. All had MDS/AML and low monocyte, B-cell, NK-cell and dendritic cell counts. Two patients also had severe infections. Unfortunately, there are no guidelines regarding the optimal timing, conditioning regimen, donor source and antimicrobial prophylaxis for HSCT. Patient 1, a female, is doing well under immunoglobulin replacement therapy nine years after chemotherapy for AML, without HSCT. Patients 2 and 3, males, both underwent allo-HSCT because of life-threatening infections and MDS, but using different conditioning regimens and donor types. Patient 2 suffered from severe chronic GVHD and died four years post-transplant from ischemic heart disease. Patient 3 was transplanted using more intensive non-myeloablative conditioning, and is currently doing well two years post-transplant.
Furthermore, mutation analysis of GATA2 turned out to be technically cumbersome. In one patient, intensive screening for mutations was negative and was only found through array-CGH.
Although there are still challenges in clinical practice that need to be overcome, increasing experience in transplanting these patients has gained insight on optimal donor and stem cell source and conditioning.
The risk of malignancy in Primary Immunodeficiency patients is high, especially with Ataxia-Telangiectasia (AT) – 30% develop malignancies, and T-cell leukaemia is frequent.
We intend to highlight the need for awareness concerning the risk of malignancy in AT, with emphasis on the importance of surveillance.
26-year-old male, diagnosed at the age of 3 with AT, presenting a homozygous mutation of the ATM gene on exon-28. He has been under surveillance ever since, with regular immunological workup including immunoglobulin levels and evaluation of lymphocyte subpopulations.
Since 2013, a population of CD8+/CD4+dim T-lymphocytes was detected by flow-cytometry (9% of T-lymphocytes), remaining relatively steady until 2019, when a considerable increase was found (20,5%). In result, T-cells were characterized in more detail.
There was no lymphocytosis nor cytopenias. TCRα/β+CD8+ T-cells (which represented 73% of peripheral blood T-cells, and from which 23% were CD4+dim) were increased in number (1145/mm3), had an immunophenotype indistinguishable from that typically found in T-cell Prolymphocytic Leukaemia (T-PLL) and strongly expressed the oncoprotein TCL-1, which is usually related with cytogenetic changes typical of T-PLL. Therefore, genetic (TCR gene rearrangements) and cytogenetic studies were requested and bone marrow evaluation was suggested.
In patients with AT, T-PLL can be preceded by a clonal (pre-leukemic) T-cell expansion.
It is imperative that clinicians are aware of the enhanced risk of malignancy in AT, namely T-PLL, so that proper surveillance and timely diagnosis are possible, allowing for a better treatment planning, so critical in these patients.
MAGT1 is a critical regulator of intracellular free Mg2+ in the immune system. Its loss-of-function mutations abolish the transient TCR-induced Mg2+ flux that is essential for optimal T-cell activation. Our aim is to report a case with XMEN disease.
The index patient is a 12yo boy, born at term from healthy, non-consanguineous parents, with family history of Burkitt Lymphoma in a maternal uncle. Since 5yo, he suffered recurrent cervical and abdominal lymphadenopathy. His EBV serologies showed past infection and EBV-PCR was persistently elevated. Immunological study showed dysgammaglobulinemia, normal CD4/CD8 ratio, increased TCRαβ CD4-/CD8- and low memory B cells. We analyzed NKG2D expression, intracellular signaling (Akt and S6 phosphorylation and Ikba degradation), in vitro activation assay with PMA and with specific stimuli (anti-CD3/CD28) and in vitro VEB-specific response.
Genetic analysis (NGS customized panel) revealed a novel hemizygous mutation in MAGT1 gene. The mutation, c.97_98delinsC (NM_032121), was confirmed in heterozygosity in his mother. His uncle was unaffected. NKG2D surface expression in NK and CD8+ cells was absent. Basal intracellular signaling (Akt and S6 phosphorylation) was similar than HD. Ikba degradation in B cells is normal, but there is a slight defect in CD3+ (pending on confirmation). Activation markers (CD69, CD25 and CD86) were decreased after anti-CD3/CD28 stimuli. Decreased NK degranulation upon incubation with K562 cells was observed, but it was normal after PMA/Ionomycin stimulation. VEB-specific response in vitro was impaired.
XMEN disease should be ruled out in male with impaired clearance of EBV-infection and EBV-driven lymphoproliferative complications.
The aim of this study is to expose the prevalence of neoplasms in patients diagnosed with Common Variable Immunodeficiency (CIVD) assisted at the Hospital das Clínicas da UFMG (HC-UFMG) and to elucidate the importance of specific investigation for lymphoproliferative complications.
Patients that were followed-up in the HC-UFMG Primary Immunodeficiency Service with diagnosis of CVID from January 1990 to April 2019 were selected. A retrospective study of neoplastic complications and their outcomes was performed.
Of the 120 patients with CVID in follow-up at our service, 7% evolved with neoplasms. Among these, 50% presented lymphoma, mainly B-cell lymphoma, 37.5% had gastric tumor and 12.5% had skin or thyroid neoplasia. In more than 75% of the exposed cases, good results were obtained.
Patients with CVID have different immunological profiles and heterogeneous phenotypes. One of the cost commonly found alteration is the decrease in B memory cells. The CVIDs have a high occurrence of malignancy explained by multifactorial factors. This fact leads to a worsening of the prognosis that requires an anticipation of the diagnosis of tumor implications. Thus, the institution of treatment is sought as soon as possible to improve the quality of life and avoid early mortality.
Ataxia-telangiectasia (AT) is associated with high incidence of malignancies. Most patients do not survive beyond the age of 30.
AT is often associated with abnormal liver function tests, and nonspecific liver histological changes. Since 1979, development of hepatocellular carcinoma (HCC) has been reported in four patients. A case of a 36-years-old male with AT treated for HCC is described
Clinical case description.
AT was diagnosed at 2 years age out of neurological signs, telangiectasia, elevated levels of alpha-fetoprotein and genetic test positive for mutation on ATM gene. Patient became wheelchair-bound during his second decade of life. Comorbidities are hypotiroidism, insulin resistance, and chronic pleural effusion after acute pericarditis.
In 2017, at the age of 35, annual liver ultrasound showed a well-defined mass of 3.77cm in the right lobe. Magnetic resonance (MRI) revealed a typical HCC. Serological and molecular markers for hepatitis, EBV and CMV were negative. After multidisciplinary discussion, local treatment was identified as the best therapeutic option.
A successful and uncomplicated transcatheter arterial chemoembolization (TACE) was done in June 2017. Periodical MRI showed complete remission for 12 months. Then, HCC relapsed and two further treatments with TACE plus LUMITM radiopaque beads were performed. Six months after the last TACE, April 2019 MRI showed six new 7mm HCC lesions around the necrotic main lesion.
Patient is well. Liver function is fair. Elevated AFP levels (200ng/mL) remain as before the diagnosis of HCC.
HCC is rare in AT, local treatment can be addressed with caution for x-ray exposition and AT complications.
Emberger syndrome, related to GATA2germline mutation, is characterized by primary lymphedema and predisposition to myelodysplasia/acute myeloid leukemia (MDS/AML).
We describe the history of 2 Emberger patients with very different evolution overtime.
The first patient, a 15-year-old girl, presented with lymphedema of the right lower limb lasting for 3 months. The initial workup revealed anemia (hemoglobin 6g/dl) and leucopenia (WBC 2,54 x109/L) with 6,5% blasts in the peripheral blood. AML with clonal monosomy 7 was diagnosed and heterozygous germline GATA2 mutation (c.954_970 del;p.Cys319Aspfs*59) was identified. Surprisingly, lymphedema regressed rapidly after initiation of chemotherapy. Despite related allogenic stem cell transplant, the patient relapsed and displayed concomitantly a resurgence of lymphedema. An unrelated transplant allowed transient AML remission and improved lymphedema but a second relapse led to the patient death after 28 months.
The second patient was 3-year-old when referred for severe progressive bilateral lymphedema of the legs. Subsequently, she developed recurrent infections including meningococcemia, genital warts, auto-immune anemia and hypothyroidism. A combine immunodeficiency with immunoglobulin, partial phagocytic, and transient complement deficiencies was demonstrated. Genetic analysis confirmed an heterozygous c.1186C>T;p.Arg396Trp GATA2 mutation. The patient has been on continuous immunoglobulin substitution for 26 years without developing MDS/AML.
This is the first report of a chronological relation between lymphedema and AML in Emberger syndrome although it was not supported by our second observation. Factors such as type of mutation, inflammation, blood viscosity and additional genetic event should be further investigated to determine the potential interactions between both disorders.
We present a case of an asymptomatic man found to have mild pancytopenia and a large spleen who was closely monitored for 6 years but deteriorated rapidly over 3 months with neutropenic sepsis, EBV viraemia and multi-organ failure despite prednisone, immunoglobulin replacement, G-CSF and antibiotic treatments. There was no family history of immune-dysregulation.
Blood tests and histopathology studies were performed at Canterbury Health Laboratories an accrediated tertiary hospital laboratory. Hospital post-mortem was performed at Christchurch Hospital. Relevant tissue samples were embedded in paraffin, stained with H&E and examined under the microscope.
Investigations (age 64-70): mild neutropaenia and thrombocytopenia; spleen 20 cm; bone marrow trephines x2 and spleen biopsy normal.
Investigations (age 71): severe pancytopenia; hepatosplenomegaly; granulomas found in bone marrow and liver; negative staining for mycobacteria/fungi; hypogammalobulinemia; very low T and B cells, EBV viraemia 572000 iu/ml; EBER + Reed-Sternberg-like cells.
Post-mortem results are pending.
The sudden rapid deterioration was suggestive of a profound combined immunodeficiency with a failure of EBV control. The lymphoma diagnosis in the setting of granulomatous/reactive bone marrow appearances was challenging. Due to uncertainty and possibility of a congenital condition, DNA was extracted and stored for future use.
In the last decade, CVID patients increased their life expectancy due to improvements in prevention and treatment of severe infections. The relevance of non-infectious complications like ILDs and malignancies in terms of morbidity and mortality is thus increasing.
In this retrospective single-centre study, we analysed a single-center cohort of CVID patients, focusing on the presence of GLILD and malignancies in their clinical history. We analysed cancer prevalence in patients with and without features of ILD.
Among a cohort of 117 patients with diagnosis of CVID, 18 patients had clinical-radiologic and/or histologic features of GLILD (15.4%). The median follow-up was 15 years. In the whole cohort, 28 patients (23.9%) presented a history of malignancy. As expected, these were mainly lymphoproliferative diseases (n=12), (T-Large granular lymphocytic leukemia, B-cell lymphomas) and gastric cancers (n=5). 6/27 patients developed more than one malignancy.Of note, 7 of 18 patients with GLILD features (39%) presented at least one cancer (2 presented T-LGLL and NHL, 1 had pancreatic carcinoma) whilst 21 of the other 99 CVID patients (21%) presented a diagnosis of malignancy; difference was not statistically significant. 6 GLILD patients (33%) presented 8 neoplastic lymphoproliferative diseases (LPDs), while 6 non-GLILD patients presented 6 LPDs (6%); difference was statistically significant (p<0.01).
GLILD patients presented a higher cancer prevalence if compared to the other CVID patients, with a significant increase in LPDs. A more careful follow-up is thus needed in presence of GLILD, since LPDs might be difficult to recognize when occurring in this context.
Non-Hodgkin lymphomas (NHL) account for approximately 6-7% of pediatric cancers and their incidence increases with age. Patients with PIDDs show a higher susceptibility to hematopoietic malignancies, in particular to NHL. Recently new gene defects responsible for PIDDs with lymphoproliferation as a key clinical sign have been identified. Our goal is to investigate possible immune-mediated mechanisms underlying malignant lymphoproliferation in children who did not show other typical symptoms of PIDDs.
We retrospectively selected and reviewed the clinical history of eight patients with NHL (6 Burkitt lymphoma, 2 large B cell lymphoma and 1 lymphoblastic T cell lymphoma). Immunophenotyping and exome analysis of known PIDDs genes were performed after lymphoma remission.
Six out of eight patients showed a mild hypogammaglobulinemia at time of presentation, not noticed before. Moreover, one patient had history of recurrent respiratory infections, one of hematologic autoimmunity and two of eight were EBV-positive at diagnosis. Preliminary results show an aberrant B cell phenotype in four patients; exome analysis reveals a novel heterozygous genetic variation in IKZF1 gene in one patient with Burkitt lymphoma and autoimmune cytopenia was identified. Concerning the remaining patients, further studies are ongoing.
A detailed review of clinical history of pediatric patients affected from NHL as well as an impaired immunophenotyping can be important indicators of immune-mediated disorder underlying lymphoproliferation and helpful signs of possible PIDDs that should promptly be investigated by genetic analysis. This will allow an appropriate diagnosis and disease management.
Malignancy may be the first presentation of primary immunodeficiency (PID). Diagnosis of PID could alter management and delay in diagnosis may result in further organ damage.
This review aimed to determine:
whether immune investigations were undertaken for children with lymphoma.
number of children with abnormal immunoglobulins prior to or during treatment and whether immunoglobulin replacement was provided.
whether any child was diagnosed with PID.
A retrospective review was performed of children diagnosed with lymphoma from 1st March 2016 – 1st March 2019. Information was collected on: diagnosis, immunological investigation undertaken and whether immunoglobulin replacement was provided.
64 children were diagnosed with lymphoma at median age 13 years 8 months (range 2 – 17 years). Ten had immunoglobulins measured prior to/at diagnosis, one was low. Nine had low IgG after diagnosis, including two that were previously normal. Five children received immunoglobulin replacement (IRT). Two had hypogammaglobulinaemia that was not rechecked after cessation of IRT. Two further children remain hypogammaglobulinaemic after treatment.
Ten patients were lymphopaenic at presentation. Two had lymphocyte subsets performed after commencing treatment, both were abnormal. Five further children had subsets measured prior to treatment, of which two were abnormal, however, both normalised after treatment. Four others had subsets only after initiation of treatment.
One child has persistent lymphopaenia and hypogammaglobulinaemia 2.5 years after treatment. Further immune investigation has been recommended. No child was diagnosed with PID.
Immune investigation was rarely undertaken and often normal. Further work is required to know who and when to investigate for PID.
PIDs are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses.
We report the incidence and the characteristics of the treatment of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia.
Out of 690 patients, 25 patients(3.6%) developed 33 tumors.Of the 25 affected patients, 8 patients suffered from CVID, 5 from CID, 3 from AT, 2 from HSP2, 2 from XLA, 2 from WAS, 2 from HIES, 1 from SCID.The age at diagnosis ranged from 1 to 52 years, with a median age of 19.6 years. The time between diagnosis of PID and onset of tumor was short, often<1 year between diagnosis and appearance of cancer in case of CID.Moreover, in two cases of CID, the diagnosis of cancer was made before the diagnosis of PID, so cancer was the onset clinical manifestation.Hematological malignancies were prevalent(22/33,66.7%) with a minority of solid tumors(11/33,33.33%).In particular Non-Hodgkin lymphomas were the most frequent(16/33,48.48%).In total 13 patients survived(52%) and tumor was the main cause of death(7 cases).Two patients underwent BMT once the disease was in remission.
Malignancies in PID patients can be successful treated if a prompt diagnosis is posed.Moreover tailored treatment is often necessary.Our data suggest an encouraging survival rate(52%) in lymphomas.
ESID Subregistry on PID and Malignancies was created with aim to analyze more in depth the phenomenon and to understand how to improve the prognosis of these patients often considered at poor prognosis.
ADA-SCID is a rare disease(10-15% of SCID) due to the mutations of the ADA-gene resulting in the accumulation of high systemic levels of ADA toxic metabolites.There are 3 treatment options:HSCT from matched sibling donor(the best therapeutic options), Enzyme Replacement Therapy(ERT) with PEG-ADA to manage disease in short term, autologous Gene Therapy(GT) or allogeneic HSCT from MUD/parents.Long term ERT is a therapeutic options although with time long-term immune reconstitution may be sub-optimal in some patients.
In our center 29 ADA patients were diagnosed,of which three were treated with ERT from diagnosis.
The patients were diagnosed early:1 prenatal diagnosis, at 2 months and 3 months of age.They started immediately ERT.Median time of ERT follow up is 20 years.They are well detoxified(median value of %dAXP is 0.65%), but have very low level of lymphocytes.An approach to correct the immunological situation by GT with peripheral stem cells, considering the bone marrow stem cell exhaustion in these patients, was hypothesized but was inapplicable.At diagnosis, approximately 20 years ago, gene therapy wasn’t a consolidates therapy and ERT seemed the more solid therapeutic option.In the process of programming HSCT, unfortunately, one of these patients has developed plasmablastic lymphoma after 21 years of ERT.Last follow up shows 12/mm3 CD3+, 10/mm3 CD19+ and %dAXP 1.7%.
