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Development of multiple gallstones in a child with lipopolysaccharide-responsive beige-like anchor protein mutation.

ABSTRACT: A defect in the lipopolysaccharide-responsive beige-like anchor protein (LRBA) gene is a newly defined rare cause of primary immunodeficiency diseases, which manifests as immune dysregulation and humoral immune deficiency. LRBA deficiency is a combined immunodeficiency. A boy with LRBA deficiency is described in this report. He had been diagnosed with Evans syndrome in a haematology clinic. He was referred to an immunology and allergy clinic for frequent respiratory tract infections. He also had hepatosplenomegaly but no lymphadenopathy. Immunological evaluation revealed hypogammaglobulinaemia, increased double-negative T cells, decreased memory B cells and switched B cells, and an inverted CD4/CD8 ratio. LRBA deficiency was considered due to common variable immunodeficiency-autoimmune lymphoproliferative overlap syndrome. A homozygote mutation (c.1964C>T) in LRBA was found through exome sequencing. Gastrointestinal investigation was performed due to unexplained abdominal pain. It revealed atrophic gastritis, partial villous atrophy, and multiple gallstones. There was no chronic diarrhoea or failure to thrive. The abdominal pain disappeared after a cholecystectomy. Multiple gallstones have not been reported in other LRBA-deficient patients who also had autoimmune haemolytic anaemia. Multiple gallstones that require cholecystectomy can develop in LRBA-deficient patients during adolescence.

SUBMITTER: Kutlug S

PROVIDER: S-EPMC6925566 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Development of multiple gallstones in a child with lipopolysaccharide-responsive beige-like anchor protein mutation.

Kutluǧ Şeyhan Ş Boztuǧ Kaan K Yıldıran Alişan A

Central-European journal of immunology 20190930 3

A defect in the lipopolysaccharide-responsive beige-like anchor protein (LRBA) gene is a newly defined rare cause of primary immunodeficiency diseases, which manifests as immune dysregulation and humoral immune deficiency. LRBA deficiency is a combined immunodeficiency. A boy with LRBA deficiency is described in this report. He had been diagnosed with Evans syndrome in a haematology clinic. He was referred to an immunology and allergy clinic for frequent respiratory tract infections. He also had ...[more]

PMID: 31871423

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Project description:BackgroundPatients with lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency have a variety of clinical symptoms, but there is no apparent genotype-phenotype correlation, and patients carrying the same mutations may have different phenotypes. Therefore, it is not easy for doctors to make a decision regarding hematopoietic stem cell transplantation (HSCT) for LRBA-deficient patients. We hypothesized that there may be a protein-phenotype correlation to indicate HSCT for LRBA-deficient patients.AimTo report on three Chinese LRBA-deficient patients and determine the correlation between residual protein expression and disease phenotypes.MethodsClinical data of three Chinese LRBA-deficient patients were collected, and protein levels were detected by Western blot analysis. In addition, LRBA mutation information of another 83 previously reported patients was summarized.ResultsAll the major clinical findings indicated enteropathy, but patients 1 and 3 presented with more severe symptoms than patient 2. Endoscopy and histology indicated nonspecific colitis for patients 1 and 3 but Crohn's disease-like colitis for patient 2. Compound heterozygous mutations in LRBA were found in patient 1, and homozygous mutations in LRBA were found in patient 2 and patient 3. Only patient 2 responded well to traditional immunosuppressive treatment. Residual expression of the LRBA protein in patients 1 and 3 was very low, but in patient 2, a more than 0.5-fold in expression of the LRBA protein was found compared to that in the control. After HSCT, patient 1 had increased LRBA protein expression. We summarized the genetic information of 86 patients, and the mutations in patients 1 and 3 were novel mutations.ConclusionWe described three Chinese LRBA-deficient patients, two of whom carried novel mutations. These patients had no genotype-phenotype correlations, but their residual LRBA protein expression might be associated with disease outcome and could be an indicator for HSCT.

Project description:Monogenic primary immunodeficiency syndromes can affect one or more endocrine organs by autoimmunity during childhood. Clinical manifestations include type 1 diabetes mellitus, hypothyroidism, adrenal insufficiency, and vitiligo. Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA) deficiency was described in 2012 as a novel primary immunodeficiency, predominantly causing immune dysregulation and early onset enteropathy. We describe the heterogeneous clinical course of LRBA deficiency in two siblings, mimicking an autoimmune polyendocrine disorder in one of them in presence of the same underlying genetic mutation. The third child of consanguineous Egyptian parents (Patient 1) presented at 6 months of age with intractable enteropathy and failure to thrive. Later on, he developed symptoms of adrenal insufficiency, autoimmune hemolytic anemia, thrombocytopenia, and infectious complications due to immunosuppressive treatment. The severe enteropathy was non-responsive to the standard treatment and led to death at the age of 22 years. His younger sister (Patient 2) presented at the age of 12 to the endocrinology department with decompensated hypothyroidism, perioral vitiligo, delayed pubertal development, and growth failure without enteropathy and immunodeficiency. Using whole exome sequencing, we identified a homozygous frameshift mutation (c.6862delT, p.Y2288MfsX29) in the LRBA gene in both siblings. To our knowledge, our patient (Patient 2) is the first case of LRBA deficiency described with predominant endocrine phenotype without immunodeficiency and enteropathy. LRBA deficiency should be considered as underlying disease in pediatric patients presenting with autoimmune endocrine symptoms. The same genetic mutation can manifest with a broad phenotypic spectrum without genotype-phenotype correlation. The awareness for disease symptoms among non-immunologists might be a key to early diagnosis. Further functional studies in LRBA deficiency are necessary to provide detailed information on the origin of autoimmunity in order to develop reliable predictive biomarkers for affected patients.

Dataset Information

Development of multiple gallstones in a child with lipopolysaccharide-responsive beige-like anchor protein mutation.

Publications

Development of multiple gallstones in a child with lipopolysaccharide-responsive beige-like anchor protein mutation.

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