Clinical and Molecular Characteristics and Long-term Follow-up of Children With Pseudohypoparathyroidism Type IA

• Published in: The journal of clinical endocrinology and metabolism Vol. 109; no. 2; pp. 424 - 438
• Main Authors: Ludar, Hanna, Levy-Shraga, Yael, Admoni, Osnat, Majdoub, Hussein, Aronovitch, Kineret Mazor, Koren, Ilana, Rath, Shoshana, Elias-assad, Ghadir, Almashanu, Shlomo, Mantovani, Giovanna, Hamiel, Orit Pinhas, Tenenbaum-Rakover, Yardena
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.02.2024
• Subjects: Adult; Age; Amenorrhea; Body height; Child; Child, Preschool; Chromogranins - genetics; Congenital diseases; Congenital Hypothyroidism; Disease resistance; Female; Follow-Up Studies; Frameshift mutation; Genetic aspects; Genetic disorders; GTP-Binding Protein alpha Subunits, Gs - genetics; Health aspects; Humans; Hypocalcemia; Hypothyroidism; Infant, Newborn; Intellectual disabilities; Medical research; Medicine, Experimental; Mental illness; Missense mutation; Mutation; Neonates; Obesity; Osteodystrophy; Parathyroid hormone; Phenotypes; Pseudohypoparathyroidism; Pseudohypoparathyroidism - diagnosis; Pseudohypoparathyroidism - genetics; Retrospective Studies; Thyroid hormones; Israel; pseudohypoparathyroidism; PHP; Albright hereditary osteodystrophy AHO; hypothyroidism; hypocalcemia; gene; GNAS gene
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgad524

Abstract Context Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis. Objective The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes. Methods A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted. Results Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean −2.5 SD) and 5 females had primary or secondary amenorrhea. Conclusion Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation.