Background and Aims

Activated phosphoinositide 3-kinase delta (PI3K) syndrome (APDS) is characterized by variable humoral and cellular defects, recurrent infections, lymphoma, autoimmune features, and growth and developmental delay.

Sweet syndrome, or acute febrile neutrophilic dermatosis, is a rare inflammatory skin condition. About half of cases have an underlying systemic disorder, mainly malignancies and autoinflammatory conditions. It has only been sporadically reported in patients with immunodeficiency.

We report a boy with APDS presenting as a combined immunodeficiency and Sweet syndrome.

Methods

Immunological tests, skin biopsies and PID gene panel analysis were performed.

Results

A boy, currently 16 years old, suffered from recurrent bacterial infections since the age of 3 years. He also developed bronchiectasis, lymphadenopathies and splenomegaly. Immunological work-up revealed low IgG2, reduced polysaccharide antibody responses, monocytopenia and T, B and NK lymphopenia. Recently, we identified a PIK3CD mutation causing APDS.

Remarkably, since 5 years of age, he had recurrent painful erythematous nodules and plaques on his limbs and abdomen, accompanied by fever and elevated inflammatory markers. Biopsies showed a dense neutrophilic infiltrate confirming the diagnosis of Sweet syndrome. Acute episodes responded well to systemic corticosteroids. Up till now, he requires dapsone maintenance therapy to prevent relapse.

Conclusions

To our knowledge, this is the first report of an APDS patient with Sweet syndrome. The pathophysiology of Sweet syndrome is unclear but involves activation of innate inflammatory signaling. Previous studies have demonstrated a role for PI3K/Akt signaling in NLRP3-inflammasome activation. Together, this suggests dysregulation of inflammasome activation in APDS patients, implying potentially therapeutic effects of IL-1 inhibition.

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Background and Aims

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.

Methods

Review of medical records of adult CVID patients.

Results

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.

Conclusions

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.

Background and Aims

Primary antibody deficiencies (PAD) are caused by developmental or functional defects of humoral immunity, resulting in increased susceptibility to bacterial and viral infections. Etiology of 40-80% of patients with PAD, the second most common type of human immune system disorders after human immunodeficiency virus infection, is yet unknown.

Methods

Monogenic patients were identified in a CVID cohort using whole exome sequencing and full-resolution MHC typing. Exome-wide polygenic scores were developed using significantly different variants and multi-variant Mendelian-randomization (MR) analyses were used to test the causality of significant genetic variants on antibody levels and susceptibility to infectious diseases.

Results

Among 83 CVID patients (44.5% females), monogenic defects were found in 40 individuals. Evaluation of the remaining patients with non-monogenic CVID showed 13 and 27 significantly associated MHC-class I and II alleles, respectively. The most significant partial haplotype linked with the non-monogenic from of CVID was W*01:01:01-DMA*01:01:01-DMB*01:03:01:02-TAP1*01:01:01 (P<0.001), where carriers had a late onset of the disease, an infections only clinical phenotype, a sporadic form of CVID, post-germinal center defects and a non-progressive form of their disease. Exclusion of monogenic diseases allowed MR analyses to identify significant genetic variants associated with bacterial infections and improved discrepancies observed in MR analyses of previous studies with low pleiotropy mainly for a lower respiratory infection, bacterial infection and Streptococcal infection.

Conclusions

The full-resolution MHC typing and polygenic scores on CVID patients showed that exclusion of monogenic forms of the disease unraveled an independent role of MHC genes and common genetic variants in the pathogenesis of CVID.

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

Our results reveal unique and common consequences of two distinct variants of TAOK2 on immune cells.

Background and Aims

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and it is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. While the consequences of excessive IL-6 signaling in humans have been well established, the effects of impairment of IL-6R have not yet been described. Here we studied two unrelated patients with homozygous mutations in IL6R, presenting with recurrent infections, abnormal acute phase responses, elevated IgE, eczema and eosinophilia.

