title: Case report of GNAS epigenetic defect revealed by a congenital hypothyroidism.
abstract: Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy, and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly, and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease.
authors: Assistance Publique Hôpitaux de Marseille, Hôpital la Conception, Laboratory of Molecular Biology, Marseille, France; Aix Marseille Université, CNRS, CRN2M-UMR 7286, Marseille, France;
authors: Pauline
authors: P
authors: Romanet
authors: Assistance Publique Hôpitaux de Marseille, Hôpital La Timone Enfant, Departments of Pediatrics, Marseille, France;
authors: Lindsay
authors: L
authors: Osei
authors: Institut National de la Santé et de la Recherche Médicale, Centre de Recherche Saint-Antoine, UMR_S 938, Paris, France; and Sorbonne Universités, Paris, France.
authors: Irène
authors: I
authors: Netchine
authors: Assistance Publique Hôpitaux de Marseille, Hôpital la Conception, Laboratory of Molecular Biology, Marseille, France;
authors: Morgane
authors: M
authors: Pertuit
authors: Assistance Publique Hôpitaux de Marseille, Hôpital la Conception, Laboratory of Molecular Biology, Marseille, France; Aix Marseille Université, CNRS, CRN2M-UMR 7286, Marseille, France;
authors: Alain
authors: A
authors: Enjalbert
authors: Aix Marseille Université, CNRS, CRN2M-UMR 7286, Marseille, France; Assistance Publique Hôpitaux de Marseille, Hôpital La Timone Enfant, Departments of Pediatrics, Marseille, France;
authors: Rachel
authors: R
authors: Reynaud
authors: Assistance Publique Hôpitaux de Marseille, Hôpital la Conception, Laboratory of Molecular Biology, Marseille, France; Aix Marseille Université, CNRS, CRN2M-UMR 7286, Marseille, France; anne.barlier@univ-amu.fr.
authors: Anne
authors: A
authors: Barlier
mesh_terms: D002864:Chromogranins; D003409:Congenital Hypothyroidism / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D015997:Neonatal Screening; D011547:Pseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: GNAS; TSH resistance; congenital hypothyroidism; epigenetic; imprinting disorder; pseudohypoparathyroidism type 1B