Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation

CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency

“…5 By contrast, LATAIE disease shows nearly complete penetrance, with only 1 clinically healthy LRBA mutation-positive individual reported. 11 Despite near universal penetrance, the severity of LATAIE disease varies substantially, even within individual kindreds.…”

“…11 These mutations may retain residual LRBA function and/or protein expression leading to a milder phenotype.…”

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.…”

“…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.…”