scholarly journals Concomitant familial hypocalciuric hypercalcemia and single parathyroid adenoma: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Simone Diedrichsen Marstrand ◽  
Charlotte Landbo Tofteng ◽  
Anne Jarløv ◽  
Line Borgwardt ◽  
Peter Schwarz
Keyword(s):  
Parathyroid Adenoma ◽  
Correct Diagnosis ◽  
Elevated Serum ◽  
Parathyroid Scintigraphy ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Clearance Ratio ◽  
Gene Encoding ◽  
Calcium Sensing ◽  
Severe Hypercalcemia ◽  
The Right

Abstract Background Primary hyperparathyroidism (PHPT) is a common endocrine disorder and the most frequent benign cause of hypercalcemia. PHPT is characterized by autonomous hypersecretion of parathyroid hormone (PTH), regardless of serum calcium levels. Familial hypocalciuric hypercalcemia (FHH) is a rare, benign syndrome only affecting the regulation of calcium metabolism. FHH is an autosomal-dominant genetic disease with high penetrance, caused by an inactivating variant in the CASR gene encoding the calcium-sensing receptor (CaSR). We present a unique case of concomitant PHPT and FHH without clinically actionable variants in MEN1. Case presentation A 47-year-old Caucasian man with severe hypercalcemia, genetic FHH, and initially normal parathyroid scintigraphy was referred for endocrine evaluation due to nonspecific symptoms. Biochemical evaluation showed elevated serum ionized calcium and PTH. The calcium–creatinine clearance ratio was low. All other biochemical measures were normal, including kidney function. Genetic evaluation was redone and confirmed FHH. A new parathyroid scintigraphy showed a significant single adenoma corresponding to the lower left gland. The patient underwent parathyroidectomy, and a parathyroid adenoma was removed. A reduced level of hypercalcemia persisted due to FHH. Conclusions The correct diagnosis of the underlying cause of hypercalcemia is important to ensure the right treatment. Patients with FHH should avoid operative treatment, and PHPT should be differentiated from MEN1 to determine whether surgery should include parathyroidectomy with removal of one adenoma or 3.5 hyperplastic parathyroid glands.

scholarly journals SAT-380 A Case of Primary Hyperparathyroidism on the Third Trimester of Pregnancy

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Maria Alexandra Carranceja Villapol ◽  
Maria Princess L Kanapi
Keyword(s):  
Blood Pressure ◽  
Abdominal Pain ◽  
Primary Hyperparathyroidism ◽  
Parathyroid Adenoma ◽  
Elevated Serum ◽  
Stable Condition ◽  
Abdominal Ultrasound ◽  
Pressure Control ◽  
Ibandronic Acid ◽  
The Right

Abstract Introduction: This is the case of a pregnant woman on her 3rd trimester who was diagnosed with primary hyperparathyroidism. Since there are two patients involved, the potential complications that can be brought about by the diagnostic tests and the treatment had to be weighed against the benefits. Case: The patient is SA, a 34-year old female on her 29th week of pregnancy, admitted due to a month history of abdominal pain described as intermittent, crampy, generalized, non-radiating, and mild-to-moderately severe in intensity. She was advised to do tests but did not comply. In the interim, there was recurrence of symptoms but with resolution. However, the crampy abdominal pain recurred, now localized at the right upper quadrant and epigastric areas, radiating to the right upper back, moderate in intensity, and with associated nausea and vomiting, leading to admission. She was first managed under OB-Gynecology, given hydration, pain management and Betamethasone. She was also referred to Cardiology for blood pressure control, and Surgery for evaluation of the abdominal pain. Due to an increasing trend of her blood glucose, she was referred to Endocrinology and started on insulin. Mild bilateral nephrocalcinoses seen in an abdominal ultrasound prompted work-up showing an elevated serum ionized calcium at 1.88 meq/L (n 1.12-1.32 meq/L), elevated intact PTH at 451.13 pg/ml (n <67.9 pg/ml), and low Vitamin D at 10.96 ng/ml (n >30ng/ml). Parathyroid ultrasound showed nonthyroidal tissue measuring 0.4 x 0.6 cm at the right inferior area. Saline hydration and diuresis with Furosemide were started to manage the hypercalcemia. A multi-disciplinary meeting was held to discuss the options for management and risks involved. The goal was to deliver the baby in stable condition possibly to term, while keeping maternal calcium levels and blood pressure normal. However on her 30th week of gestation, she had persistent elevated blood pressure and underwent emergency caesarian section. After delivery, the patient was advised against breastfeeding for adequate management of her hypercalcemia. She was started on Cinacalcet, Calcitonin, and Ibandronic Acid. A Parathyroid Sestamibi Scan done showed a parathyroid adenoma on the right inferior lobe, and she underwent right inferior parathyroidectomy, with left thyroidectomy and isthmusectomy. Findings showed a right inferior parathyroid adenoma and a benign follicular nodule on the left thyroid. She was started on Calcium Carbonate and Calcitriol, and discharged stable. Conclusions: This case shows that when two lives are at stake every step of the management, whether diagnostic or therapeutic, must be communicated well to the patient and to the other members of the team. It is ultimately a choice made by the expectant mother but through the proper guidance and updated knowledge of the team, combined with a good clinical eye especially in the treatment of pregnant women.

