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- Garkaby, Jenny9
- Merico, Daniele8
- Roifman, Chaim M7
- Scott, Ori6
- Abrego Fuentes, Laura4
- Dadi, Harjit4
- Upton, Julia4
- Willett Pachul, Jessica4
- Abrego Fuentes, Laura Edith3
- Feanny, Stephen3
- Grunebaum, Eyal3
- Mandola, Amarilla B3
- Reid, Brenda3
- Sham, Marina3
- Vong, Linda3
- Brager, Rae2
- Fraser, Meghan2
- Haynes, Alison2
- Hong-Diep Kim, Vy2
- Kim, Vy H D2
- Murguia-Favela, Luis2
- Pereira, Myra2
- Roifman, Maian2
- Upton, Julia E M2
- Watts-Dickens, Abby2
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- Introduction: Agammaglobulinemia is a primary immunodeficiency characterized by absent B cells and originates from X-linked or autosomal mutations affecting B cell maturation. While the most common agammaglobulinemia is X-linked, one well-documented site of autosomal recessive agammaglobulinemia is within the immunoglobulin μ heavy chain protein, encoded by the IGHM gene. Such variants frequently result in clinical presentations of recurrent bacterial infections early in life.Aim: To describe a case of a five-year-old female with agammaglobulinemia resulting from a novel homozygous IGHM variant, presenting with pneumonia complicated by empyema and H. influenzae bacteremia.Methods: Case data was compiled retrospectively from the patient’s medical chart, including relevant laboratory testing for immunoglobulins, quantitative B cell subsets, and genetic testing using a primary immunodeficiency panel.Results: The proband is a 5-year-old female with a history of recurrent pneumonia, presenting with H. influenzae bacteremia in the context of pneumonia complicated by an empyema. Investigations revealed low immunoglobulin levels, absent vaccine responses, and undetectable B cells on flow cytometry. Genetic testing revealed a novel homozygous variant in the IGHM gene: c.775T>C, p.Trp259Arg.Conclusion: Autosomal recessive agammaglobulinemia is a rare but severe, treatable disorder of the immune system which typically presents in early childhood. Hypomorphic mutations, while less commonly reported in the literature, are an important consideration in atypical presentations of primary immunodeficiencies, such as in the case presented.Statement of Novelty: Herein, we report a case of agammaglobulinemia presenting with a novel homozygous variant in the IGHM gene leading to later onset agammaglobulinemia in a 5-year-old female.
- Introduction: Hyper IgM (HIGM) syndrome is an inborn error of immunity (IEI) that occurs due to defects in immunoglobulin class switch recombination (Ig-CSR). HIGM syndrome typically presents with recurrent infections in early childhood, and is often characterized on investigation with decreased IgG, IgA, and IgE titres, alongside normal or elevated IgM. A common cause of HIGM syndrome is a disruption to the CD40-CD40 ligand (CD40L) interaction that triggers Ig-CSR, of which variants in CD40 are much rarer than those in CD40L. We present a case of an 11-year-old female with HIGM syndrome caused by two novel variants of in the CD40 gene.Aim: To describe a case report of an eleven-year-old female with HIGM syndrome presenting with recurrent pneumonia.Methods: Data was collected retrospectively from the patient’s medical records. Laboratory investigations included quantitative immunoglobulins, quantitative B and T cell subsets, genetic testing using a primary immunodeficiency panel, and a functional assay for CD40 expression.Results: The proband is an 11-year-old female, who presented with recurrent pneumonia, otitis, and septic arthritis. Investigations revealed neutropenia, low IgA, elevated IgM and normal IgG, along with absent vaccine responses. She was identified to harbour two novel variants in CD40: an intronic variant c.52-13A>G p.(?) and a missense variant c.466T>C p.(Ser156Pro). Functional assay indicated low expression of CD40 compared to healthy control, confirming the diagnosis of CD40 deficiency.Conclusion: Class switch defects, such as CD40 deficiency, are rare but significant diagnoses within the spectrum of IEI. This case demonstrates that despite the absence of some clinical red flags for immunodeficiency in infancy, IEIs remain an important consideration in pediatric patients regardless of age. Increasing clinical awareness of IEI will lead to earlier diagnoses, initiation of appropriate treatment, and prevention of potential complications.Statement of novelty: We describe a patient with a late presentation of hyper IgM syndrome due to two novel variants in the CD40 gene, thus expanding the spectrum of CD40 gene variants.
