scholarly journals SAT-350 A Tale of Two Mutations: Familial Hypocalciuric Hypercalcemia Caused by a Novel CaSR Start Codon Mutation Found in the Setting of a CaSR Hypercalciuric Variant

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Sindhura Bandaru ◽  
Elaine Michelle Pelley
Keyword(s):  
Start Codon ◽  
Calcium Excretion ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Clearance Ratio ◽  
Casr Gene ◽  
Increased Risk ◽  
Vitamin D Levels ◽  
Activating Mutation ◽  
Low Prevalence ◽  
Codon Mutation

Abstract Background: The calcium-sensing receptor (CaSR) mediates PTH production and renal calcium excretion by sensing circulating calcium levels. Activating mutations in the CaSR can cause a spectrum of phenotypes from overt hypoparathyroidism to isolated hypercalciuria. Inactivating mutations of the CaSR lead to the syndrome of familial hypocalciuric hypercalcemia (FHH) where the protein produced is less sensitive to calcium. A mutation in the start codon of the CaSR leading to FHH has not previously been reported. Case: 60-year-old female was seen for evaluation of osteoporosis with lowest T- score of -2.9 at spine. She had no family history of calcium disorders. Biochemical evaluation for secondary etiologies of bone loss showed persistent PTH-dependent hypercalcemia (with albumin-corrected serum calcium of 10.4-10.8 mg/dl, and PTH 64-78 pg/ml), initially raising suspicion for primary hyperparathyroidism. Subsequent testing showed a low 24-hour urine calcium (82 mg/day) despite adequate daily calcium intake, robust 25-hydroxy vitamin D levels (47 ng/ml), and normal renal function. Calcium/creatinine clearance ratio was low at 0.0064 and FHH was suspected. CaSR gene sequencing revealed two heterozygous abnormalities: (1) a likely pathogenic mutation in the start codon of the CaSR (c.3G>A (p.M1?)) that has not been previously reported (p.M1? indicates that it is not known whether the mutation leads to no CaSR being produced from that allele or if an abnormal protein is produced using an alternate methionine start codon) and (2) a low-prevalence activation mutation variant of the CaSR (p.R990G), which is associated with hypercalciuria and increased risk of kidney stones but generally does not cause hypocalcemia. Genetic testing was unable to determine if these two mutations were on the same (cis) or opposite (trans) alleles. If they are on opposite alleles, the phenotype represents the heterozygous loss-of-function CaSR abnormality with compensation by an activating mutation in the opposite allele. If they are on the same allele, the activating variant is either not expressed at all due to nontranslation or is located on an abnormal/shortened protein. CaSR sequencing of the patient’s daughter was normal. In the absence of recombination occurring between the two loci, this strongly suggests the two were on the same allele in this case. Discussion: Thus far, > 100 mutations in the CaSR gene causing FHH have been described; but to our knowledge, this case is the first report of a start codon mutation causing FHH. This happened to be identified in the setting of a low-prevalence hypercalciuric variant. Familial testing strongly suggested the two mutations were on the same allele. The activating mutation, therefore, was likely functionally silenced in this case.

scholarly journals A Novel Mutation of the Calcium-Sensing Receptor Gene Causing Familial Hypocalciuric Hypercalcemia Complicates Medical Followup after Roux-en-Y Gastric Bypass: A Case Report and a Summary of Mutations Found in the Same Hospital Laboratory

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
Elin Rebecka Carlsson ◽  
Mai-Britt Toft Nielsen ◽  
Anne Mette Høgh ◽  
Rikke Veggerby Grønlund ◽  
Mogens Fenger ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Novel Mutation ◽  
Calcium Supplementation ◽  
Receptor Gene ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Clearance Ratio ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Increased Risk

Heterozygous inactivating mutations in the calcium-sensing receptor (CaSR) gene are known to cause familial hypocalciuric hypercalcemia (FHH), usually a benign form of hypercalcemia without symptoms of a disrupted calcium homeostasis. FHH can be mistaken for the more common primary hyperparathyroidism (PHPT), for which surgical treatment may be needed. We describe a case of a 36-year-old woman with hypercalcemia and elevated PTH, initially suspected of having PHPT. Sequencing of the CaSR-gene revealed a mutation in nucleotide 437, changing the amino acid in position 146 from Glycine to Aspartate. The mutation was previously undescribed in the literature, but a very low calcium:creatinine clearance ratio supported the diagnosis FHH. A few years later, the patient’s two daughters were tested and the association between mutation and hypercalcemia could be confirmed. The patient was gastric bypass-operated and therefore, due to malabsorption and increased risk of fracture, was in need of adequate calcium supplementation. The chronically elevated calcium levels challenged medical followup, as calcium sufficiency could not be monitored in a traditional manner. Eventually the patient developed elevated alkaline phosphatase, a further increased PTH and a decreased DXA T-score indicating calcium deficiency and bone resorption. As a supplement, all CaSR-mutations found at our hospital, 2005-2018.

scholarly journals Atypical Presentation of Familial Hypocalciuric Hypercalcemia: Case Report

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A182-A183
Author(s):  
Dalal S Ali ◽  
Karel Dandurand ◽  
Aliya Aziz Khan
Keyword(s):  
Vitamin D ◽  
Primary Hyperparathyroidism ◽  
Dna Analysis ◽  
Receptor Gene ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Clearance Ratio ◽  
Subtotal Parathyroidectomy ◽  
Casr Gene ◽  
Calcium Sensing

Abstract Background: Differentiation between familial hypocalciuric hypercalcemia (FHH) and primary hyperparathyroidism (PHPT) can be challenging in certain cases in the absence of DNA analysis of the calcium sensing receptor gene. The distinction between those two clinical entities with overlapping biochemical features therefore relies on the calcium to creatinine clearance ratio (CCCR), which is expected to be low in FHH (<0.01 in 80% of cases and between 0.01 and 0.02 in approximately 20% of patients)1. Patients with PHPT usually have a CCCR of>= 0.02. A lower CCCR between 0.01 and 0.02 can be seen in approximately 20% of patients1,2and is more commonly seen in the presence of vitamin D insufficiency, impaired renal function, low calcium intake or being of African descent. It is advised to stop drugs which can contribute to hypercalcemia and lower the CCCR such as thiazide diuretics prior to evaluating the CCCR. Clinical Case: A 56-year-old lady was referred for evaluation of persistent hypercalcemia post parathyroidectomy and fatigue. She had mildly elevated ionized serum calcium (iCa) and a mid-normal PTH with a CCCR of 0.024. She had a normal BMD with no prior fragility fractures and passed a kidney stone prior to her presentation. Physical exam was unremarkable. She had previously travelled to Tampa and had a subtotal parathyroidectomy 3 glands (RU, LU, RL) for a possible diagnosis of PHPT, tissue biopsy showed hyperplastic parathyroids. Her MEN1 gene analysis was negative for MEN1 mutation and MRI of the abdomen was unremarkable. Her mother had a diagnosis of PHPT and osteoporosis. The iCa remained mildly elevated at 1.43 mmol/L (1.15–1.3) with a 24 hr urinary CCCR at 0.024 and a mid-normal PTH of 4.4 pmol/L (1.6–6.9). Her eGFR was 104 mls/min, 25 vitamin D 82 nmol/L (75–250), 1,25 dihydroxy vitamin D 122 pmol/L (60–206), PO4 0.90 mmol/L (0.8–1.45) and alkaline phosphatase 46 U/L (35–120) were all normal. She continued to have mild symptoms of hypercalcemia and her bone scan was negative for underlying skeletal pathology. DNA studies for mutations in the CaSR gene were completed. This confirmed the presence of a heterozygous loss of function mutation in the CASR gene at c493-2A>G which appears to be pathogenic. Conclusion: The CCCR is useful in differentiating PHPT from FHH however in certain cases of FHH the CCCR may be higher then expected and we have now confirmed the presence of FHH with a molecular diagnosis in a patient with a CCCR as high as 0.02. References: 1 Gunn, IR, Gaffney, D. Clinical and laboratory features of calcium-sensing receptor disorders: a systematic review. Ann Clin Biochem 2004; 41:441–58 2 Stephen J. Marx, Letter to the Editor: Distinguishing Typical Primary Hyperparathyroidism From Familial Hypocalciuric Hypercalcemia by Using an Index of Urinary Calcium, The Journal of Clinical Endocrinology & Metabolism, 2015