Our experience shows that ERT gives a good therapeutic option as bridge therapy for HSCT.For patients in long-term ERT, would be beneficial the use of the newly approved recombinant PEG-ADA.Nevertheless strict monitoring would be necessary to check the results of this new therapeutical approach.
X-linked agammaglobulinemia (XLA) is characterized by hypogammaglobulinemia and absent B cells resulting from defects in Bruton’s Tyrosine kinase (BTK). Despite immunoglobulin replacement, patients experience consequences of immune dysregulation including nodular regenerative hyperplasia (NRH) of the liver and malignancy. We describe a case of metastatic hepatic angiosarcoma in a patient with XLA consented to an IRB-approved NIH protocol, 93-I-0119.
Retrospective chart review.
30-year-old male with XLA developed thrombocytopenia and abdominal ascites. A transjugular liver biopsy confirmed NRH and elevated portal pressures. Screening MRI of the liver discovered innumerable suspicious hyperintensities. Biopsy revealed atypical vascular proliferation concerning for angiosarcoma. Interval MRI showed multiple arterial enhancing lesions throughout the liver and osseous enhancement consistent with metastatic disease. Paclitaxel chemotherapy was complicated by neutropenia, fever, pulmonary consolidation and an occipital brain lesion concerning for invasive aspergillosis. Despite antifungal therapy and aspergilloma resection, the patient developed a right parietal hematoma with progressive midline shift resulting in herniation. He was placed on comfort measures and expired shortly thereafter.
XLA has been associated with increased risk of hematologic and solid organ malignancy. NRH of the liver, common to many immune dysregulation disorders, may lead to the development of hepatic malignancies. Angiosarcoma is a high-grade vascular neoplasm that presents with abdominal pain, ascites, hepatomegaly, and thrombocytopenia. Metastases commonly occur lending to poor prognosis often resulting from liver failure or intraperitoneal hemorrhage. Unfortunately, beyond surgical resection, no standard chemotherapeutic regimen exists. This case highlights the importance of prompt diagnosis and therapy in patients with underlying immunodeficiency and dysregulation.
T/NK-CAEBV is characterized by Epstein-Barr(EBV) infected T and/or NK cells that lead to lymphoproliferation, organ damage, hemophagocytic lymphohistiocytosis (HLH) and/or lymphoma. The best treatment modality is unknown. We sought to characterize a modern cohort of CAEBV patients, focusing on current treatment practices and outcomes.
Retrospective multi-institutional cohort of patients diagnosed with T/NK CAEBV
Thirty-three patients were evaluated. Median age at diagnosis was 13 (1-30) years, with mean blood EBV DNA 2.2 million copies/mL (range 0-39x106). 70% of patients had cytopenias and liver dysfunction; 45% were clinically diagnosed with HLH. Bortezomib-gancyclovir was upfront therapy in 13 (39%) patients with 61% responders. Twenty-one (64%) patients received lymphoma-type chemotherapy with an 86% overall response. Twenty-nine (88%) patients proceeded to transplant (HCT). With a median 19 months follow up, 1 year overall and event-free survival were 58% and 45%. Fourteen patients died; 71% from progressive disease. No statistically significant improvement in survival was observed with use of chemotherapy (p=0.07) or undetectable viral load pre-HCT (p=0.1), which may be confounded by small sample size. In those undergoing HCT, there was no statistically significant difference in survival between reduced intensity or myeloablative regimens (p=0.73).
NK/T-CAEBV remains extremely challenging to treat. Lymphoma-type chemotherapy results in excellent response rates. HCT remains accepted as the most likely approach to achieve long term remission. With 1 year EFS of <50%, future studies evaluating larger prospective cohorts are required to evaluate whether the use of lymphodepleting chemotherapy to achieve undetectable viral loads prior to HCT improves survival.
Primary Immunodeficiencies (PID) are inherited disorders associated with increased risk of infections, autoimmunity and malignancy. The later may be related to impaired antitumor immune responses or a direct role of germline mutations in tumorigenesis. We recently identified germline hypomorphic mutations in Janus Associated Kinase 1 (JAK1) causing primary immunodeficiency, characterised by mycobacterial infections and early onset fatal bladder carcinoma. JAK1 is required for immune cell signalling in response to different cytokines including interferons (IFNs). Somatic mutations in JAK1 have been associated with several cancer cell types and anti-tumour immune evasion, but pathogenic mechanisms remain largely unexplored.
Considering that our patient was diagnosed with an uncommon high grade metastatic bladder carcinoma at an early age, we investigated the role of partial JAK1 deficiency in tumour immune evasion, using aurothelial cell model generated with lentiviral vectors expressing short hairpin RNA (shRNA).
Here we demonstrate that JAK1 is required for the intrinsic IFNγ response of urothelial cells impacting on immunogenicity and cell survival. Specifically, urothelial cells with reduced JAK1-function showed lower cell surface levels of major histocompatibility complex class 2 (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1 (PD-L1) after IFNγ stimulation and were resistant to apoptosis and lymphocyte-mediated killing. In addition, we identified a previously unknown role for IFNγ signalling in modulating urothelial cell differentiation.
Together, our findings support a role for JAK1 in tumorigenesis and immune surveillance. Our results have implications for patients with PID and the development of biomarkers and targeted therapies for urothelial carcinoma.
Common variable immunodeficiency disorder (CVID) is the most frequent and most diagnosed inborn errors of immunity. The deficiency of immune system increases the development of malignancies (either lymphomas, either other solid cancers). But multifactorial etiology, including virsal infections, chronic inflammation, or genetic background, contribute to tumor development.
The aim: We evaluate our patients with CIVD for developed tumors.
53 CVID patients were followed for 5 years.
11 pts were diagnosed with malignancies lymphoma, leukemia, colorectal cancer, tyroid cancer). The most common neoplasia were lymphoma (in 6 pts).
The incidence of malignancy in our CVID cohort is high. Lymphomas were the most frequently diagnosed tumors. It is possible that a common causative or modifying gene variants pointed to errors in mechanisms may contribute to both immunodeficiency and malignancy.
To describe clinical, genetic and histopathologic correlations of a patient with commune variable immunodeficiency (CIVD) who developed autoimmune cytopenia, pulmonary granulomatosis, chronic Epstein–Barr virus (EBV) infection and Burkitt lymphoma.
A 50-years-old man was admitted to our Hospital in 2018 with complains of weakness, left eye ptosis, back pain and chronic EBV infection. He is known case of CVID with Evans syndrome since he was 26 y/o under treatment with IVIG and corticosteroid. At age 36 y/o he underwent splenectomy for a spontaneous spleen rupture due to medical therapy refractory. In 2013 he developed respiratory symptoms with dyspnea on exertion leading to bronchoscopy with lung and lymph node biopsies provided the histological evidence of diffuse non-caseating granulomas. The patient underwent blood and cerebrospinal fluid (CSF) tests, bone marrow and vertebral biopsy, 18FDG-PET, brain and spinal MRI with neurological examination. A genetic analysis for the main genes associated with CVID was performed.
18FDG-PET showed severe hypemethabolismin in multiple bone lesions, bilateral lungs, kidneys, stomach and several lymph nodes (upper paratracheal right, retrosternal, periaortic, common and external right iliac and perirecta). MRI showed several sclerotic vertebral lesions. Bone marrow evaluation provided histopathologic evidences of Burkitt lymphoma. Genetic analysis revealed a rare variant of JAK2 mutation, previously associated with chronic myelomonocytic leukemia.
We have described the first case of CVID patient with pulmonary granulomatosis, Burkitt lymphoma and the association of a rare variant of JAK2 mutation. Distinguishing between different phenotypes of CVID is critical, given the poor prognosis and the different underlying genetic mutation.
Ectodermal dysplasia/dystrophy(ED) is a disease shown to associate with primary immunodeficiencies(PID). ED classically consists of hair (hypotrichosis), tooth (anodontia/hypodontia) and sweat gland (anhydrosis/hypohidrosis) anomalies. The aim of our study is to identify the clinical findings and immunological characteristics of the patients with ED and to determine the treatment goals.
The clinical and laboratory findings of the patients with ED were evaluated between 01.08.2018 and 31.12.2018.
We included nine patients (Male/Female=5/4). The median age at diagnosis was 13 years(4-51). Parental consanguinity ratio was 30%. Skin related(n=9), fever due to thermoregulation failure(n=4) were the most common clinical findings. The others were frequent upper respiratory tract infections(n=6), pneumonia(n=4), bronchiolitis(n=4). Six patients had hospitalized due to pneumonia. The most common hair findings were sparse(n=8), fine-stranded hair(n=4), alopecia(n=3). Hypothyroidism was the most common comorbidity(n=4). Others were systemic juvenile idiopathic arthritis(n=1), immune thrombocytopenic purpura (n=1), well-differentiated squamous cell carcinoma(n=1). The most common laboratory findings were lymphopenia (n=3) and hypogammaglobulinemia (n=3) which were recorded in 30% of the patients. Next generation molecular genetic study was done in 4 of the patients, and the defects (NFKB2, STAT1 GOF defects) were documented in two of the patients.
Early diagnosis of ED is important if it is associated with PID.Thus, early control of infections could be provided. In our study, the most common findings of ED are about hair, teeth and nail similar with the literature.The thermoregulation failure was found in 44% of the patients. The physicians should be aware that infections, autoimmune, inflammatory, allergic diseases and malignancies may accompany ED.
We would like to report the specific problem of lymphoproliferation in patients with CVID.
This case reports 65 years old lady with CVID, diagnosed in 2013. Later splenomegaly and decreas in thrombocytes and leukocytes were detected.Flow cytometry of peripheral blood showed patological lymphocytes. Bone marrow(BM): flow cytometry: 9.1% B-lymfocytes, 50% of B ly with pathological phenotype CD23-/+/CD5-/CD10- , mFLCKappa - dg. B chronic lymphoproliferative disease B-CLPD. Histology: NO evidence of malignant changes and NO evidence of infiltration with malignant lymohoma. Clinicaly was patient stable, with No evidance of B symtomatology. Splenomegaly did not progreeded and changes in blood count stayed mild. In terapy we administered immunoglobulins substitution regularly.
Four years later splenomegaly and lukopenia progreeded. New BM biopsy shows 15% infiltration of bone marrow with patological lymphocytes, morphologicaly consistnet with small cellular CD 20+malignant lympfoma, most likely splenic marginal zone lymphoma. Because there are porgessive leukopenia we decided to star the therapy with anti CD20 rituximab.
|Date||Spleen (cm)||Lekocytes (x 109/L)||Thrombocytes (x 109/L)|
Primary immunodeficiency is complex immune system dysregulation. This can lead to broken balance of lymphocytes and formation of lymphoproliferation. Lymphocytes proliferate from polyclonal to oligoclonal and finaly to monoclonol, malignat lyphoproliferative disease. Ethiology of this proces is multifactorial. Management of lyphoproliferation is complicated and has to consider risk associated with conventional cytostatik agent, or splenectomy. Therfore is better to choose newer drug, e.g. monoclonal antibodies. Crucial is immunoglobulin substitution and infections prevention.
Defective antibody formation is the main phenotypic feature in the majority of primary immunodeficiency diseases, with common variable immunodeficiency (CVID) as the most common clinically severe form of primary immunodeficiency. In addition to susceptibility to infections CVID patients show non-infectious disease manifestations such as B cell lymphoma.
We measured serum immunoglobulins, IgG subclasses, IgG- and –IgM-antibodies against T-dependent and T-independent, bacterial, viral and vaccination antigens, lymphocyte subsets including B cell subsets and lymphoproliferative responses in patients in whom susceptibility to infections developed after or during treatment for B cell malignancy.
Upon diagnosis of CVID all ten patients presented with undue susceptibility to infections which normalized upon initiation of immunoglobulin replacement therapy. The median delay between the diagnosis of lymphoid malignancy as the first clinical manifestation and the diagnosis of CVID was 5 years (range 0.5 to 19 years). The decrease in serum IgG in these patients was variable (range 42 – 671 mg/dl), but an impaired IgG response to vaccination against tetanus, diphtheria or TBEV and a decreased IgG antibody responses against ubiquitous microbial antigens [staphylococcal and streptococcal toxins, bacterial polysaccharides, viral antigens such as MMR and VZV] confirmed the diagnosis of CVID and thus the need to initiate long-term immunoglobulin replacement therapy.
Our findings indicate that immunological examination of patients with hematological malignancy, in particular B cell tumors, should be mandatory at diagnosis and during follow-up in order to achieve early diagnosis and treatment of clinically relevant antibody deficiency such as CVID.
X linked hyper IgM (X-HIGM) is caused by CD40LG mutations, resulting in absent CD40L on T cells. Patients typically present with low serum IgG & IgA, but normal or elevated IgM and recurrent infections.
Although not a common complication, malignancy has been reported, the US Immunodeficiency Network registry reported 4 cases of malignancy in a series of 82 X-HIGM patients.
Here we present a case of X-HIGM with metastatic spindle cell carcinoma. The patient was diagnosed at the age of 1 having presented with infections and a family history of infection-related male infant death. IgM was elevated, but IgA & IgG undetectable. Immunophenotyping subsequently revealed absence of CD154 on activated T cells, and genetics confirmed CD40LG mutation. He was treated with immunoglobulin replacement, Co-trimoxazole prophylaxis and remained reasonably well into adulthood.
At the age of 46 he developed a blistering lesion on his left anterior scalp which gradually increased in size. Histology confirmed a poorly differentiated spindle cell squamous cell carcinoma. Further investigation was declined. Two years later, he presented with worsening dyspnoea and weight loss. CT of his chest revealed large biapical well-defined opacities with significant mass effect and compression of his superior vena cava. Histology confirmed a malignant spindle cell neoplasm, likely representing metastasis of his previous SCC.
This is the first case report of X-HIGM with metastatic spindle cell carcinoma. It is not known why these patients have a higher predisposition to malignancy but a postulated mechanism involves inadequate anti-tumour immunity in the context of absent CD40L.
Management of lymphoma in patients with PID remains challenging. Prognosis are worse, with difficult therapeutic approaches.
We conducted a systematic literature review in the medline (Pubmed) of the association of lymphoma and PID (articles reporting one or more original cases). We describe the characteristics, treatment and outcomes of lymphoma occurring in PID and the type of PID concerned.
Our bibliographic research identified 782 articles on Medline of wich 386 single cases with lymphoma (F/M Sex Ratio: 0.7) were retained for analyses. Median age at diagnosis of PID and lymphoma was 9.5 and 12 years, respectively. T-cell deficiencies were the main PID concerned by lymphoma (57%) followed by CVID (21.5%). A previous benign lymphoproliferation and autoimmunity was reported in 15.7% and 18.5 % of cases. The diagnosis of lymphoma was made 2 to 5 year after PID in 89.8% of patients. Most represented lymphomas were DLBCL (33.5%). Lymphomas were diffuse (stage III/IV) (67.2%) and extranodal (76.4%). EBV-driven lymphoma (52.8%) were mostly present in innate deficiencies, represented by DLBCL (38.2%), follicular lymphoma (13.2%) and mixed cellularity classical HL (10.5%). Complete response to treatment was observed in 65.8%. Death occurred in 38.2% and was caused by infections in 32.3%. Few stem cell transplantations were performed (19 cases).
This detailed analysis of individual cases provide a landscape of the type and the course of lymphoma occurring in PID and open the door to dedicate studies in specific sub-group of patients at risk, and dedicated therapeutic protocols. Finally, lymphoma could also revealed PID.
The safety of intravesical Bacillus Calmette-Guerin (BCG), a live attenuated strain of Mycobacterium bovis, in primary antibody deficiency (PAD) is unknown. Here we report outcomes of intravesical BCG used to treat non-muscular-invasive bladder cancer in 3 patients with PAD.
Immunological phenotype, biopsy results, and treatment outcomes were collected via retrospective chart review.
Patient-A: 69-year-old female with hypogammaglobulinemia (IgG 500s/IgM 30s/normal IgA), suboptimal polysaccharide vaccine responses, and lymphopenia (CD3/CD4/CD8 408/334/74), normal lymphocyte proliferation to mitogens (PHA/Con-A/Pokeweed) and decreased to Candida/Tetanus. Diagnosed with non-invasive low-grade papillary urothelial (PU) carcinoma December 2018, underwent transurethral resection of bladder tumor (TURBT) followed by intravesical BCG. She had complete response (CR), follow-up bladder biopsy 1 year later showed no evidence of recurrence.
