ABSTRACT
BACKGROUND: Hyperimmunoglobulin E syndrome (HIES) constitutes a group of rare primary immunodeficiency disorders. The diagnosis relies on the National Institutes of Health (NIH) scoring system, incorporating clinical and laboratory data. Scores≥15 raise a strong suspicion of the disease. In an isolated Israeli population, Zinc Finger (ZNF)341 deficiency, a subtype of HIES, has a carrier incidence of 1:20, but the prevalence of the clinical syndrome within this community remains unknown. OBJECTIVE: This study seeks to estimate the prevalence of potentially undiagnosed HIES cases within this population by utilizing the NIH scoring criteria. METHODS: This retrospective cohort study obtained requisite clinical and laboratory data for NIH score computation from the electronic medical records of Clalit Health Services for the isolated village under scrutiny in comparison to a neighboring village. Subsequently, clinical scores were assigned to each subject, enabling comparative analysis of suspected diagnosis rates between the two populations. RESULTS: Among the 29,390 studied subjects, 12 had a documented diagnosis of HIES. All were in the study village, and none were from the control village (0.08% vs. 0%, p<0.01). Within the study village, 235 individuals (1.62%) had an NIH score≥15 and were suspected to suffer from HIES almost doubled compared to the control group 130 (0.87%) (p<0.001). CONCLUSION: This is the first time the NIH clinical score system has been used for population screening. The significant disparity in the prevalence of suspected, undiagnosed cases between the study village and the control village strongly suggests the potential utility of this tool for preliminary screening.
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BACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting.
Subject(s)
Lipopolysaccharides , Toll-Like Receptor 4 , Humans , Cytokines/metabolism , Lipopolysaccharides/pharmacology , Lymphocyte Antigen 96/metabolism , Signal Transduction , Toll-Like Receptor 4/genetics , Toll-Like Receptors/metabolismABSTRACT
Introduction: Hyper IgE syndromes (HIES) are a group of rare primary immunodeficiency characterized by high levels of serum IgE, cold abscesses, pulmonary infections, and eczema. ZNF341 deficiency was described in 2018 in 11 patients clinically diagnosed previously with HIES. Eight of those patients, all offspring of consanguineous couples, are from three families who live in a Muslim village in Israel which has approximately 15,000 residents. Objective: Our study aimed to evaluate the prevalence of ZNF341 mutation in the population of the village. Methods: Three hundred DNA samples of females were included in the study. The samples belong to females that were referred to the Meir Medical Center for prenatal genetic testing before pregnancy, during 2017-2019: 200 samples were from the village, and 100 samples of Muslim females were from other villages.All samples were tested by Sanger sequencing for the ZNF341 mutation (c.904C>T, NM_001282933.1). Results: Heterozygous nonsense mutation in ZNF341 was found in ten samples (5%) of the study group compared to zero in the control group (p<0.01). Conclusion: The carrier frequency of the mutation in ZNF341 in the studied village population is 1:20. This high frequency is probably due to founder mutation and consanguineous marriages.
Subject(s)
Job Syndrome/epidemiology , Job Syndrome/genetics , Transcription Factors/genetics , Carrier State , Codon, Nonsense , Eczema , Female , Humans , Immunoglobulin E/immunology , Islam , Israel/epidemiology , Job Syndrome/immunology , Population , Transcription Factors/deficiencyABSTRACT
Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features. Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants. Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis. Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients. Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.
