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- Garkaby, Jenny8
- Roifman, Chaim M7
- Scott, Ori6
- Dadi, Harjit5
- Abrego Fuentes, Laura4
- Mandola, Amarilla B4
- Reid, Brenda4
- Upton, Julia4
- Willett Pachul, Jessica4
- Abrego Fuentes, Laura Edith3
- Feanny, Stephen3
- Grunebaum, Eyal3
- Mandola, Amarilla3
- Merico, Daniele3
- Sham, Marina3
- Vong, Linda3
- Fraser, Meghan2
- Haynes, Alison2
- Hong-Diep Kim, Vy2
- Kim, Vy H D2
- Murguia-Favela, Luis2
- Pereira, Myra2
- Roifman, Maian2
- Sharfe, Nigel2
- Upton, Julia E M2
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- OPEN ACCESSBackground: Chronic mucocutaneous candidiasis (CMCC) has traditionally encompassed endocrinopathy, autoimmunity, and infection of the skin, nails, oral and genital mucosa. It is typically caused by Candida albicans, an organism that is found to be commensal in healthy individuals. To date, most patients with CMCC have mutations in AIRE or STAT1. While chronic Candida spp. infection is a feature of multiple profound T cell deficiencies, it has also been identified in rare cases involving selective immune defects, including interleukin-17 receptor A (IL-17RA) deficiency. An association between Staphylococcus aureus infections and candidiasis due to IL-17RA deficiency has recently been proposed.Aim: We sought to identify the genetic defect in a patient presenting with recurrent oral thrush and S. aureus infections, but otherwise unremarkable immune workup.Methods: Whole exome sequencing and Sanger confirmation was performed, and protein expression analysis utilized to assess the impact of the genetic aberration. A comprehensive immune workup was completed to characterize any possible deficits in his immune system.Results: Next generation sequencing techniques identified a homozygous mutation in IL17RA, c.1696insAG, resulting in the frameshift mutation p.Q566fs. Western blot analysis confirmed the loss of IL-17RA expression.Conclusion: We describe here a novel frameshift mutation in IL17RA. Clinically, the patient was a diagnostic challenge as he did not present with a classic CMCC phenotype. This case emphasizes the importance of genetic analysis in patients presenting with recurrent infections.Statement of novelty: We identify a novel frameshift mutation in IL17RA in a patient presenting with recurrent bacterial and fungal mucocutaneous infections.
- OPEN ACCESSBackground: The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) signaling pathway is a critical regulator of many important adaptive and innate immune responses. The NF-κB transcription factor family consists of 5 structurally related core proteins, one of which is NFKB1. Mutations in the NFKB1 gene has been reported in patients with common variable immune deficiency (CVID) as well as with a large spectrum of clinical features including recurrent viral, bacterial, and fungal infections, autoimmunity, inflammation, and malignancy.Aim: We describe the clinical characteristics of a pediatric patient with a novel mutation in NFKB1.Methods: Patient informed consent was obtained in accordance with approved protocols from the Research Ethics Board at the Hospital for Sick Children. Gene panel testing was employed to identify the immune aberration.Results: Our patient, a previously well 18-month-old boy of Philippines descent, presented with multi-lineage cytopenias (thrombocytopenia, hemolytic anemia, neutropenia), splenomegaly, and lymphadenopathy. He did not have prior history of recurrent infections. Immunological work-up showed normal numbers of T and B cells, normal quantitative immunoglobulins, and adequate vaccination titres. Gene panel testing revealed a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene. Due to persistent cytopenias unresponsive to steroids and IVIG, he was started on Sirolimus with improvement in symptoms.Conclusion: NFKB1 encodes for p105, which is processed to generate the active p50 transcription factor that can interact with different proteins to activate or inhibit downstream signaling. Our patient was found to have a missense mutation in the Rel homology domain (RHD) of p50, which has distinct functions including DNA binding, protein dimerization, and inhibitory protein binding. The clinical presentation described here broadens the scope of characteristics associated with heterozygous NFKB1 mutations.Statement of novelty: We report a novel heterozygous missense variant c.425T>C (p. Ile142Thr) in the NFKB1 gene in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been previously reported.
