Dharmaraj, Poonam, Gorvin, Caroline M, Soni, Astha, Nelhans, Nick D, Olesen, Mie K 
ORCID: 0000-0003-0338-5690, Boon, Hannah, Cranston, Treena, Thakker, Rajesh V and Hannan, Fadil M ORCID: 0000-0002-2975-5170
(2020)
Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1).
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 105 (5).
dgaa111-.
Abstract
<h4>Context</h4>Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy.<h4>Objective</h4>The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1.<h4>Methods</h4>A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent.<h4>Results</h4>The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation.<h4>Conclusions</h4>Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | hypercalcemia, hypocalcemia, hypoparathyroidism, calcium-sensing receptor, mutation, loss-of-function |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 06 Jul 2021 10:02 |
| Last Modified: | 08 Feb 2024 09:41 |
| DOI: | 10.1210/clinem/dgaa111 |
| Open Access URL: | https://doi.org/10.1210/clinem/dgaa111 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3128993 |
Dimensions
Dimensions