Patient-B: 65-year-old female with common variable immunodeficiency (CVID) IgG 300s/IgM 20s/low normal IgA, and low memory-B-cells (CD19+CD27+ <1%), on IgG replacement (IgGR) diagnosed with non-invasive low-grade PU carcinoma October 2018, underwent TURBT followed by intravesical BCG. Repeat cystoscopy April 2019 showed CR.
Patient-C: 74-year-old female, with hypogammaglobulinemia (IgG 400s, normal IgA/IgM) on IgGR. She had Non-invasive low-grade PU carcinoma diagnosed in 2003. It was excised but had new superficial/non-invasive lesions, had re-excision in 2011 and intravesicular BCG in 2013 with apparent resolution. Follow-up cystoscopy every 3 months shows CR.
Intravesical BCG was well tolerated in all patients, without any infectious complications.
Intravesical BCG might be considered safe in treating non-invasive bladder cancer in PAD. Further studies with larger sample size are warranted to adequately capture side effects and efficacy of this therapy in immunodeficiency.
RASGRP1 is a guanine-nucleotide-exchange factor that is involved in lymphocyte development and function. RASGRP1 deficiency was first described as a severe immunodeficiency in 2016. It is characterized by lymphopenia, recurrent infections, autoimmune features, hepatosplenomegaly, lymphadenopathy, EBV-associated lymphoproliferation and B cell lymphoma. Here, we report a patient with RASGRP1 deficiency developing Hodgkin’s Lymphoma following immune cytopenias.
Case: 8 year-old-boy referred with suspicion of primary immunodeficiency. He was born to consanguineous parents. He had hospitalized due to fever, immune thrombocytopenia and autoimmune hemolytic anemia at 4 years. He treated with glucocorticoids and IVIG. Then he had recurrent fever, otitis media and tonsilitis that require intravenous antibiotic treatments. At 8 years he developed Hodgkin’s Lymphoma. Lymphopenia, positive EBV serology. elevated TCR γδ T cells and decreased follicular T helper cells were detected in the laboratory assessment. Genetic analysis revealed a homozygous homozygous mutation in RASGRP1 gene.
He successfully completed chemotherapy and radiotherapy regimens. He had a sister and we are waiting her genetic results. They are HLA matched siblings.
RASGRP1 deficiency is an immune dysregulation disorder that should be considered in patients with EBV-related lymphoproliferation or malignancy as well as patients with recurrent infections, autoimmune cytopenias and other aoutoimmune diseases. Early diagnosis is important and HSCT can be a curative treatment for patients with RASGRP1 deficiency.
CTLA-4 haploinsufficiency is an immune dysregulation syndrome characterized by lymphoproliferation, lymphocytic infiltration in non-lymphoid organs, autoimmune cytopenias, hypogammaglobulinemia, recurrent infections. These patients are also at high risk of hematological and non-hematological malignancies.
Our case suffered from persistent Epstein-Barr virus viremia and refractory thrombocytopenia from 3-year-old, which necessitated long-term corticosteroid use, intravenous immunoglobulin, and rituximab. He is diagnosed as CTLA-4 haploinsufficiency at 5-year-old. At the age of eleven, he complained of sudden onset nausea and headache and magnetic resonance imaging of the brain revealed multiple space-occupying lesions. Whole body computed tomography revealed asymptomatic multiple pulmonary infiltrates. His medical history urged us to perform brain and lung biopsy to exclude the possibility of malignancy and lymphoproliferative disorders.
Flow cytometric analysis revealed that a majority of infiltrating cells were activated CD4 T cells, supporting that these lesions are lymphocytic infiltration to brain and lung. Although almost all of the lesions disappeared after administration of high dose corticosteroid and sirolimus, existence of oligoclonal CD19-negative B cells with light chain restriction suggested the possible co-existence of lymphoproliferative disorder (LPD) or low-grade lymphoma. So, we are planning haploidentical hematopoietic cell transplantation from his mother, as there were no HLA-matched related or unrelated donors.
Careful assessment and management are required for multiple organ lesions observed in CTLA-4 haploinsufficiency case with long-term medical history, as these cases are at high risk of LPD or malignancies.
Plasmacytoma-like post-transplant lymphoproliferative disorder is a rare form of post-transplant lymphoproliferative disorder (PTLD), which is of plasma-cell origin. Its etiology remains unclear because of its rare presentation.
A XIAP deficient patient developed recipient-derived EBV-negative plasmacytoma-like PTLD with multiple autoimmune diseases. Immunological and genetic analyses were performed including high-throughput sequencing of immunoglobulin heavy-and light-chain genes using total RNA from PTLD cells.
The histopathologic analyses of PTLD cells were positive for IgG and lambda light-chain. Several serum autoantibodies were also restricted in the IgG and lambda light-chain, suggesting that these autoantibodies were produced by PTLD cells. Repertoire analysis revealed a clonal expansion of IGHV3-33/IGHD7-27/IGHJ5 in IGH and IGLV1-47/IGLJ3 in IGL. While the IGH and IGL sequences were predominant in one and two subclone, respectively, other multiple subclonal variants were also identified. Most constant regions consisted of IGHG4, but a small fraction consisted of IGHG1, IGHG3, IGHA2, IGHE and IGHM. The frequency of somatic hypermutation (SHM) was significantly reduced, with only 1.3 ± 0.9 and 1.7 ± 1.1 mutations in IGHV and IGLV, respectively.
The plasmacytoma-like PTLD cells were found to originate from a germinal center B cell exposed to on-going class switch recombination but lack SHM, and committed to be a plasma cell. Decreased SHM frequency is in contrast to the high frequency in non-PTLD myeloma cells, which may contribute to the production of autoantibodies. This study provides new insights into the etiology of EBV-negative PTLD and autoimmune diseases in immunodeficient patients.
Primary EBV infection is mostly seen as an asymptomatic infection in childhood. It may cause self-limiting infectious mononucleosis in adolescent period or adulthood. However, some primary immunodeficiency types have a selective predisposition for EBV-related diseases.
CD27-CD70 interaction is required for T cell expansion and survival; germinal center formation, B cell activation, antibody production and NK cell function. In CD27 or CD70 deficiency, EBV-associated lymphoproliferative disease, lymphoma and/or hypogammaglobulinemia are observed.
In this study, we present the features and follow up of the first 3 cases who underwent hematopoietic stem cell transplantation.
3 case form 2 families. All are male. Age of lymphoma diagnosis were 2,5; 3 and13 years old respectively. All of them have consanguinity. In laboratory all of them have hypogammaglobulinemia and EBV PCR positivity. Two of them are diagnosed with Hodgkin lymphoma, the third one with non-Hodgkin Lymphoma. All of them have a history of relapse. Two of them are transplanted from a MUD, one from MSD. Treosulfan, fludarabine in combination with Rituximab (± ATG ) is used for conditioning. All patients engrafted following HSCT. All of them completed 6 months after HSCT. However complicated with serious GVHD even if transplanted from a MSD.
* This study was supported under TÜBİTAK 1003 Project no 315S125.
CD70 deficiency should be considered in patients with parental consanguinity and relapsing EBV associated malign lymphoma. Allogeneic hematopoietic stem cell transplantation seems to be only curative option; but further evaluation is needed.
Primary disorders (PID) are inborn errors of the immune system. (1,2). Developed countries have registries to estimate the prevalence, incidence, and patterns of PIDs. Costa Rica is a country with a population of 5 million where pediatric PIDs are followed in one center that is part of the Latin American Society for immunodeficiencies (LASID)(1,3). Among the latin-american countries Costa Rica represents the 6% of all reported cases of PIDs (1).
The epidemiology of major PIDs diagnosis and the frequency of malignancy at the National Children´s Hospital (HNN), San José Costa Rica is described in period of ten years.
We performed a preliminary retrospective analysis of the patients that attended our clinic in the last 10 years and describe the malignancy presentation.
Table 1: Number of cases of the most common PIDs and number of cases with malignancy
AT is the most common PID in Costa Rica and it represents 60% of the patients registered so far. Malignancy presented predominately in AT patients as expected. It was distributed as 1 gastric adenocarcinoma, 2 nasopharyngeal NHL, 1 T-cell lymphoma, 1 ovarian cancer, 1 hepatoblastoma. 2 AT patients had two malignancies (non Hodgkin and Hodgkin lymphoma).
Costa Rica has a high prevalence of AT.
DNA-breakage disorders represent a unique subgroup among syndromologic primary immunodeficiencies (PID). Sometime they are named as XCIND (X-ray hypersensitivity, Cancer susceptibility, Immunodeficiency, neurological abnormalities, DNA-breakage). Besides typical symptoms resulting from variable immunodeficiency, an important part of clinical picture is a broad spectrum of malignancies.
We analysed our group of XCIND syndromes followed in National Centre for PID in University Teaching Hospital in Martin, Slovakia.
Our group consists from 18 XCIND patients (males 8, 64%; aged 16 years; 15 living): 7 patients with Nijmegen breakage syndrome (NBS), 6 patients Ataxia telangiectasia (AT), 3 patients with Bloom syndrome and 2 with Fanconi anaemia. All of them were genetically confirmed. Oncological complications were observed in 7 patients (39%): 4 lympho-reticular malignancies (non-Hodgkin lymphoma and acute lymphoblastic leukaemia) and 3 solid tumours (rhabdomyosarcoma, lipoblastoma, gastric adenocarcinoma). 2 patients died due to oncological complications, 1 due to invasive infection of CNS. All the patients across various forms of XCIND suffered from recurrent complicated respiratory infections. Other comorbidities included herpetic infections, skin abnormalities (vitiligo, cafe-au-lait), amenorrhea, allergies (asthma, rhinitis, eczema), malnutrition. All the patients yielded various degree of antibody defects or cellular immunodeficiency. 8 patients were treated with regular immunoglobulin substitution. Antibiotic prophylaxis was applied in 7 patients (3 trimetoprim, 4 azithromycin).
PID associated with DNA instability are associated with significant clinical complications and co-morbidities, among which oncological disorders represent a substantial part. Regular screening for all the associated complications is highly recommended in these patients to improve in general bad unpleasant prognosis.
GATA2 mutations have a variable clinical presentation including non-tuberculous mycobacterial infection (NTMs), severe HPV infection with associated cancer, herpes-virus family infections and lymphedema. In addition, one-third of the patients progress to myelodysplastic syndrome (MDS)/acute myelogen leukemia. We aimed to describe the characteristics and outcome of adult patients diagnosed with GATA2 mutation at our hospital.
The information was retrieved from the patients’ medical records.
Six patients were diagnosed with GATA2 mutation between 2013-2018. All of the patients had cytopenia, but none of the patients had NTMs. The other characteristics of the patients are given in Table1. Patient 1 presented critically ill with a disseminated HSV infection involving the liver. Patients 2 and 3 (monozygotic twins) had massive pulmonary involvement (without NTMs or alveolar proteinosis) at least partly caused by interstitial pneumonitis, and disseminated HPV infection (with carcinoma in-situ in the urogenital tract). Patients 1-4 were transplanted successfully, but Patient 2 died after 8 months due to a cerebral hemorrhage (secondary to thrombocytopenia). Patient 5 is currently being considered for HSCT, whereas patient 6 is followed with regularly BM biopsies to monitor the development of MDS. Half of the patients initially presented to a Hematologist due to cytopenia and the other half to an Infectious Disease Specialist due to severe infections and/or pulmonary involvement.
The Norwegian GATA2 patients presented with a wide spectrum of clinical features from disseminated viral infection, HPV associated cancer, sterile pulmonary involvement and BM disease, but not with NTMs.
Common Variable Immunodeficiency (CVID) patients are prone to autoimmune disorders, granulomatous disease and malignancies (mostly aggressive lymphomas and neoplasms of the gastrointestinal tract). In CVID patients the main histological type of gastrointestinal tract neoplasms, according to various publications, is adenocarcinoma of the stomach (Gastric Cancer, GC). In these studies, the risk of GC in CVID patients was estimated to be 1% and less. The aim of this study was to investigate the incidence of GC in our adult CVID patients.
Between 1972 and 2018, 90 CVID adult patients were diagnosed in our hospital. Thirty of them were lost in follow up. In this study we describe eight cases of adult CVID patients (8/60, 13%), who developed GC.
Four of these patients were male and four of them female. Their age at diagnosis of GC ranged between 42 and 70 years (median: 58 years). CVID had been identified several years before the diagnosis of GC. Pernicious anemia and atrophic gastritis were identified in four patients before GC diagnosis. Helicobacter Pylori infection (HP) was diagnosed in all three patients investigated for this infection. All eight patients underwent total gastrectomy. Currently, three of them are alive under immunoglobulin substitution treatment.
Conclusively, it is obvious that the incidence of gastric cancer in our CVID patients is much higher (13%) than that reported in other studies (1% and less). Probably, this fact is related to our patients’ age (exclusively adults), as atrophic gastritis and HP infection play an aggravating role in GC development.
Malignancy is not an infrequent presentation of PIDD. High index of suspicion and rapid confirmation of radio-sensitive PIDDs are crucial for timely therapy modification.
Molecular variants were identified via NGS. Flow cytometry was utilized to assess DNA repair in patient 2 via measurement of phosphorylated [p]ATM and γH2AX in lymphocytes following exposure to 2Gy radiation.
Patient 1 presented at 12 years with pre-T cell ALL and received standard therapy. Persistent disease prompted therapy escalation including cranial radiation and nelarabine. Nelarabine was held following disclosure of balance issues in toddlerhood. Her course was complicated by significant ataxia and severe lymphopenia. She re-presented at 20 years with alpha-beta hepatosplenic T cell lymphoma and succumbed to disease. Results available post-mortem identified a pathogenic variant in ATM (p.V242G).
In comparison, patient 2 presented at age 6 years with peripheral T cell lymphoma-NOS. Clumsiness, drooling, and an atypical malignancy raised concern for radiosensitive PIDD. Upfront genetic sequencing identified a pathogenic variant (c.2921+1G>A) and a VUS (c.8041G>A; p.V2681M) in ATM. A rapid flow radiosensitivity assay demonstrated an inability to autophosphorylate ATM at 1h post-low dose irradiation (2Gy), and lack of dephosphorylation of γH2AX at 24h post-irradiation confirmed pathogenicity of the VUS and diagnosis of ataxia telangiectasia (AT). Initial consideration of an autologous transplant was abandoned in favor of reduced intensity allogeneic transplant based on these results.
Rapid genetic testing and functional confirmation of suspected radiosensitive PIDD, such as AT, presenting as malignancy is essential to mitigating therapy-related toxicities and optimizing survival.
There is no data regarding the prevalence of malignancies in patients with PID in Turkey. Along with the frequency of malignancy, we aimed to present the types of cancer and define the underlying immune deficiency of patients.
Between 1992 and 2018 years, from 5 tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features and prognosis. The data were obtained from the hospital records retrospectively.
The prevalence of malignancy in our cohort was found as 0.9% (59/6538). The male/female ratio was 1.8 (38/21) and the median age of patients was 14 years (range 2- 51). The median age at diagnosis of malignancy was 10 years (range 2-51). The highest number of patients with malignancy had ataxia telangiectasia (n=17,28.8%), non-Hodgkin lymphoma was the leading malignancy (n=27,45.7%), the highest cancer rate was observed in patients with DOCK8 deficiency (16.3%) in all patients. The frequency and subtypes of malignancies are given in Table 1, Table 2 respectively. EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Two patients had dual malignancies. Remission was detected in 24 patients (40.6%), however 31 patients (52.5%) died.
The incidence of PIDs-associated malignancy has increased in recent years. While lymphoid malignancies are the most common cancer and observed more frequently in AT patients, higher susceptibility to cancer was detected in patients with DOCK8 deficiency. This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey.
Background: Primary immune deficiencies (PID) are disorders predisposing individuals to recurrent infections, allergy, autoimmunity and malignancy. Malignancies are seen more frequently in primary immune deficient patients than the general population. In daily practice the diagnosis and treatment of malignancy in PID are challenging. Due to the complexity of the disease pathophysiology, sometimes the clear cut-off between benign and malignant differentiation may not be possible, requiring special expertise for diagnosis.
Aim: We aimed to describe our PID patients thought to develop cancer which finally concluded as non-neoplastic lymphoproliferation.
Methods: The demographic and clinical features of the patients were recorded retrospectively.
Results: Five patients (female:3, male:2) were misdiagnosed at first evaluation. The PID diagnoses included EBV related lymphoproliferation (n=1), PIK3R1 deficiency (n=1), Nijmegen-Breakage Syndrome (NBS) (n=1), Ataxia telangiectasia (n=1) and combined immune deficiency with unknown genetic background (n=1). All patients first had a diagnosis of non-Hodgkin lymphoma, two patients received one course chemotherapy. Following the diagnosis of non-malign lymphoproliferation one patient with EBV related PID showed excellent response to rituximab. With sirolimus therapy partial response was achieved in NBS patient who had atypical T cell proliferation in liver.
Conclusion: The lymphoma diagnosis is challenging in PID patients. This could be related to the complexity of primary disease, which leads in nature for abnormal cell proliferation and infiltration or due to lymphoma classification, which always is not harmonious between histopathologists. To avoid these discrepancies, collaboration among clinician, histopathologist and molecular biologist will be beneficial.
Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterised by neurodegenerative symptoms, skin manifestations, immune deficiency and increased susceptibility to cancer.
27AT(16F/11M) patients were collected for their demographic, clinical and laboratory data.
27 patients were diagnosed with ataxia telangiectasia according to ESID registry diagnostic criteria. The current mean age was 10.9±6,3 years. Seventeen (60.7%) of patients were female, 11(39.3%) were male. The mean age at diagnosis was 3.5±3 years. Nine (33.3%) patients were on IVIG replacement therapy, 11 (%40.7) received antibiotic prophylaxis. Median absolute lymphocyte count (ALC) of patients was 1900/mm3(600-9800). Immunoglobulin levels were as follows: low IgG in 3 (%12), normal IgG in 19 (%76) and elevated in 3(%12), low IgA in 22 (%88), low IgM in 1 patient, normal IgM in 19(%76) and elevated IgM in 5(%20). Malignancy developed in 2 (7.4%) of the patients. One of the female patients diagnosed with disgerminoma at age of 17, the other was diagnosed with T cell lymphoma at age of 5. One mother of AT patient developed breast cancer and was treated accordingly.
Ataxia-telangiectasia is a complex DNA repair disease, causing various clinical phenotypes, immune deficiency, malignancies, hypotonia and ataxia. Some patients may even be diagnosed with immunological abnormalities before the progression of neurological symptoms. AT patients and parents should be regularly monitored for malignancy development in the follow-up.
Heterogenous defects of the NADPH-complex are known to cause chronic granulomatous disease (CGD). Recently described autosomal recessive p40phox-deficiency is a related but distinct entity. Patients with p40phox-deficiency may remain asymptomatic or most often present with a lupus like inflammatory skin or bowel disease and arthritis (1).
A 17-year-old girl of consanguineous parents was suffering from therapy resistant acne inversa-type lesions from the age of 7 and a mild polyarthitis. In addition to typical inflammatory nodules, abcess formation and scaring in the axillae and inguinal areas, she developed a markedly disseminated pustulosis on her trunk. Atypical bacteria could be extracted from skin lesions (E. coli, Enterococcus faecalis, Pseudomonas aeruginosa, Staph. aureus (Methicillin sensible, PVL negative) and Staph. Epidermitis). Retinoid medication resulted in partial stabilization, but had to be discontinued due to side effects. While dapson treatment was ineffective, improvement was achieved by combination of clindamycin and rifampicin-treatment over several months. Her brother showed milder but comparable symptoms. Therefore an genetically defined immune defect was suspected. As the only finding production of reactive oxygen species in neutrophils was present but repeatedly below the first 1% percentile of the normal ranges upon stimulation with PMA and E. coli.
A homozygous mutation NCF4 p.R57H, resulting in a modified p40phox protein, was identified in whole exome sequencing.
Patients with “acne inversa” or any similar inflammatory skin disease should be investigated for p40phox deficiency or another NADPH defect with residual function
Van de Geer et al, J Clin Investigation, 2018
The risk of carcinogenesis in primary immunodeficiencies (PID) is increased by 25% compared to the general population. The type and incidence of cancer manifestations correlate with PID form, patients age and spectrum of certain type viral infectious.
During 25 years we observed 785 patients with different forms of PID.
Oncology diseases developer in 37 cases (5%). The main frequency of cancer was in patients with NBS1 – 20 of 41 (51%): 15 –ALL/lymphoma, 2 – AML, 1-embrional rabdomyosarcoma, 1-Hodgkin disease, 1-CNS-cancer. Six patients received standard course of chemotherapy for malignancy type they had previous NBS1 diagnosis. All of them had infectious complications, prolonged periods of cytopenias. In all patients diagnosed as NBS1 before malignancies development was used reduced doses of MTX and ciclophosphamide; rituximab in cases B-cell lyphomas/ALL with good effect.
Malignant diseases developed in 9 of 84 patients with ataxia-teleangiectasia (10,7%): 3 - Hodgkin disease with relapses and death, 4 – ALL/lymphoma, 1- CNS-glioma with death, 1 – stomach cancer. In 4 cases parents refused from treatment.
B-cell lymphoma observed in 5 of 12 boys with XLP (36%). Remission > 1 year in 4, relapse after 3 years remission -1.
B-cell lymphoma developed in 2 and Hodgkin disease in 1 of 51 WAS patients (5,8%). Patients with lymphomas had prolong cytopenias after chemotherapy.
Severe T-cell lymphoma with death developed in 1 of 76 with CVID (1,3%).
Our data showed the highest frequency of malignancies in NBS1 (51%), main common types of malignancy were ALL/lymphoma and Hodgkin disease – 88%.
Non-Hodgkin's lymphoma (NHL) is the predominant malignancy in CVID patients, accounting for 47 to 64% of all tumors. The coexistence of immunodeficiency and malignancy presents a challenge for the diagnosis and treatment of this group of patients. Herewith we present a pediatric patient who developed NHL early after CVID diagnosis.
laboratory and immunological tests
A six year old boy was diagnosed with CVID based on the clinical manifestations for recurrent respiratory infections, oligoarthritis and agammaglobulinemia. One year after diagnosis and initiation of IVIG therapy, abdominal pain, fever and diarrhea occurred. Laboratory tests made show leukocytosis, elevated CRP and ESR. The laparotomy revealed generalized abdominal lymphadenomegaly. The histological evaluation pointed to NHL - EBV+ high-grade B-cells lymphoma. The administration of Rituximab, CHOP and IVIG had a good effect.
Lymphoma, may develop in pediatric CVID patients with no previous signs of lymphoid hyperplasia and even early after CVID diagnosis. Therefore, strategies for cancer prevention and/or early diagnosis are required in pediatric CVID patients. This case is an example of good collaboration between immunologist, pediatricians, oncologist and other professionals.
Common variable immunodeficiency (CVID) has a high incidence of gastrointestinal manifestations and an increased risk of malignancy. From 2 to 10% of patients with CVID develop malignant lymphoid type, usually non-Hodgking B-cell lymphomas. They frequently involve extranodal sites, which includes the gastrointestinal tract.
A 33-year-old (y/o) male patient.
14 y/o: autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura.
20 y/o: 2 abscesses one malar and axillary. Severe pneumonia, so protocol is performed for primary immunodeficiency and concludes CVID.
30 y/o: intermittent diarrhea, steatorrhea with foamy stools.
Colonoscopy: chronic inflammation with lymphoid hyperplasia.
Celiac disease is diagnosed, gluten-free and dairy-free diet begins, with symptom improvement.
33 y/o: Hematochezia and diarrhea.
Colonoscopy and endoscopic capsule: non-Hodgkin's lymphoma of B cells in ileum by biopsy.
Treatment with chemotherapy is started. 6 months later due to complications of chemotherapy, he presents massive hemorrhage of the lower digestive tract and dies.
The manifestations of gastrointestinal malignancy in patients with CVID are the 2nd cause of death, so patients should be suspected and evaluated routinely when presenting symptoms, since celiac disease or the syndrome of irritable bowel can progress to malignancy. Patients with CVID may also develop gastrointestinal nodular lymphoid hyperplasia, leading to misdiagnosis of indolent gastrointestinal lymphoid malignancies.
The monitoring of patients is recommended endoscopies every 24 months in patients with normal histology, every 12 months in patients with gastritis atrophy or intestinal metaplasia and every 6 months with dysplasia.
Background: Underlying oncogenic mechanisms in PID are multiple and not completely defined, thus, establishing the prevalence of cancer in each particular group of immune disorders is relevant. According to epidemiological data in Argentina, cancer incidence rate in the general pediatric population is 129.9 per million.
Aims: To document cancer incidence in our cohort of PID patients (pts) and PID type involved.
Review of clinical charts of our Hospital’s PID registry from March/1989 to March/2018 screening for neoplasia occurrence (follow-up:1-18years).
38 from 956 PID pts, (607 males/349 females) developed malignancy(4%). Mean age:7.8 (1-17)years.
Cancer cases distribution according to 2017-IUIS-Classification was:
Immunodeficiencies affecting cellular/humoral immunity: n:2/78(2.6%): 2 Hodgkin Lymphoma(HL).
CID with associated or syndromic features: 22/473pts (4.7%): 15 Non-HL, 2 HL, 3 Leukemia(AL) and 3 Solid tumors. Considering only Ataxia-Telangiectasia, 12/65 developed cancer. No Di George Syndrome patient (n:331) developed neoplasia.
Predominantly Antibody Deficiencies: 11/194pts (4.6%): 4NHL, 3HL, 3 Solid tumors and 1 AL.
Diseases of Immune Dysregulation: 3/82pts (3.7%) 2 NHL, 1AL.
Congenital Phagocyte Defects: 2/84pts (2.4%), although therapy-related carcinomas.
This is the first pediatric registry of malignancy in PID in our country, involving in addition a significant number of cases. The Incidence rate disclosed 1284 cases/million, well above that of the general Argentinian pediatric population. The CID associated to Syndromic features group showed the highest prevalence of cancer. NHL (53%) was the most prevalent neoplasm overall. Documentation and better understanding of oncogenic mechanisms involved will help prevent in some degree the occurrence of neoplasia in PID patients.
Background and aims: MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2. The disease is characterized by progressive multilineage cytopenia, a heterogenous clinical presentation with an infectious phenotype, particularly involving infection by mycobacteria and herpesviruses, as well as malignant complications. We wanted to describe localization of variants in the GATA2, antiviral and inflammatory responses to herpesviruses and relevant microbial ligands, as well as development of malignancy in a small group of patients with GATA2 mutations.
Methods: Patients with identified GATA2 mutations and a relevant immunological and clinical presentation were included. PBMCs from patients and controls were infected with herpes simplex virus (HSV)-1, varicella zoster virus (VZV) or stimulated by relevant PAMPs. Antiviral and inflammatory innate immune responses were measured at mRNA and protein level by RT-qPCR and mesoscale technology, respectively. Moreover, T cell activation and NK cell degranulation was measured.
Results: We included seven patients with mutations located within the two DNA binding domains of GATA2. Two of four individuals with germline GATA2 mutations had severe monocytopenia, impaired antiviral responses, and one developed myelodysplastic syndrome. Three patients with AML harbored somatic GATA2 mutations but did not display any infectious phenotype. Two healthy carriers of GATA2 mutations had normal monocyte numbers and inflammatory responses.
Conclusions: This study clearly demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by different mutations in the same transcription factor. Germline mutations result in classical MonoMAC with impaired antiviral responses and incomplete penetrance, whereas somatic mutations may cause AML.
Background and Aims: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to NFκB, c-Jun N-terminal kinase, and mTORC1. This case report describes the unusual clinical presentation of an adult with a dominant negative (DN) monoallelic mutation in CARD11.
Methods: Analysis of medical records, laboratory results, tissue biopsies and gene sequencing information.
Results: Our patient was referred to us for the consideration of allogeneic HSCT at the age of 40 years. His history dated back to childhood with early onset atopy, multiple food allergies and eczema. At the age of 29 years he presented with multiple intrathoracic and hepatic tumours, which on biopsy were shown to be EBV-associated leiomyomas. Immunology investigations demonstrated a mild reduction in B cells with normal total T and NK cells, preserved immunoglobulin levels but a suboptimal response to polysaccharide pneumococcal vaccine. Targeted chip sequencing identified a previously described monoallelic missense mutation (c.214C>G; NM_032415.4:c.214C>G, R72G) with dominant negative effect. The previous cases were characterised in two patients by alopecia, joint pain, oral ulcers, pulmonary TB; and in a third by persistent skin infections (VZV, HPV), EBV viremia, progressive B-cell lymphopenia and frequent osteomyelitis.
Conclusion: EBV-associated leiomyomas are a rare complication of PID, described in less than 20 cases to date with a range of underlying genetic causes. To our knowledge, this is the first case of EBV leiomyomatosis in CARD11 related PID and expands the spectrum of clinical phenotype of CARD11 mutations.
Incidence of malignancies in PID patients is known to be substantially increased in comparison with age-adjusted non-PID population and varies between different groups of PIDs.
We analyzed data of 2563 patients from 3.5 months to 87 years of age (Me-13 years), collected in the Russian PID Registry between 2017 and May 1, 2019. Of these patients, 1793 were children under 18 years.
Malignancies were reported in 101 children, with estimated incidence of 5.6%, and in 4 adults (0.4%), with highest prevalence in combined syndromic PID (62), followed by combined PID (19), including 2 SCID patients, antibody defects (12), immune dysregulation (10), phagocytes defects (1-severe congenital neutropenia). As expected PID with DNA repair defects had the highest incidence of malignancies and included Nijmegen breakage syndrome (30), Ataxia telangiectasia (19), Bloom’s syndrome (1). Other syndromic PID included Wiskott-Aldrich syndrome (6), DiGeorge syndrome (1), Hyper-IgE syndrome (1), Kabuki syndrome (1), ICF2 (1), Cartilage Hair Hypoplasia (1), PNP deficiency (1). Humoral disorders included CVID (6), NFKb1 defect (1), sIgA deficiency (2), APDS1 (1), hypogammaglobulinemia (2). Immune dysregulation group consisted of XLP1 (7), ALPS (2) and CTLA4 defect(1).
Lymphomas were reported in 46%, leukemia in 17%, solid tumors in 8% and lymphomatoid granulomatosis in 7% of patients.
Russian registry data supports previous observations of high malignancies rate in children with PID (5.6%) with highest incidence in DNA-repair disorders (48%). Low numbers of CVID cases in the registry due to adults’ PID underreporting reflects low incidence of cancer types common for adult population.
Kaposi sarcoma (KS) is a rare neoplasm caused by human herpesvirus-8. It is typically associated with acquired immunodeficiency syndrome. Nevertheless, some cases result from primary immunodeficiency diseases (PID).
We report a case of childhood KS.
A 4-year-old boy presented with purple and red macules as well as nodules on hands and legs. Within a few months, neck and groin lymph nodes were enlarged and two episodes of pneumonia occurred. The patient was screened for Tuberculosis, but the Mantoux test was negative. Subsequently, the patient developed generalized lymphadenopathy and was additionally tested for toxoplasmosis (positive). Because of the unusual presentation, a lymph node biopsy was performed and KS was diagnosed. HIV testing turned out to be negative. Further investigations revealed impaired cellular immunity: very low CD4+ (311-383 cells/mm3), CD19+ (130 cells/mm3) and nearly undetectable naïve T-helper and T-cytotoxic cells. T-cell receptor excision circles were also very low (0.001-0.004%), suggesting abnormal T-cell development. Whole genome sequencing revealed a missense variant in CORO1A c.415T>G (p.Trp139Gly) in hemizygous state due to the presence of a ~630kb deletion at the 16p11.2 region encompassing CORO1A on the other allele. Coronin-1A deficiency was confirmed by Western-blot analyses showing complete loss of protein expression. KS treatment with pegylated liposomal doxorubicin resulted in a good response, facilitating hematopoietic stem cell transplantation for PID from a sibling donor.
We report a new PID gene associated with KS and suggest that it is included in screening panels of new cases. Treatment of underlying PID could lead to the better KS outcomes.
ImmunoHUB® is a comprehensive information and resource HUB that describes human diseases characterized by deficiencies of immune function and regulation. The HUB is an interactive web-based system that provides a simple method for students of clinical immunology to learn about the rapidly-expanding field of primary immunodeficiencies (PID) and their molecular causes. The association of PID with lymphoreticular malignanices was recognized over 50 years ago. This is illustrated by Bruton tyrosine kinase, in which case absence of or LOF function results in a failure of B cell production and GOF is observed in overproduction as occurs in chronic lymphocytic leukemia. (CLL).
Methods: We have organized mutations to date that cause loss-of-function (LOF) and result in a deficiency of immunity function. This we connected to an easy to navigate path to GOF mutations that are implicated in cancer..
