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  • OPEN ACCESS
    A novel mutation in TRAC in a patient with abnormal newborn screening for severe combined immunodeficiency
    LymphoSign Journal • Vol. 9 • No. 1 • pp. 5 - 10
    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
    Novel mutation in PIK3CD affecting the Ras-binding domain
    LymphoSign Journal • Vol. 9 • No. 1 • pp. 11 - 16
    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 ACCESS
    Case report of a novel mutation in Bruton’s tyrosine kinase gene with confirmed agammaglobulinemia and absent B lymphocytes
    LymphoSign Journal • Vol. 9 • No. 1 • pp. 1 - 4
    Background: 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 ACCESS
    Wiskott-Aldrich syndrome caused by a novel mutation in the WAS gene and presenting with a mild phenotype
    LymphoSign Journal • Vol. 8 • No. 3 • pp. 94 - 98
    Background: 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 ACCESS
    Chronic mucocutaneous Candidiasis caused by a novel STAT1 mutation: a report of 4 patients
    LymphoSign Journal • Vol. 8 • No. 2 • pp. 64 - 67
    Background: 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
    A novel splice site variant in FOXN1 in a patient with abnormal newborn screening for severe combined immunodeficiency and congenital lymphopenia
    LymphoSign Journal • Vol. 8 • No. 1 • pp. 1 - 4
    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 ACCESS
    Identification of a novel RAG1 hypomorphic mutation in a child presenting with disseminated vaccine-strain varicella
    LymphoSign Journal • Vol. 8 • No. 1 • pp. 5 - 10
    Background: 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 ACCESS
    Novel mutations in the CYBB gene causing X-linked chronic granulomatous disease: a case report of 2 patients
    LymphoSign Journal • Vol. 7 • No. 2 • pp. 61 - 65
    Introduction: 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 ACCESS
    Novel heterozygous PIK3CD mutation presenting with only laboratory markers of combined immunodeficiency
    LymphoSign Journal • Vol. 7 • No. 2 • pp. 49 - 55
    Introduction: 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 ACCESS
    An atypical presentation of ataxia telangiectasia in a school-aged boy secondary to an intronic mutation
    LymphoSign Journal • Vol. 7 • No. 2 • pp. 57 - 60
    Background: 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.
  • OPEN ACCESS
    Positive newborn screen: a case of a novel variant in DCLRE1C in a patient with SCID
    LymphoSign Journal • Vol. 7 • No. 1 • pp. 46 - 48
    Background: Artemis enzyme, encoded by the DCLRE1C gene, is essential to V(D)J recombination in both T and B lymphocytes. Artemis functions as an important component of the nonhomologous end-joining DNA double-strand break repair pathway. Artemis deficiency leads to a T-B-NK+ severe combined immune deficiency (SCID) associated with radiosensitivity.Clinical presentation: We present a case of a positive newborn screen for SCID in a patient who was subsequently shown to have a T-B-NK+ phenotype. Further immune evaluation showed profound T and B lymphopenia, near-absent response to mitogen stimulation, and absent immunoglobulins A and M. Genetic investigation demonstrated a novel and putative pathogenic variant in the DCLRE1C gene.Conclusion: This case identifies a novel variant in the DCLRE1C gene in a patient with SCID identified by newborn screening.Statement of novelty: This case report identifies a novel variant in the DCLRE1C gene in a patient with T-B-NK+ SCID.
  • OPEN ACCESS
    Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy
    LymphoSign Journal • Vol. 6 • No. 2 • pp. 61 - 67
    Background: 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 ACCESS
    Interleukin-2 receptor common gamma chain (IL2RG) defects present a diagnostic challenge
    LymphoSign Journal • Vol. 5 • No. 4 • pp. 130 - 134
    Background: 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 ACCESS
    A novel homozygous mutation in CIITA resulting in MHC Class II deficiency in an adult patient
    LymphoSign Journal • Vol. 5 • No. 4 • pp. 135 - 140
    Introduction: 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 ACCESS
    Leukocyte adhesion deficiency-I caused by a novel mutation in ITGB2 presenting with pyoderma gangrenosum
    LymphoSign Journal • Vol. 5 • No. 3 • pp. 86 - 90
    Background: 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
    The novel p.Gly306Asp perforin mutation causes familial hemophagocytic lymphohistiocytosis type 2 (FHL-2) probably due to a critical role of Gly306 in the pore-forming perforin domain
    LymphoSign Journal • Vol. 4 • No. 3 • pp. 101 - 112
    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
    Interstitial lung disease in infancy: an unusual presentation of CD40 ligand deficiency
    LymphoSign Journal • Vol. 4 • No. 2 • pp. 63 - 69
    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
    CD40 deficiency: a unique adult patient with hyper immunoglobulin M syndrome and normal expression of CD40
    LymphoSign Journal • Vol. 4 • No. 2 • pp. 70 - 76
    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.
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    A novel mutation in LIG4 in an infant presenting with severe combined immunodeficiency with thymic medullary dysplasia
    LymphoSign Journal • Vol. 4 • No. 1 • pp. 31 - 41
    Background: 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 ACCESS
    Immunodeficiency and severe gastrointestinal manifestations in a patient with novel DKC1 mutations causing Hoyeraal–Hreidarsson syndrome
    LymphoSign Journal • Vol. 3 • No. 3 • pp. 119 - 126
    Background: 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.
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