title: Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation.
abstract: BACKGROUND
  Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare.
  
  
  OBJECTIVE
  Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing.
  
  
  METHODS
  Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4(+)/CD25(+) and CD25(high)/FoxP3(+) cells were diminished, whereas an unusual CD25(-)/FoxP3(+) population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges.
  
  
  RESULTS
  By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells.
  
  
  CONCLUSIONS
  We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schreiner
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Plamper
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Gesche
authors.initials: G
authors.lastname: Dueker
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schoenberger
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Gámez-Díaz
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Gohlke
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.affiliation: Pediatric Endocrinology (F.S., M.P., B.Go., J.W.), Pediatric Gastroenterology and Hepatology (G.D.), and Pediatric Hematology and Oncology (S.S.), Children's Hospital, University of Bonn, 53113 Bonn, Germany; Center for Chronic Immunodeficiency (L.G.-D., B.Gr.), University Medical Center and University of Freiburg, 79085 Freiburg, Germany; Institute for Human Genetics (A.C.H., H.R.), University of Bonn, 53113 Bonn, Germany; and Department of Neonatology and Pediatric Intensive Care (H.R.), Children's Hospital, University of Bonn, 53113 Bonn, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Woelfle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001827:Body Height; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006130:Growth Disorders / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C428703:LRBA protein, human