Long-term calcium management in **Neonatal Severe Hyperparathyroidism** (NSHPT) requires individualization due to altered renal handling

Neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening genetic disorder characterized by severe hypercalcemia and elevated parathyroid hormone (PTH) in infants. It stems from biallelic inactivation of the CASR gene, which encodes the calcium-sensing receptor. While total parathyroidectomy often cures the initial hypercalcemia, the long-term management of calcium balance and supplementation needs post-surgery remains poorly understood. Current hypoparathyroidism guidelines, largely based on acquired forms, may not adequately address the unique physiological adaptations in NSHPT patients, particularly concerning renal calcium handling.

This study presents a 25-year follow-up of a single female patient diagnosed with NSHPT due to a homozygous CASR p.Arg680His variant. She underwent total parathyroidectomy with autotransplantation at 32 days of age. Following initial normalization, graft failure led to permanent hypoparathyroidism, necessitating long-term calcium and active vitamin D supplementation. The researchers meticulously tracked her calcium and calcitriol requirements, PTH levels, and episodes of hypercalcemia over the 25-year period to understand the long-term calcium balance and treatment needs.

Over the 25-year follow-up, the patient's calcium and calcitriol requirements progressively decreased, despite persistently undetectable PTH levels. This decline was punctuated by recurrent episodes of hypercalcemia, necessitating careful dose adjustments of supplementation. The findings suggest impaired renal calcium excretion and an altered calcium-PTH set point, characteristic of CASR inactivation, as underlying physiological adaptations. These adaptations challenge conventional supplementation strategies, indicating that standard hypoparathyroidism guidelines, typically derived from acquired or autoimmune forms, may not be appropriate for patients with homozygous CASR variants. This case reinforces the complexity of long-term management in NSHPT patients.

This case represents one of the longest documented follow-ups of genetically confirmed homozygous CASR-related NSHPT, revealing a unique trajectory of calcium management.