Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports
Abstract 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 urina...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
|
| Series: | BMC Endocrine Disorders |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12902-022-01231-z |
| _version_ | 1828086999064510464 |
|---|---|
| author | Aoife Courtney Arnold Hill Diarmuid Smith Amar Agha |
| author_facet | Aoife Courtney Arnold Hill Diarmuid Smith Amar Agha |
| author_sort | Aoife Courtney |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T05:06:04Z |
| format | Article |
| id | doaj.art-1ba55bce38884b7bacd3e6a0f76ba1ac |
| institution | Directory Open Access Journal |
| issn | 1472-6823 |
| language | English |
| last_indexed | 2024-04-11T05:06:04Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Endocrine Disorders |
| spelling | doaj.art-1ba55bce38884b7bacd3e6a0f76ba1ac2022-12-25T12:19:10ZengBMCBMC Endocrine Disorders1472-68232022-12-012211510.1186/s12902-022-01231-zFamilial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reportsAoife Courtney0Arnold Hill1Diarmuid Smith2Amar Agha3Department of Endocrinology and Diabetes Mellitus, Beaumont Hospital/RCSI Medical SchoolDepartment of General Surgery, Beaumont Hospital/RCSI Medical SchoolDepartment of Endocrinology and Diabetes Mellitus, Beaumont Hospital/RCSI Medical SchoolDepartment of Endocrinology and Diabetes Mellitus, Beaumont Hospital/RCSI Medical SchoolAbstract 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.https://doi.org/10.1186/s12902-022-01231-zFamilial hypocalciuric hypercalcaemiaPrimary hyperparathyroidismPTH dependent hypercalcaemiaCaSR gene mutationCalcium metabolism |
| spellingShingle | Aoife Courtney Arnold Hill Diarmuid Smith Amar Agha Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports BMC Endocrine Disorders Familial hypocalciuric hypercalcaemia Primary hyperparathyroidism PTH dependent hypercalcaemia CaSR gene mutation Calcium metabolism |
| 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 | Familial hypocalciuric hypercalcaemia Primary hyperparathyroidism PTH dependent hypercalcaemia CaSR gene mutation Calcium metabolism |
| url | https://doi.org/10.1186/s12902-022-01231-z |
| work_keys_str_mv | AT aoifecourtney familialhypocalciurichypercalcaemiatype1causedbyanovelheterozygousmissensevariantinthecasrgenephis41argtwocasereports AT arnoldhill familialhypocalciurichypercalcaemiatype1causedbyanovelheterozygousmissensevariantinthecasrgenephis41argtwocasereports AT diarmuidsmith familialhypocalciurichypercalcaemiatype1causedbyanovelheterozygousmissensevariantinthecasrgenephis41argtwocasereports AT amaragha familialhypocalciurichypercalcaemiatype1causedbyanovelheterozygousmissensevariantinthecasrgenephis41argtwocasereports |