scholarly journals Rare Case of Severe Hypercalcemia Secondary to Atypical Sestamibi Negative Parathyroid Cystic Adenoma

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A266-A267
Author(s):  
Timur Gusov ◽  
John Chen Liu ◽  
Sowjanya Naha ◽  
F N U Marium ◽  
Joseph Theressa Nehu Parimi ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
Parathyroid Adenoma ◽  
Parathyroid Gland ◽  
Severe Hypercalcemia ◽  
Parathyroid Adenomas ◽  
Sestamibi Scan ◽  
Serum Pth ◽  
The Right ◽  
99Mtc Sestamibi ◽  
Cystic Adenoma

Abstract Primary hyperparathyroidism (PHPT) is defined as excessive secretion of parathyroid hormone (PTH) originating from the parathyroid gland. The most common cause is a single parathyroid adenoma which is typically solid. Cystic parathyroid adenomas (CPA) are the cause of about 1–2% of cases of primary hyperparathyroidism. It is known that cystic parathyroid adenomas are a result of degeneration of an existing parathyroid adenoma. SestaMIBI is an imaging study based on uptake of radioactive technetium99 and used to localize parathyroid adenomas. We describe an unusual case of severe hypercalcemia secondary to 99mTc sestaMIBI negative atypical parathyroid cystic adenoma. A 56-year-old male presented to our facility with nausea and vomiting. His past medical history included hypertension and hepatitis C with no history of fractures or kidney disease. Physical examination was normal. Upon admission the patient was afebrile with blood pressure of 170/120 mmHg and heart rate of 62 bpm. Chemistry showed Calcium of 14.5 mg/dL (8.6–10.2mg/dL), phosphorus 2.2 (2.7–4.5) mh/dL, magnesium 1.8 (1.7–2.6)mg/dL, intact PTH of 375 (15–65) pg/mL, PTH-related peptide <2.0 pmol/L(<2 pmol/L), 25-OH vitamin D of 19 ng/ml (30–80), Creatinine 1.22 (0.7–1.2)mg/dL, alkaline phosphatase 95 (40–129) units/L. He was started on aggressive hydration, calcitonin 4 units/kg, 4 mg of IV Zolendroninc acid. Neck sonogram revealed a large, complex, predominantly anechoic lesion with solid vascular components and thick internal septations in the inferior and medial aspect of the right thyroid lobe measuring 3 x 2 x 5.5 cm. Findings were confirmed with CT of the neck. Since Sestamibi scan (planar and SPECT/CT) did not show uptake in parathyroid glands, the cyst was thought to be of thyroid origin. Fine needle aspiration was not able to detect cellular material, but PTH was >100 pg/ml on the FNA sample. Otolaryngology service was consulted for parathyroidectomy. During the surgical treatment, the right upper parathyroid gland was removed with no changes in serum PTH. Next, the cystic lesion was removed with normalization of serum PTH (from 218 pg/ml to 35.2 pg/ml respectively). Intraoperative frozen section analysis was read as a cystic parathyroid adenoma. The final pathology report revealed cystic parathyroid tissue favoring parathyroid adenoma with focal atypia. Hypercalcemia resolved. Conclusions: Atypical cystic parathyroid adenomas are a rare cause of PHPT. 90% of parathyroid cysts are nonfunctional. Above mention is a case of a patient presenting with hypercalcemic crisis secondary to cystic parathyroid adenoma, which posed a diagnostic challenge as both neck ultrasound and 99mTc sestaMIBI scan were inconclusive. These findings should trigger suspicion for functional parathyroid lesions. Cystic components should be evaluated for PTH levels and if significantly elevated should be treated as a parathyroid adenoma.

scholarly journals Familial Hypocalciuric Hypercalcemia: The Challenge of Diagnosis

2021 ◽  
Author(s):  
David Taïeb ◽  
Adele Lasbleiz ◽  
Nunzia Cinzia Paladino ◽  
Pauline Romanet ◽  
Frédéric Castinetti ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Elevated Serum ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Clearance Ratio ◽  
Molecular Alterations ◽  
Genes Encoding ◽  
High Level ◽  
Inactivating Mutation ◽  
Very High

