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Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants.

ABSTRACT: Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.

SUBMITTER: Totsune E

PROVIDER: S-EPMC8072023 | biostudies-literature |

REPOSITORIES: biostudies-literature

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2019-09-02 | PXD011355 | Pride

Various phenotypes of <i>LRBA</i> gene with compound heterozygous variation: A case series report of pediatric cytopenia patients.

Project description:ObjectiveLPS-responsive beige-like anchor (LRBA) deficiency is one of the most common monogenic disorders causing common variable immunodeficiency (CVID) and CVID-like disorders. However, the clinical spectrum of compound heterozygous (CHZ) LRBA variation should be extended. In this study, we presented five cases of compound heterozygous LRBA with various refractory cytopenias.Materials and methodsRetrospective analysis of the clinical manifestations, management, and outcomes of five cases (from five pedigrees) with LRBA gene CHZ variants which initially manifested as single/multilineage immune cytopenias was performed.Results1. Gene variations: All five patients inherited the compound heterozygous LRBA variations from their parents which were thought to be pathogenic. BEACH, DUF4704, and LamG were the main affected domains of LRBA gene in this case series. 2. Immune dysregulation of clinic: (1) Hypogammaglobulinemia were recorded in four patients, and the proportion of Treg was decreased in two patients. Only one patient had been with increased TCRαβ+CD4/CD8 double-negative T cells (DNT). (2) Lymphoproliferative manifestations were seen in three patients. (3) All five patients were complained with cytopenia, although they showed different clinical manifestations. None of the parents was asymptomatic. (4) Other immune disorders: P5 also had relapsed infections and autoimmune endocrinopathy. 3. Management and outcomes: P1 and P5 responded well to immunomodulatory therapy and P3 was effectively treated with hemophagocytic lymphohistiocytosis (HLH) first-line regimen chemotherapy. P4 showed no responses to steroids and IVIG. However, TPO-R agonist was effective.ConclusionUnlike homozygous mutations, compound heterozygous LRBA variation should always be kept in mind for the various phenotypes and different treatment responses.

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