Prenatal features and neonatal management of severe hyperparathyroidism caused by the heterozygous inactivating calcium-sensing receptor variant, Arg185Gln: A case report and review of the literature

Abstract

Background Loss-of-function variants in the calcium-sensing receptor ( CASR ) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH. NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs. Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype. Case presentation We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful. Discussion An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.

Prenatal bone abnormalities in three cases of familial hypocalciuric hypercalcemia

“…In addition, the maternal vitamin D deficiency could aggravate prenatal lesions. A similar case of antenatal presentation of FHH has recently been described, 14 transmitted by the father. Bone abnormalities were diagnosed during the 2 nd US, and combined short ribs, renal hyperechogenicity and a possible craniosynostosis.…”

Off-label use of cinacalcet in pediatric primary hyperparathyroidism: A French multicenter experience

“…Our results are similar to previous reports, demonstrating stable renal function and no direct effects of cinacalcet on urinary calcium ( 22 – 24 , 27 , 28 , 30 , 35 , 37 ). Only one paper has reported the onset of nephrocalcinosis after 6 months of cinacalcet therapy in a patient with heterozygous CASR mutation ( 44 ). Multiple CASR mutations have been identified ( 53 ) which reduce receptor function or produce truncated inactive CaSR and heterogenous response to cinacalcet have been observed and influence urinary calcium excretion ( 22 – 24 , 27 , 28 , 30 , 35 , 37 ).…”