Results: We collected and input over 425 PID genes that cause monogenic disorders of immunity. The immunoHUB.com version 2.0 integrates the genes assoicated with lymphoma, leukemia, bone marrow failure, combined T and B cell deficiency genes, signal trsnsduction pathway abnormalities, cyotskeleton and motiliy disorders, telemeropthties and others, into a seamless web-based system that consolidates and shares what is known regarding LOF and GOF mutations in PID and cancer through May 1, 2019.
Conclusion: Early reports of deficiencies of immunity being risk factors for lymphoreticular malignances is extended to the "newer" deficiencies caused by LOF mutations. This important connectivity will be useful to students, researchers, clinicians and pharmaceutical concerns with interest in this area.
The increased risk of Diffuse-Large-B-cell-Lymphomas (DLBCL) in the course of B-cell primary immunodeficiencies is well established. Little is known about the frequency and the clinical and prognostic relevance of hypogammaglobulinemia discovered at DLBCL diagnosis.
We retrospectively extracted from the monocentric lymphoma database of Caen-University-Hospital all patients diagnosed with DLBCL between January 2015 and December 2016 who had a serum electrophoresis (SEP) at diagnosis, before receiving any specific treatments. Patient’s presentation and outcome were analyzed according to the presence or not of a hypogammaglobulinemia (total gammaglobulin level (TGL) <5.5 g/L).
Out of 122 patients diagnosed with DLBCL, 96 (74.8%) had a SEP and 12 (12.5%; 8 males; median age 68 [55—82]) showed a hypogammaglobulinemia. When compared to the 84 patients with normal TGL, no difference was seen regarding demographics, DLBCL stages, or CRP levels. The albuminemia/gammaglobulinemia ratio was higher in patients with hypogammaglobulinemia (7 [4.6—12.2] versus 5 [2.3—7.1], p<0.0001). The hypogammaglobulinemia group had a shorter follow-up duration (median 14 [0.3—35] months versus 25 [0.3—51] months; p<0.001) because of more frequent deaths (83% versus 26%, p=0.03), secondary to infections in 10 out of the 12 patients.
Hypogammaglobulinemia at DLBCL diagnosis was observed in 12.5% of our cohort and may be associated with a worse prognosis. The higher albuminemia/gammaglobulinemia ratio suggests that hypogammaglobulinemia was not linked to metabolic or inflammatory causes. Further studies are needed to determine whether these immunodeficiencies are secondary to DLBCL or primary and the best therapeutic strategy.
X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by mutations in Bruton's tyrosine kinase (BTK). Because a few XLA patients have been reported with hematological malignancies, we here performed genomic analysis of the tumor cells to investigate whether BTK mutations predispose to this.
We collected clinical information and samples of two patients with B cell precursor acute lymphoblastic leukemia (BCP-ALL) and one patient with acute myeloid leukemia (AML). Informed consent for the genetic analysis was obtained from the patients and parents. We performed whole exome sequencing (WES) with a pair of tumor and germline sample in 2 cases of BCP-ALL.
Patient 1 presented with BCP-ALL at 10 years of age following diagnosis with XLA at 3 years of age. He achieved complete remission following chemotherapy. Patient 2 received a diagnosis of XLA at 2 years of age, and developed BCP-ALL at 24 years of age. He underwent allogeneic stem cell transplantation due to minimal residual disease after chemotherapy. Patient 3 was identified to have hypogammaglobulinemia at 5 months of age. He developed AML with myeloid sarcoma at 9 months of age, and was successfully treated with chemotherapy. He was later diagnosed as having XLA. WES revealed a frameshift mutation of MLL2 in Patient 1 and multiple pathogenic mutations including one in TP53 in Patient 2.
These case series identified that germline BTK mutation and additional somatic mutations might induce hematological malignancies in XLA patients.
X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by mutations in the signalling lymphocyte activation molecule - associated protein gene (SH2D1A). This causes dysregulation of the immune system, with defects in both cellular and humoral immunity. Patients usually present with Epstein-Barr virus (EBV) infection. Most affected individuals have no apparent disease prior to presentation. Common clinical manifestations are fulminant infectious mononucleosis, dysgammaglobulinemia, lymphoma.
Our aim was to report a clinical case of a patient with X-linked lymphoproliferative disease, who manifested with Burkitt lymphoma and hypogammaglobulinemia.
Case is reported of a 7-year-old boy with complaints of right sided submandibular lymphadenopathy. Lymph node biopsy, bone marrow aspiration, trephin biopsy were performed, no data of lymphoproliferative disease was found. In 2 month time lymph node conglomerate in the neck area increased in size, MRI of the head and neck was performed and large mass with extra- and intracranial distribution was found. Biopsy was performed and Burkitt lymphoma -specific morphology and immunophenotype was found. Chemotherapy was started, during which patient had several episodes of sepsis, he was EBV DNA positive. Boy reached complete remission, but developed persistent hypogammaglobulinemia. Primary immunodeficiency was suspected. Mutation was detected in SH2D1A gene and diagnosis XLP was confirmed. Boy now recieves intravenous immune globulin regulalry and condition is stable.
This case report demonstrates a patient with XLP, who manifested with Burkitt lymphoma and persistent hypogammaglobulinemia.
Management of XLP consists of treatment of disease manifestations, prevention of further sequelae and hematopoietic cell transplantation, which is the only curative therapy.
Introduction: Common Variable Immunodeficiency (CVID) is a heterogene group of disorders encompassed under a single term presented as autoimmunity, granulomatous disease, recurrent infections, and malignancy.
Objective: to present two cases of papillary thyroid carcinoma in adult with CVID.
Patient 1: Female 28 years, diagnosis of CVID in childhood, Freiburg IB phenotype, history of granulomatous disease and recurrent infections. At age 23 diagnosis of papillary thyroid carcinoma, total thyroidectomy and reactive iodine administration.
Patient 2: Female 38 years, diagnosis of CVID at 25 years, Freiburg IB phenotype, history of ITP, enteropathy associated with CVID, bronchiectasis and pulmonary fibrosis. At 37 years diagnosis of papillary thyroid carcinoma, treatment with total thyroidectomy and administration of radioactive iodine.
Discussion: prevalence of malignancy in CVID is 126.96.36.199%; occurs between 4th-6th decades of life; in these patients one of them differs.
The most frequent type of malignancy are non-Hodgkin's B-cell lymphomas, followed by gastric, bladder, breast and cervical epithelial tumors. Sporadic cases of papillary thyroid carcinoma have been reported, as in the López-Rocha cohort study in Mexico and in a study conducted by Sánchez in 2017 in the USA.
Of the risk factors found: female sex, high levels of IgM and ITP; In our cases, both female patients, only one with ITP, both IB group according to the Freiburg classification, none with high IgM levels.
Conclusions: it is important identify potential risk factors for malignancy in patients with CVID, since they have an increase of 5-12 times the risk than in the general population.
Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder in childhood with frequent extranodal presentation and involvement of the respiratory system. It is one of the EBV related malignancies seen in immuncompromised patient. LYG is usually associated with primary immune deficiency. Herein we report a 5-year-old girl admitted with a pulmonary LYG with common variable immune deficiency (CVID).
A 5-year-old girl was first admitted to pediatric hematology and oncology department for evaluation of pulmonary mass. She was diagnosed as pneumonia 3 months ago, but no clinical and radiological improvement achieved despite oral and parenteral antibiotherapies. Medical history revealed repeated penumonia, autoimmune hemolytic anemia and perianal/vulvar granulomatous lesion with no signifaicant daignossis. On admission she had no systemic pathologic lymphadenopathy or organomegaly but had lymphopenia and thrombocytopenia with normal peripheral smear and also blood chemistry was normal. A 4x5 cm infiltrative mass was seen on right lower lung.
The pathological examination was consistent with LYG Grade III. She had no isohemaglutinins, no vaccine response, low immunglobulin levels, and lymphocyte subgroup examination revealed significantly low CD3 and CD4 counts. She had been suspected to have CVID (common variable immune deficiency) and genetic testing was scheduled. R-CHOP protocol was started with regular IVIG replecement and she has still on treatment with complete response.
Atypical pulmonary malignant (EBV related or not) lesions should have rise the suspicion of primary immune deficiency in childhood. Through medical histroy and pre-treatment evaluation of immune status is very important for treatment plan and prediciton of prognosis.
Primary immunodeficiencies (PIDs) are genetic disorders that predispose patients to recurrent infections, autoimmunity, allergy and malignancy. This study aimed to investigate the clinical, genetical and histopathological characteristics of malignancies in PIDs.
Materials and Methods:
Herein, 8 malignancies in patients (4 boys, 4 girls) with PIDs are presented dating between 2015 and 2019 at department of pediatric immunology. The patients were analyzed retrospectively.
In the 4- year period, there were 8 malign cases associated with PIDs. The age of cases ranged from 2 months to 10 years at the time of diagnosis of malignancies. Lymphomas were observed in 87.5% (7/8) of patients. Non-Hodgkin’s lymphomas (NHL), Hodgkin’s lymphomas (HL) and juvenile myelomonocytic leukemia (JMML) were seen in 50 % (4/8), 37.5 % (3/8) and 12.5 % (1/8) of patients respectively. The diagnosis of malignancies in two patients was diffuse large B-cell lymphoma, with one of them having Nijmegen breakage syndrome and the other of them having XLF syndrome. Two patients had Burkitt lymphoma (1 CD137 deficiency and 1 ataxia-telangiectasia). Three patients (1 hereditary lymphohistiocytosis (HLH),1 common variable immune deficyiency and 1 homozigous ITK deficiency) had HL. One patient with Omenn syndrome (OS) had also JMML. Hematopoeitic stem cell transplantation were performed in two patients with OS and HLH and they are healthy at now. Two patients with XLF syndrome and ITK deficiency died.
Conclusion: PID are at an increased risk of malignancy compared with the normal population. After infections, malignancy is the second most common cause of death in these patients.
Epidermodysplasia verruciformis (EV) is characterized by susceptibility to human β-papillomavirus (β-HPV) infection and is strongly associated with skin carcinomas. Typical EV is caused by mutations in two proteins involved in the keratinocyte-intrinsic immunity, EVER1 and EVER2. However, clinical symptoms of EV have been associated with a variety of mutations causative of T cell defects. The aim of this study was to identify a possible primary immunodeficiency in a patient with a severe atypical EV.
A 32-year-old woman presented with multiple overinfected ulcers. She was diagnosed of EV during her infancy due to her skin lesions. She has been suffering from multiple squamous-cell carcinomas since she was 20. A stable circulating monoclonal CD4+/CD8+ T-cell population was demonstrated accounting 10% of total lymphocytes. A hypocellular bone marrow was detected on a biopsy. A high-risk HPV was found on a cervical cytology. Lymphocyte subpopulations were analyzed by an extensive flow cytometry study. A targeted NGS panel focused in genes causing primary immunodeficiencies was performed to achieve the genetic diagnosis.
General lymphopenia was detected, with severely diminished B cells. IgG levels were slightly low. CD4+ T cells showed an effector-memory phenotype, mainly Th1-T17. CD8+ T cell showed a terminally differentiated (CCR7lowCD45RAhigh) phenotype. A recently described dominant activating mutation (c.101C>A/p.P34H) was found in RAC2 gene coding the small GTPase, RAC2.
This is the first reported case with activating RAC2 mutation presenting as an atypical EV. Additional in vitro studies are being conducted for a better functional characterization of this mutation.
Ataxia teleangiectasia (AT) is rare, autosomal recessive, neurodegenerative genetic disorder, characterized by cerebellar ataxia, oculocutaneous teleangiectasias, variable immunodeficiency, recurrent sino-pulmonary infections and progressive neurological impairment. Mutation in ATM gene cause loss of cell cycle control and defect DNA repair that predispose patients to increased radiosensitivity and cancer. It reduces life expectancy. The most common type of malignancies are Hodgkin and non-Hodgkin lymphoma, leukemia, but solid organ tumours can also occur. We present a unique case of 16-year-old girl with ataxia teleangiectasia and gastrointestinal obstruction due to gastric adenocarcinoma.
Review of the patient's records.
The patient was a 16-year old girl with AT (diagnosis was established at the age of 1 year). She had 4 weeks complaints of fever, abdominal pain, nonbilious vomiting and weight loss. Nonspecific laboratory inflammatory markers were elevated and positive sings of peritoneal irritation were present. There was suspicion to acute appendicitis. Acute laparotomy with appendectomy was performed, but the clinical and laboratory symptoms persisted. There was a suspicion to gastrointestinal obstruction and the diagnostic imaging was done. Inhomogeneous infiltrative tumorous mass was found in the pylorus of the stomach and gastrofibroscopy with biopsy was performed. Histologic finding revealed the gastric adenocarcinoma. Later on, the patient died due to multi-organ dysfunction failure.
Solid organ tumours are rare complications of AT. In case of obstructive gastrointestinal symptoms, the possible presence of gastric adenocarcinoma should be taken into account and appropriate diagnostic approach should be performed. According to the literature, this is the second youngest reported patient with this complication.
Common variable immunodeficiency (CVID) is a primary immunodeficiency with heterogeneous clinical manifestations which include recurrent infections, chronic lung diseases, heightened susceptibility to lymphoma and autoimmunity.
Here we describe a 16 year-old boy that presented with recurrent pneumonia since 4 months of age, several upper respiratory tract infections, recurrent herpes zoster and chronic diarrhea. Immunoglobulin levels were below the 3rd percentile for the age and the number of B, T and NK cells was normal. The diagnosis of CVID was performed and he was kept on antibiotic prophylaxis and intravenous human immune globulin (IVIG) from the age of 16 years. Two years later he presented with urticaria that in the beginning seemed to be related with the IVIG, but evoluted as a chronic urticaria with no relation with IVIG or antibiotic prophylaxis. At the same year he presented with immune thrombocytopenia that disappeared after a high dose of IVIG. Diagnostic imaging revealed lymphonodular hyperplasia and a solid oval mass in right iliac fossa compressing and shifting the bladder. The biopsy was performed and Hodgkin lymphoma grade IA was confirmed. The patient was kept on IVIG, ABVD chemotherapy was initiated with partial response and autologous hematopoietic cell transplantation was performed. Since then he presented with no recurrence of the lymphoma.
This patient illustrates a case of CVID and concomitant severe clinical manifestations that can be presented in this disease. It also reinforces the importance of thinking in cancer, especially in lymphoma, in patients with CVID even in childhood or adolescence.
The correct repair of DNA double strand breaks by non-homologous end joining is vital for antibody and lymphocyte receptor diversity. NHEJ1 represents its most recently discovered component with less than 20 published cases of NHEJ1 deficiency worldwide.
We identified a 22-year old patient with recurrent pulmonary infections and mild pancytopenia who had been diagnosed with a hypocellular myelodysplastic syndrome at 6 years of age. At diagnosis, cytogenetics showed a premalignant monosomy 7-positive clone. Hematopoietic stem cell donor search remained unsuccessful. Intriguingly, patient blood counts stabilized, and repeat bone marrow punctures showed a complete resolution of the premalignant clone several weeks later. At 14 years of age, a 20q12 deletion clone became apparent and remains detectable with varying relative contribution to date.
To identify disease etiology, we employed our previously established, targeted NGS-based panel for hematological disorders (Kager et al., Br J Haematol 2017) and identified a novel mutation of the NHEJ1 gene (NM_024782.2:c236T>C, p.Leu79Pro), coding for the XRCC4 binding site of the protein and predicted highly damaging by CADD (score 31.0) and other computational gene prediction tools. The patient’s phenotype (microcephaly, short stature) as well as his progressive lymphopenia with telomere shortening fit the diagnosis of NHEJ1 deficiency.
This is the first patient worldwide described with myelodysplastic syndrome due to NHEJ1 deficiency, and only the second patient with NHEJ1 deficiency reaching adulthood without allogeneic HSCT. This case underlines the utility of NGS-based approaches for efficient identification of genetic etiologies of unresolved hematological and immunological disorders.
An increased prevalence of lymphoma has been observed in common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Herein, we analyzed data on the prevalence of hematological, cancer risk, mortality and survival rate in a cohort of 455 Italian adult CVID patients compared to normative population. Detailed data on CVID patients diagnosed with lymphoma, histology, outcome and possible associated risk-factors were reported.
Lymphoma incidence rates were evaluated in 455 subjects with CVID enrolled in PID care centres in Rome, Padua and Naples from 1993 to 2017 and compared with incidence rates in AIRTUM database.
