Background and Aims

TCR/CD3 complex is crucial for the development and regulation of T cells. In humans, CD3D, CD3E, and CD3Z gene defects cause severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity.

Methods

Bearing recurrent sinopulmonary infections without opportunistic infections compatible to hypogammaglobuliemia but normal PHA lymphocyte proliferation, a male 36-year-old adult receives genetic analysis after regular IVIG over 15 years. His lymphocyte subsets, CD3 expression, T regulatory (Treg) cells and suppression are assessed. To comprehensively review this rare disease, we analyze the phenotypes, genotypes, treatment and prognosis from a PubMed search to hopefully guide optimal management.

Results

In contrast to the previous CD3G mutations presenting as autoimmunity, the novel CD3G mutation maintains sufficient Treg number and suppression makes him free of autoimmunity of autoimmune thyroiditis, inflammatory bowel disease, and pancytopenia. CD27+memory B cells are almost absent. Pubmed research reveals 7 Turkish and 2 Spanish patients (5 unrelated families). They are the splicing mutations 80(-1)G>C (in 14), missense mutations c.1G>A (2), and nonsense mutations c.250A>T (2). Three only present with isolated autoimmune thyroiditis without significant infections. Only our patient has neither any autoimmunity nor detectable autoantibody. Three mortalities were severe infection at 31 months, post-transplant viral pneumonia at 17 months and graft vs host disease (GvHD) at 47 months.

Conclusions

With the novel CD3G mutation, the patient presents as predominantly B cell deficiency mimicking the CVID phenotype and lacking the recognizable autoimmunity. This finding expands the phenotype in patients with CD3G mutations.

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Background and Aims

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

Methods

Retrospective analysis of NHL clinical course in NBS patients

Results

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

Conclusions

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

Background and Aims

Subcutaneous immunoglobulin (SCIG) is increasingly utilized in primary immunodeficiency (PID). Understanding patient treatment experiences is critical to improve outcomes. We analyzed Immune Deficiency Foundation (IDF) survey data to evaluate relationships between SCIG training, infusions, and patient-reported outcomes.

Methods

Multivariate logistic models identified predictors of high scores (top third) in Treatment Satisfaction Questionnaire for Medication (TSQM) domains (convenience, side effects, effectiveness, and global). Independent predictors were determined by backward selection of covariates significant in univariate analyses.

Results

Among 366 SCIG respondents, favorable training characteristics drove higher odds (p<0.05*, <0.01**) of being top third for TSQM domains including: convenience (confidence post-training: Odds Ratio [OR] = 3.0** and absence of training barriers: OR = 2.2*); side effects (confidence post-training: OR = 2.04*); effectiveness (no training barriers: OR = 2.4**); and global (trainer competence: OR = 3.5**). Efficient infusions increased odds of high TSQM domain scores: convenience (infusion preparation <20 minutes: OR = 1.95**); side effects (infusion preparation: OR = 1.88**, actual infusion: OR = 1.70*); and global (infusion preparation: OR = 1.76*). Age (<18 years) and treatment experience ≥ 2 years also increased odds of high TSQM domain scores. Compared with least favorable, those with most favorable training/infusion characteristics had higher predicted probabilities of high TSQM domain scores: (convenience, 55% vs 5%; side effects, 75% vs 5%; effectiveness, 44% vs 24%; global, 50% vs 7%).

Conclusions

Results suggest that improvements in SCIG training and infusion characteristics can drive better patient outcomes including convenience, reduced side effects, effectiveness and overall satisfaction.

Background and Aims

CHAPLE syndrome was recently described as a cause for early-onset protein losing enteropathy (PLE) and thrombosis secondary to biallelic CD55 mutation. We describe a 39-year-old female with adult onset intermittent gastrointestinal symptoms and hypoalbuminemia who was referred for evaluation of hypogammaglobulinemia.

Methods

Targeted CD55 gene sequencing, confirmatory CD55 flow assay and B and regulatory T cell (Treg) immunophenotyping.

Results

The patient presented with intermittent diarrhea and hypoalbuminemia at the age of 25. Symptoms subsided spontaneously after two years, but at the age of 35 the patient presented again with superior mesenteric vein thrombosis, PLE, hypoalbuminemia and hypogammaglobulinemia. Endoscopy studies showed occasional lymphangiectasia and physical examination was significant for peripheral edema and clubbing. Targeted CD55 sequencing was performed and revealed a novel homozygous c.976C>T mutation, resulting in C-terminus truncated protein (p.Gln326X). Accordingly, CD55 staining showed near absent CD55 expression with maternal carrier showing reduced CD55 MFI at around 50% compared to healthy control (Fig1A). In addition, B cell phenotyping showed skewed B cell maturation with reduced percent of CD38^highCD24^high naïve cells and most cells expressing a CD38^lowCD24^high memory phenotype (Fig1B). Treg phenotyping showed reduced proportion of FOXP3^posCD25^high cells and an increased proportion of FOXP3^negCD25^high activated CD4+ (Fig1C).

Conclusions

CD55 deficiency can cause adult onset PLE and could be easily screened by whole blood CD55 staining. In addition, CD55 deficiency is associated with abnormal B and Treg phenotyping. The patient is awaiting Eculizumab treatment.

Background and Aims

Background:Bare II lymphocyte syndrome is characterized by the absence of expression of HLA class II molecules. It is the result of a mutation in the genes encoding one of the 4 elements that regulate the expression of HLA class II molecules. Patients present recurrent infections characteristic of combined immunodeficiency.

Methods

Methods:
Child is two years old. At 12 months presented protracted diarrhea, enterorrhagia, failure to thrive . He presented multiple pulmonary and gastrointestinal infections and required gastrostomy and parenteral nutrition. At 18 months he presented non-infectious hepatitis. Several months later he had intestinal intussusception that it reduced by manual in a laparoscopy procedure.

Results

Results:
Lung CT scan showed imagen suggestive a lipoid pneumonia or pneumonia by Pneumocystis jirovecii. Intestinal MRI showed thickening of distal ileum, caecum, similar an inflammatory bowel disease (IBD), probable Crohn disease. Gastrointestinal biopsies ruled out BID.Flow cytometry: CD3+ 49. 60%/1858 cel/uL, CD4+: 7. 35%/275 (low), CD8+: 40. 47%/1515 , BCD19+: 44. 58%/153. IgA 0. 0 mg/dL, IgG 49, IgM 110, IgE 0. 10 IU/ml. It was observed total absence of the expression of MHC Class II molecule in T lymphocyte and monocyte in our patient.

We performed the mutation analysis of genes (NGS)encoding CTIIA, RFX5,RFXAP, RFXNK. We report a new mutation in CIITA gene cr16:c. 925C>T in exon 9;p. (Arg309) probably a pathogenic variantnot yet reported in the literature.

Conclusions

Conclusion:
Bare class II lymphocyte syndrome went confirmed by absence of the expression of MHC Class II molecule in T lymphocytes and Monocytes in our patient and the identified new mutation in CIITA.

Background and Aims

CVID courses with infections, autoimmunity, benign lymphoproliferations, and increased incidence of malignancies, configuring a state of persistent immune activation and alterations in oxidative metabolism. There is evidence that paraoxonase-1 (PON-1), a factor controlling oxidative stress and tissue damage, is implicated in disease severity and survival. Our objective was to relate arilesterase (AA) activity, genotypes and alleles of PON1-L55M polymorphisms to disease severity and survival.

Methods

We analyzed 101 adult patients for demographic data, comorbidities, mortality and survival. PON1 genotyping (PCR-RFLP) and AA were compared to 130 healthy controls (p <0.05).

Results

Genotypic distribution was similar between groups and AA was lower in patients, which may contribute to intense inflammatory state. Patients with 55MM-genotype presented a more severe disease due to higher frequency of lymphadenopathy, splenomegaly, hepatomegaly, portal hypertension, sepsis, neoplasms and deaths compared to LM/LL-genotypes. This difference was not due to deleterious characteristic of the MM-genotype, but a protective role of the 55L allele, since patients with at least one copy of it (LM or LL) had lower prevalence of malignancies, hepatomegaly, sepsis and deaths. They also presented greater survival rates in relation to disease time and diagnostic delay. Risk of death was lower in patients with L-allele and higher in patients with chronic obstructive pulmonary disease, lymphadenopathy, neoplasms, splenomegaly, hepatomegaly and sepsis.

Conclusions

Our results suggest that 55L-allele may play a protective role in CVID, since patients with 55LL/55LM-genotypes presented lower prevalence of hepato/splenomegaly, portal hypertension, malignancies, sepsis and deaths, along with higher survival, compared to those with 55MM genotype.

Background and Aims

Mutation in the FAS gene is the main cause of autoimmune lymphoproliferative syndrome (ALPS). It causes defective cellular apoptosis and clinically manifests by lymphoproliferation, increased risk of lymphoma and autoimmune diseases. Here, we report a case of ALPS-FAS initially manifested by multilineage cytopenia in a patient attended at the Children´s Hospital –Brasilia/Brazil.

Methods

Laboratory and clinical data were reviewed from medical records. FAS sequencing was done by Sanger method and protein expression measured by flow cytometry.

Results

KRCS, male, 5yo, second child of consanguineous parents. No family history of immunodeficiency. At 3yo7mo he was hospitalized due to cutaneous rash, fever and pancytopenia. No infectious disease was identified. Bone marrow aspiration were negative for malignancy and the diagnosis of autoimmune hemolytic anemia was made, with response to oral corticoids. Due to the high levels of serum vitamin B12 and IgG, associated to lymphoproliferation and increased percentages of circulating CD3+TCRab+CD4-CD8-DNT cells (4%), ALPS was suspected. Genetic analysis confirmed FAS mutation c.748C>T p.R250*, which was inherited from his asymptomatic father (DNT=6.9%). Flow cytometry analysis showed low FAS expression on T cells of proband and his father. The mother and the sister have normal % of DNT (<1.5%).

Conclusions

The nonsense mutation FAS:c.748C>T results in a defective protein and its subnormal surface expression causing impairment in the apoptotic signaling pathway of lymphocytes. Although the proband and his father have the same mutation, they have different clinical manifestations. This is an intriguing query that could be related to environmental, other genetic factors or a trigger such as infections.

