Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants

Purpose: The main purpose of this study was to provide a comprehensive characterization of adult patients with Autosomal Dominant Hypocalcemia type 1 (ADH1), focusing on clinical and biochemical features, with particular attention to renal involvement, skeletal features and ectopic calcifications. The secondary aims were to explore potential genotype-phenotype correlations, describe two previously unreported CASR variants, and report pregnancy outcomes in affected women. Methods: We conducted a retrospective, single-centre study of 11 adults with genetically confirmed ADH1 followed at a tertiary Endocrinology Unit between March 2012 and May 2025. Clinical presentation, biochemical data, renal and cerebral involvement, skeletal status and treatment history were collected at first evaluation and during follow-up. CASR variants were identified by next-generation sequencing with Sanger confirmation, and genotype-phenotype relationships were explored. Results: At diagnosis, 64% of patients reported hypocalcemia-related symptoms, while 36% were asymptomatic. Nephrolithiasis, nephrocalcinosis and basal ganglia calcifications were frequent, in patients exposed to long-term calcium and active vitamin D therapy, although causal relationships cannot be established. Axial BMD was normal or increased, whereas radial BMD was often reduced and bone turnover markers were low-normal; no fragility fractures were documented. We identified two novels CASR missense variants and observed marked intra- and interfamilial variability. Four pregnancies in three women with ADH1 resulted in favourable maternal and neonatal outcomes. Conclusions: In our ADH1 patients we found a wide clinical variability, from asymptomatic hypocalcemia to severe early-onset disease, with a high burden of renal complications and ectopic calcifications. Genotype alone does not fully predict clinical severity, even for the same CASR variant. Pregnancies can have good outcomes under close biochemical monitoring and tailored therapy but should be managed as high-risk.