Endocrine Abstracts

Introduction: Autoimmune hypothyroidism (AIH) associated with thyroid peroxidase antibodies (TPOAb) is a common cause of thyroid dysfunction. Disease etiology includes genetic predisposition (e.g., HLA-DR3, thyroid genes) and environmental triggers (e.g., iodine). AIH usually manifests during young adulthood and rarely under three years of age. Early-onset AIH may arise from monogenic disorders (e.g., STAT3, AIRE) with severe symptoms like immunodeficiency or endocrinopathies. STAT3 is a transcription factor involved in cell differentiation, proliferation, and immunosuppression. Gain-of-function mutations in STAT3 are associated with a spectrum of early-onset autoimmune disorders.

Case report: A six-year old boy (1A) of Finnish origin presented with primary AIH since 16 months of age. His birth at 30+6 weeks was premature and prompted by C-section due to abnormal heart sounds. Newborn screening for congenital hypothyroidism was normal. At 16 months, he showed growth retardation, underdeveloped motor skills, constipation, and loss of appetite. AIH was diagnosed with TSH at 700 mU/l (reference: 0.5-4.5), fT4 < 1.3 pmol/l (reference: 12-22), and TPOAb > 1542 IU/ml (reference: <25) and thyroxine treatment was initiated. Medication improved his symptoms. At one year- nine months, he was treated with acyclovir for shingles (varicella-zoster infection). At two years- seven months, he had recurrent rashes that tested Staphylococcus positive. Standard thyroxine dosage was continued. Patient 1A’s sister (1B) was born at week 37+1. Her newborn TSH screening was normal. At five months of age, she was diagnosed with AIH (TSH- 200mU/l, fT4- 5.9 pmol/l, TPOAb- 522IU/ml), having constipation, weak appetite, sleepiness, and slight growth retardation. Thyroxine medication improved her conditions. Hitherto there are no other major autoimmune manifestations in the siblings. Whole exome-sequencing revealed a known heterozygous STAT3 (c.2147C>T, p.Thr716Met) mutation in patients 1A, 1B and their mother. The mother had HLA-B27-negative juvenile idiopathic arthritis, prolonged leukocytosis and multiple dermatofibromas. No other known pathogenic variant in thyroid-specific or autoimmune genes were identified.

Conclusion: We report two siblings with very early-onset AIH carrying a pathogenic STAT3 _p.Thr716Met variant. Symptoms of AIH have been managed effectively with thyroxine treatment and they have not presented any other autoimmune manifestations. Given that they are young, there is possibility of developing additional autoimmune diseases with age. For new severe conditions, novel therapies could be tested, based on reports of effective treatment in STAT3 gain-of-function patients with Jakinib and IL-6 inhibitors. Hence, genetic testing of AIH should be considered in children under three years of age to aid in early diagnosis and personalized disease management.