- OPEN ACCESSIntroduction: Coronin 1A belongs to a large family of actin regulatory proteins with a role in T cell homeostasis. A role for coronin 1A was also observed in macrophages, NK, and neuronal cells. To date, coronin 1A deficiency has been described in relatively few patients with combined immunodeficiency.Aim: We studied here the molecular and genetic basis of immunodeficiency detected by newborn screening for severe combined immunodeficiency.Methods: Patient data was collected in accordance with REB approved protocols. Immune work up, including T and B cell proliferative responses and serum concentrations of immunoglobulins, was performed. Next generation sequencing techniques and cellular analyses were also utilized.Results: The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia. Uniquely, she also had persistent severe neutropenia. Whole exome sequencing and Sanger confirmation revealed a novel homozygous mutation in coronin 1A.Conclusion: Coronin 1A deficiency can be detected after birth by T cell receptor excision circle-based newborn screening.Statement of novelty: We report here a patient with a novel mutation in coronin 1A, identified during newborn screening with low T cell receptor excision circle levels and neutropenia, which is a unique finding in this condition.
- OPEN ACCESSBackground: The protein encoded by interleukin-2 receptor common gamma chain (IL2RG) is an important signaling component of many interleukin receptors, including those of interleukin-2, -4, -7, and -21, known as the common gamma chain. Mutations in the gene encoding the common gamma chain of the interleukin-2 receptor cause X-linked severe combined immunodeficiency (SCID). In this report, we present an unknown genetic defect of a patient diagnosed with SCID whose genetic analysis was performed 2 decades later.Methods: Whole genome sequencing and Sanger confirmation were used to identify a novel frameshift mutation in IL2RG. Massively parallel sequencing of genes associated with SCID were performed on the patient’s mother and sister.Results: Next generation sequencing techniques identified a heterozygous frame-shift deletion in the gene encoding the common gamma chain of IL2RG in our patient. The patient’s mother had a low level mosaicism for the same deletion. The sister had no detectable deletion.Conclusion: We have identified a novel mutation in IL2RG resulting in an X-linked SCID phenotype. The genetic analysis of the patient’s mother revealed a mosaicism which was not passed on to his sister. The importance of genetic analysis in family members and SCID patients with an unknown genetic defect should be emphasized for family planning and subsequent genetic counseling.Statement of novelty: Genetic testing is an extremely important component in evaluating severe combined immunodeficiency as it impacts treatment course and prognosis, and allows for genetic analysis and counselling of family members.
- OPEN ACCESSIntroduction: Major histocompatibility (MHC) class II deficiency is a rare autosomal recessive primary immunodeficiency with fewer than 200 patients reported worldwide. Patients usually present within their first year of life with severe and recurrent infections, failure to thrive, and chronic diarrhea. The disorder is caused by absent or reduced MHC class II expression on cell surfaces, leading to defective cellular and humoral immune responses. The disease is associated with a poor prognosis, with most patients dying in early childhood due to infectious complications.Aim: To report the clinical, immunological, and genetic features of an adult patient with MHC class II deficiency who did not undergo hematopoietic stem cell transplant (HSCT). We also explore proposed theories as to why some patients with MHC class II deficiency survive to adulthood, beyond the typical life expectancy.Results: We present a 23-year-old gentleman who was diagnosed with MHC class II deficiency at the age of 6 months based on a near complete absence of Human Leukocyte Antigen - DR isotype on peripheral blood mononuclear cells and CD4+ lymphopenia. He is one of a few patients with the condition reported in the literature to have survived to adulthood despite not having undergone HSCT. Next generation sequencing revealed a novel homozygous mutation in the CIITA gene, 1 of 4 genes involved in the regulation of MHC class II transcription.Discussion: MHC class II deficiency is considered a single entity phenotypic condition where the main problem lies in reduced or absent MHC class II expression and results in downstream immunologic effects, including CD4+ lymphopenia and impaired antigen specific responses. However, phenotypic differences between patients are emerging as more cases are described in the literature. Our patient, now 23 years old, has survived significantly beyond life expectancy despite not having HSCT.Statement of novelty: We describe a case of an adult patient diagnosed with MHC class II deficiency due to a novel homozygous intronic splice site variant in the CIITA gene.
