ESPE Abstracts

Introduction: Gain-of-function mutations in the STAT-3-Gene are associated with multisystemic autoimmune disease. The spectrum of disorders described in this context is highly variable and includes lymphoproliferative disease and (poly-) autoimmune endocrinopathies.

Case History: A three-year-old boy was admitted with acute liver failure of unknown cause, necessitating a liver transplant. His medical history included congenital hypothyroidism with measurement of a highly elevated TSH in the newborn screening and detection of thyroid-specific autoimmune antibodies that where not of maternal origin. Concurrently, atopic dermatitis and a generalized developmental delay emerged within the first year of life.

Diagnostics: Initial serum TSH elevation of 643 µU/ml in the first week of life prompted immediate L-thyroxine therapy. Transmission of maternal thyroid-autoantibodies was excluded. Allergy specific diagnostics were unremarkable. Autoimmunological investigations and initial genetic analyses (i.a. FOXP3 gene – IPEX-Syndrome) revealed no abnormalities. Despite extensive diagnostic work-up and with only slightly elevated antinuclear antibodies, the etiology of the acute liver failure initially remained unclear. Finally, whole-generation-sequencing revealed a pathogenic de novo missense variant in the STAT-3-gene as the most likely underlying cause of the various autoimmune manifestations seen in the patient.

Conclusion: Autoimmune thyroiditis as a cause of congenital hypothyroidism is extremely rare. The early development of additional autoimmune diseases in this case suggested a genetic predisposition, despite negative family history. In our patient, the detected pathogenic STAT-3 variant has thus far manifested as autoimmune thyroiditis, severe atopic dermatitis and autoimmune hepatitis. While hepatitis has been described in this condition, acute liver failure has not been previously reported. Given the possible fulminant multisystemic effects, close multidisciplinary care and collaboration is necessary to timely recognize and manage autoimmune manifestations in this group of patients.