ESPE Yearbook of Paediatric Endocrinology (2018) 15 2.12 | DOI: 10.1530/ey.15.2.12

Recessively Inherited LRBA Mutations Cause Autoimmunity Presenting as Neonatal Diabetes

Johnson MB, De Franco E, Lango Allen H, Al Senani A, Elbarbary N, Siklar Z, Berberoglu M, Imane Z, Haghighi A, Razavi Z, Ullah I, Alyaarubi , Gardner D, Ellard S, Hattersley AT, Flanagan SE

To read the full abstract: Diabetes 2017 Aug;66(8):2316-2322

Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized early-onset hypogammaglobulinemia, severe autoimmune manifestations, enteropathy, lymphoproliferation, and recurrent respiratory tract infections. Neonatal diabetes mellitus (NDM) has not been previously described in patients with LRBA mutations. In this study, the proband was diagnosed at 7 weeks of age with diabetes and additional autoimmunity and 3 other patients presented before 6 months of age. The other patients had diabetes onset between 6 and 12 months. Only 1 patient was positive for GAD antibody of those that were tested. However these patients had other autoimmune conditions including hematological manifestations, autoimmune enteropathy, and hypothyroidism. Identifying the underlying genetic etiology is clinically important for these patients as understanding the disease mechanism may allow the use of personalized therapy.

Abatacept, a CTLA-4 mimetic that replaces the action of the lost suppressive receptor, has been used to treat patients with LRBA mutations and all showed improvement in their autoimmune features. However it has not been used to treat patients with LBRA mutations and diabetes yet. Interestingly LRBA-deficient mice do not manifest features of diabetes mellitus. This study suggests that mutations in LRBA are a relatively common etiology of neonatal or infancy-onset diabetes when patients have additional early-onset autoimmune disease and are born to consanguineous parents. Testing for LRBA mutations should be considered in all patients with newly diagnosed neonatal diabetes and in those with infancy-onset diabetes (<12 months), especially when a recessive inheritance is suspected or additional autoimmune features are present. A genetic diagnosis is critical not only for counseling on recurrence risk but also for allowing immunomodulatory agents such as abatacept to be considered as part of the treatment regimen. This study increases the total number of genetic causes of neonatal diabetes to 25, and the genetic causes of severe early-onset autoimmunity that includes neonatal diabetes to 4; the others being FOXP3, IL2RA, and STAT3.