- OPEN ACCESSBackground: Leukocyte adhesion deficiency (LAD) syndromes are primary immunodeficiency disorders caused by defects in adhesion molecules on leukocytes resulting in impaired migration into tissues. Common cutaneous manifestations of LAD include bacterial infections, omphalitis with delayed separation of the umbilical cord, impaired pus formation and poor wound healing. LAD is associated with significant morbidity and mortality, making early diagnosis and management integral in the care of these patients.Methods: Molecular testing and flow cytometry for expression of CD18 were performed on 2 siblings presenting with cutaneous lesions including pyoderma gangrenosum (PG).Results: We describe 2 siblings with a novel homozygous mutation in ITGB2 (c.2070del, p.Asp690Glufs*25) resulting in an atypical presentation of LAD-I with PG.Conclusion: LAD should be considered in patients presenting with unexplained PG, even in the absence of significant infections or umbilical cord complications.Statement of novelty: To the best of our knowledge, we describe a novel homozygous mutation in ITGB2 (c.2070del, p.Asp690Glufs*25) resulting in LAD-I. Patients with LAD-I may present with unexplained PG and may lack classic symptoms including umbilical cord complications.
- OPEN ACCESS
- Ramón Urrea Moreno,
- Itziar Astigarraga,
- Ana Fernández-Teijeiro,
- Carmen Rodríguez-Sainz,
- María Alonso-Martinez,
- Lydia Martín-Martín,
- Susana García-Obregón, and
- Juana Gil-Herrera
Background: Three substitutions at either Gly305 or Gly306 within the membrane attack/complex perforin domain (MACPF) of perforin have been previously identified in a number of patients with hemophagocytic lymphohistiocytosis (HLH). However, their pathogenic impact remains unclear since all the cases reported so far carried heterozygous genotypes and showed very heterogeneous clinical presentations. Here, we report a new substitution (p.Gly306Asp) and use in silico tools to elucidate the pathogenic mechanisms and severity associated with human Gly306 and Gly305 mutations.Methods: The immunological workup included perforin expression and perforin gene (PRF1) mutation analysis. Computer algorithms based on conservation, secondary, and tertiary protein structure analyses were applied to assess the role of the mutations in disease pathogenesis.Results: In our patient, we found a previously undescribed homozygous c. 917G>A (p.Gly306Asp) mutation in the PRF1 gene that was associated with null perforin expression in her natural killer lymphocytes. Sequence alignments revealed that Gly306 and Gly305 are highly conserved positions among vertebrate perforins, as well as in other related pore-forming proteins such as bacterial cytolysins. Further in silico analyses consistently predicted mutations in these 2 positions to be pathogenic due to diminished stability of the perforin molecule.Conclusion: Age of HLH onset, severity of the disease and undetectable perforin in our p.Gly306Asp homozygous patient along with the in silico results unmask this novel mutation as highly detrimental. Our results highlight the need of combining all clinical features, in vitro phenotypes and computer based approaches to classify human perforin mutations accurately.Statement of novelty: The study of these PRF1 mutations points to an important role of the 2 glycine amino acids (Gly305 and Gly306) in the molecular stability of perforin, which may also be likely in other pore-forming proteins. Our in silico results conclude that the pathogenicity of mutations in highly conserved Gly305 and Gly306 is likely to be associated with a serious destabilization of the native perforin conformation. - OPEN ACCESS
- Victoria E. Cook,
- Connie L. Yang,
- Anna F. Lee,
- Alexia Dabadie,
- Joanne Luider,
- Kyla J. Hildebrand,
- Anne Junker, and
- Stuart E. Turvey
Introduction: Childhood interstitial lung disease (chILD) syndrome describes findings of respiratory symptoms and diffuse abnormalities on lung imaging. Immunodeficiency and immune dysregulation are increasingly recognized as potential causes of these clinical findings. Patients with CD40 ligand (CD40L) deficiency typically present with sinopulmonary and opportunistic infections secondary to impairments in both humoral and cellular immunity. chILD syndrome has not previously been reported as a presenting feature of this disease.Objectives: We describe a patient with CD40L deficiency, caused by a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln), who presented in infancy with chILD syndrome and lung biopsy findings of chronic interstitial pneumonitis and patchy pulmonary glycogenosis.Methods: A left lingula wedge lung biopsy was fixed with formalin and stained for analysis. Whole blood samples from the patient and parents were sent for whole exome sequencing. Flow cytometry to assess CD40L expression on activated CD3+CD8− T cells was performed.Results: Lung biopsy demonstrated lymphoid aggregates and patchy pulmonary interstitial glycogenosis. Whole exome sequencing revealed maternal inheritance of a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln). Functional studies demonstrated absent CD40L expression on activated CD3+CD8− T cells.Conclusion: This novel mutation in CD40LG, c.464 T>A, is disease-causing based on the patient’s clinical features and absent CD40L expression. This is the first report of CD40L deficiency presenting as chILD syndrome.Statement of novelty: The missense mutation observed in our patient (c.464 T>A, p.Leu155Gln), is novel; CD40L deficiency secondary to a different missense variant at the same amino acid position has been described (c.464 T>P, p.Leu155Pro). To our knowledge, this is the first report of CD40L deficiency with an initial clinical picture consistent with interstitial lung disease. - OPEN ACCESS