- Background: The prevalence of atopic disease, which consists of conditions such as atopic dermatitis, allergies, and asthma, has been on the rise in recent decades. In children, atopic dermatitis often acts as an initial manifestation of atopic disease and frequently precedes the development of food allergies, asthma, and allergic rhinitis. Mutations in the FLG gene, encoding the fillagrin precursor profillagrin, serve as a genetic risk factor for these diseases. Approximately 25%–50% of individuals with atopic dermatitis carry FLG mutations. It has been proposed that FLG mutations exhibit variations specific to different populations, indicating distinct patterns within each population.Severe allergic symptoms could indicate the presence of an underlying immunodeficiency or immune dysregulation and in patients with severe, early-onset, or simultaneous allergic conditions, these could be suggestive of an underlying Primary Atopic Disorder. Specifically, the allergic triad characterized by elevated IgE levels, eosinophilia, and eczema is a common feature in various inborn errors of immunity that could be mistakenly diagnosed as severe allergic conditions.Method: Our patient’s medical record was analyzed retrospectively, including her medical history, as well as results from immune laboratory tests and genetic analyses.Results: We present a 9-year-old female of mixed ethnicity with a history severe eczematous rash diagnosed with atopic dermatitis. Whole exome sequencing analysis revealed an initially novel heterozygous variant in the FLG gene (NM_002016: EXON3:c.C2218T: p.R740X).Conclusion: Healthcare providers caring for patients with atopic dermatitis and recurrent staphlococcus infections should be aware of the significant link between filaggrin gene mutations and the development of severe, persistent atopic dermatitis that begins in childhood, as well as its association with recurring staphlococcus infections. Additionally, they should keep in mind that certain inborn errors of immunity may predominantly manifest as severe and treatment-resistant atopic disorders.Statement of novelty: We have identified a rare variant in the FLG gene associated with severe atopic dermatitis and allergies.
- Background: The Nuclear Factor-kappa B (NF-kB) signaling pathway plays a critical role in regulating a wide range of cellular processes such as immune function, inflammation, and tumor regulation. There are two major pathways that play a role in NF-kB activation: the canonical NF-kB1 pathway and the non-canonical NF-kB2 pathway. Abnormalities in non-canonical NF-κB2 signaling are linked with significant impairments in the immune system, mainly B cell maturation, antibody production, as well as T helper and regulatory T cell function through its effect on germinal center regulation.Methods: Our patient’s medical record was analyzed retrospectively, including her medical history, results from immune laboratory tests, and genetic analyses.Results: We present a 16-year-old female with a history of chronic cough complicated with episodes of hemoptysis and diagnosed with bronchiectasis secondary to common variable immunodeficiency. Whole exome sequencing analysis revealed a novel heterozygous variant in the NFKB2 gene (NM_001077494.3), c.931C>T resulting in p.Arg311Cys.Conclusion: The presence of NFKB2 mutations can lead to the development of early-onset common variable immunodeficiency.Statement of Novelty: We have identified a novel variant in the NFKB2 gene associated with antibody deficiency.
- FREE ACCESSBackground: Lipopolysaccharide-responsive beige-like anchor (LRBA) is an intracellular protein that regulates the recycling of cytotoxic T lymphocyte-associated protein 4 (CTLA4), an immune checkpoint molecule which prevents ongoing activation of T cells. Deficiency of LRBA results in increased trafficking and degradation of CTLA4, and consequently, uncontrolled T cell responses. The phenotypic spectrum of LRBA deficiency arising from biallelic loss-of-function typically includes recurrent infections, autoimmunity, lymphoproliferation, chronic diarrhea, hypogammaglobulinemia, and cytopenia.Aim: To report an atypical presentation of LRBA deficiency arising from a set of compound heterozygous LRBA variants, encompassing recurrent hemophagocytic lymphocytosis (HLH) and neurological manifestations.Methods: Clinical data was gathered through retrospective chart review. Expanded genetic analysis including whole exome sequencing was performed.Results: Our patient initially presented at age 15 months with fever, seizures, and encephalopathy. HLH-work-up showed bicytopenia, elevated ferritin and triglyceride, and low fibrinogen, however, he did not yet meet the diagnostic criteria for HLH. MRI brain and EEG at diagnosis was suggestive of acute necrotizing encephalopathy of childhood. He responded to pulsed IV methylprednisolone treatment with minimal residual neurological deficit on follow-up. At 36 months of age, he had a repeat presentation and rapidly deteriorated. He developed severe encephalopathy with fixed dilated pupils. Whole exome sequencing revealed a set of compound heterozygous missense variants in the LRBA gene, a novel c.2206A>T (p.R736W) and c.5989C>T (p.R1997C) variant.Conclusion: Compound heterozygous mutations in the LRBA gene caused an atypical presentation of recurrent HLH with central nervous system (CNS) manifestations in our patient.Statement of Novelty: We herein report a novel set of compound heterozygous mutations in LRBA with atypical presentation of recurrent HLH with CNS manifestations, thus expanding the known phenotypic spectrum of LRBA deficiency.
- FREE ACCESSBackground: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia.Aim: To describe a novel splice-site variant in STAT3 resulting in HIES.Methods: Case report of two family members with HIES.Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES have mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis.Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice-site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.Statement of Novelty: We present a novel splice-site mutation in the DNA-binding domain of STAT3 leading to autosomal dominant hyper-IgE syndrome.
- FREE ACCESSIntroduction: NF-κB proteins are transcription factors that modulate various functions of the immune system. NF-κB2 (or p100/p52) has particularly important roles in B cell development and function. Primary immunodeficiency due to mutations in the NFKB2 gene, encoding NF-κB2, range from combined immunodeficiency with susceptibility to viral or opportunistic infections to primarily antibody deficiency.Methods: A comprehensive chart review of our patient was performed.Results: Our patient, currently a 19-year-old male, presented with multiple autoimmune cytopenia resistant to treatment and generalized granulomatous lymphadenopathy. Whole exome sequencing identified a novel pathogenic variant in NFKB2 (c.1700C>T; p.A567V) that is the cause of our patient’s presentation.Conclusion: We present a novel pathogenic variant in NFKB2 with an unusual presentation.Statement of novelty: Here, we report a novel mutation in NFKB2 and the clinical presentation of the affected patient, which helps in further understanding the NF-κB2 pathway and its associated disease.
- FREE ACCESSBackground: Eosinophilic gastrointestinal disease (EGID) is an umbrella term for a heterogeneous group of disorders affecting the GI tract. In contrast to the relatively common eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EGE) remains poorly understood in terms of both its pathophysiology and genetic etiology, while treatment options remain limited.Aim: To expand the genotypic spectrum of EGE and describe our long-term experience of treatment with ketotifen.Methods: Case report of a patient with EGE followed by our team for over 27 years.Results: Our patient was diagnosed with EGE at the age of 4 years, accompanied by multiple other atopic manifestations and serum eosinophilia. He was later diagnosed with a heterozygous variant in RUNX1, a gene implicated in multi-lineage hematopoiesis, inhibition of Th2 polarization and T regulatory cell function. The patient has experienced long-term symptom improvement while treated with the mast cell stabilizing H1 antihistamine, ketotifen, with substantial symptomatic worsening after this agent was briefly stopped.Conclusion: We expand the genotypic spectrum of EGID etiology to include mutations in RUNX1, and suggest ketotifen as a viable option for patients with treatment-refractory EGE.Statement of novelty: This case reports on a possible novel genetic cause of EGID and describes long-term successful clinical management with ketotifen.
