The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency

Abstract

This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.

Recessively InheritedLRBAMutations Cause Autoimmunity Presenting as Neonatal Diabetes

“…For example patient 3 presented with neonatal diabetes (diagnosed at 4 months) and has immunodeficiency, autoimmune lymphoproliferative disease, hepatosplenomegaly, lymphocytic interstitial pneumonia and recurrent chest infections diagnosed before the age of 8 years, whereas patient 7 was diagnosed with diabetes at the age of 10 months and has coeliac disease, pernicious anaemia and subclinical hypothyroidism at the age of 26 years (see table 1). The variable phenotype of patients with homozygous missense mutations seen in previous studies was not statistically different from those with protein truncating mutations; the age of onset of the first symptom is similar in both groups (median age of onset; missense mutations: 1.75 years versus nonsense mutations: 2 years, p = 0.79) (1,5,7,8,11). It therefore seems likely that additional genetic and/or environmental factors influence the severity of the disease and the specific organs affected in these patients.…”

“…(CVID-8, MIM #614700)(7) which often includes early-onset autoimmunity, immune dysregulation, recurrent infections and hypogammaglobinaemia with variable penetrance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)27). Neonatal diabetes had not been confirmed as a feature of this disorder.…”

“…Abatacept, a CTLA-4 mimetic that replaces the action of the lost suppressive receptor, has been used to treat 12 patients with LRBA mutations so far and all showed improvement in their autoimmune features (1,5). Therapy with abatacept had not been attempted in our patients at the time of reporting.…”

“…Rarely, a mutation in a single gene is the aetiological cause and the identification of the underlying monogenic defect can give important insights into mechanisms of beta-cell autoimmunity and pathways of immune tolerance (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Due to significant clinical overlap, discriminating patients with causative mutations in a single gene from those with a polygenic aetiology remains a challenge.…”

Old and new faces of neutropenia in children

“…40 Other mutations may either generate deficiency of the suppressing T-cell molecule CTLA-4, 41 or impair its exposure on the cell membrane because of the deficiency of another anchor protein named LRBA (LPSResponsive beige-like anchor protein deficiency). 42 These immune dysregulation diseases have a heterogeneous clinical phenotype which may include neutropenia. For these reasons children with atypical AIN, due to late onset, late recovery and involvement of additional cell lineage over time, require extensive immunological workup, including the evaluation of lymphocyte subsets with double negative T-cells and immunoglobulin serum level measurement.…”