Background: Disorders of the calcium sensing receptor (CaSR) cause hyper- and hypo- calcemia, depending on the location and type of mutation. Familial hypocalciuric hypercalcemia is a benign disorder in which calcium levels are slightly elevated in the presence of slightly elevated parathyroid hormone (PTH). Neonatal severe hyperparathyroidism (NSHPT) is a rare life-threatening disorder in which there are high levels of calcium accompanied by high levels of parathyroid hormone.
Most cases of NSHPT are autosomal recessive and caused by homozygous mutations of the CaSR gene.
Calcimimetic drugs such as cinacalcet enhance calcium's effect on the CaSR. Cinacalcet has been shown to help regulate calcium levels in some children with NSHPT.
A female baby born at 39 weeks of gestation, 3.2 kg via normal vaginal delivery. After birth she displayed respiratory distress, a small bell-shaped thorax and multiple rib fractures, osteopenia, and osteodysplasia. Serum calcium was 11mg/dl (norm 8.5-10.5) but PTH was 1590 pg/ml (norm up to 65). Urine calcium was low. Serum calcium rapidly rose up to 15 mg/dl and she received one dose of pamidronate 0.5mg/kg with a good response. Cinacalcet was added as calcium continued to rise, until calcium stabilized at 12.5 mg/dl. PTH remained extremely elevated - over 1100 pg/ml. Due to high calcium levels and no reduction in PTH, she underwent total parathyroidectomy. At four months she is still hospitalized, and still depends on nasogastric tube for feeding. She is on calcium and vitamin alpha-D3 supplementation with stable serum calcium levels.
Genetic testing is positive for a homozygous CaSR mutation (c659G>A, pp Arg220Glu). This mutation has only once been described in FHH. Her mother has FHH and is heterozygous for the mutation, but her father is normocalcemic and does not carry a mutation on the CaSR gene. Possibly, the baby has maternal uniparental isodisomy and has inherited both mutations from the mother. There might be a deletion on the paternal allele. We are now completing genetic testing.
The missense mutation in the CaSR gene (c.554G > A, p.R185Q), is a known pathogenic mutation causing NSHPT and is responsive to cinacalcet. Other mutations described are not responsive. Knowing the mutation can facilitate treatment choices.
Conclusion: We describe a rare case of neonatal hyperparathyroidism with a formerly undocumented homozygous mutation. This mutation can shed light on novel modes of inheritance for this rare disease and better understanding of treatment modalities for this disease.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology