The efficiency of cinacalcet treatment in delaying parathyroidectomy in a case with neonatal severe hyperparathyroidism caused by homozygous mutation in the CASR gene

**Background:** Neonatal severe primary hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder caused by loss-of-function mutations in the calcium-sensing receptor (CASR) gene. It presents shortly after birth with marked hypercalcemia, elevated parathyroid hormone (PTH), and hyperparathyroid bone disease. Without treatment, NSHPT can be fatal. Standard medical management includes hydration, bisphosphonates, calcitonin, and calcium restriction, but these are often insufficient. Cinacalcet, a type II calcimimetic that acts as a positive allosteric activator of CASR, has been used off-label in pediatric NSHPT cases, though its efficacy may depend on the specific CASR genotype.

**Methods:** The authors report a 6-day-old full-term male infant (birth weight 3600 g) born to consanguineous parents (third-degree relatives) who presented with poor feeding and was found to have a serum calcium of 23.7 mg/dL (reference 9–11 mg/dL) and PTH of 1120 ng/dL (reference 11–88 ng/dL). Initial treatment included hydration and pamidronate (1 mg/kg/dose, two doses within 48 hours), which was ineffective (calcium remained at 19.2 mg/dL). On day 3 of follow-up, cinacalcet was started at 20 mg/m²/day along with a calcium-poor formula (basic-CaD, 35 mg Ca/100 g). Serum calcium normalized to 9.7 mg/dL by day 6 of treatment. The patient was discharged after 2 weeks with normal calcium (10.3 mg/dL) on cinacalcet 20 mg/m²/day, vitamin D 400 IU/day, and calcium-restricted formula. Genetic analysis revealed a homozygous NM_001178065.2(CASR):c.222_226delGATAT (p.Met74IlefsTer24) frameshift deletion, classified as likely pathogenic per ACMG 2015 guidelines. A second homozygous variant (c.740C>T, p.Ser247Phe) was classified as a variant of unknown significance.

**Key Results:** The patient maintained normocalcemia on cinacalcet and calcium restriction through monthly follow-up until 13 months of age. At 13 months, milk and dairy products were added to the diet (250 mg calcium/day). One week later, serum calcium was 9.8 mg/dL, but by the second week it rose to 21.3 mg/dL. Cinacalcet was gradually increased to 85 mg/m²/day but failed to control hypercalcemia. Total parathyroidectomy without autotransplantation was performed at 17 months of age. Histopathology showed all four parathyroid glands slightly larger than normal, poor in fat, with evident clear cells and essential cells, consistent with NSHPT. At age 2 years, the patient maintained normal calcium, phosphate, and alkaline phosphatase on calcitriol (0.05 µg/kg/day) and calcium supplements (75 mg/kg/day), and had achieved appropriate neuromotor milestones. No side effects (vomiting or diarrhea) were observed during cinacalcet therapy. Mild nephrocalcinosis (millimeter-sized echogenicity in medullary pyramids) developed during follow-up.

**Clinical Implications:** This case demonstrates that a homozygous CASR mutation (c.222_226delGATAT) previously reported as unresponsive to cinacalcet can still show a clinically meaningful response, delaying parathyroidectomy from 45 days (as in a prior case with the same mutation) to 17 months. The authors emphasize that factors beyond genotype may influence cinacalcet response, and an empirical trial of cinacalcet should be considered in all NSHPT patients regardless of mutation type. Cinacalcet may serve as a bridge therapy to delay parathyroidectomy until the infant is older and surgery is safer, though sustained long-term response is not guaranteed.