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).
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.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology