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

Abstract

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.