eP124 - Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR gene: A rare cause of life-threatening hypercalcemia

Document Type

Conference Paper


Paediatrics and Child Health


Background: Neonatal Severe Hyperparathyroidism (NSHPT) is a life-threatening disorder caused by homozygous inactivating calcium sensing receptor (CASR) mutations. In some cases, the CASR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.
Objective: To describe a case of NSHPT with a previously undescribed CASR pathogenic variant, unresponsive to cinacalcet.
Case summary: A 2 month old male was admitted with poor weight gain, feeding issues, hypotonia, and dehydration. The parents were first cousins, and there were no significant prenatal concerns. He had poor feeding and failure to thrive noted in the first few weeks of life, and was admitted for further workup. Investigations showed serum Calcium >18 mg/dl; (8.6–10.2 mg/dl), Phosphorus 2.6 mg/dl (4–7 mg/ dl) with normal Magnesium 2.6 mg/dl (1.6–2.6 mg/dl), normal serum alkaline phosphatase activity 305IU/L (54–369IU/L), sufficient 25 – hydroxyvitamin D 49.8 ng/ml (<20 deficient, 21–29 insufficient, >30 sufficient), normal renal functions and elevated urine calcium at 22 mg/dl with urine Ca/Cr ratio of 2.2. Forced diuresis along with IV fluids was started, but due to only transient improvement in serum calcium, IV Pamidronate (0.5 mg/kg) was given after 36 hours of which calcium showed a declining trend up to 11.7 mg/dl only to increase again after a week. The second dose of IV pamidronate was given at 1 mg/kg and furosemide was continued. There was only a transient response, so oral Cinacalcet was started initially at low dose that had to be increased. Molecular genetic testing was sent suspecting NSHPT, which showed a previously undescribed homozygous variant of uncertain significance (VUS) in CASR (Intron 3, c.493–12G>A). We believe this is disease causing, given the matching phenotype, as well as the fact that algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Response of serum calcium level to Cinacalcet was transient, so parents were counselled regarding the need of Pamidronate until curative parathyroidectomy. Although the treatment of choice in homozygous CASR defects is parathyroidectomy, this is very challenging to perform in infancy, even at the most experienced medical centers. Currently the baby is on cinacalcet, has gained weight and feeding issues have improved, and is awaiting parathyroidectomy.
Conclusion: The predicted nonfunctional CASR is consistent with the lack of response to cinacalcet, and total parathyroidectomy is recommended in such cases. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Publication (Name of Journal)

Molecular Genetics and Metabolism