Background and Aims

Pathogenic variants in the protein kinase C delta (PRKCD) gene cause autoimmunity, humoral immunodeficiency and recurrent infections. Previously described patients showed B-cell lymphopenia with normal T-cell numbers, dysgammaglobulinemia and impaired class-switching without notable pulmonary manifestations.

Methods

Chart review and clinical care of patient.

Results

A Palestinian male with consanguineous parents presented at 15 months with joint swelling, splenomegaly, rash and fevers. Elevated inflammatory markers and positive ANA, anti-phospholipid, anti-Smith, and anti-double stranded DNA antibodies were noted. At 6 years, he developed immune-mediated cytopenias (positive DAT and anti-neutrophil antibodies). CD3, CD4 and CD8 absolute values were decreased; T-cell proliferation to antigens was reduced. CD19 absolute value was normal; IgG and IgM were low. Alpha/beta CD3+CD4-CD8- T-cells were 13.7% but pathogenic variants in FAS were not identified. Mycophenolate improved his lymphoproliferation and cytopenias. His course was complicated by frequent fungal/bacterial infections (sinusitis, orbital cellulitis and pneumonias) resulting in bronchiectasis and chronic atelectasis requiring azithromycin treatment and daily chest physiotherapy. At 18 years he was referred for further immunologic evaluation with genetic testing revealing a novel homozygous PRKCD variant (c.1872+1G>A). Reduced class-switch (CD19+CD27+IgD-) and total memory B-cells were noted. IVIG replacement was initiated.

Conclusions

Our patient expands the clinical, immunologic and genetic phenotype of PRKCD deficiency by showing prominent pulmonary manifestations, displaying quantitative & qualitative T-cell deficits in-addition to B-cell abnormalities, and harboring a novel pathogenic variant. Undefined immunologic dysregulation patients should be regularly assessed for newly discovered genetic alterations given the ever-changing genetic landscape of immunodeficiency conditions.

Background and Aims

A 5-year-old girl presented with three episodes of otomastoiditis caused by Candida species. The last episode was complicated with persistent Staphylococcus Aureus cervical lymph node abscess. She was treated with transtympanic drains, mastoidectomy and long-term antibiotics and antifungal therapy, as well as drainage and curettage for the cervical abscess.

Methods

Immunological work-up consisted of standard blood analysis, lymphocyte proliferation test and respiratory burst assay. Subsequently, based on the results, genetic testing for chronic granulomatous disease (CGD) (CYBA, CYBB, NCF1, NCF2 and NCF4) and myeloperoxidase deficiency (MPO) was performed, as well as histochemical staining of leukocytes.

Results

General immunological testing was normal, except for a very weak response in the respiratory burst assay (<10% at multiple testing), suggesting CGD. However, gene testing for CGD was negative. Subsequently, MPO expression on neutrophils was absent. Analysis of the MPO gene showed a homozygous splice site mutation in intron 11 (c.2031-2A>C), producing an abnormal precursor without the enzymatic activity. Subsequent familial screening revealed the same mutation in her younger brother presenting with recurrent oral candidiasis.

Conclusions

MPO deficiency should be considered in patients with recurrent Candida infections and reduced respiratory burst. It is the most frequent congenital phagocytic cell disorder leading to an increased risk of infections with Candida and Aspergillus species. The majority of patients are asymptomatic or only exhibit minor infections, but some will develop major infections, especially in presence of concomitant diabetes mellitus. Our patient was successfully treated with a prophylactic dose of fluconazole.

Background and Aims

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.

Methods

We analyzed 220 patients aged 0-18 years, diagnosed with PID in the period 1990 – 2018.

Results

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%.

Conclusions

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.

Background and Aims

Common Variable Immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. A significant proportion of patients present decreased number of circulating B cells, and defective or deregulated pre-germinal center B cell compartment.

We aim to precisely trace the maturation pathway of the pre-germinal center compartment in CVID patients, to identify if a deregulated or derailed maturation could already indicate an impaired early development in bone marrow, or suggest alterations in peripheral B cell homeostasis in a proportion of patients.

Methods

A total of 100 CVID patients and 56 HD were studied with standardized protocols within the collaborative and multicenter frame of the PID-group of the EuroFlow consortium. Patients samples and clinical data were collected at 7 different sites.

The distribution of distinct B-cell subsets were analyzed by flow cytometry, with the EuroFlow 8-color pre GC B-cell tube. CD19⁺ B-cells were subclassified into 11 different subpopulations.

Results

We created a normal maturation B cell pathway focused in the pre GC B cell compartment of HD with the maturation tool of the Infinicyt software. We performed the same analysis to a cohort of 100 CVID patients and plotted the individual results to the normal, in order to detect aberrant populations in preGC in CVID that may have followed a diverse maturation pathway, and identify aberrant expression of markers in CVID patients.

Conclusions

We sought for correlations among alterations in the preGC compartment (absolute counts and expression markers) with clinical data records looking for potential implications of phenotypic aberrancies and clinical complications.