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

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. 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. A retrospective search for all patients diagnosed with PHPIA in two referral centers in Israel was conducted. Nine children (eight females) belonging to six families were included in the study. Five patients had GNAS missense mutations, two had deletions and two 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 PTH 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 standard deviation) and five females had primary or secondary amenorrhea. 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.

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