- FREE ACCESS
- Laura Edith Abrego Fuentes,
- Jenny Garkaby,
- Jessica Willett Pachul,
- Abby Watts-Dickens,
- Meghan Fraser,
- Vy H.D. Kim, and
- Chaim M. Roifman
Background: Forkhead-box protein N1 (FOXN1) plays a critical role in the proper development and function of thymic epithelial cells, required for T cell ontogeny. Homozygous variants in the FOXN1 gene, encoding FOXN1, cause severe combined immunodeficiency (SCID), whereas heterozygous mutations are associated with variable presentations and over time, improving T cell function.Aim: To highlight the importance of broader genetic investigations to attain a definitive molecular diagnosis following abnormal newborn screening for SCID.Methods: Case report of a patient with immunodeficiency due to a novel de novo FOXN1 mutation.Results: The patient was identified following abnormal newborn screening for SCID in which T cell receptor excision circles were absent/very low. Initial immune investigations revealed severe T cell lymphopenia and poor lymphocyte function and she was diagnosed with T-B+NK+SCID. During work-up for hematopoietic stem cell transplantation, extensive genetic investigations identified a novel heterozygous mutation in FOXN1. A more conservative management approach was taken, and over the following months, the patient’s immune parameters improved.Conclusion: Newborn screening for SCID has facilitated the detection of SCID, as well as other T cell immunodeficiencies, before infectious complications and organ damage occur. Heterozygous mutations in FOXN1 are associated with more variable presentations including improving immune indices with age. Here, results of genetic investigations were essential for informing the management of this case.Statement of Novelty: We report a novel heterozygous mutation in FOXN1, presenting initially as T-B+NK+ SCID with gradual improvement of immune parameters over time. - FREE ACCESSBackground: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) haploinsufficiency is characterized by a variety of phenotypes, ranging from autoimmune disorders, enteropathy, fatal combined immunodeficiency, as well as lymphoproliferation and malignancy.Aim: To broaden the genotypic spectrum and clinical presentations of patients with CTLA4 variants.Methods: We evaluated a female patient with autoimmunity and lymphopenia. Immune workup and whole exome sequencing (WES) were performed.Results: The proband presented at 11 years of age with hypothyroidism and later developed Evans syndrome, alopecia, eczema, and lymphocytic interstitial pneumonia. Immune evaluation revealed T, B, and NK lymphopenia with normal humoral immunity. Following a negative genetic panel for autoimmune lymphoproliferative syndrome (ALPS), WES analysis identified a novel heterozygous intronic variant predicted in-silico to cause skipping of exon 2 of the CTLA4 gene.Conclusion: A novel heterozygous mutation in CTLA4 caused variable presentations of immune dysregulation, one of the hallmarks of CTLA4 haploinsufficiency.Statement of Novelty: We herein report a novel mutation in CTLA4 resulting in various features of autoimmunity.
- OPEN ACCESS
- Jenny Garkaby,
- Laura Edith Abrego Fuentes,
- Jessica Willett Pachul,
- Abby Watts-Dickens, and
- Meghan Fraser
Background: The T cell receptor (TCR)-α chain plays a key role in TCR structure and function. Biallelic mutations in TRAC, encoding the constant region of the TCR-α chain, obliterates TCR expression and results in immunodeficiency. TCR-α chain deficiency presents at infancy or childhood with repeated viral and bacterial infections, enlarged liver, spleen, and lymph nodes as well as autoimmune features and lymphoma (OMIM #615387).Aim: To broaden the genotypic and phenotypic spectrum of TCR-α chain deficiency.Methods: We present a case report of a patient with severe combined immunodeficiency (SCID) due to a novel autosomal recessive mutation in TRAC.Results: Our patient was identified at 13 days of life due to abnormal T cell receptor excision circle levels detected by newborn screening (NBS). Immune evaluation revealed profound lymphopenia, depressed responses to the mitogen PHA and a skewed T cell repertoire, all consistent with SCID. The patient was found to carry a novel homozygous mutation in the TRAC gene.Conclusion: A novel homozygous mutation in the TRAC gene caused profound T cell lymphopenia and aberrant in vitro mitogenic response, the hallmarks of SCID.Statement of Novelty: TCR-α chain deficiency is a rare and relatively new condition and not very well defined. We herein report a novel mutation in TRAC resulting in SCID. - OPEN ACCESS
