Neonatalsevere hyperparathyroidism (NSHPT) is a rare, life-threatening disorder caused by biallelic inactivation of the CASR gene, resulting in severe hypercalcemia and markedly elevated parathyroid hormone (PTH) levels in early life. Although total parathyroidectomy is often curative, long-term calcium balance and treatment requirements remain poorly understood. We describe the 25-year follow-up of a woman with NSHPT due to a homozygous CASR p.Arg680His variant who underwent total parathyroidectomy with autotransplantation at 32 days of age. Despite initial normalization of calcium levels, graft failure led to permanent hypoparathyroidism requiring long-term calcium and active vitamin D supplementation. Over time, calcium and calcitriol requirements progressively decreased despite persistently undetectable PTH, with recurrent episodes of hypercalcemia requiring careful dose adjustments. This case represents one of the longest documented follow-ups of genetically confirmed homozygous CASR-related NSHPT. The progressive decline in calcium requirements reflects impaired renal calcium excretion and an altered calcium-PTH set point characteristic of CASR inactivation. These physiological adaptations challenge the conventional supplementation strategies and suggest that standard hypoparathyroidism guidelines - largely derived from acquired or autoimmune forms - may require cautious individualization in patients with homozygous CASR variants, given their distinct renal calcium handling and the possibility of lower urinary calcium excretion. Our findings reinforce the complexity of long-term management in NSHPT patients and illustrates how calcium requirements may change over time. Long-term follow-up cases such as this may contribute to a better understanding of the physiological mechanisms and inform future guideline development for this rare condition.
Meira et al. (Fri,) studied this question.