Abstract Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant genetic disorder classically characterized by lifelong mild-to-moderate asymptomatic hypercalcemia with inappropriately normal to elevated serum parathyroid hormone (PTH) concentrations and hypocalciuria, best expressed by a urine calcium-to-creatinine clearance ratio (CCCR)<0.01[1,2]. FHH prevalence is estimated between 1:10 000 to 1:100 000[3,4]. In 60% of cases, FHH is due to CASR inactivating mutation[5]. More rarely FHH is due to AP2S1 or GNA11 inactivating mutation, both genes encoding for proteins involved downstream of CASR activation[6]. These molecular alterations are found in all parathyroid cells, explaining disease persistence following partial parathyroidectomy and the ineffective surgical management of these patients. FHH phenotypes could however overlap with primary hyperparathyroidism (PHPT). Indeed, even if patients with FHH are currently asymptomatic, some of them present chondrocalcinosis, kidney stones or bone fracture and very high level of PTH or calcemia[7]. Nonetheless, the distinction has to be adressed since the therapeutic approach significantly differs between these two conditions. Surgery is usually recommended for PHPT[8] while follow-up is preferred in the latter case[9,10]. We report and discuss 7 cases, 6 out 7 being operated for a presumed PHPT.

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 (&lt;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&gt;= 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&gt;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 Identification of a Second Kindred with Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Narrows Localization to a <3.5 Megabase Pair Region on Chromosome 19q13.3

2010 ◽  
Vol 95 (4) ◽  
pp. 1947-1954 ◽  
Author(s):  
M. Andrew Nesbit ◽  
Fadil M. Hannan ◽  
Una Graham ◽  
Michael P. Whyte ◽  
Patrick J. Morrison ◽  
...  
Keyword(s):  
Elevated Serum ◽  
Urinary Calcium ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Coding Region ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Polymorphic Loci ◽  
Calcium Sensing ◽  
Serum Pth ◽  
Type 3

Abstract Context: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogenous disorder that consists of three defined types, FHH1, FHH2, and FHH3 whose chromosomal locations are 3q21.1, 19p, and 19q13, respectively. FHH1, caused by mutations of the calcium-sensing receptor (CASR), occurs in more than 65% of patients, whereas the abnormalities underlying FHH2 and FHH3, which have each been described in single North American kindreds, are unknown. Objective: The aim of this study was to determine the basis of FHH in a proband, who did not have CASR mutations, and her kindred. Patients and Methods: The proband was a 43-yr-old woman who presented with a corrected serum calcium of 2.74 mmol/liter (normal = 2.15–2.55 mmol/liter), a serum PTH of 47 pg/ml (normal = 10–65 pg/ml), and a urinary calcium clearance:creatinine clearance of 0.006. She did not have a CASR mutation within the coding region and splice sites, and 24 members from three generations of her kindred were ascertained and investigated for serum abnormalities and cosegregation with polymorphic loci from chromosomes 3q21.1 and 19q13 using leukocyte DNA. Results: Sixteen members were hypercalcemic with normal or elevated serum PTH concentrations and mild hypophosphatemia, features consistent with FHH3. Use of microsatellite and single nucleotide polymorphic loci from chromosome 19q13.3 demonstrated cosegregation with FHH in the kindred, with a peak LOD score = 5.98 at 0% recombination with D19S412. Analysis of recombinants mapped FHH to a 3.46-Mbp interval flanked centromerically by single nucleotide polymorphism rs1990932 and telomerically by D19S604. Conclusions: FHH3 may explain the calcium homeostasis disorder in those FHH patients who do not have CASR mutations.

scholarly journals Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients

2018 ◽  
Vol 2018 ◽  
Author(s):  
E Mogas ◽  
A Campos-Martorell ◽  
M Clemente ◽  
L Castaño ◽  
A Moreno-Galdó ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Rare Condition ◽  
List Type ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Severe Hypercalcemia ◽  
The Right ◽  
Learning Points

Summary Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. Learning points: Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity. Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed. Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients. Treatment has been well tolerated and no side effects have been detected.