- Laura Abrego Fuentes,
- Jenny Garkaby,
- Ori Scott,
- Jessica Willet Pachul,
- Harjit Dadi,
- Daniele Merico, and
- Linda Vong
Introduction: The phosphoinositide 3-kinase (PI3K) pathway plays critical roles in diverse cellular processes, including differentiation, proliferation, motility, survival, and growth. PI3Kδ, comprised of the catalytic subunit p110δ and regulatory subunit p85α, is essential for normal lymphocyte and myeloid development and function. Gain-of-function mutations in PIK3CD (encoding p110δ) cause a combined immunodeficiency known as activated PI3Kδ syndrome (APDS), in which patients frequently present with recurrent respiratory infections, severe recurrent (or persistent) infections with herpes family viruses, and lymphadenopathy.Aim: To describe the clinical presentation, immune evaluation, and genetic work-up of 2 patients (daughter and mother) with recurrent sinopulmonary, soft tissue, and skin infections.Results: Both daughter and mother presented with recurrent sinopulmonary and soft tissue infections. Immune evaluation of the daughter revealed intermittent hypogammaglobulinemia and abnormal specific vaccine responses, while immune parameters of her mother were normal. Whole exome sequencing identified a novel mutation in PIK3CD (NM_005026), c.C719T, resulting in p.T240M. Western blot analysis of downstream AKT levels revealed increased basal phosphorylation, in line with gain-of-function mutations of PIK3CD.Conclusion: The novel missense mutation in PIK3CD occurs in the region encoding the Ras-binding domain (RBD) of p110δ, and likely alters the structural configuration of the domain. To date, pathogenic mutations targeting the RBD of p110δ have not yet been described. Our results expand on the genotypic spectrum of APDS.Statement of Novelty: We describe a novel mutation in the Ras-binding domain of PIK3CD leading to a presentation of recurrent sinopulmonary and soft tissue infections in the context of APDS. - OPEN ACCESSBackground: X-linked agammaglobulinemia type 1 (XLA) is one of the most common pediatric inborn errors of immunity affecting the humoral immune system. The condition is caused by a mutation in the Bruton’s tyrosine kinase gene (BTK), located in the long arm of the X-chromosome. BTK is crucial for B lymphocyte differentiation and activation. Therefore, a defect in BTK results in B lymphocyte maturation arrest, absence of plasma cells, and failure of immunoglobulin production. XLA affected individuals present with a history of frequent severe pyogenic infections such as pneumonia, conjunctivitis, otitis media, and bacteremia. Laboratory evaluation classically reveals undetectable immunoglobulins and the absence of B cells. The mainstay treatment is immunoglobulin replacement which can be administered intravenously (IVIG) or subcutaneously (SCIG). Aggressive antimicrobial treatment is also administered to reduce complications such as bronchiectasis or invasive bacterial infections during active infections.Aim: To report the clinical presentation, immune features, and genetic mutation in a case of a four-year-old boy with a novel mutation in the BTK gene leading to XLA.Results: The patient’s chart was reviewed. We describe the phenotypical and diagnostic characteristics of an established case in a four-year-old boy who suffered from recurrent infections. Genetic analysis revealed a pathogenic novel mutation in the BTK gene (c.1953C>A; p.Tyr651*), while flow cytometry found 0% CD19+ (B cells), and low serum Ig levels.Discussion: We report the clinical presentation, immune features, and genetic mutation in a patient with a novel mutation in the BTK gene causing XLA. Genetic analysis along with patient history, physical examination, and laboratory results are necessary to identify and diagnose XLA associated with pathogenic mutations in the BTK gene.Statement of novelty: We present an established case of a novel mutation in the BTK gene (c.1953C>A; p.Tyr651*), based on genetic analysis, absent CD19+cells (B cells), and low Ig serum levels.
- OPEN ACCESSBackground: Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder associated with combined immunodeficiency, microthrombocytopenia, eczema, and an increased risk of autoimmunity and cancer.Aim: To report the clinical presentation, immune features, and genetic mutation in a patient with a novel mutation in the Wiskott-Aldrich syndrome (WAS) gene, causing a mild phenotype of WAS.Methods: The patient’s chart was reviewed. We report the phenotypical and laboratory characteristics of a patient with a mild phenotype of WAS identified by WAS gene sequence analysis.Results: Our patient presented with thrombocytopenia and 3 episodes of otitis media at 24 months of age, with no other significant manifestations suggestive of immunodeficiency or immune dysregulation. A missense mutation was found in exon 12 of the WAS gene, C1498>T, leading to a Trp500Arg amino acid change. Currently, he is 15 years old and remains in good health, free of infections or other complications to date.Conclusion: Genetic analysis is helpful for the diagnosis of WAS; our patient’s mutation was found to cause a mild phenotype.Statement of novelty: We describe a patient with a mild phenotype of WAS with a novel mutation in the WAS gene, thus, expanding the spectrum of WAS gene mutations.
- OPEN ACCESSBackground: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases.Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations.Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed.Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p. Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members.Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred.Statement of novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.
- OPEN ACCESS
- Ori Scott,
- Jenny Garkaby,
- Jessica Willett-Pachul,
- Amarilla B. Mandola,
- Daniele Merico, and
- Yehonatan Pasternak
Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations.Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency.Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation.Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother.Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.Statement of novelty: Heterozygous FOXN1 deficiency is a relatively new entity, attributed in most cases to missense mutations in FOXN1. To further expand the knowledge basis regarding this emerging disorder, as well as its genotypic repertoire, we herein report a case of heterozygous FOXN1 deficiency caused by a splice site mutation. - OPEN ACCESSBackground: Recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) encode unique lymphocyte endonuclease proteins that are crucial in T and B cell development through V(D)J recombination. RAG1 gene defects lead to variable phenotypes, ranging from immunocompetent to severe combined immunodeficiency (SCID). Curative therapy for severe manifestations can be achieved through hematopoietic stem cell transplantation (HSCT). Advances in genomic sequencing have led to the discovery of new variants and it is recognized that the level of recombinase activity correlates with disease severity.Aim: To report the clinical presentation, immunological work-up, decision process to undergo HSCT, and confirmatory genetic diagnosis in a patient who was well until her initial presentation with disseminated vaccine-strain varicella.Methods: Clinical data was gathered through retrospective chart review. Immunological investigations, targeted gene sequencing, and thymic biopsy results were reviewed. Further genetic analysis, including whole exome and whole genome sequencing was performed.Results: Whole exome sequencing identified a single missense mutation in RAG1, R474C (c.1420C>T), which would not account for the clinical presentation. Healthy individuals with only 1 mutation have been reported. Subsequently, whole genome sequencing revealed a novel second heterozygous missense variant, H945D (c.2833G>T) in the RAG1 gene.Conclusion: Hypomorphic RAG1 mutations with residual activity have a diverse phenotypic expression. Identifying and understanding the implications of these mutations is crucial for disease prognostication and tailoring management.Statement of novelty: We present a novel RAG1 missense variant, with likely complete or partial loss of function, in a patient with significant impairment in cellular immunity.
- OPEN ACCESSIntroduction: Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency caused by mutations in the NADPH complex characterized by recurrent infections, inflammation and autoimmunity. While autosomal recessive forms exist, X-linked CGD makes up the majority of cases, which is caused by mutations in the CYBB gene. Patients are at high risk for infections with catalase positive bacteria and fungi. The prognosis has improved significantly with improvements in disease detection and management, including prophylactic antibiotic and antifungal therapy. Hematopoietic stem cell transplantation (HSCT) is a curative option for patients with a suitable donor.Aim: To report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD who underwent HSCT.Results: Case 1: Patient 1 is a 14-year-old patient who initially presented with disseminated aspergillosis at the age of 3. He was noted to have an abnormal neutrophil oxidative burst index (NOBI) and genetic testing revealed a mutation in the CYBB gene (c.883_87dupGTGGT) consistent with CGD. He successfully underwent HSCT at age 4. At age 10 he developed a primary intracranial rhabdomyosarcoma in the posterior cranial fossa. Case 2: Patient 2 is a 4-year-old male who was worked up for CGD after developing a perianal abscess at 1 month of age followed by Moraxella bacteremia at 2 months of age. He had 2 abnormal NOBIs and genetic testing identified a novel mutation in the CYBB gene that was thought to explain his phenotype (c.941delA). He underwent an HSCT (10/10 HLA matched unrelated donor). Both patients have had normalization of their NOBI post-transplant and remain free of significant infections.Discussion: We report the clinical presentation, immune features and genetic mutations in 2 patients with novel mutations in the CYBB gene causing X-linked CGD. Identifying pathogenic mutations causing CGD is important for a better understanding of genotype–phenotype associations and disease course in this patient population.Statement of novelty: We describe 2 pediatric patients diagnosed with X-linked chronic granulomatous disease due to novel mutations in the CYBB gene.
- OPEN ACCESSIntroduction: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Delta (PIK3CD) is one part of a heterodimer forming the enzyme phosphoinositide 3-kinase (PI3K), found primarily in leukocytes. PIK3CD generates phosphatidyl-inositol 3,4,5-trisphosphate (PIP3), and is involved in cell growth, survival, proliferation, motility, and morphology. An increasing number of patients have been described with heterozygous PIK3CD gain-of-function (GOF) mutations, leading to combined immunodeficiency with both B- and T-cell dysfunction. Patients suffer recurrent respiratory infections, often associated with bronchiectasis and ear and sinus damage, as well as severe recurrent or persistent infections by herpesviruses, including EBV-induced lymphoproliferation.Aim: To present the clinical phenotypic variability of a novel PI3KCD mutation within a family.Methods: Patient information was collected prospectively and retrospectively from medical records. Comprehensive immune work up, genetic, and signaling evaluation was performed.Results: We describe here 2 patients, daughter and mother, with heterozygous PIK3CD mutation identified by whole exome sequencing and Sanger confirmation. The child was screen-positive by newborn screening for severe combined immunodeficiency (SCID). Cellular assays revealed an increase in the baseline phosphorylation of T cells in the patient. Furthermore, both patients had hyper-activation of the catalytic domain, resulting in increased phosphorylation of AKT upon activation.Discussion: GOF mutations affecting the PIK3CD gene are associated with an increased risk for lymphoproliferation leading to Activated PIK3-delta syndrome (APDS). The clinical course of APDS is highly variable, ranging from combined immunodeficiency with recurrent infections, autoimmune complications, and requiring stem cell transplantation, through isolated antibody deficiency, to asymptomatic adults. Our patient is the first to be identified by newborn screening for SCID. Surprisingly, the clinical course has so far been unremarkable, as well, the mother appears to be completely asymptomatic. Nevertheless, the persistent lymphopenia indicates PIK3CD dysfunction. Because of the wide gap between laboratory findings and clinical manifestations, this kindred poses both a diagnostic as well treatment challenge.Statement of novelty: We report here a novel PIK3CD mutation diagnosed due to abnormal newborn screen for SCID.
- OPEN ACCESSBackground: Ataxia telangiectasia typically presents in early pre-school years with progressive cerebellar ataxia and oculocutaneous telangiectasias. Referral to Immunology is often made after diagnosis has been established, as patients are prone to both humoral and cellular immune abnormalities.Case presentation: We herein report a 10-year old boy, previously undiagnosed, who presented with recurrent pneumonias. On history, frequent falls and speech difficulty were reported, with no telangiectasias on exam. Screening with alpha-fetoprotein was abnormal, followed by ATM gene sequencing, showing a homozygous intronic mutation. Over the next 3 years the patient deteriorated neurologically, and developed appreciable telangiectasias.Conclusion: A review of the literature demonstrates that intronic/splicing mutations may result in atypical ataxia telangiectasia phenotypes and delayed presentations. We advise immunologists to have a high index of suspicion for ataxia telangiectasia when assessing a patient with immunodeficiency and neurologic regression, regardless of age, and even in the absence of telangiectasias.Statement of novelty: We present a case of phenotypically atypical (“leaky”) ataxia telangiectasia resulting from a novel homozygous splice-site mutation in the ATM gene. Given high reported prevalence of intronic and splice-site mutations in ATM, we recommend full gene sequencing in patients suspected to have ataxia telangiectasia, especially in those with late onset or unusual manifestations.
