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Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports
BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calci...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761639/ https://www.ncbi.nlm.nih.gov/pubmed/36536367 http://dx.doi.org/10.1186/s12902-022-01231-z |
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author | Courtney, Aoife Hill, Arnold Smith, Diarmuid Agha, Amar |
author_facet | Courtney, Aoife Hill, Arnold Smith, Diarmuid Agha, Amar |
author_sort | Courtney, Aoife |
collection | PubMed |
description | BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calcium excretion in spite of high serum calcium. CASE PRESENTATION: We report two cases of FHH in a family caused by a novel pathogenic missense variant in the CaSR gene, p. His41Arg. Case 1, describes a 17 year old female with no significant past medical history, admitted with acute appendicitis requiring laparoscopic appendectomy and reporting a six month history of polydipsia. Routine investigations were significant for hypercalcaemia, corrected calcium 3.19 mmol/L (2.21-2.52mmol/L), elevated parathyroid hormone of 84pg/ml (15-65pg/ml) and a low 24-hour urine calcium of 0.75mmol/24 (2.50-7.50mmol/24). She was initially managed with intravenous fluids and Zolendronic acid with temporary normalisation of calcium though ultimately required commencement of Cinacalcet 30 mg daily for persistent symptomatic hypercalcaemia. Genetic analysis was subsequently positive for the above variant. Case 2, a 50-year-old female, was referred to the endocrine outpatient clinic for the management of type 2 diabetes and reported a longstanding history of asymptomatic hypercalcaemia which had not been investigated previously. Investigation revealed hypercalcaemia; corrected calcium of 2.6 mmol/L (reference range: 2.21–2.52 mmol/L); PTH of 53.7ng/L (reference range: 15–65 ng/L) and an elevated 24-hour urine calcium of 10 mmol/24 (2.50–7.50 mmol/24hr) with positive genetic analysis and is managed conservatively. Despite sharing this novel mutation, these cases have different phenotypes and their natural history is yet to be determined. Two further relatives are currently undergoing investigation for hypercalcaemia and the family have been referred for genetic counselling. CONCLUSION: Accurate diagnosis of FHH and differentiation from classic primary hyperparathyroidism can be challenging, however it is essential to avoid unnecessary investigations and parathyroid surgery. Genetic analysis may be helpful in establishing a diagnosis of FHH in light of the biochemical heterogeneity in this population and overlap with other causes of hypercalcaemia. |
format | Online Article Text |
id | pubmed-9761639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97616392022-12-19 Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports Courtney, Aoife Hill, Arnold Smith, Diarmuid Agha, Amar BMC Endocr Disord Case Report BACKGROUND: Familial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calcium excretion in spite of high serum calcium. CASE PRESENTATION: We report two cases of FHH in a family caused by a novel pathogenic missense variant in the CaSR gene, p. His41Arg. Case 1, describes a 17 year old female with no significant past medical history, admitted with acute appendicitis requiring laparoscopic appendectomy and reporting a six month history of polydipsia. Routine investigations were significant for hypercalcaemia, corrected calcium 3.19 mmol/L (2.21-2.52mmol/L), elevated parathyroid hormone of 84pg/ml (15-65pg/ml) and a low 24-hour urine calcium of 0.75mmol/24 (2.50-7.50mmol/24). She was initially managed with intravenous fluids and Zolendronic acid with temporary normalisation of calcium though ultimately required commencement of Cinacalcet 30 mg daily for persistent symptomatic hypercalcaemia. Genetic analysis was subsequently positive for the above variant. Case 2, a 50-year-old female, was referred to the endocrine outpatient clinic for the management of type 2 diabetes and reported a longstanding history of asymptomatic hypercalcaemia which had not been investigated previously. Investigation revealed hypercalcaemia; corrected calcium of 2.6 mmol/L (reference range: 2.21–2.52 mmol/L); PTH of 53.7ng/L (reference range: 15–65 ng/L) and an elevated 24-hour urine calcium of 10 mmol/24 (2.50–7.50 mmol/24hr) with positive genetic analysis and is managed conservatively. Despite sharing this novel mutation, these cases have different phenotypes and their natural history is yet to be determined. Two further relatives are currently undergoing investigation for hypercalcaemia and the family have been referred for genetic counselling. CONCLUSION: Accurate diagnosis of FHH and differentiation from classic primary hyperparathyroidism can be challenging, however it is essential to avoid unnecessary investigations and parathyroid surgery. Genetic analysis may be helpful in establishing a diagnosis of FHH in light of the biochemical heterogeneity in this population and overlap with other causes of hypercalcaemia. BioMed Central 2022-12-19 /pmc/articles/PMC9761639/ /pubmed/36536367 http://dx.doi.org/10.1186/s12902-022-01231-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Case Report Courtney, Aoife Hill, Arnold Smith, Diarmuid Agha, Amar Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title | Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title_full | Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title_fullStr | Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title_full_unstemmed | Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title_short | Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports |
title_sort | familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the casr gene, p(his41arg): two case reports |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9761639/ https://www.ncbi.nlm.nih.gov/pubmed/36536367 http://dx.doi.org/10.1186/s12902-022-01231-z |
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