Variability of endocrine findings with age and clinical severity in the long-term follow-up of pseudohypoparathyroidism: evidence of TRH resistance with central hypothyroidism.

BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare disorder with clinical and genetic heterogeneity, resulting from inactivating variants or epigenetic alterations of the GNAS locus. OBJECTIVE: To characterize the natural course of PHP, focusing on rarely defined endocrine features. METHODS: Nineteen children (11 girls) from 17 families from a single center, diagnosed with PHP from 1992 to 2025, were enrolled. Genetic/epigenetic analyses, age at onset, and evidence of hormone resistance, radiologic findings, and long-term follow-up of anthropometric measurements were retrospectively reviewed, and cases were classified according to clinical and genetic features as PHP1A, PHP1B, or PPHP. RESULTS: The study group consisted of children with PHP1A (n=10), PHP1B (n=8), and PPHP (n=1). PHP1A cases harbored six different GNAS point mutations, one of which was novel. PHP1Bs exhibited GNAS methylation abnormalities. Except for one PHP1A case, all PHP1A/1Bs displayed PTH resistance, which developed earlier in PHP1A (6 years vs 11.2 years). All PHP1A and 5 PHP1B cases had clinical or subclinical hypothyroidism. One PHP1A and two PHP1B cases had low free T4 with inappropriately normal TSH, suggesting central hypothyroidism due to presumed TRH resistance. Clinical signs of gonadal dysfunction were observed in four of six girls with PHP1A. Skeletal features of AHO were present in 7 PHP1A and 3 PHP1B patients. Intellectual disability was identified in 50% of PHP1A. Phenotypic variability was noted among subjects with the same mutation. CONCLUSION: Overlapping PHP1A and PHP1B features may complicate differential diagnosis, necessitating molecular genetic analysis. The pattern and severity of endocrine involvement, including possible central hypothyroidism, vary widely among affected children.