Subject(s)
Dermatitis, Atopic , Eczema , Job Syndrome , STAT3 Transcription Factor , Adult , Humans , Male , Abscess , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/genetics , Job Syndrome/diagnosis , Job Syndrome/genetics , Job Syndrome/therapy , Retrospective Studies , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , FemaleABSTRACT
BACKGROUND: Traditionally, most children diagnosed with Henoch-Schonlein Purpura (HSP) were hospitalized. This policy gradually changed towards selective hospitalization, yet there are still no criteria for admitting pediatric patients with HSP. OBJECTIVES: To examine the clinical features and criteria for hospitalization of pediatric patients with HSP. METHODS: A retrospective analysis was conducted of medical records of pediatric patients with HSP examined in the emergency department (ED) of Schneider Children's Medical Center, during 2005-2015. We compared children who were admitted with those not admitted to the hospital. RESULTS: During the study period, 116 children diagnosed with HSP were examined in the ED of Schneider Children's Medical Center: 14(12%) were admitted at first referral, and 22 (19%) of the children were hospitalized subsequently. The average age of all the children with HSP was 7.4 years, 57% were boys, and approximately 10% of the children had additional diseases, most of them auto-inflammatory. The main indications for hospitalization were gastrointestinal involvement (abdominal pain or bleeding), renal involvement (hematuria or proteinuria), and inability to walk. Most of these symptoms were also present in the children who were not admitted. CONCLUSIONS: Approximately 30% of the children were admitted to the hospital, most of them not at first referral. No clear criteria for admission were found, except for gastrointestinal bleeding.
Subject(s)
IgA Vasculitis , Child , Hospitalization , Humans , IgA Vasculitis/diagnosis , IgA Vasculitis/epidemiology , Male , Proteinuria , Retrospective StudiesABSTRACT
Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.
Subject(s)
Ichthyosiform Erythroderma, Congenital/epidemiology , Ichthyosiform Erythroderma, Congenital/genetics , Cohort Studies , Genotype , Humans , Middle East/epidemiology , Molecular Epidemiology , Mutation , PhenotypeSubject(s)
Asthma/history , Medical Errors/history , Famous Persons , History, Medieval , Humans , Physicians/historyABSTRACT
Myeloperoxidase (MPO) is an enzyme expressed mostly by neutrophils and is a primary mediator of neutrophils oxidative stress response. While a profound body of evidence associates neutrophil-derived MPO in the pathogenesis of Alzheimer's disease (AD), this role has not been assessed in an animal model of AD. Here, we produced hematologic chimerism in the 5XFAD mouse model of AD, with MPO deficient mice, resulting in 5XFAD with hematologic MPO deficiency (5XFAD-MPO KO). Behavioral examinations of 5XFAD-MPO KO showed significant superior performance in spatial learning and memory, associative learning, and anxiety/risk assessment behavior, as compared to 5XFAD mice transplanted with WT cells (5XFAD-WT). Hippocampal immunohistochemical and mRNA expression analyses showed significantly reduced levels of inflammatory mediators in 5XFAD-MPO KO mice with no apparent differences in the numbers of amyloid-ß plaques. In addition, immunoblotting and mRNA analyses showed significantly reduced levels of APOE in 5XFAD-MPO KO. Together, these results indicate a substantial involvement of neutrophil-derived MPO in the pathology of 5XFAD model of AD and suggest MPO as a potential therapeutic target in AD.
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INTRODUCTION: In 1966, Davis et al. coined the term "Job Syndrome", reporting on a new pediatric immunodeficiency disease characterized by "cold" staphylococcal abscesses. This term is widely used in association with several immunodeficiencies with very high levels of IgE, which are also known as "Hyperimmunoglobulin E Syndromes". The assumed similarity between the biblical disease of Job and the "new" immunodeficiency was probably due to the King James' classical translation of the Bible (in 1611), wherein the disease of Job (biblically termed as "Shin") was translated as "boils". However, the biblical word "Shin" is a general term for skin disease or dermatitis, and according to the Talmud, there are 24 different skin diseases called "Shin". New scientific data states that hyper-IgE syndromes are genetic and not acquired (as was in the biblical disease of Job). Therefore, in view of the stigma associated with the name and story of Job, it is recommended to abandon the name of "Job syndrome" and refer to the immune disorders by their genetic source, such as "STAT 3 disease" or "DOCK 8 disease".
Subject(s)
Immunologic Deficiency Syndromes , Job Syndrome , Child , HumansABSTRACT
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Autoimmune polyendocrine syndrome type-1 (APS-1) (APECED, OMIM 240300) is a rare, childhood onset, monogenic disease caused by mutations in the Autoimmune Regulator (AIRE) gene. The overall mortality is increased compared to the general population and a major cause of death includes malignant diseases, especially oral and esophageal cancers. We here present a case series of four APS-1 patients with oral tongue cancers, an entity not described in detail previously. Scrutiny of history and clinical phenotypes indicate that chronic mucocutaneous candidiasis and smoking are significant risk factors. Preventive measures and early diagnosis are important to successfully manage this potentially fatal disease.
ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
Subject(s)
Immunocompetence/genetics , Job Syndrome/genetics , STAT3 Transcription Factor/genetics , Th17 Cells/immunology , Transcription Factors/genetics , Adolescent , Adult , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Nucleus/metabolism , Child , Codon, Nonsense , Consanguinity , Exons/genetics , Female , Genes, Recessive/genetics , Genes, Recessive/immunology , Humans , Immunoglobulin E/blood , Immunoglobulin E/immunology , Infant , Job Syndrome/blood , Job Syndrome/immunology , Male , Pedigree , Promoter Regions, Genetic/genetics , STAT3 Transcription Factor/immunology , Th17 Cells/metabolism , Transcription Factors/immunology , Transcription Factors/metabolism , Young Adult , Zinc Fingers/geneticsABSTRACT
Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott-Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.
Subject(s)
Actin-Related Protein 2-3 Complex/genetics , Blood Platelets/pathology , Frameshift Mutation , Immunologic Deficiency Syndromes/genetics , Lymphopoiesis/genetics , T-Lymphocytes/pathology , Thrombopoiesis/genetics , Actin Cytoskeleton/metabolism , Actin-Related Protein 2-3 Complex/deficiency , Actin-Related Protein 2-3 Complex/metabolism , Actin-Related Protein 2-3 Complex/physiology , Child, Preschool , Codon, Nonsense , Consanguinity , Fatal Outcome , Humans , Infant , Male , Multiprotein Complexes , Pedigree , Polymerization , V(D)J Recombination , Wiskott-Aldrich Syndrome/genetics , Zebrafish Proteins/deficiency , Zebrafish Proteins/geneticsABSTRACT
BACKGROUND: Several studies link the pathogenesis of nephrotic syndrome to tumor necrosis factor-alpha (TNFα). However, data on the serum TNFα level in children with nephrotic syndrome are sparse. OBJECTIVES: To investigate serum TNFα levels and the effect of steroid therapy in children with nephrotic syndrome. METHODS: A prospective cohort pilot study of children with nephrotic syndrome and controls was conducted during a 1 year period. Serum TNFα levels were measured at presentation and at remission, or after a minimum of 80 days if remission was not achieved. RESULTS: Thirteen patients aged 2-16 years with nephrotic syndrome were compared with 12 control subjects. Seven patients had steroid-sensitive and six had steroid-resistant nephrotic syndrome. Mean baseline serum TNFα level was significantly higher in the steroid-resistant nephrotic syndrome patients than the controls (6.13 pg/ml vs. 4.36 pg/ml, P = 0.0483). Mean post-treatment TNFα level was significantly higher in the steroid-resistant than in the steroid-sensitive nephrotic syndrome patients (5.67 pg/ml vs. 2.14 pg/ml, P = 0.001). In the steroid-resistant nephrotic syndrome patients, mean serum TNFα levels were similar before and after treatment. CONCLUSIONS: Elevated serum TNFα levels are associated with a lack of response to corticosteroids. Further studies are needed to investigate the role of TNFα in the pathogenesis of nephrotic syndrome.
Subject(s)
Nephrotic Syndrome/blood , Tumor Necrosis Factor-alpha/blood , Adolescent , Case-Control Studies , Child , Cohort Studies , Drug Resistance , Female , Glucocorticoids/therapeutic use , Humans , Male , Nephrotic Syndrome/drug therapy , Pilot Projects , Remission InductionABSTRACT
Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor ß1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.
Subject(s)
Autoimmune Diseases/genetics , Autoimmunity/genetics , Interleukin-12 Receptor beta 1 Subunit/deficiency , Photosensitivity Disorders/genetics , Autoimmune Diseases/diagnosis , Biopsy , Child , Humans , Lung/pathology , Male , Photosensitivity Disorders/diagnosis , Tomography, X-Ray ComputedABSTRACT
Hereditary angioedema (HAE) may manifest with swelling of the face, extremities, and upper airways. Gastrointestinal symptoms are also common and may include abdominal pain, vomiting, and diarrhea. However, pancreatic involvement is rare and has been reported only in a few adults with previously diagnosed HAE. We describe a 6-year-old boy who presented with recurrent severe abdominal pain accompanied by an elevation in pancreatic enzyme levels, without subcutaneous or cutaneous angioedema. His symptoms had begun 18 months earlier, and he was hospitalized several times before the present admission with a diagnosis of acute pancreatitis. More comprehensive analysis yielded low levels of C2, C4, CH50, and C1 esterase inhibitor, establishing the diagnosis of HAE. One year after diagnosis, swelling of the extremities appeared for the first time. This is the first report of a child in whom pancreatic disease was the presenting symptom of HAE. HAE should be included in the differential diagnosis of recurrent pancreatitis in children.
Subject(s)
Angioedemas, Hereditary/diagnosis , Pancreatitis/etiology , Acute Disease , Angioedemas, Hereditary/complications , Child , Humans , Male , RecurrenceABSTRACT
BACKGROUND: Nonbullous erythema multiforme (NBEM) is an acute, immune-mediated, self-limiting skin disease with distinctive target lesions. Its pathogenesis is unclear, but most cases are considered to be infection related or drug related. In adults, the main precipitating factor is infection. This study reviewed a 10-year experience with hospitalized children with NBEM in a tertiary pediatric medical center in Israel with a focus on precipitating factors. METHODS: The medical files of all children hospitalized from 2001 to 2011 with the diagnosis of NBEM were reviewed. RESULTS: Ninety-seven patients (55 boys and 42 girls) met the inclusion criteria. The mean age was 4.0 years. At least one precipitating factor was recognized in 72 cases; the remainders were classified as idiopathic. The most common factor was drugs (n = 45), particularly penicillin (n = 30), followed by infection with various pathogens (n = 27) including Epstein-Barr virus (7), group A Streptococcus (n = 6), Mycoplasma pneumoniae (n = 5) and herpes simplex virus (n = 4). Analysis according to age showed that medication was the most common precipitating factor in the first year of life, and infection was as common as drugs in the older age groups (1-18 years). CONCLUSIONS: Unlike adult NBEM, the majority of pediatric NBEM is associated with medications, especially penicillin. This may be due to the frequent use of antibiotics in children.
Subject(s)
Erythema Multiforme/etiology , Adolescent , Child , Child, Hospitalized , Child, Preschool , Drug Eruptions/etiology , Erythema Multiforme/diagnosis , Female , Humans , Infant , Israel , Male , Retrospective Studies , Risk Factors , Surveys and QuestionnairesABSTRACT
Primary varicella infection may be associated with neurologic complications, such as cerebritis and meningoencephalitis. Several cases of varicella infection with elevated intracranial pressure have been reported. We describe a 13-year-old immunocompetent girl who presented with a clinical picture of headaches and elevated intracranial pressure as the only manifestation of primary varicella zoster infection. The working diagnosis at first was pseudotumor cerebri based on complaints of headache of 2 weeks' duration, in addition to vomiting and papilledema, without fever or skin eruption. On lumbar puncture, opening pressure was 420 mmH2O, but mild pleocytosis and mildly elevated protein level ruled out the diagnosis of pseudotumor cerebri. Our patient had no history of previous varicella infection, and she did not receive the varicella zoster vaccine. Serology tests, done on admission and repeated 2 months later, suggested primary varicella infection. The literature on varicella infection associated with pseudotumor cerebri or elevated intracranial pressure is reviewed.
