Clinical spectrum and long-term follow-up of non-surgical hypoparathyroidism with novel AIRE and GATA3 variants from India.

PURPOSE: Non-surgical hypoparathyroidism is a rare endocrine disorder associated with substantial long-term morbidity, with limited data from low- and middle-income countries. MATERIALS AND METHODS: This single-centre ambispective observational cohort study included 27 patients with non-surgical hypoparathyroidism evaluated at a University Hospital between 2013 and 2025. Clinical manifestations, biochemical parameters, treatment requirements, complications, and outcomes were prospectively recorded. Patients with syndromic features underwent whole-exome sequencing. RESULTS: The median age at presentation was 16 years (range 1-60), with a mean follow-up of 6.9 ± 2.9 years. Neuromuscular manifestations of hypocalcaemia were the most frequent presenting features. Severe hypocalcaemia was observed in 23(85.2%) of patients, with inappropriately low parathyroid hormone levels in all cases. Conventional therapy significantly improved mean serum calcium concentrations to 7.95 ± 0.59 mg/dL. Basal ganglia calcification was detected in 15(55.6%), cataracts in 7 (25.9%), QT prolongation in 5(18.5%), and nephrocalcinosis in 4(14.8%). Four patients had syndromic hypoparathyroidism. Genetic analysis identified a novel homozygous splice-site variant in AIRE (c.308-1G > C), a novel frameshift heterozygous AIRE variant (c.758_771del; p.Lys253SerfsTer13), and a novel heterozygous frameshift duplication in GATA3 (c.159dup; p.Asp54Argfs*250). Calcium dose correlated positively with 24-hour urinary calcium excretion (ρ = 0.59, p = 0.002) and nephrocalcinosis (ρ = 0.45, p = 0.018). CONCLUSION: Non-surgical hypoparathyroidism is associated with significant long-term neurological and renal complications. Renal morbidity is primarily related to treatment intensity and hypercalciuria, whereas extra-renal manifestations appear independent of urinary calcium losses. Identification of novel AIRE and GATA3 mutations expanded the genetic spectrum of syndromic hypoparathyroidism in Indian patients.