ESPE Abstracts (2015) 84 P-1-150

ESPE2015 Poster Presentations Poster Category 1 Miscelleaneous (22 abstracts)

Severe Immunodysregulation Phenotypes Including Infancy-Onset Type 1 Diabetes Mellitus in Two Siblings with a Homozygous Mutation in the LPS-Responsive Beige-Like Anchor (LRBA) Gene

Felix Schreiner a , Michaela Plamper a , Gesche Düker b , Stefan Schoenberger c , Janine Altmueller d , Alina Hilger e , Heiko Reutter e & Joachim Woelfle a

aPediatric Endocrinology, Children’s Hospital, University of Bonn, Bonn, Germany, bPediatric Gastroenterology and Hepatology, Children’s Hospital, University of Bonn, Bonn, Germany, cPediatric Hematology and Oncology, Children’s Hospital, University of Bonn, Bonn, Germany, dCologne Center for Genomics, University of Cologne, Cologne, Germany, eInstitute for Human Genetics, University of Bonn, Bonn, Germany

Background: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against the pancreatic beta-cell. Although a significant number of T1DM patients develop further autoimmune disorders during lifetime, coexisting severe immunodysregulation is rare.

Objective and hypotheses: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM in two siblings born to consanguineous parents, we performed whole exome sequencing (WES).

Method: WES.

Results: Patients 1 and 2 are born to consanguineous Libyan parents. In patient 1, T1DM was diagnosed at age 2 years. From early infancy the girl suffered from recurrent pneumonic infections, merging into severe chronic restrictive lung disease, resembling lymphocytic interstitial pneumonia. FACS analysis revealed B-cell deficiency, going along with decreased IgG levels. CD4+/CD25+ and CD25high/FoxP3+ cells were diminished, while an unusual CD25/FoxP3+ population was detectable. In addition, she presented with short stature (<-4 SDS), GH-deficiency and mild symptoms of enteropathy. Her younger brother (patient 2) also suffers from infancy-onset T1DM. He has no history of respiratory problems but chronic diarrhea since infancy, leading to severe electrolyte disturbance and growth failure. Another sibling, who was diagnosed to have T-cell deficiency and Evans-syndrome, died before the family immigrated to Europe. By WES and filtering for autosomal-recessive disease-genes, we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the LPS-responsive beige-like anchor (LRBA)-gene in both patients. LRBA-mutations have previously been reported to cause autoimmunity and immunodysfunction presumably due to alteration of Treg cell function and, very recently, have been identified in two patients with IPEX-like syndromes.

Conclusion: We identified a homozygous truncating LRBA-mutation in two siblings with T1DM and severe immunodysregulation disease. 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 linked to altered Treg-cell function.

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