Subject(s)
Chickenpox/complications , Chickenpox/diagnosis , Headache/virology , Herpesvirus 3, Human/immunology , Intracranial Hypertension/virology , Adolescent , Chickenpox/physiopathology , Diagnosis, Differential , Female , Headache/diagnosis , Herpesvirus 3, Human/pathogenicity , Humans , Intracranial Hypertension/physiopathology , Papilledema/physiopathology , Papilledema/virology , Pseudotumor Cerebri/complications , Pseudotumor Cerebri/diagnosis , Spinal PunctureSubject(s)
Anaphylaxis/prevention & control , Drug Hypersensitivity/diagnosis , Lactose/metabolism , Methylprednisolone Hemisuccinate/metabolism , Milk Hypersensitivity/diagnosis , Administration, Oral , Adolescent , Allergens/immunology , Anaphylaxis/etiology , Child , Child, Preschool , Drug Hypersensitivity/complications , Female , Humans , Immunization , Immunoglobulin E/blood , Lactose/immunology , Male , Methylprednisolone Hemisuccinate/adverse effects , Methylprednisolone Hemisuccinate/immunology , Milk Hypersensitivity/complications , Pharmaceutical Preparations/metabolism , Prospective Studies , Skin TestsABSTRACT
BACKGROUND: Comèl-Netherton syndrome is a rare congenital autosomal recessive disorder characterized by congenital ichthyosis, hair shaft abnormalities and atopic diathesis. It is caused by mutations in SPINK5, which encodes the serine protease inhibitor LEKTI. OBJECTIVES: To delineate the spectrum of mutations carried by a series of Israeli patients in an attempt to establish an effective diagnostic strategy for this disease in Israel. METHODS: Mutations were identified by direct sequencing of the entire coding sequence of SPINK5 and confirmed using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Three mutations were identified in seven families, of which two were novel. All mutations were predicted to result in premature termination of protein translation. CONCLUSIONS: This report presents the first case series of patients affected with Comèl-Netherton syndrome in Israel and suggests that some mutations reoccur in a substantial portion of cases in our country, a fact that should be taken into consideration when designing molecular analysis in new cases.
Subject(s)
Family , Mutation , Netherton Syndrome/genetics , Proteinase Inhibitory Proteins, Secretory/genetics , Adolescent , Adult , Child , Child, Preschool , Dermatitis, Atopic/genetics , Frameshift Mutation , Genetic Markers/genetics , Hair/abnormalities , Humans , Ichthyosis/genetics , Infant , Israel , Jews/genetics , Netherton Syndrome/diagnosis , Pedigree , Protein Biosynthesis/genetics , Serine Peptidase Inhibitor Kazal-Type 5 , Serine Proteinase Inhibitors/genetics , Severity of Illness IndexABSTRACT
BACKGROUND AND PURPOSE: Autosomal dominant Hyper IgE syndrome (AD-HIES) is a rare and complex primary immunodeficiency that affects multiple systems. Mutations in signal transducer and activator of transcription 3 (STAT3) gene cause AD-HIES. These mutations have a dominant-negative effect and the presence of such mutations is associated with a clinical phenotype. We aim to describe genetic and clinical characteristics of patients with AD-HIES in our clinic and to highlight the variability of clinical patterns in the same family. METHODS: We describe six patients, four individuals of the same family and two unrelated patients. All patients were given a clinical score based on disease phenotype according to the National Institute of Health (NIH) score. Mutation analysis of STAT3 was done by PCR amplification of all coding exons followed by bidirectional sequencing using the BigDye kit v1.1 and an ABI3700 genetic analyzer (Applied Biosystems). RESULTS: All six patients had DNA binding region point mutations: a proband and his three children with p.Phe384Leu mutation, a patient with p.Arg382Trp substitution and a patient with p.Arg382Gln mutation. All of these mutations were previously reported. Patients differed in infectious, immunologic and somatic features. We observed an extreme variability in disease phenotype within the reported family with one genetically affected patient displaying an 'unaffected' phenotype. CONCLUSIONS: Although the genetic cause of AD-HIES is known, more studies are required to better understand the possible additional factors that may affect disease expressivity within families and the clinical diversity of the disease.