Renal and systemic complications in autosomal dominant hypocalcemia type 1: a case series from North East England

Abstract

Abstract Context Autosomal dominant hypocalcemia type 1 (ADH1) is a rare genetic disorder caused by activating CASR variants, characterized by hypocalcemia, low/normal parathyroid hormone, and hypercalciuria. While managed with conservative calcium targets to prevent renal damage, the long-term systemic burden remains poorly defined. Objective To describe a case series of adults with genetically confirmed AHD1. Methods We reviewed 9 adults with genetically confirmed ADH1 in North East England (2005-2024). Clinical, biochemical, and imaging data were retrospectively analyzed from electronic records. Pathogenic CASR variants were identified via accredited genomic panels. Results The cohort (n = 9; 5 female; age 24-57) was 89% familial, with all exhibiting persistent hypocalcemia and 66% presenting with hypomagnesemia. Renal involvement affected 78%, including nephrocalcinosis (56%), nephrolithiasis (67%), and chronic kidney disease (CKD), with 2 patients from 1 kindred progressing to kidney failure (KF) and death. Extrarenal features included seizures, intracranial calcifications, dental abnormalities, and neuropsychiatric symptoms, often persisting despite conservative strategies to limit calcium supplementation post diagnosis. No clear correlation was found between mean serum calcium levels and disease severity, highlighting substantial phenotypic variability. Conclusion ADH1 is a multisystem disorder with substantial morbidity, including nephrocalcinosis, CKD, and a risk of KF despite cautious management. Other significant features include hypocalcemic seizures and intracranial calcification. These findings emphasize the necessity of early genetic diagnosis, family screening, and longitudinal renal surveillance. The high complication burden under conventional therapy underscores the need for targeted treatments, such as CaSR antagonists (calcilytics), to improve long-term outcomes.