Cargando…

SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)

Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety...

Descripción completa

Detalles Bibliográficos
Autores principales: Hannan, Fadil M, Dharmaraj, Poonam, Gorvin, Caroline M, Soni, Astha, Nelhans, Nick D, Olesen, Mie Kronborg, Boon, Hannah, Cranston, Treena, Thakker, Rajesh V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208433/
http://dx.doi.org/10.1210/jendso/bvaa046.729
_version_ 1783530844393046016
author Hannan, Fadil M
Dharmaraj, Poonam
Gorvin, Caroline M
Soni, Astha
Nelhans, Nick D
Olesen, Mie Kronborg
Boon, Hannah
Cranston, Treena
Thakker, Rajesh V
author_facet Hannan, Fadil M
Dharmaraj, Poonam
Gorvin, Caroline M
Soni, Astha
Nelhans, Nick D
Olesen, Mie Kronborg
Boon, Hannah
Cranston, Treena
Thakker, Rajesh V
author_sort Hannan, Fadil M
collection PubMed
description Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. Objective: To further characterise the range of calcitropic phenotypes in the children of a mother with FHH1. Methods: We assessed a three generation FHH kindred by clinical, biochemical and mutational analysis following informed consent. Results: The kindred comprised a hypercalcemic male, his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient hypocalcemic seizures during infancy. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (normal, 2.0-2.8) and PTH of 2.2 pmol/L (normal, 1.0-9.3) as a consequence of maternal hypercalcemia, and required treatment with I-V calcium gluconate infusions. Mutational analysis identified a novel heterozygous p.Ser448Pro CaSR variant in the hypercalcemic family members, but not in the children with hypocalcemia or normocalcemia. Three-dimensional modelling using a reported crystal structure of the dimeric CaSR showed the mutated Ser448 residue to be located in the CaSR extracellular domain, and predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction across the extracellular CaSR dimer interface. The variant Pro448 CaSR, when expressed in HEK293 cells, was shown to significantly impair CaSR-mediated intracellular calcium mobilisation and mitogen-activated protein kinase (MAPK) responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. Conclusion: These studies have identified a novel loss-of-function CaSR mutation which caused asymptomatic hypercalcemia in a mother and her children who had inherited the mutation. However, one child who did not inherit the mutation developed transient neonatal hypocalcemic seizures as a consequence of maternal hypercalcemia. These findings highlight the importance of assessing serum calcium and undertaking CaSR mutational analysis in the newborn offspring of a mother with FHH1. Reference: (1) Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018; 15(1): 33-51.
format Online
Article
Text
id pubmed-7208433
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-72084332020-05-13 SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1) Hannan, Fadil M Dharmaraj, Poonam Gorvin, Caroline M Soni, Astha Nelhans, Nick D Olesen, Mie Kronborg Boon, Hannah Cranston, Treena Thakker, Rajesh V J Endocr Soc Bone and Mineral Metabolism Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. Objective: To further characterise the range of calcitropic phenotypes in the children of a mother with FHH1. Methods: We assessed a three generation FHH kindred by clinical, biochemical and mutational analysis following informed consent. Results: The kindred comprised a hypercalcemic male, his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient hypocalcemic seizures during infancy. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (normal, 2.0-2.8) and PTH of 2.2 pmol/L (normal, 1.0-9.3) as a consequence of maternal hypercalcemia, and required treatment with I-V calcium gluconate infusions. Mutational analysis identified a novel heterozygous p.Ser448Pro CaSR variant in the hypercalcemic family members, but not in the children with hypocalcemia or normocalcemia. Three-dimensional modelling using a reported crystal structure of the dimeric CaSR showed the mutated Ser448 residue to be located in the CaSR extracellular domain, and predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction across the extracellular CaSR dimer interface. The variant Pro448 CaSR, when expressed in HEK293 cells, was shown to significantly impair CaSR-mediated intracellular calcium mobilisation and mitogen-activated protein kinase (MAPK) responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. Conclusion: These studies have identified a novel loss-of-function CaSR mutation which caused asymptomatic hypercalcemia in a mother and her children who had inherited the mutation. However, one child who did not inherit the mutation developed transient neonatal hypocalcemic seizures as a consequence of maternal hypercalcemia. These findings highlight the importance of assessing serum calcium and undertaking CaSR mutational analysis in the newborn offspring of a mother with FHH1. Reference: (1) Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018; 15(1): 33-51. Oxford University Press 2020-05-08 /pmc/articles/PMC7208433/ http://dx.doi.org/10.1210/jendso/bvaa046.729 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Bone and Mineral Metabolism
Hannan, Fadil M
Dharmaraj, Poonam
Gorvin, Caroline M
Soni, Astha
Nelhans, Nick D
Olesen, Mie Kronborg
Boon, Hannah
Cranston, Treena
Thakker, Rajesh V
SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title_full SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title_fullStr SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title_full_unstemmed SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title_short SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
title_sort sat-404 neonatal hypocalcemic seizures in offspring of a mother with familial hypocalciuric hypercalcemia type 1 (fhh1)
topic Bone and Mineral Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208433/
http://dx.doi.org/10.1210/jendso/bvaa046.729
work_keys_str_mv AT hannanfadilm sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT dharmarajpoonam sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT gorvincarolinem sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT soniastha sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT nelhansnickd sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT olesenmiekronborg sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT boonhannah sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT cranstontreena sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1
AT thakkerrajeshv sat404neonatalhypocalcemicseizuresinoffspringofamotherwithfamilialhypocalciurichypercalcemiatype1fhh1