RF30 | PSAT178 Severe Hyperparathyroidism in a Newborn: Response to Cinacalcet

Abstract

Abstract Background Neonatal severe hyperparathyroidism (NSHPT) is a rare potentially lethal disorder caused by inactivating mutations in the calcium sensing receptor (CASR) gene. In newborns it presents with multiple bone fractures often confused with forms of osteogenesis imperfecta. Diagnostic and therapeutic experience with this condition is limited, hence here we describe a term baby we identified and treated with this disorder. Case Description A 39-week-old Hispanic female, born small for gestational age (BW 2.38 kg) via vaginal delivery to a 33-year-old G3P2 healthy mother was noted to have relative asymmetry of the thighs/hips. X-rays revealed bone demineralization and multiple fractures including distal femur and proximal tibia bilaterally and rib fractures in various stages of healing. Initially, osteogenesis imperfecta was thought likely and Endocrinology was consulted. Laboratories showed hypercalcemia (calcium 12.1 mg/dL (normal 8.5-11.2), elevated serum PTH 439 pg/mL (12-72). Serum phosphorus (4.2 mg/dL), 25-OH Vitamin D (44 ng/mL) and alkaline phosphatase (232 IU/L) were normal; urine calcium/creatinine ratio was low (0.006 mg/mg). EKG showed non-specific T wave abnormalities and echocardiogram mild pulmonary hypertension. Neck ultrasound and sestamibi scan showed no parathyroid mass. She was placed on oxygen due to desaturations and had poor tone and suck. Father had documented hypercalcemia (calcium 12.6 mg/dL, PTH 53 pg/mL). Paternal aunt and grandmother also had history of hypercalcemia. Serum levels of calcium and PTH remained elevated for 2 weeks despite treatment with IV fluids and furosemide and a low calcium/vitamin D formula. On day 12 we began a trial of cinacalcet, a type 2 calcimimetic, at starting doses of 0.4 mg/kg/day divided BID orally. Over 4 days the patient showed a dramatic reduction in serum levels of calcium and PTH to 8.6 mg/dL and 24 pg/mL, respectively. Over time her clinical course improved with better tone and suck and normal oxygenation. Cinacalcet was titrated up to 2.3 mg/kg/day (2mg PO tid) and baby discharged on day 20. Gene sequencing revealed a known heterozygous pathogenic variant in an exon 4 hotspot of the CASR gene, c.658C>T (p.Arg220Trp), consistent with familial hypocalciuric hypercalcemia. Father was confirmed to have the same pathogenic variant as the child. She has now been followed for 6 months, all fractures are healing with persistently normal PTH and calcium levels. She is thriving, her development appears to be normal, able to eat orally, sit, track and smile. Conclusion Neonatal severe hyperparathyroidism can occur in infants who are heterozygous for a CASR mutation and can manifest as multiple congenital fractures. A family history of asymptomatic parental hypercalcemia/hyperparathyroidism and targeted gene sequencing can be diagnostic of NSHPT. Activators of the CASR are a promising therapy for heterozygous CASR loss-of-function pathogenic variants and can lead to reversal of skeletal demineralization and markedly improved clinical status. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 1:18 p.m. - 1:23 p.m.