Long-Term Clinical Course of Hypoparathyroidism and Pseudohypoparathyroidism in Children and Adolescents: Retrospective Observational Cohort Study

Hypoparathyroidism and pseudohypoparathyroidism (PHP/iPPSD) are rare pediatric disorders of parathyroid hormone deficiency or resistance, with limited longitudinal outcome data after childhood presentation. We assessed presentation, treatment exposure, biochemical control, genotype-phenotype associations, and renal outcomes in a single-center cohort. We retrospectively studied 120 children and adolescents managed from 2003 to 2025. Diagnoses were based on clinical, biochemical, and genetic findings. Treatment used active vitamin D analogs (aVD), dietary calcium optimization, and limited long-term oral calcium supplementation. Longitudinal biochemical control was assessed using time-weighted averages (TWA); renal outcomes were assessed by ultrasonography and estimated glomerular filtration rate. Eighty patients had hypoparathyroidism, with 754 patient-years of follow-up. GCM2, CASR variants and Sanjad-Sakati syndrome presented earliest, whereas AIRE variants and gene-negative cases presented later. Nephrocalcinosis occurred in 23/80 (28.8%) and was associated with severe genotypes, younger age at diagnosis, lower TWA-adjusted calcium, more time below target, higher TWA urine calcium/creatinine, and higher aVD dose/kg. eGFR was generally preserved, and three patients had resolution of nephrocalcinosis. Hypoparathyroidism resolved in 11/26 (42%) patients with 22q11.2 deletion, especially when diagnosed in infancy. Median TWA-adjusted calcium was 2.12 mmol/L (IQR 2.03-2.21), with 63% of time in target; TWA calcium-phosphate product in patients aged ≥12 years was 3.52 mmol2/L2 (3.11-3.98; target <4.4). Forty patients had PHP/iPPSD, with 429 patient-years of follow-up. PHP1A/iPPSD2 presented earlier than PHP1B/iPPSD3, while epigenetic PHP1B/iPPSD3 often overlapped clinically with PHP1A-like features. No nephrocalcinosis was seen in 19 imaged patients. Median TWA-adjusted calcium was 2.21 mmol/L (2.16-2.26), with 92% of time within the acceptable range. In childhood-onset hypoparathyroidism, genotype and age at diagnosis influenced renal risk, while 22q11.2 deletion had a milder, often resolving course. PHP/iPPSD showed favorable renal safety. aVD with dietary counseling supported sustained biochemical control with limited long-term oral calcium use.