scholarly journals Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Maryam Zahedi ◽  
Reyhane Hizomi Arani ◽  
Maryam Rafati ◽  
Atieh Amouzegar ◽  
Farzad Hadaegh
Keyword(s):  
Vitamin D ◽  
Laboratory Data ◽  
Vitamin D Supplementation ◽  
Dietary Calcium Intake ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Normal Range ◽  
Clearance Ratio ◽  
Vitamin D Levels ◽  
History Of ◽  
25 Oh Vitamin D

Abstract Background Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia. Case presentation A 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3–11.3 mg/dL; (normal range: 8.8–10.4)), and non-suppressed PTH levels (range, 37.2–58.1 pg/mL; (normal range: 10–65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her. Conclusion We presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

scholarly journals A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Sachin K. Majumdar ◽  
Tess Jacob ◽  
Allen Bale ◽  
Allison Bailey ◽  
Jeffrey Kwon ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Novel Variant

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

scholarly journals Familial Hypocalciuric Hypercalcemia in an Index Male: Grey Zones of the Differential Diagnosis From Primary Hyperparathyroidism in a 13-Year Clinical Follow up

2020 ◽  
pp. S321-S328
Author(s):  
K. ZAJÍČKOVÁ ◽  
M. DVOŘÁKOVÁ ◽  
J. MORAVCOVÁ ◽  
J. VČELÁK ◽  
D. GOLTZMAN
Keyword(s):  
Differential Diagnosis ◽  
Family History ◽  
Primary Hyperparathyroidism ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Clearance Ratio ◽  
Japanese Family ◽  
Casr Gene ◽  
History Of ◽  
Inactivating Mutation

Familial hypocalciuric hypercalcemia (FHH) type 1, caused by a heterozygous inactivating mutation of the gene encoding the calcium-sensing receptor (CaSR), is characterized by mild to moderate hypercalcemia, hypocalciuria and inappropriately normal or elevated parathyroid hormone (PTH). FHH must be differentiated from primary hyperparathyroidism (PHPT) because parathyroidectomy is ineffective in the former. Herein, we report a 39-year-old male patient with a 13-year history of asymptomatic PTH-dependent hypercalcemia (mean calcium of 2.88 mmol/l; reference range 2.15-2.55 mmol/l) and calcium-to-creatinine clearance ratio (Ca/Cr) ranging from 0.007 to 0.0198, which is consistent with either FHH or PHPT. Although a family history of hypercalcemia was negative, and PET-CT with fluorocholine was suggestive of a parathyroid adenoma, genetic analysis of the CaSR gene identified a heterozygous inactivating mutation NM_000388.4:c.1670G>A p. (Gly557Glu) in exon 6 and a polymorphism NM_000388.4:c.1192G>A p. (Asp398Asn) in exon 4. The G557E mutation has been previously reported in a Japanese family in which all family members with the mutation had Ca/Cr below 0.01 consistent with FHH. The biochemical profile of FHH and PHPT may overlap. Our FHH patient with a G557E CaSR mutation illustrates that the differential diagnosis can be difficult in an index case with no family history, (false) positive parathyroid imaging and higher calciuria than expected for FHH. Calcium intake, vitamin D status and bone resorption might have contributed to the Ca/Cr variations over a 13-year clinical follow up. This case thus emphasizes the irreplaceable role of genetic testing of the CaSR gene when clinical evaluation is inconclusive.