Methods

Peripheral blood mononuclear cells were assessed for their responsiveness to IL-6, IL-21, IL-27 through downstream STAT3 phosphorylation by flow cytometry. PBMCs from both patients were also used to assess the composition of differentiated T-helper cell subsets as well as cytokine release upon stimulation by flow cytometry. Single cell RNA sequencing was performed to for granular assessment of the immune cell phenotype

Results

Our results reveal the role of IL6 signaling on the differentiation of T helper subsets, indicated by diminished but present Th17 and Th1 populations. Similar to STAT3 deficient patients, B cell development was also impaired reflected by reduced percentage of memory B cells. In addition, pathological effector Th2 cells associated with chronic eosinophilic inflammation were elevated in both patients, in concordance with severe atopy and elevated IgE.

Conclusions

This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3 and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of targeting the IL-6R.

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

MDWH can present with severe late-onset extra-skeletal manifestations and thus should be re-classified and managed as CHH.

Background and Aims

ARPC1B deficiency results in defective Arp2/3 actin filament branching and is associated with heterogeneous systemic disease. Here, we present the first case of ARPC1B deficiency in Algeria.

Methods

Data was collected from the patient's file during hospitalization in our pediatrics department. To elucidate the genetic etiology, whole exome sequencing has been conducted.

Results

We reported 10-year-old boy from the Northwest of Algeria who was born as second child of consanguineous parents and admitted for a severe, refractory inflammatory bowel disease. The patient presented with early onset chronic diarrhea at the age of 2 months, failure to thrive, and recurrent invasive infections such as pneumonia and otitis media. Physical examination at admission revealed superficial vasculitis in both lower limbs .

Laboratory work up showed thrombocytopenia and signs of combined immune dysregulation, including elevated IgA level, T cell lymphopenia, and reduced numbers of naïve T cells. Colonoscopy depicted a severe colitis reminiscent of UC.
A genetic screen revealed a homozygous mutation of the ARPC1B gene . Clinical management included treatment with corticosteroids and prophylactic antibiotics for this particular immune deficiency were initiated, along with a dedicated follow-up .this patient repsonded to treatment

Conclusions

Our study undescored that ARPC1B deficiency should be considered among the panel of primary immunodeficiencies in young patients with very early onset inflammatory bowel disease .

Background and Aims

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.

Methods

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.

Results

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.

Conclusions

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.

Background and Aims

Chronic granulomatous disease (CGD) is an inherited immunodeficiency predisposing to recurrent invasive infections and non-infectious granulomatous disease. Autoimmune manifestations, mainly discoid lupus erythematosus (DLE), have been described in CGD patients and reported in about one quarter of X-linked carriers. However, systemic lupus erythematosus (SLE) has been rarely reported as a prominent feature of CGD patients.

Methods

We report on a case of familial SLE revealing late-onset X-linked CGD.

Results

A 15-year-old man from a non-consanguineous French family developed photosensitivity with typical malar rash eruption, Raynaud phenomenon, peripheral synovitis and cutaneous vasculitis. Isolated lupus anticoagulant was detected and SLE was diagnosed. Hydroxychloroquine treatment led to clinical improvement. Past medical history was remarkable for recurrent skin abscesses. Familial history taking revealed maternal SLE and Sjögren syndrome. 15 years later, at the age of 30, the patient was admitted for prolonged fever and cough. CT-scan revealed lingular condensation and left pleural effusion. Burkholderia multivorans grew up from the thoracentesis specimen. Lung infection resolved after prolonged antibiotic therapy. Dihydrorhodamine test (DHR) showed severely impaired respiratory burst in the patient’s leukocytes (1% activity). Her mother showed a typical mosaic pattern. X-linked CGD was genetically confirmed with the finding of CYBB missense mutation in the this kindred.

Conclusions

Familial SLE belongs to the spectrum of X-linked CGD. Autoimmune manifestations can be at the foreground of the clinical picture with only secondary development of typical infectious manifestations. Infections in SLE patients may point to an underlying primary immune defect.

Background and Aims

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.

Methods

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.

Results

Histology and genetic analysis might reveal importance of the PI3K delta pathway in the development of this bilateral dysgerminoma.

Conclusions

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.