CVID patients showed an increased incidence for non-Hodgkin lymphoma (NHL) (Obs=33, SIR=14.3; 95%CI=8.4–22.6), and Hodgkin's lymphoma (HD) (Obs=5, SIR=12.5, 95%CI=3.4-22.4) (Fig.1).The age at lymphoma diagnosis was 32.8 ± 4.6 years for HD and 52.4 ± 13.1 years for NHL. CVID-associated lymphomas were more likely to be of B-cell origin and occurred at extra-nodal sites in 30% of cases reported. T-cell lymphomas (peripheral T-cell lymphoma, angio-immunoblastic T-cell lymphoma and anaplastic T-cell lymphoma) and one primitive effusion cavity lymphomas were also observed. Patients with lymphoma were more likely to have lymphopenia (lymphocytes < 1,000 cell/mm3, OR=3.0, 95%CI=1.1–8.3, p=0.030) and polyclonal lymphocytic infiltration (OR=2.7, 95%CI=1.2–6.3, p=0.016) before cancer diagnosis.CVID patients with lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.2, 95%CI: 2.8–44.4, Fig.2). Lymphoma was the tird cause of death, following gastric cancer and respiratory infections,
Based on this large series, we highlighted the need of a strategy for hematological malignancy surveillance based on epidemiological studies.
Interleukin-2 inducible T cell kinase(ITK) is an autosomal recessive primary immunodeficiency disease(PID) associated with Epstein-Barr virus(EBV)-driven lymphoproliferative disorder, lymphoma, and, hemophagocytic lymphohistiocytosis. It is characterized by progressive reduction in CD4+T‐cells along with hypogammaglobulinemia.
We present a consanguineous family from upper Egypt with three siblings sharing the presentation. The eldest was a girl who presented at the age of 6 years with severe pneumonias and generalized lymphadenopathy. Malignancy and tuberculosis were excluded. She died at 10 years of age from pneumonia-associated respiratory failure. The second patient was a boy who presented at the age of 7 years with EBV-positive lymphoma and was successfully treated, but 2 years later he also died from respiratory failure. The third patient was a girl who presented with EBV-positive lymphoma at the age of 7 years responsive to chemotherapy. Two years later, she began having recurrent pneumonias and was found to have CD4+ lymphopenia and hypogammaglobulinemia(Table:1).
Targeted next-generation sequencing for a panel of 264 genes associated with PID identified a homozygous missense variant in ITK(c.236C>T: p.Pro79Leu). She was treated with intravenous immunoglobulin and is undergoing evaluation for bone marrow transplantation.
Table 1: Laboratory Results:
Malignancy can be the first and only presentation of PID. The occurrence of malignancy in more than one family member should raise suspicion for an underlying PID.
The term Hodgkin’s disease like Virchow’s subsequent term lymphoma was named after Thomas Hodgkin in 1832 to designate swollen lymph nodes of unknown cause("neoplasm"). Lymphoma is a malignant neoplasm of the immune system. Innate and adaptive immune responses are dependent on lymphocyte ontogeny and location based proteins triggered by many genes including receptors and regulators. Epidemiology of lymphoid neoplasia includes auto-inflammation, chronic infections, antigen stimulation, oncogenic viruses, proliferation/apoptosis, immune check point imbalance, chemical and environmental exposure as well as genetic background. Recent advances in the diagnostic genomics have led to identification of many new germline and somatic genetic syndromes of immune dysregulation orchestrating the interplay between nonmalignant lymphoproliferation and lymphoma.
The cancer and lymphoma susceptibility lessons learnt from ALPS-FAS (Autoimmune Lymphoproliferative Syndrome) and RALD (RAS Associated Leukoproliferative Disorder) over many years can be used as a paradigm for lymphoma risk assessment in many recently described genetic disorders of immune system including CTLA4 haploinsufficiency, PIK3CD, and MagT1defects (XMEN).
Diligent long term follow up at NIHCC with subspecialist collaboration fostered critical thinking needed for diagnosis and management of these immune-mediated lymphoma predisposition syndromes. Rare genetic disorders elucidate the critical immune surveillance pathways to malignant neoplasia and help us to treat them better with targeted therapeutics.
Studying patients with germline and somatic genetic variants leading to immunedysregulation and cancer susceptibility, profiling both germline and tumor DNA in all cancer patients at diagnosis should provide tools towards better patient care through early anticipation, diagnosis, management and prevention of malignancies within the affected families and general population.
ARTEMIS plays an important role in somatic recombination of VDJ genes. Mutations in ARTEMIS complex result in hypersensitivity to DNA double strand break-inducing agents. Pediatric craniopharyngioma (CPG) usually presents at the age of 5-10 years.
We describe a case of CPG diagnosed at the age of 2 years 4 months in a child who underwent a HSCT because of SCID due to the mutation in DLCRE1C gene.
A 10 month old boy from non-consanguineous parents presented with severe skin erythema, respiratory insufficiency caused by Parainfluenza virus 3, failure to thrive. Since 6 months of age he underwent several episodes of respiratory and gastrointenstinal infections. Laboratory evaluation detected low lymphocyte count and immune globulin level. Next-generation sequencing revealed two missense variants (c.103C>G and novel c.53G>T) in DCLRE1C gene. An allogeneic HSCT from MUD was performed at the age of 12 months following preparative regimen containing Fludarabin/Treosulfan/Campath. After the engraftment the patient developed an acute GvHD grade III and disseminated BCG infection. Fifteen months after HSCT at the age of 2 year 3 months the patient was off immune suppression but continuing isoniazid/rifampicin when tumor mass was detected in suprasellar region. The total tumor resection revealed an adamaninomatous CPH.
It is known from other conditions (e.g. Fanconi anemia) that HSCT does not eliminate, or even increase, the risk of cancer in conditions with hereditary DNA repair defects. Our case suggests that presence of mutations in DCLRE1C gene could predispose non-immune cells to clonal evolution even after successful replacement of immune system.
X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease is caused by loss of function (LOF) mutations in the magnesium transporter 1 gene (MAGT1). Patients have an inverted CD4:CD8 ratio with CD4 lymphocytopenia, increased B cells, and invariably, decreased expression of the activator receptor “Natural-Killer Group 2, member D” (NKG2D) on natural killer (NK) and CD8+ T cells. NKG2D loss results in impaired cytotoxicity and increased susceptibility to malignancies.
We reviewed the medical records and pathology slides of 9 patients with genetic confirmation of XMEN disease and histopathological diagnosis of malignancy. Patients with XMEN disease and no history of malignancy were excluded for this analysis. All subjects had variants in the MAGT1 gene that resulted in loss of protein expression. Decreased NKG2D surface expression was confirmed by flow cytometry. All subjects provided written informed consent in accordance with the Declaration of Helsinki.
The most common neoplasia associated with XMEN disease was classical Hodgkin lymphoma (n=4). Burkitt’s lymphoma, diffuse large B cell lymphoma, EBV-positive lymphoproliferative disease, and liposarcoma were less frequently observed. Age of cancer onset varied from 7 to 45 years.
XMEN disease is a combined primary immunodeficiency that results in chronic EBV infection and increased risk for malignancy. EBV-encoded RNA (EBER)-positive Hodgkin lymphoma is the most common form of malignancy observed in our cohort of XMEN patients.
Secondary immunodeficiencies are often induced by oncohaematological diseases and their treatments. But sometimes an haematological malignancy may be the first manifestation of a primary immunodeficiency. Our aim was to characterize the immunodeficiency of a patient with frequent respiratory infections and a previous history of Hodgkin´s Lymphoma.
The patient, a male 53 years old, was diagnosed with a nodular lymphocyte-predominant Hodgkin´s lymphoma at 18 years and treated with systemic chemotherapy (COPx4), irradiation and splenectomy. He suffered several mediastinic and infradiaphragmatic recurrences (at 21 years, 37 years and 43 years), treated with irradiation and chemotherapy (CVPx8 and R-CHOPx6), respectively. Since then he remains in remission. Immunological evaluation included the study of the genomic DNA for a panel of 200 genes of the immune system by Next Generation Sequencing.
The patient referred recurrent respiratory infections since childhood. Blood analyses showed a moderate lymphocytosis (5.1 x 109/L) composed predominantly of T cells (3.8 x 109/L). Levels of IgG and IgE were normal with slightly decreased IgA and IgM levels. Genomic DNA analysis showed the heterozygous mutation p. Pro553His in CARD11, a muti-domain scaffold lymphocyte-specific protein linking antigen receptor with downstream NF-kB activation. Heterozygous gain of function CARD11 mutations have been previously involved in BENTA disease (B cell Expansion with NF-kB and T cell Anergy) and associated with B-cell lymphoma.
We have identified a germline heterozygous CARD11 mutation (p.Pro553His) in a patient with immune-dysregulation and previously diagnosed with recurrent Hodgkin´s lymphoma. Functional studies are required to confirm the causal relation genotype-phenotype.
Gastric adenocarcinoma (GA) is considered a major cause of death in patients with primary antibody deficiencies (PAD). The risk of developing GA was found to be 5-16 times higher in CVID patients than in the general population, with the mean age at diagnosis being significantly younger. Importantly, a monogenic origin has been identified in less than 10% of CVID patients and it is currently thought that most cases have a polygenic origin.
Whole-Exome/Genome Sequencing (WES/WGS) opens new opportunities to study the genetic background of PAD and to identify variants that perturb pathways relevant for the development of GA in these individuals.
We generated the WES profile of 41 PAD patients, including 9 patients (5F/4M) with GA (median age at diagnosis: 45 (27-62)). We then performed genome-wide studies to identify differences that might explain this increased oncogenic risk, by comparing these 9 patients with healthy individuals and the remainder of the PAD cohort.
We identified 394 potentially deleterious variants (CADD>15) with an allele frequency below 0.05 (GNOMAD NFE population), with none of these being present in the top 20 genes with somatic mutations associated with GA (Cosmic database). Exome-wide association demonstrates that PAD patients with GA have 368 variants with significantly higher frequency than healthy controls. The pathways associated with the identified genes are currently under investigation.
This first analysis of the exome of a cohort of primary antibody deficiency patients focused on gastric adenocarcinoma identified germline variants that may explain mechanisms underlying their susceptibility to this particular malignancy.
Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations. Early diagnosis and management of the PID have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Our aim was to define the oncohaematological warning signs of primary and secondary IDs in paediatric and adult patients.
A multidisciplinary group of six experts conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement.
This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology specialists. Peripheral cytopenia and lymphoproliferative disorders are key diagnostic pointers. The diagnosis should be based on a detailed clinical history and physical exam, complete blood count and stratified laboratory tests according to the level of care. Patients who are candidates for immunoglobulin replacement therapy should be carefully selected, and treatment offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients.
The resulting document is a useful tool for primary care physicians and oncohaematologists in the suspicion of ID. This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications.
Common Variable Immune Deficiency (CVID) is associated with an increased risk of malignancies, and in particular of gastric cancer. The aim of this study was to compare the incidence of gastric cancer in a German and an Italian CVID cohort.
Risk for cancers among 491 CVID German patients within a single centre cohort (CCI Freiburg) was compared to cancer incidence from the German Cancer Registry Database. Risk of cancer among 455 CVID Italian patients of three centres (Rome, Padua and Naples) was compared to cancer incidence from the Italian Cancer Registry Database.
CVID patients showed an increased cancer incidence for all sites combined in the Italian cohort (Obs = 133, SIR = 2.4; 95%CI = 1.7–3.5),and in the German cohort (Obs = 20, SIR = 1.7 95%CI = 1.05–2.6). Gastric cancer in the Italian cohort (Obs = 25; SIR = 6.4; 95%CI = 3.2–12.5) and in the German cohort (Obs = 3, SIR = 7.9 95%CI = 1.6–23.0) were significantly increased with respect to the general population.
Despite the regional differences in the gastric cancer incidence in the general population between Italy and Germany, CVID patients carry a similar increased risk of gastric cancer in both cohorts. Additional studies aimed to identify major risk factors and prevention plans need to be established for the long-term follow up of CVID patients.
Biallelic mutations in tetratricopeptide repeat domain 7A (TTC7A) gene have been shown to cause several overlapping clinical phenotypes in 56 patients worldwide. TTC7A is key factor to bridge the process of both immune system and digestive tract development. Most patients presented with multiple intestinal atresia (MIA) isolated or in association with immunodeficiency.
Here we present a 12-years-old female patient of Slavic origin (Belarus) with EBV positive Hodgkin lymphoma, bronchiectatic and celiac disease with biallelic mutations of the TTC7A gene.
A 8-year-old girl, born to non-consanguineous Belarus parents, presented with chronic obstructive pulmonary disease, multiple bronchiectasias due to repeated pneumonias and bronchitis, was hospitalized for detailed immunologic evaluations. The patient had low T cell (CD3+-470 cells/µL) with expansion of TCRgd T cells, accompanying with diminished numbers of recent thymic emigrants (CD4+CD45RA+CD31+-2.8%), with minor abnormalities in TCRVb repertoire. Humoral abnormalities included low level of IgA (0.03g/L) and diminished percentage of naïve (CD19+CD27-IgD+) B cells (30.8%).
In the age of 10 years generalized lymphadenopathy appeared and classic EBV positive Hodgkin Lymphoma Lymphocyte-rich CD20-negative was established on a resected lymph node. Treatment (2-OPPA; 2-COPP) was complicated with severe mucositis and esophagitis. After treatment patient suffered from lung insufficiency, celiacia (anti-gliadin Ab) and failure to thrive. Accidentally, patient died due to food aspiration at the age of 12 years and later found to have compound heterozygous mutations in TTC7A (p.K606R and p.S672P).
To our knowledge, this is the first case of a potential association between TTC37A mutation and lymphoma development.
Patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. The aim of this study was to assess the spectrum of genes and type of malignancies in PID patients in Belarus.
We analyzed the malignancy type, age of onset and genetic bases of PIDs with malignancy onset.
36 PID patients from 35 families of Belarus origin were identified in the National PID registry, 55.5% (n=20) males and 44.5% (n=16) females. Age of malignancy diagnosis ranged 6 m.–21,5 yrs (median–6,5yrs). Fourteen patients (39%), of median age 11.8 years, remained alive at the time of analysis, six out of 14 alive after HSCT. Non-Hodgkin's lymphomas predominate, accounting for 56% of cases (n=20), 28% (n=10) patients experienced acute leukemia (n=3 T-ALL, n=3 AML, n=1 bi-phenotypic), 11% (n=4) patients had Hodgkin lymphoma, n=1 myelodysplastic syndrome, n=1 rhabdomyosarcoma.
All patients had PID diagnosis according strong immunologic abnormalities in cellular and/or humoral immunity. 23 out 36 (64%) had definite genetic diagnosis. The most common genetic abnormality was Nijmegen syndrome (NBS1 Slavic mutation) 39% (n=9), followed by ataxia-telangiectasia 17% (n=4) and one patient with BLM (Bloom syndrome), SH2D1A (XLP I), DNMT3B (ICF), WAS, FOXN1, TTC37A, UNC13D, MYSM1, ELA (Neutropenia), CYBB (X-CGD after HSCT).
In Belarus PIDs more often associated with cancer, include Nijmegen breakage syndrome, ataxia-telangiectasia and combined T/B deficiency.
Neoplasia, particularly gastric adenocarcinoma, has been increasingly recognized as an important cause of death in CVID, but the mechanisms underlying this increased oncogenic risk remain largely unknown. We report here a patient with primary hypogammaglobulinemia that presented synchronous and rapidly progressing gastric adenocarcinoma and hepatocellular carcinoma.
Clinical report with immune profile and WGS.
Poorly differentiated antral adenocarcinoma and high-grade pyloric dysplasia were diagnosed at 45y during a screening protocol with gastroscopy every 1-3y. The tumor staging evaluation revealed multiple lesions of hepatocellular carcinoma that led to the patient death within one month. There was no evidence of previous liver disease, including viral hepatitis or increased alcohol consumption. The patient reported intermittent treatment with omeprazole since 21y due to gastritis, and diffuse gastric atrophy and intestinal metaplasia were diagnosed at the age of 39 prompting H. pylori eradication that was achieved after 2 treatment courses. Primary antibody deficiency was diagnosed at 15y due to recurrent sino-pulmonary infections (since 6y), meningitis, giardiasis and severe autoimmune cytopenias. Subsequently, he featured lymphadenopathy, lung and gut granulomatous-lymphocytic infiltration, and Pseudomonas and BK infections, in agreement with concomitant T cell deficiency, as attested by the marked loss of naïve CD4+ T cells. WGS did not reveal mutations in genes typically associated with familial gastric cancer or CVID, but there were multiple potentially pathogenic variants in genes of interest favoring a polygenic basis.
This case points to a reappraisal of cancer surveillance in primary antibody deficiencies and reinforces the need of WGS validation algorithms for multigenic diseases.