Serum levels of 25(OH)D are not associated with venous thromboembolism in the elderly population

2016 ◽  
Vol 115 (01) ◽  
pp. 169-175 ◽  
Author(s):  
Aurélien Delluc ◽  
Marie-Pierre Moineau ◽  
Cécile Tromeur ◽  
Maelenn Gouillou ◽  
Karine Lacut ◽  
...  
Keyword(s):  
Vitamin D ◽  
Venous Thromboembolism ◽  
Seasonal Variations ◽  
Elderly Population ◽  
Serum Levels ◽  
The Elderly ◽  
Vitamin D Status ◽  
Increased Risk ◽  
Vitamin D Levels ◽  
Walking Capacity

SummaryThe prevalence of both vitamin D deficiency and venous thromboembolism (VTE) is important in the elderly. Previous studies have provided evidence for a possible association between vitamin D status and the risk of VTE. Thus, we aimed to investigate the association between vitamin D levels and VTE in the population aged 75 and over included in the EDITH case-control study. The association between vitamin D status and VTE was analysed. We also analysed the monthly and seasonal variations of VTE and vitamin D. Between May 2000 and December 2009, 340 elderly patients (mean age 81.5 years, 32 % men) with unprovoked VTE and their controls were included. The univariate and multivariate analysis found no significant association between serum levels of vitamin D and the risk of unprovoked VTE. In the unadjusted analysis, a higher BMI was statistically associated with an increased risk of VTE (OR 1.09; 95 % CI 1.05–1.13) whereas a better walking capacity and living at home were associated with a decreased rate of VTE: OR 0.57; 95 % CI 0.36–0.90 and 0.40; 95 % CI 0.25–0.66, respectively. Although not significant, more VTE events occurred during winter (p=0.09). No seasonal variations of vitamin D levels were found (p=0.11). In conclusion, in contrast with previous reports our findings suggest that vitamin D is not associated with VTE in the elderly population.

scholarly journals A NovelMLH1Initiation Codon Mutation (c.3G>T) in a Large Chinese Lynch Syndrome Family with Different Onset Age and mRNA Expression Level

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Yanni Zhang ◽  
Huishuang Chen ◽  
Zhiyu Peng ◽  
Santasree Banerjee ◽  
Wei Li ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mrna Expression ◽  
Germline Mutation ◽  
Peripheral Blood ◽  
Expression Level ◽  
Onset Age ◽  
Mrna Expression Level ◽  
Increased Risk ◽  
Lynch Syndrome Family ◽  
Codon Mutation

Lynch syndrome is a genetically and clinically heterogeneous disorder; it is caused by a germline mutation in DNA mismatch repair (MMR) genes. Individuals with a heterozygous mutation in MLH1 have an increased risk for developing colorectal cancer. Here we described a 5-generation Chinese Lynch syndrome family with different severity and onset age. A novel heterozygous germline mutation (c.3G>T, p.Met1Ile) inMLH1gene was discovered by next generation sequencing. Our study also revealed by qPCR that the MLH1 mRNA expression in peripheral blood of patients in this family was remarkably lower than that of the unaffected carriers and non-carriers. The research results indicated that the mRNA expression level may provide predictive suggestions of treatment and management for carriers with the initiation codon mutation ofMLH1in this family. Further studies are undertaken in this family as well as other families with Lynch syndrome to interrogate the exact reasons affecting the MLH1 mRNA expression level and whether mRNA expression in peripheral blood could be a significant factor for early diagnosis and surveillance of Lynch syndrome.

scholarly journals O3-3.3 Association of low vitamin D levels with increased risk of stroke in older adults

2011 ◽  
Vol 65 (Suppl 1) ◽  
pp. A34-A34
Author(s):  
M. Busch ◽  
C. Scheidt-Nave ◽  
U. Thiem ◽  
I. Burghaus ◽  
H. J. Trampisch ◽  
...  
Keyword(s):  
Older Adults ◽  
Vitamin D ◽  
Increased Risk ◽  
Vitamin D Levels
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