Background
Cutaneous manifestations of dedicator of cytokinesis 8 gene (DOCK8) deficiency, a combined type of T and B cell immunodeficiency, previously designated as autosomal recessive hyper IgE ...syndrome, includes dermatitis and skin infections. There are limited treatment options for dermatitis related to the syndrome.
Objective
To describe a cohort of patients with DOCK8 deficiency with a focus on the treatment of their cutaneous manifestations.
Methods
A retrospective study on all children with the genetic diagnosis of DOCK8 deficiency treated at the Sheba Medical Center between 1/1/2003 and 1/1/2021 was preformed. Collected data included: demographic features, family history, laboratory, genetic testing, skin manifestations, treatment, and disease course. Description of two cases of severe recalcitrant dermatitis treated with dupilumab is detailed.
Results
Nine children with a genetic diagnosis of DOCK8 deficiency were included, of whom six were girls (66%) with a median age of 8.5 (±2.2 SD) years. The median age at diagnosis was 2.8 (±2.6 SD) years. Six patients were born to consanguineous parents. Five out of six patients who received hematopoietic stem cell transplantation (HSCT) had a complete response, and one was recently transplanted. Of note, two patients, while awaiting HSCT, were treated with dupilumab for their severe dermatitis resulting in a marked improvement of the cutaneous manifestations and pruritus.
Conclusions
Hematopoietic stem cell transplantation is the gold standard and most effective therapy for patients with DOCK8 deficiency. Dupilumab, a biological therapy indicated for atopic dermatitis and other Th2 derived dermatoses, is an excellent option for dermatitis in patients with DOCK8 deficiency and can be used as a bridge before HSCT. Larger studies are needed to confirm this observation.
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
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
ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of
is restricted to hematopoietic cells, potentially explaining why a mutation in
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.
MALT1 (mucosa-associated lymphoid tissue lymphoma-translocation gene 1) is an intracellular signaling protein that activates NFκB and is crucial for both the adaptive and innate immune responses. ...Only 6 patients with immune deficiencies secondary to inherited mutations in the
MALT1
gene have been described.
Purpose
To provide clinical and immunological insights from 2 patients diagnosed with MALT1 immunodeficiency syndrome due to a novel
MALT1
mutation.
Methods
Two cousins with suspected combined immunodeficiency underwent immunological and genetic work-up, including lymphocyte phenotyping, lymphocyte activation by mitogen stimulation, and next-generation sequencing (NGS) of T cell receptor gamma chain (TRG) repertoire. Whole exome sequencing was performed to identify the underlying genetic defect.
Results
Clinical findings included recurrent infections, failure to thrive, lymphadenopathy, dermatitis, and autoimmunity. Immune work-up revealed lymphocytosis, low to normal levels of immunoglobulins, absence of regulatory T cells, and low Th17 cells. A normal proliferative response was induced by phytohemagglutinin and IL-2 but was diminished with anti-CD3. TRG repertoire was diverse with a clonal expansion pattern. Genetic analysis identified a novel autosomal recessive homozygous c.1799T>A; p. I600N missense mutation in
MALT1
. MALT1 protein expression was markedly reduced, and in vitro IL-2 production and NFκB signaling pathway were significantly impaired.
Conclusions
Two patients harboring a novel
MALT1
mutation presented with signs of immune deficiency and dysregulation and were found to have an abnormal T cell receptor repertoire. These findings reinforce the link between MALT1 deficiency and combined immunodeficiency. Early diagnosis is crucial, and curative treatment by hematopoietic stem cell transplantation may be warranted.
Introduction
Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive ...mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations.
Methods
Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed.
Results
Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel.
Conclusions
Consanguineous marriages account for a genetic “founder effect.” SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.
The T cell receptor (TCR) signaling pathway is an ensemble of numerous proteins that are crucial for an adequate immune response. Disruption of any protein involved in this pathway leads to severe ...immunodeficiency and unfavorable clinical outcomes. Here, we describe an infant with severe immunodeficiency who was found to have novel biallelic mutations in SLP76. SLP76 is a key protein involved in TCR signaling and in other hematopoietic pathways. Previous studies of this protein were performed using Jurkat-derived human leukemic T cell lines and SLP76-deficient mice. Our current study links this gene, for the first time, to a human immunodeficiency characterized by early-onset life-threatening infections, combined T and B cell immunodeficiency, severe neutrophil defects, and impaired platelet aggregation. Hereby, we characterized aspects of the patient's immune phenotype, modeled them with an SLP76-deficient Jurkat-derived T cell line, and rescued some consequences using ectopic expression of wild-type SLP76. Understanding human diseases due to SLP76 deficiency is helpful in explaining the mixed T cell and neutrophil defects, providing a guide for exploring human SLP76 biology.
Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots ...obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both
and
deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries.
Background
The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic ...reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature.
Methods
Two patients with neutropenia underwent hematological, immunological, and genetic work‐up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole‐exome sequencing, and in silico proteomic analysis.
Results
Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life‐threatening infection requiring leg amputation. Immunological and hematological work‐up showed isolated neutropenia with normal lymphocyte subpopulations, immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in‐frame deletion in the SRP54 gene, c.342‐344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability.
Conclusions
We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene.
Signal transducer and activator of transcription (STAT)1 heterozygous gain‐of‐function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous ...reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In‐depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non‐consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58–24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole‐exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon‐α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin‐17‐producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.
Signal transducer and activator of transcription (STAT)1 gain‐of‐function (GOF) mutations are known to induce immune dysregulation. Immune phenotyping of these patients presenting with Demodex infection is lacking. Here, we summarize an in‐depth immune analysis of 5 patients with STAT1 GOF from 2 non‐consanguineous families presenting with chronic demodicosis. Thus, management of chronic demodicosis should include the evaluation of an underlying primary immune deficiency disorder.
Purpose
RAS guanyl-releasing protein 1 (RASGRP1) deficiency has recently been shown to cause a primary immunodeficiency (PID) characterized by CD4
+
T cell lymphopenia and Epstein-Barr virus ...(EBV)-associated B cell lymphoma. Our report of three novel patients widens the scope of RASGRP1 deficiency by providing new clinical and immunological insights on autoimmunity, immune cell development, and predisposition to lymphoproliferative disease.
Methods
One patient of Turkish origin (P1) and two Palestinian patients (P2, P3) were evaluated for immunodeficiency. To decipher the molecular cause of disease, whole exome sequencing was conducted. Identified mutations were validated by immunological and biochemical assays.
Results
We report three patients presenting with similar clinical characteristics of immunodeficiency and EBV-associated lymphoproliferative disease. In addition, P2 and P3 exhibited overt autoimmune manifestations. Genetic screening identified two novel loss-of-function mutations in
RASGRP1
. Immunoblotting and active Ras pull-down assays confirmed perturbed ERK1/2 signaling and reduced Ras-GTPase activity in heterologous Jurkat cells with ectopic expression of RASGRP1 mutants. All three patients had CD4
+
T cell lymphopenia. P2 and P3 showed decreased mitogen-induced lymphocyte proliferation, reduced T cell receptor excision circles, abnormal T cell receptor (TCR) Vβ repertoires, and increased frequencies of TCRγδ cells. TCR gamma repertoire diversity was significantly reduced with a remarkable clonal expansion.
Conclusions
RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies. Early diagnosis is critical and hematopoietic stem cell transplantation might be considered as curative treatment.
Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an ...R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far.
A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect.
WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient's serum, compared to controls.
A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.
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