- Luis Murguia-Favela,
- Nigel Sharfe,
- Ariana Karanxha,
- Andrea Bates,
- Harjit Dadi,
- Lorand Cimpean, and
- Chaim M. Roifman
Background: CD40 deficiency is an autosomal recessive, combined primary immunodeficiency characterized by defects of immunoglobulin class switch recombination and somatic hypermutation. It is part of an expanding group of diseases collectively known as hyper immunoglobulin M syndromes. Clinical manifestations of the disease usually begin early in life with recurrent sinopulmonary bacterial infections and susceptibility to opportunistic organisms. Only 16 patients from 12 unrelated families have been reported to date, all with lack of membrane expression of CD40 molecule.Methods: Prospective and retrospective data was collected from the patient’s medical records, and Sanger sequencing, flow cytometry analysis, real-time polymerase chain reaction and western blotting were performed.Results: In contrast with the patients reported previously, our patient’s mutation permits CD40 expression on the cell membrane and adds 37 amino acids to the cytoplasmic domain of the protein. We predict this change to affect 1 of the 2 known TRAF2 binding sites, as well as generate defective internalization of the receptor, both of which are required processes for functional signaling by CD40.Conclusion: Our patient’s unique phenotype is an opportunity to further understand the biology and function of the CD40 receptor. As illustrated by this case, relying solely on flow cytometry for diagnosis of CD40 deficiency has the potential of overlooking patients with mutations that may allow residual protein expression. Therefore, confirmatory mutation analysis should always be performed.Statement of novelty: We report on a patient with a novel mutation in CD40 and a unique phenotype, characterized by a complete lack of CD40 function despite normal protein expression. To our knowledge, this has not been reported previously. The patient has a milder phenotype than described for other patients with CD40 deficiency. - OPEN ACCESSBackground: DNA ligase IV deficiency is a rare autosomal recessive condition resulting from mutations in LIG4, an essential component of the non-homologous end-joining pathway that prevents mutagenesis and apoptosis. Patients with LIG4 deficiency present with varying degrees of combined immunodeficiency, or less commonly, severe combined immunodeficiency (SCID). Assessment of thymus pathology has been instrumental in defining a growing number of T cell deficiencies. In this case report, we present thymic histopathology of a LIG4 deficient patient who presented with SCID.Methods: Whole exome sequencing and Sanger confirmation were used to identify a novel mutation in LIG4. Standard immune work up and histopathology were completed to characterize deficits in immune function and dysplastic thymic architecture in our patient.Results: Next generation sequencing techniques identified a homozygous c.1102G>T, resulting in amino acid change D368Y in the adenylation domain of LIG4. Histopathology revealed a distinct absence of Hassall’s corpuscles, lack of cortico-medullary demarcation, as well as lack of T cells and Langerhans histiocytes in the thymic medulla.Conclusion: We have identified a novel mutation in LIG4 resulting in a SCID phenotype. Underdevelopment of the thymus, characterized by a lack of Hassall’s corpuscles and competent thymocytes, likely contributes to the immune defects observed in patients with mutations in LIG4.Statement of novelty: We report here a novel mutation in LIG4 as well as the first description of detailed thymus pathology in this condition.
- OPEN ACCESSBackground: Hoyeraal–Hreidarsson syndrome (HHS) is considered a clinically severe variant of dyskeratosis congenita (DKC) and represents the extreme phenotype caused by aberrant telomere biology. Unlike patients with DKC who present later in life, most cases of HHS present in the first years of life. Clinical features include intrauterine growth restriction and microcephaly, which are universal but not pathognomonic, as well as gastrointestinal, immunological and neurological manifestations. The immunological profile is varied as a result of cellular immunodeficiency, humoral defects, or both, and may be the presenting symptom of these patients. Moreover, the immunological phenotype can change over time, making HHS a diagnostic challenge.Methods: This case report highlights the clinical presentation and immune investigations of a male patient with a novel mutation in DKC1, causing HHS.Results: Here, we describe a patient with HHS who presented with Pneumocystis jiroveci pneumonia and low T cells, which is typical of severe combined immunodeficiency. Over time, he developed agammaglobulinemia whereas T-cell function improved. He also presented with extremely severe gastrointestinal manifestations, and died at 3 years of age.Conclusion: This case report highlights a novel compound heterozygous mutation in DKC1, and the need to consider HHS as the differential diagnosis of patients with combined immunodeficiency.Statement of novelty: The case reports on a novel mutation in DKC1.
- OPEN ACCESSBackground: X-linked severe combined immunodeficiency (SCID) is caused by mutations in the IL2RG gene and classically presents with absent T cells and natural killer (NK) cells. Mutational analysis has contributed to the understanding of this gene.Methods: The primary immunodeficiency (PID) registry was reviewed for patients with SCID with novel IL2RG mutations. The clinical phenotype was assessed using a retrospective chart review.Results: We describe 3 novel mutations in the IL2RG. The first was a guanine to adenine substitution at position 215 (c.215 G > A) in exon 2 leading to a cysteine to tyrosine substitution at position 72 (p.Cys72Tyr), with a typical T− B+ NK− phenotype. The second was a deletion of thymine at position 618 and adenine at position 619 (c.618_619TA) in exon 5, leading to a frameshift at the 206 amino acid (p.His206fs). The phenotype was characterized by a classic SCID presentation and immunophenotyping revealed a low number of absolute lymphocytes with mostly B cells, low levels of immunoglobulins, as well as very low NK cells. Finally, the third mutation was a guanine to cytosine substitution at position 341 (c.341 G > C) in exon 3 leading to a glycine to alanine substitution at position 114 (p.Gly114Ala), presenting with a T+ B+ NK+ phenotype. The presence of T and NK cells in IL2RG are discussed in the context of other mutations allowing for T and NK cells in IL2RG mutations, as well as in the setting of maternal engraftment.Conclusion: To the best of our knowledge we describe 3 novel mutations in the IL2RG gene and the associated phenotypes. These mutations illustrate that these patients can have atypical immunological evaluations.Statement of novelty: To the best of our knowledge, this paper describes 3 novel mutations in the IL2RG gene.
- OPEN ACCESSIntroduction: Heterozygous mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with selective deficiencies to mycobacterial or fungal infections. Recent reports revealed that patients found to carry de novo heterozygous mutations in STAT1 encoding specific amino acid substitutions can go on to develop progressive combined immunodeficiency, distinct from the limited susceptibilities to infection previously reported for heterozygous STAT1 mutations.Objectives: We present a case of a mother and her son with chronic mucocutaneous candidiasis and T-cell dysfunction, both of whom lived longer than projected life expectancy with a heterozygous STAT1 mutation. The son lived to the age of 20 years and the mother to the age of 32 years.Methods: The son's blood sequencing of STAT1 was performed on a pure T-cell lineage at The Hospital for Sick Children and the Canadian Center for Primary Immunodeficiency, Toronto, Ontario.Results: STAT1 analysis revealed a heterozygous DNA binding domain mutation at Thr385Met. The patient proceeded to develop fulminant progressive multifocal leukoencephalopathy that ultimately led to his death. The patient's mother, although never confirmed to have STAT1 mutation with formal blood sequencing, had multiple comorbidities including progressive lymphopenia, hypogammaglobulinemia, recurrent Pseudomonas pneumonias with associated bronchiectasis, end-stage kidney disease requiring hemodialysis, and ultimately death due to multiple end organ failure associated sepsis.Conclusion: This is the first autosomal dominant transmission of the STAT1 DNA binding domain Thr385Met mutation with an extended lifespan.Statement of Novelty: Previous patients found to have heterozygous mutations of STAT1 that were associated with progressive combined immunodeficiency, arose de novo in each case. Presumed autosomal dominant transmission of a heterozygous STAT1 DNA binding domain Thr385Met mutation has not been reported.
- OPEN ACCESS
- Michaela Cada,
- Irene Lara-Corrales,
- Yigal Dror,
- Stephen Feanny,
- Vy Hong-Diep Kim, and
- Eyal Grunebaum
GATA2-associated disorders include: (i) monocytopenia with mycobacterial infections (MonoMAC); (ii) dendritic cell, monocyte, B and NK lymphoid deficiency; (iii) familial myelodysplastic syndrome (MDS) and acute myeloid leukemia; and (iv) congenital deafness with lower limb lymphedema deficiency (Emberger syndrome). Markedly reduced or absent monocytes have been considered as the hallmark of the disease. Here we report on a patient that presented in infancy with hearing loss and lymphedema. By 4 years of age the patient developed acne, disseminated warts, lymphadenopathy, and MDS, yet with increased monocyte as well as normal NK- and B-cell numbers. The patient was found to have a novel mutation in GATA2 that was predicted to disrupt the C-terminal zinc finger. Importantly, and in contrast to common concepts, GATA2-associated syndromes might present with monocytosis.Statement of novelty: We describe a novel mutation in GATA2 associated with monocytosis. - OPEN ACCESSBackground: Hyper IgE syndrome (HIES) is a primary immunodeficiency with sporadic, autosomal dominant (STAT3 mutation) and autosomal recessive (DOCK8 and TYK2 mutations) inheritance patterns. HIES secondary to DOCK8 mutation is characterized by extensive cutaneous viral and staphylococcal infections, recurrent sinopulmonary infections, severe allergic diseases, increased susceptibility to malignancy with lymphopenia, eosinophilia, and elevated immunoglobulin E (IgE). Methods: This case report highlights the clinical presentation and immune investigations of a male patient with a novel DOCK8 mutation. Results: Our patient presented with cutaneous viral infections including severe molluscum contagiosum and herpes simplex virus plus skin abscesses and acute otitis media. In addition to infections, he developed intermittent diarrhea, eczematous lesions, abnormal fingernails, oral ulcers, and Bell's palsy. Immune evaluation revealed lymphopenia, in particular low CD8 cells, low mitogen stimulation response, and poor specific antibody production requiring immunoglobulin replacement. Genetic sequencing confirmed a novel mutation in DOCK8. Conclusion: Patients with significant cutaneous viral and bacterial infections, recurrent sinopulmonary infections, severe allergic diseases, and lymphopenia with associated elevated IgE should be investigated for DOCK8 mutation. This case report highlights a novel mutation in the DOCK8 exon 45 aa1970, c.5908 G>C change alanine to proline homozygous change A1970 to P1970Statement of novelty: This case reports on a novel mutation in DOCK8
- OPEN ACCESS
- Luis Murguia-Favela,
- Vy Hong-Diep Kim,
- Julia Upton,
- Paul Thorner,
- Brenda Reid,
- Adelle Atkinson, and
- Eyal Grunebaum
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency caused by inherited defects in the FOXP3 gene that impair regulatory T cells. IPEX syndrome can be cured by hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD); however, the best conditioning prior to HSCT for IPEX syndrome is not known.Here we report on a patient suffering from IPEX syndrome, including immune-mediated colitis and membranous nephropathy, without polyendocrinopathy, caused by a novel mutation in the Forkhead domain of the FOXP3 gene. The patient's symptoms resolved following MUD HSCT after myeloablative conditioning performed at 16 months of age. The patient is clinically well, 3 years after HSCT, with robust immune reconstitution and fully engrafted. The lack of extensive autoimmune damage might have contributed to the patient's favourable outcome following MUD HSCT with myeloablative conditioning.Statement of novelty: We describe a novel mutation in the FOXP3 gene causing IPEX syndrome and the correction of IPEX syndrome with bone marrow transplant from a HLA-matched unrelated donor following myeloablative conditioning. - OPEN ACCESS
- Amit Nahum and
- Ilan Dalal
Monoallelic mutations in STAT1 are associated with a variety of clinical patterns. We studied patients with novel mutations in the coiled-coil domain of STAT1. We found that clinical manifestations can vary from mild Candida infections limited to the oropharyx to serious serial strokes and skin cancer. Autoimmune manifestations were found to be rare and limited to hypothyroidism. Immune evaluations were normal or near normal in all patients with the exception of anergy to Candida. Mutation in the coiled-coil domain results in susceptibility to mucus membrane candidiasis as well as brain vascular anomalies.Statement of novelty: We describe novel mutations in the coiled-coil domain of STAT1. - OPEN ACCESSIntroduction: Presentation with severe autoimmune manifestations in early infancy is rare, especially when the gut is not involved.Methods: Lymphocyte phenotyping, determination of autoantibodies, and Sanger sequencing were employed to investigate this case.Results: A novel homozygous mutation in CD25 was identified in the patient who presented in the first weeks of life with insulin-dependent diabetes mellitus (IDDM) and subsequently developed autoimmune cytopenia and pulmonary hemorrhage.Conclusion: CD25 deficiency is present in the Gulf (Oman) and cases with early autoimmune manifestations should be tested for this possibility.Statement of novelty: A novel mutation in CD25 leads to an early presentation of IDDM and pulmonary hemorrhage.