Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients

Abstract

SummaryNeonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11–12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders.Learning points NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels.

Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype

“…In NHPT patients, vitamin D deficiency is common (Table 1 and (19, 20, 23)), and as in FHH patients, sufficient calcium and vitamin D supply reduces PTH and improves metabolic bone disease (13,20). By contrast, calcium restriction can lead to a further rise in PTH and a lack of clinical improvement (26). This model of calcium deficiency and an exaggerated secondary hyperparathyroidism explains quite well the observed pathologic changes in NHPT patients.…”

TRPV6 compound heterozygous variants result in impaired placental calcium transport and severe undermineralization and dysplasia of the fetal skeleton

“…Neonatal severe hyperparathyroidism (NSHPT) was considered, based on marked PTH elevation and periosteal abnormalities, despite the absence of hypercalcemia; pamidronate single dose Day 16 then daily cinacalcet (calcimimetic) were used preemptively to avoid anticipated severe hypercalcemia (Fisher, Cabrera, & Imel, ). PTH normalized, serum calcium did not rise, including after cinacalcet cessation.…”

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

“…General measures, however, like hydration or forced diuresis and calcitonin do not yield clinically sufficient responses in both variants of neonatal hyperparathyroidism (15,66,67,68,69). Restriction of calcium intake is also mostly ineffective and further aggravates total body calcium deficiency in NSHPT and NHPT patients (70,71,72,73).…”