CVID is a clinically relevant type of PID with manifestations including recurrent infections, autoimmune diseases, and malignancies. The risk of B-cell NHL, diffuse, and high grade with extranodal primary sites is especially increased.
Patients. A 60-yr-old female has been suffering from sinobronchial infections and splenomegaly for years. Later due to persistent lymphocytosis NHL/CLL was diagnosed with sec. immunodeficiency. Six cycles of FC were administered. A 41-yr-old male displayed recurrent infections, splenomegaly, pulmonary infiltrates, and hypogammaglobulinemia for years. Pulmonary biopsy indicated NHL/MZL. Six cycles of CVP were administered. A 33-yr-old male with recurrent fever, pulmonary infiltrates, and lymphadenopathy starting 3 years ago was diagnosed with NHL/DLBCL by lymph node biopsy, and with sec. immunodeficiency. Six cycles of R-CHOP were administered. A 39-yr-old female with a 3-month presentation of splenomegaly, pancytopenia, and low Ig-levels was diagnosed upon crista biopsy with NHL/THRLBCL. Six cycles of R-CHOP were administered. The patients were referred to our division for evaluation of the persisting Ig-abnormalities.
Upon the ESID criteria we diagnosed all 4 patients with CVID; (marked reduction of Ig-isotypes and class-switched CD27+IgD−IgM− memory B-cells, increased number of CD19+CD21− immature B-cells.) In their cases NHL probably developed on the basis of immune dysregulation. Their PID status now is stable with regular, monthly given IVIG (Intratect).
The association of CVID with malignancy is well established. In general, NHL develops after a period of the CVID onset. Our cases reflect the difficulty of CVID diagnosis, mainly in respect of potential sec. causes of immunodeficiency, like NHL.
Lymphoid hyperplasia and splenomegaly are found in 20% of patients with common variable immunodeficiency (CVID). The incidence of lymphoma, the most common malignancy, is increased (3-8%). Distinguishing between benign and malignant lymphoid proliferation presents challenges. We present 5 patients with known CVID in which non-Hodgkin’s lymphoma (NHL) was diagnosed; 4 cases underwent chemotherapy.
Original pathology reports, slides and tissue blocks were submitted to the NIH/National Cancer Institute Hematopathology Section for expert pathology review. Immunohistochemical studies (CD20, CD3, CD79a, IgD, kappa, lambda, Ki-67, BCL2, BCL6 and MUM1; CyclinD1, CD5 in selected cases), in situ hybridization for Epstein-Barr virus and gene rearrangement analysis were performed.
Five CVID patients (3 males and 2 females; age at diagnosis: 25-46 years) were diagnosed with NHL (4 with marginal zone lymphomas, 1 with diffuse B-cell lymphoma; age at cancer diagnosis: 27-63 years) often based on evidence of clonality (Table 1). None were EBV positive. Chemotherapy was given to 4 patients and suggested for the fifth, who declined and sought a second opinion. However, on expert review, histologic morphology, cell markers and molecular characteristics were not consistent with lymphoma but benign lymphoproliferation characteristic of CVID.
There is a risk of lymphoma in CVID due to immune defects and dysregulation; however, B-cell proliferation and clonality may be mistaken for lymphoma. Expert hematopathology review including histology, thorough immunophenotyping, molecular and genetic studies are required in such cases to prevent unnecessary and potentially deleterious therapy.
DOCK8 deficiency is a combined primary immunodeficiency with clinical hallmarks including atopic dermatitis, allergies, respiratory tract infections, viral skin infections and early onset malignancy. The prognosis of DOCK8 deficient patients is poor with a median survival of 20 years in historic patient cohorts without hematopoietic stem cell transplantation (HSCT). Mortality usually results from infections, malignancies, or both. This paper describes the clinical course of two siblings with a compound heterozygous mutation causing DOCK8 deficiency. We also systematically reviewed the literature on DOCK8 deficiency and malignancies.
In Januari 2019 a literature search focused on DOCK8 deficiency and malignancies was performed in Pubmed that yielded 26 articles and an additional 32 papers were included through snowballing.
The increased malignancy risk of DOCK8 deficient patients can likely be explained by multiple factors, being chronic viral infections with oncogenic viruses, impaired immune surveillance and a possible tumor suppressor function of DOCK8. Previous studies reported that 8 to 19% of the DOCK8 deficient patients develop malignancy, with an associated mortality of 7 to 10%. HPV associated squamous cell carcinoma and EBV related lymphomas are the most prevalent malignancies in DOCK8 deficiency.Currently, HSCT is considered standard of care for DOCK8 deficient patients, but it is unclear whether HSCT protects against future malignancies.
There is no long-term data on malignancy risk post HSCT in DOCK8 deficiency. Furthermore, it is unclear whether a subpopulation of DOCK8 deficient patients exists that do not require HSCT. This underscores the need of prospective cohort studies to anlyse HSCT effectifness and individual malignancy risk.
Malignancies are often observed in pediatric patients with combined immunodeficiency and it is the most prevalent cause of death after infections in these patients.
Here, we report clinical, immunological and genetic evaluation in two young sisters that presented with combined immunodeficiency, where one patient developed EBV related B cell lymphoma and the other had systemic EBV infection and suspected lymphoma.
By whole exome sequencing we identified a novel homozygous missense c.721G>A mutation in exon 5 of UNG gene, generating a p.V241I mutant protein. The mutation led to a significant loss of UNG expression. Immunodeficiency associated with mutations in the UNG is rare and is known to present as hyper IgM syndrome 5 . Nevertheless, our patients displayed clinical and laboratory signs of combined immunodeficiency severe T cell lymphopenia, poor proliferative reaction to mitogens, abnormal T cell repertoire, and restriction and clonal expansions of the TRG repertoire of the gdT cells. class-switch recombination was grossly not impaired. The analysis of the IGH repertoire revealed abnormal IGHV gene usages and somatic hyper mutation (SHM) pattern.
Our findings demonstrate for the first time, the importance of UNG in T cell development and its role in protecting against the development of B cell lymphomas in humans. We believe that thesenew insights will help in unveiling yet unknown functions of UNG in adaptive immunity.
Primary immunodeficiencies (PID) are frequently complicated by non-Hodgkin’s lymphomas (NHLs). We present three cases with compound heterozygous mutations in DOCK8, NBAS and PGM3 transcripts. All had an extraordinary disease course.
We compared DOCK8, NBAS and PGM3 versus IgG-RNA expression within plasma cell malignancy.
Case 1. A 19-year-old woman with compound heterozygous DOCK8 mutations, severe infections and impaired vaccination response developed undefined necrotic inflammations in liver and kidneys, after spontaneous involution she developed a large B-cell NHL, stage IV (EBV negative). Treatment was successful with chemo/radiotherapy. Three years later she developed refractory Hodgkin’s lymphoma. Bone marrow transplantation (BMT) was complicated by lethal GVH reaction.
Case 2. A 45-year-old woman with achromatopsia, dwarfism, hypothyroidism and hypogammaglobinemia due to a mutation in NBAS developed stage IV, pelvic marginal zone NHL. She had longstanding oligoclonal CD8+ T cell lymphocytosis and was EBV-DNA positive. Treatment was successful with chemotherapy/rituximab.
Case 3. A 37-year-old woman with hypogammaglobulinemia, B- and T-lymphopenia, granulopenia and hyper-IgE due to heterozygous mutations in PGM3 presented with gastrointestinal large cell diffuse B-cell NHL of the gut. She was successfully treated with BMT after chemotherapy/rituximab. No EBV infection was detected.
High expression of DOCK8, NBAS, and PGM3 correlated with high IgG production in myeloma samples (NCBI GEO dataset GSE19784).
DOCK8 and PGM3 mutation frequently develop NHL, we also present a NBAS patient with NHL and suggest that impairment of these genes may affect the IgG synthesis.
Defects in the interleukin-21 receptor (IL-21R) gene are recently defined causes of primary immunodeficiency diseases. IL-21R defects result in combined immunodeficiency by affecting the functions of innate and adaptive immune system components.
A six year old girl was admitted to our hospital with complaints of chronic diarrhea that started after the newborn period and generalized rash over the last three months. At the age of 4 the patient had severe respiratory distress due to Cytomegalovirus (CMV) pneumonia requiring mechanical ventilation and diagnosed as combined immunodeficiency at another hospital. The physical examination on admission revealed erythematous rash on cheeks, extremities and gluteal region and lymphadenopathies in the cervical, axillary and inguinal regions. CMV DNA in plasma and Cryptosporidium parvum in stool were positive. Marginal zone lymphoma (Epstein-Bar virus negative) was detected in the lymph node biopsy. Targeted next generation sequencing Ion AmpliSeq™ primary ımmunodeficiency panel showed a novel homozygous IL21R c.132delC (p.Ser45fs) mutation.
This case is presented to emphasize that IL21R defects should be considered in the differential diagnosis of the patients with recurrent respiratory infections, chronic diarrhea, Cryptosporidium parvum infection, chronic liver disease, sclerosing cholangitis and malignancy; and early hematopoietic stem cell transplantation (HSCT) is life saving.
A total of eight cases with IL21R gene defects have been reported in the world. The importance of this case is that it is the first case of malignancy among the IL-21R deficient patients published in the literature.
Primary immunodeficiency are genetically determined diseases characterized by lack of the function/a component of the immune system. Malignancies are one of the causes of death in PID. It has been demonstrated by epidemiological studies that cancer risk is 1.6-2.3 times higher in primary immunodeficiency than in the general population. The most common types of malignancies in PID are hematological malignancies, especially lymphomas.
Aim: evaluation of cases of hemoblastosis in patients diagnosed with primary immunodeficiency in the Republic of Moldova
were evaluated 51 patients (36 patients – post-mortem) aged 0-18 years diagnosed with primary immunodeficiency at the Mother and Child Institute of the Republic of Moldova. For the diagnosis of hematological malignancies were used: bone marrow biopsy, biopsy and lymph node histology, immunohistochemistry.
Of the total number of cases, 3 (5.8%) children were identified with malignant neoplasms; with a boys : girls ratio=2:1. The mean age of diagnosis of malignancy was 9.5±8,6 years. In a child with Louis Bar syndrome and marked cervical lymphadenopathy, at the thoracic CT with multiple paraaortal and peribronchial ganglia, after thelymph node biopsy and histology, the diagnosis of non-Hodgkin's lymphoma, lymphoblastic form was etablished. For the other two children, non-Hodgkin's lymphoma, lymphoblastic form (in the patient with CVID) and acute lymphoblastic leukemia (in the Louis Bar patient) were identified in the morphopathological evaluation.
Patients with primary immunodeficiency have a high risk of developing cancer. Hematological malignancies is one of the most common types of malignancy in these patients.
Thousand and one amino-acid kinase 2 (TAOK2), is a transmembrane protein which belongs to mammalian sterile 20 (STE20)-like kinase family To this day, only one report documented that TAOK2 might regulate T cell proliferation. Whether TAOK2 has any role in CD4+ T cell subset generation or cytokine secretion has not been assessed. In this study we aimed to characterize helper T cell signature cytokines and innate lymphoid cells in three patients with two novel TAOK2 mutations.
After whole exome sequencing mutations were confirmed by Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll-Paque and stimulated with phorbol myristate acetate/Ionomycin or CD3/28. IL-17, IL-22, GM-CSF, IFN-γ production by T cells were assessed by intracellular cytokine staining. T cell proliferation, apoptosis was quantified by flow cytometry. IL-6, IL-12 induced STAT3 and STAT4 phosphorylation was tested by phospho-flow based assay. Innate lymphoid cell frequency was measured by flow cytometry.
Patient-1 has presented with severe invasive fungal infection and had TAOK2 (NM_016151.3: c.3259C>T, p.Arg1087Trp) mutation. The T cells of this patient were hyperproliferative to CD3/CD28 stimulation, showed reduced IL-17, IL-4 and IFN-γ production. IL-1B-induced ERK1/2 phosphorylation was defective but, STAT3 phosphorylation was augmented in patient PBMCs. Patient 2 and 3, which were siblings (with rhabdomyosarcoma, and osteosarcoma, respectively) had TAOK2 (NM_016151.3: c.1324C>T, p.Pro442Ser) mutation. Their T cells showed reduced IL-4 and IFN-γ. Patient one had reduced ILC3 subset, while patient 2 and 3 had normal ILC levels.
Our results reveal unique and common consequences of two distinct variants of TAOK2 on immune cells.
Loss of Function (LOF) STAT3 (AD-HIES; Job’s Syndrome) is a rare primary immunodeficiency characterized by sinopulmonary infections, eczema, connective tissue, and vascular complications. Increased STAT3 activity is thought to drive malignancies, mostly adenocarcinomas. With the dominant negative mutations in STAT3, less malignancy may be expected. However, increased rates of lymphoma are described.
We reviewed 143 LOF STAT3 patients seen at NIH to determine the spectrum of malignancies, treatments provided, and outcomes.
We identified nine patients with history of malignancy. Six (4%) were treated for non-Hodgkin lymphoma (5 DLBCL, 1 Burkitt’s). Five with DLBCL were treated with EPOCH at standard doses. 4/5 patients are alive, with one dying of heart failure 16 years after treatment. Two (1%) were treated for papillary thyroid carcinoma with thyroidectomy and radioactive iodine. They have been in remission for 7 and 20 years. One was later diagnosed with DLBCL. Two had localized skin cancers; one with squamous cell CAs treated topically with 5FU, and one with basal cell CA treated with Moh’s surgery complicated by poor wound healing.
Papillary thyroid carcinoma and non-Hodgkin lymphoma appear to occur at higher rates in AD-HIES and should be considered in patients with thyroid nodules or lymphadenopathy. Skin cancer should be considered, especially in patients treated with voriconazole. As survival increases, more malignancy may be seen in this population. It is possible that decreased STAT 3 signaling may prove to be protective of some cancers.
Metaphyseal dysplasia without hypotrichosis (MDWH) is a rare form of chondrodysplasia with no extra-skeletal manifestations. MDWH is caused by RMRP mutations but it is differentiated from the allelic condition cartilage-hair hypoplasia (CHH), which in addition to chondrodysplasia is characterized by thin hair, immunodeficiency and increased risk of malignancy. The long-term outcome of MDWH remains unknown. We diagnosed severe agranulocytosis in a subject with RMRP mutations and normal hair. Based on this observation, we hypothesized that MDWH is not a separate nosological entity but may, similar to CHH, associate with late-onset extra-skeletal manifestations.
We collected clinical and laboratory data for a cohort of 80 patients with RMRP mutations followed prospectively for over 30 years and analyzed outcome data for those with features consistent with MDWH.
In our prospective cohort, we identified 10 patients with skeletal but no extra-skeletal features during pre-school age. Eight of these patients developed malignancy or clinically significant immunodeficiency during follow-up. Two of them died during chemotherapy for malignancy. At the time of the first extra-skeletal manifestation, patients were school-aged, 20, 43 and 50 years old. Laboratory signs of immunodeficiency (impaired lymphocyte proliferative responses) were demonstrated in four patients before the onset of symptoms. The patient outside this cohort, who had RMRP mutations, skeletal dysplasia, normal hair and severe agranulocytosis at 18 years of age, underwent hematopoietic stem cell transplantation.
MDWH can present with severe late-onset extra-skeletal manifestations and thus should be re-classified and managed as CHH.
Common Variable Immunodeficiency (CVID) encompass a group of antibody deficiencies characterized by markedly decreased immunoglobulins and defective specific antibody responses or decreased memory B cell counts. CVID patients suffer, generally, recurrent bacterial infections, but can also present potentially severe complications as autoimmune diseases, lymphoproliferative disorders, enteropathy and malignancies. We describe a patient diagnosed with CVID that presented two malignant hematological complications of different cell lineage that received an allogenic HLA-identical related HSCT with complete immunological reconstitution.
The immunophenotype was studied by flow cytometry. Genetic analysis was performed by a next-generation sequencing customized targeted panel containing known PID related and several PID candidate genes. Immunological reconstitution was evaluated a regular time-points after HSCT.
We present the case of a 37-year-old woman, that has been followed-up since her childhood in our Clinical Immunology out-patient clinic with the diagnosis of CVID. She presented autoimmunity, recurrent infections and two lymphomas of different lineage (nodular sclerosis and lymphoplasmacytic).
The immunological study showed hypogammaglobulinemia, positive antinuclear antibodies, lymphopenia with a decrease in B lymphocytes, increase in NK cells, inversion of CD4/CD8 ratio and loss of post-vaccinal response.
The genetics did not reveal pathogenic variants. Due to the onco-hematological complications, at 35-years-old she received an hematopoietic stem cell transplant with a good clinical and immune response, that currently allowed the progressive suspension of her habitual treatments.
HSCT can be a curative procedure, preventing complications and improving quality of life of CVID and monogenic CVID-like disorders in adults. Risk-assessment and personalized evaluation depending on donor source is mandatory.
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kd). The clinical hallmarks of this syndrome are recurrent sinopulmonary infections, non neoplastic lymphproliferation, herpesvirus infections and auto-immunity. 13% of patients develop malignant lymphoma.
We present the case of an 8 year old patient with APDS syndrome. At the age of 7 years old she presented with an ileocolic intussusception requiring ileocolic resection. Pathology of the resected bowel showed lymphproliferation but no malignancy. During follow up, abdominal ultrasound revealed a mass close to the right ovary. Biopsy was done and showed no signs of lymphoma, revision suggested a dysgerminoma. Right sided ovariectomy and a biopsy of the -also enlarged- left ovary was performed and showed a bilateral dysgerminoma. Ascites showed atypical cells. The diagnosis of a bilateral dysgerminoma FIGO stadium 1C3 was made and treatment with 2 courses of Cisplatinum and Etoposide were started according to MAKEI 2005 protoocol.
Immune histochemistry for p85a, p110delta and phospo AKT and whole exome sequencing will be performed to investigate involvement of the PI3K delta pathway in this dysgerminoma.
Histology and genetic analysis might reveal importance of the PI3K delta pathway in the development of this bilateral dysgerminoma.
This is the first case of a patient with APDS syndrome developing a bilateral dysgerminoma presented in literature. Further investigation will unravel the involvement of the PI3Kdelta pathway in the etiology of this tumor.
Background: Several PID have higher risk of neoplasia compared to the general
population. The incidence of neoplasia depends on the specific PID. After infections,
neoplasia is the second cause of death.
Aim: Review all PID patients followed at CHUP between 1998 and 2018, focusing on
the development of benign or malignant neoplasms.
Methods: Retrospective analysis based on clinical and laboratory records.
Results: From 517 PID patients identified, 24 (8 males and 16 females) had neoplasia
(5%), 8 of them at pediatric age (33% of all patients with neoplasm). For 65 patients
with CVID, 15 (23%) developed neoplasia: 9 non-Hodgkin lymphoma (NHL), 4 gastro-
intestinal malignancies, 2 uterine carcinoma and 1 CNS tumor; 1 patient had gastric and
colorectal cancer. Neoplasms in patients with other PID were: NLH (1 patient with XL-
Lymphoproliferative Disease, 1 with Nijmegen breakage syndrome, 1 with Hyper-IgE
Syndrome (HIES), and 1 with MST deficiency); thymoma (1 patient with Good
Syndrome); ependymoma (1 patient with XL-CGD); vulvar papilloma and carcinoma (1
patient with HIES); vulvar papilloma (1 patient with GATA2 deficiency); and benign
neoplasia of the maxilla (1 patient with MyD88 deficiency). Eight patients died, 5 in
consequence of the neoplasms, 2 CVID patients from respiratory insufficiency and 1
patient with GATA2 deficiency, from Herpes simplex encephalitis.
Conclusion: The incidence of neoplasia in PID patients in our Center (5%) is similar to
other cohorts (4-25%). Cancer surveillance in PID patients is mandatory, allowing an
early diagnosis and adequate treatment to achieve better outcomes.
NBS is a rare syndrome of chromosomal instability which predisposition to lymphomas. Due to delay of NHL diagnosis and treatment problems the outcome in these patients remains poor
W present 25 NBS patients complicated by NHL from one center
Retrospective analysis of NHL clinical course in NBS patients
From 1997, 25 NBS patients (aged 3,8-23ys)with NHL were diagnosed and/or treated in Department of Oncology CMHI. Ten children developed DLBCL, 8 TLBL, 3 Burkitt, 4 peripheral T-cell lymphoma. Two patients were classified as stage II, 17 as III, 6 as IV. Time from symptoms to diagnosis was delayed in 17/25. Thirteen patients received chemotherapy for mature B-cell lymphoma (11 LMB 89/2001, 2 R-CHOP), 11 for lymphoblastic lymphoma (BFM 90, EURO-LB04), one girl with angio-immunoblastic T-cell lymphoma was treated with steroids and cyclosporine and the second with CHOP with Bortezomib. None of the patients complied with chemotherapy time schedule due to treatment related complications. Six patients underwent high dose chemotherapy and alloHSCT. Nineteen patients died: 7 of progression, 6 of relapse, 3 of second leukemia/lymphoma, 3 of treatment related complications. One patient died from fifth identical molecularly episode of DLBCL 17 years after first diagnosis. Six patients are alive, three of them underwent alloHSCT in first remission, one is currently under treatment and alloHSCT is planned
Delay of NHL diagnosis, treatment complications and consecutive events of lymphoid malignancies results in poor outcome of NBS patients. AlloHSCT procedure should be performed in each NBS patient with NHL in first remission
X-MEN syndrome is a X-linked PID due to loss-of-function mutations in MAGT1 gene, characterized by variable immunological alterations and high risk of lymphoproliferation. We describe four X-MEN patients from two unrelated families carrying novel pathogenic MAGT1 mutations. Targeted therapy with Mg2+ could represent a curative option, although currently HSCT is indicated in presence of lymphoma.
Next-generation sequence, Flow-cytometry, Western-Blot.
Pt1 (male, 14yo) suffers from isolated hypertension, severe autoimmune hemolytic anemia, recurrent warts and lymphadenomegaly. His older brother (Pt2, 17 yo) suffers from recurrent otitis media, cutaneous warts, and frequent muco-cutaneous HSV-reactivation. Both patients showed EBV-DNA < 1.000 cp/ml and normal CBC and Ig-levels. Increased double negative T-cells and reduced memory B-cells were detected. Pt3 (male, 5yo) was admitted for lymphadenomegaly, recurrent fever, weight loss and night sweats. He had EBV infection without complete seroconversion, decreased B memory cell and poor response to pneumococcal vaccine, and severe thrombocytopenia. Lymph node biopsy was consistent with Hodgkin Lymphoma. His maternal uncle (Pt4) was treated in childhood for non-Hodgkin lymphoma and developed in adult age a severe persistent thrombocytopenia and a second lymphoma.
NGS revealed, in MAGT1 gene, a splice variant (c.628-2A>G) in Pt1 and Pt2 and a variant resulting in a premature stop codon (c.370C>T) in Pt3 and Pt4. In all patients, MAGT1 expression is impaired and results in down-regulation of NKG2D.
X-MEN phenotype is extremely variable requiring different specialist to reach early diagnosis and institute a personalized therapy; in this context NKG2D evaluation could be represent a useful diagnostic marker.
It is known that patients with primary immunodeficiency (PID) are more prone to malignancies. In this report, we present six patients with different types of malignancies who had PID.
We retrospectively reviewed the files of 6 patients with malignancy who had suffered from PID before the development of the cancer. This study underwent in a tertiary pediatric hospital.
Six cases, 5 men and 1 female, were evaluated in this report. The mean age of the patients was 5 (ranged, 3 to 7) and 7 (ranged, 4 to 13) years at the time of PID and cancer diagnosis, respectively. There was one case of ataxia-telangiectasia with development of lymphoma. Two cases with squamous cell carcinoma (who was known as a genetic case of IKAROS deficiency) and Hodgkin lymphoma that had the previous diagnosis of common variable immunodeficiency. One case with Nijmegen breakage syndrome who developed non-Hodgkin lymphoma. One case with signal transducer and activator of transcription 3 (STAT3) deficiency that later progressed to large B cell lymphoma and the last case with agammaglobulinemia (autosomal recessive) that developed acute lymphoblastic leukemia. All patients were primarily diagnosed as PID before the development of malignancies except one case who had had Hodgkin lymphoma before the diagnosis of PID.
The result of this case series emphasizes the importance of early recognition of malignancy in children with PID and indeed the early recognition of PID in children with malignancy. The early diagnosis may improve the life expectancy and the quality of life in such patients.
GATA-2 deficiency is a novel clinical entity with protean clinical manifestations. We describe the experience of managing a child with monosomy 7 associated myeloid leukemia who was diagnosed to have a frameshift deletion in GATA2 gene.
14-year-old boy, born of non-consanguineous couple was diagnosed to have monosomy 7 associated acute myeloid leukemia following evaluation for anemia, macrocytosis and growth failure. He received standard AML chemotherapy without bone marrow transplantation which he tolerated without any life threatening infections. At initial evaluation for AML, he was noted to have black warts along the hairline of forehead which would shed off occasionally. 6 months aftere AML treatment completion, he started developing episodes of severe diarrhea caused by cryptosporidium parvum resulting in hypokalemic periodic paralysis. One episode of quadriparesis improved with potassium supplementation. Progressive weight loss was noted during this period. 14 months after AML treatment he developed bilateral lobar consolidation with fatal pulmonary haemorrhage despite aggressive antimicrobial support.
Lymphocyte subset analysis showed low absolute lymphocyte count associated with absent CD 19 and CD 56 cells. Next generation sequencing for cancer predisposition genes revealed a frameshift deletion (chr3:128205727: TG>T; c.147del) resulting in amino acid change and subsequent termination of the protein, 31 amino acids downstream to codon 49 (p. Phe49LeufsTer31) was detected in the GATA2 gene. This is a loss of function mutation which is not reported in ExAC and 1000 genomes databases.
Looking beyond AML, helps us diagnose primary immune deficiencies that have consquences in clinical decision making and genetic counseling for the family.
Myelodysplastic syndromes (MDS) are heterogeneous neoplastic diseases affecting elderly individuals although they can rarely affect younger individuals. Primary Immunodeficiencies Disorders (PIDs) are a group of congenital disorders often depicted in early age, associated with an increased susceptibility to infections, immune-dysregulation and a higher risk of malignancy.
We retrospectively examined a cohort of younger patients with MDS (2000-2018) to verify the frequency of genetic predisposition and recurrence of immune-dysregulation phenomena.
Fiftyfour consecutive patients < 60 years (median age 52) were analysed. Data were collected at time of first bone marrow examination, corresponding to diagnosis or at revaluation consequent to second opinion.
Autoimmune phenomena were present in 22.2% of patients, including arthritis, thyroiditis and dermatological manifestations. Although autoimmunity is more frequently associated to hypoplastic bone marrow, none of them presented hypoplastic-MDS. Immunodeficiency were discovered in 5 patients: a late onset of GATA-2 deficiency, two patients with PID-associated genetic disorders (Noonan syndrome and a case highly suggestive for congenital dyskeratosis) and a Combined Immunodeficiency (CD4penia and epidermodysplasia verruciformis-like syndrome). Moreover, 4 patients debuted with isolated neutropenia in young age, at least 10 years before MDS diagnosis: Whole Exome Sequencing on DNA of each patient is ongoing, in order to identify causative variants.
PIDs and early onset MDS could represent two features of unique congenital disorder, in which myeloid impairment in MDS is justified by loss of immune-surveillance or immune-dysregulation. Immunological assessment in young MDS is required, albeit idiopathic cytopenia in PID patient could demand a close follow-up in the risk of developing MDS.
Failure to thrive in children with adenosine deaminase (ADA)-severe combined immunodeficiency (SCID) has a wide variety of causes ranging from infections to autoimmune or malignant diseases. Specifically, the development of immunodeficiency-associated lymphoproliferative disorders, especially related to Epstein–Barr virus (EBV), is a life-threatening phenomenon.
We describe a 3-years-old ADA-SCID patient of Turkish origin. She was diagnosed at 2 months of life and started on PEG-ADA. When 7-months-old, she underwent an ileostomy due to diverticulosis and abscess perforation with consequent weight loss. In absence of a HLA-identical sibling donor, the patient was referred at 3 years of age to our institution for ex-vivo gene therapy with Strimvelis®. She showed severe malnutrition and developmental delay. Thus, immunohematological, histological and radiological investigations were performed in order to ascertain the possible cause of her clinical condition.
Brain MRI detected meningoencephalitis with frontal lobes involvement. Total-body PET showed high metabolic activity of a tongue lesion. Similar metabolic features have been identified in the ipsilateral para-pharyngeal space, in the retro-angle-mandibular area and in the larger nodules of the left upper pulmonary lobe, difficult to differentiate between infectious or inflammatory localizations. CSF revealed high EBV-DNA load (93350 copies/mL) and the biopsy of the tongue confirmed an EBV–positive diffuse large B-cell lymphoma.
Failure to thrive can delay a diagnosis of malignancy in the setting of immunodeficiencies. If the deterioration of the nutritional status is unexplained by infections or autoimmune phenomena, given the lack of appropriate immune-surveillance, malignancy should be considered even in young children.
Dedicator of Cytokinesis 8 (DOCK8) deficiency; an autosomal recessive form of Hyper-IgE syndrome (HIGE), is primary immunodeficiency. It has various clinical manifestations including allergic diseases, high susceptibility to viral and bacterial infections, and high risk for malignancy.
We describe two siblings; 5-years old girl who was transferred to us with persistent fever for 1-month not-responding to antibiotics and renal mass for investigations. Since two months of age, she had recurrent purulent otitis media and pneumonias requiring hospitalizations for IV antibiotics. She has severe generalized dermatitis, and multiple food and drug allergies. The 2-years older sister was asymptomatic and healthy.
The index patient was febrile with generalized dermatitis and lymphadenopathy. Her white blood cell counts; 14,000, neutrophils; 10,290, thrombocytes; 562,000 and lymphocytes; 1,990 with CD3+/CD4+/CD8+; 666 (cells/µL). Hemoglobin; 8.6g/dl, immunoglobulin-G;15g/L, immunoglobulin-M; 0.42g/L and immunoglobulin-E; 43,177IU/ml (N:25–440 IU/mL). Molecular genetic analysis revealed novel homozygous mutation in DOCK8 gene; chr9(GRCh37):g.368136G>T. DOCK8 variant c.1797+1G>T. Viral screen; EBV-PCR<40IU/ml and high Cytomegalovirus-PCR; 3,709IU/ml. CT scans: showed multiple pulmonary nodules, generalized lymphadenopathy and large right kidney mass. Histopathology of lymph node, lung and kidney biopsies confirmed high grad diffuse large B-cell lymphoma (stage-IV). She was started on standard chemotherapy protocol, but died due to Escherichia Coli sepsis and multiorgan failure. Genetic screen for her sister showed the same homozygous mutation.
DOCK8 deficiency is known to cause combined immunodeficiency and risk for malignancy. However, our described novel mutation in DOCK8 gene could be associated with positive gene modifier that caused discrepancy in the clinical manifestations of the disease.
Ataxia-telangiectasia (A-T) is an infrequent autosomal recessive disorder caused by mutations in ataxia-telangiectasia mutated (ATM) gene that involves multiple systems - progressive cerebellar ataxia, oculocutaneous telangiectasias, radiosensitivity, immunedeficiency and risk for malignancies. Non-Hodgkin lymphoma, Hodgkin lymphoma, Acute Leukemia, mostly T-cell acute lymphoblastic leucemias (T-cell ALL) are common before 20 years of age. The aim is to report B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in a AT patient.
Medical record review of 13-year-old, brazilian, female patient presenting pallor, astenia, osteoarticular pain 2 weeks before admission. AT had already been diagnosed at the age of 4 years due to progressive ataxia, ocular telangiectasia, increased alpha-fetoprotein, vitiligo and IgA deficiency.
On admission, hepatomegaly and small cervical lymphadenopathies. Hb 6.2 Ht 19.2 WBC 92.800 - 1.856 Bt 3.172 Sg 72.384 Lymph 2.784 Mo 12.064 blasts. Myelogram Bone marrow (BM) infiltrated 87% by L1 lymphoblasts (FAB) Immunophenotyping ALL early pre-B, DNA index diploide. Molecular biology negative ETV6-RUNX01, TCF3-PBX1, BCR-ABL01, MLL-KMT2A. Diagnosis High risk Acute Lymphoblastic Leukemia (age > 10 Yo WBC >50.000). IgA < 25.9 IgG 2360 IgM 273 mg/dL, CD4+ 416,3 CD8+ 1787,1 CD19+ 208 cells/mm3. EBV and CMV PCR negative. Therapy: RE-ALL 05 protocol standard doses (prednisone, doxorrubicina, Vincristine and PEG-asparaginase). Reassessment of induction D19 BM without blasts, MRD positive (3,8% blasts). Evolved with sepsis and admitted to UCI.
AT has a dramatic increased of developing malignancies and it´s one the most common cause of death in A-T patients. We herein report a case of A-T with BCP-ALL that occurs rarely in A-T patients.