Sare Betul Kaygusuz1, Esra Arslan Ates2, Maria Lillina Vignola3, Burcu Volkan4, Bilgen Bilge Geckinli2, Serap Turan1, Abdullah Bereket1, Carles Gaston-Massuet3, Tulay Guran1. 1. Department of Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Turkey. 2. Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Turkey. 3. Centre for Endocrinology, William Harvey Research Institute, Barts & The London Medical School, Queen Mary, University of London, Charterhouse Square, London, United Kingdom. 4. Department of Pediatric Gastroenterology, Marmara University School of Medicine, Istanbul, Turkey.
Abstract
CONTEXT: Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development. OBJECTIVE: To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects. RESULTS: We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. CONCLUSIONS: Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.
CONTEXT: Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extra-pituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The Forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut and pancreatic development. OBJECTIVE: To characterize two patients with syndromic hypopituitarism due to FOXA2 gene defects. RESULTS: We report a novel heterozygous nonsense c.616C>T (p.Q206X) variant, which leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the GLUT2-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 megabase (Mb) deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. CONCLUSIONS: Our two cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.