Endocrine Abstracts

Hypocalcaemia is most commonly caused by hypoparathyroidism, vitamin D deficiency, or renal disease. In young patients with a strong family history and co-existing autoimmune endocrinopathies, autoimmune polyglandular syndrome type 1 (APS-1) is often suspected. APS-1, caused by pathogenic variants in the AIRE gene, classically presents with autoimmune hypoparathyroidism, chronic mucocutaneous candidiasis, and adrenal insufficiency. Autoimmune hypothyroidism and type 1 diabetes can also be associated with APS-1. However, genetic causes of hypocalcaemia can also be present, and distinguishing them is crucial for diagnosis, prognosis, and management. We describe a 57-year-old woman with chronic hypocalcaemia due to childhood-onset hypoparathyroidism. She was diagnosed with type 1 diabetes at the age of 10 and autoimmune hypothyroidism in her 40 s. The coexistence of multiple autoimmune endocrinopathies, combined with a younger sister who also had chronic hypocalcaemia, initially raised suspicion of APS-1. However, genetic testing was negative for pathogenic variants in the AIRE gene. Subsequent genetic testing of the sibling and the index patient revealed a heterozygous activating mutation in the CASR gene, establishing a diagnosis of autosomal dominant hypocalcaemia type 1 (ADH1). ADH1 is a rare, inherited form of non-surgical hypoparathyroidism caused by heterozygous gain-of-function mutations in CASR (Roszko et al., 2022; Roszko et al., 2016). These mutations increase CaSR sensitivity to extracellular calcium, resulting in suppression of parathyroid hormone secretion and enhanced renal calcium excretion. The biochemical hallmark is hypocalcaemia with hyperphosphataemia, low or inappropriately normal PTH, and frequent hypercalciuria (Roszko et al., 2022; Chang et al., 2025; Dershem et al., 2020). Clinical expression is variable: some individuals remain asymptomatic, while others develop neuromuscular irritability, muscle cramps, or seizures. Chronic complications include nephrocalcinosis, nephrolithiasis, renal impairment, and occasionally basal ganglia calcifications (Roszko et al., 2022; Kinoshita et al., 2014). ADH1 is increasingly recognised as a cause of hypoparathyroidism but remains underdiagnosed, as shown by population-based studies (Chang et al., 2025; Dershem et al., 2020). Management is challenging: conventional treatment with calcium and calcitriol may exacerbate hypercalciuria and renal complications, so therapy aims to maintain calcium at the lowest level that prevents symptoms. Thiazide diuretics can reduce urinary calcium, and calcilytics (CaSR antagonists) are under investigation but are not yet in routine use (Roszko et al., 2016; Gafni et al., 2019). This case highlights a diagnostic pitfall, where coexisting autoimmune endocrinopathies initially suggested APS-1 but genetic confirmation revealed ADH1. Importantly, ADH1 and APS-1 require different counselling and management strategies. This underscores the importance of considering genetic causes of hypocalcaemia, even in the presence of autoimmune conditions, and of incorporating CASR mutation analysis into the diagnostic pathway for familial hypocalcaemia.