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 Familial hypocalciuric hypercalcemia as a differential diagnosis of primary hyperparathyroidism with negative images

Medunab ◽  
2022 ◽  
Vol 24 (3) ◽  
pp. 347-352
Author(s):  
Edwin Antonio Wandurraga-Sánchez ◽  
Mario Alejandro Buitrago-Gómez ◽  
María Camila Uribe-Forero ◽  
Nestor Andrés Díaz-Posada ◽  
María Camila Amaya-Muñoz
Keyword(s):  
Differential Diagnosis ◽  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Creatinine Clearance ◽  
Parathyroid Adenoma ◽  
Receptor Gene ◽  
Hormone Secretion ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Clearance Ratio ◽  
Metabolism Disorder

Introduction. Familial hypocalciuric hypercalcemia is a rare inherited calcium metabolism disorder in which an alteration of the parathyroid hormone secretion set-point causes hypercalcemia with relative hypocalciuria. Some data suggest that its prevalence is around 74.1 per 100,000 inhabitants. Often, patients are asymptomatic. However, they can develop mild symptoms and an overactive parathyroid adenoma, its main differential diagnosis. The objective was to describe a patient’s case and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas. Case report. This is the case of a 40-year-old man with a biochemical profile compatible with primary hyperparathyroidism with anatomical and functional images negative for adenoma and a calcium/creatinine clearance ratio below 0.001, considering familial hypocalciuric hypercalcemia. Genetic studies evidence a mutation in the calcium sensor receptor gene and confirm the diagnosis. Discussion. Familial hypocalciuric hypercalcemia’s main differential diagnosis is an overactive parathyroid adenoma. For both, mild or no symptoms may be present; serum calcium exceeds the upper limit, and parathormone is more than 25pg/ml. The calcium/creatinine clearance ratio should be used to differentiate one from the other and avoid unnecessary surgical neck explorations. Besides the lack of information on this topic, evidence supports the use of calcimimetics to treat symptomatic hypercalcemia. Conclusions. Patients with mild hypercalcemia with parathyroid hormone readings above 25pg/ml and a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative imaging, should not undergo surgical neck explorations. In these cases, familial hypocalciuric hypercalcemia is a reliable diagnosis; Cinacalcet may be administered in cases of symptomatic hypercalcemia.

scholarly journals New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT)

2011 ◽  
Vol 55 (1) ◽  
pp. 67-71 ◽  
Author(s):  
Luiza Souza Rodrigues ◽  
Ana Carolina Arias Cáu ◽  
Luciane Zgoda Bussmann ◽  
Gabriela Bastida ◽  
Oscar H. Brunetto ◽  
...  
Keyword(s):  
Homozygous Mutation ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Severe Hypercalcemia ◽  
Threatening Condition ◽  
Life Threatening ◽  
Intracellular Domains ◽  
Inactive Protein

A loss of calcium-sensing receptor (CASR) function due to inactivating mutations can cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). NSHPT represents the most severe expression of FHH and courses as a life-threatening condition. The aim of this study was to identify and characterize a CASR mutation in a female infant brought to the health service due to dehydration, apathy, lack of breast feeding and severe hypercalcemia. Molecular analysis was performed on genomic DNA of the index case and her parents. A novel homozygous mutation (p.E519X) in CASR was identified in the proband; both mother and father had the same mutation in heterozygous state, confirming their FHH condition. The mutation results in a truncated and inactive protein due to the lack of transmembrane and intracellular domains. The identification of this novel CASR gene mutation established the basis of hypercalcemia in this family and allowed a genetic counseling.

scholarly journals AP2S1 and GNA11 mutations – not a common cause of familial hypocalciuric hypercalcemia

2017 ◽  
Vol 176 (2) ◽  
pp. 177-185 ◽  
Author(s):  
Silje Hovden ◽  
Lars Rejnmark ◽  
Søren A Ladefoged ◽  
Peter H Nissen
Keyword(s):  
Cross Sectional Study ◽  
Control Group ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Gene Encoding ◽  
Cross Sectional ◽  
Calcium Sensing ◽  
Pathogenic Mutations ◽  
Type 3

Objective Familial hypocalciuric hypercalcemia (FHH) type 1 is caused by mutations in the gene encoding the calcium-sensing receptor (CASR). Recently, mutations affecting codon 15 in the gene AP2S1 have been shown to cause FHH type 3 in up to 26% of CASR-negative FHH patients. Similarly, mutations in the gene GNA11 have been shown to cause FHH type 2. We hypothesized that mutations in AP2S1 and GNA11 are causative in Danish patients with suspected FHH and that these mutations are not found in patients with primary hyperparathyroidism (PHPT), which is the main differential diagnostic disorder. Design Cross-sectional study. Methods We identified patients with unexplained hyperparathyroid hypercalcemia and a control group of verified PHPT patients through review of 421 patients tested for CASR mutations in the period 2006–2014. DNA sequencing of all amino acid coding exons including intron–exon boundaries in AP2S1 and GNA11 was performed. Results In 33 CASR-negative patients with suspected FHH, we found two (~6%) with a mutation in AP2S1 (p.Arg15Leu and p.Arg15His). Family screening confirmed the genotype–phenotype correlations. We did not identify any pathogenic mutations in GNA11. No pathogenic mutations were found in the PHPT control group. Conclusions We suggest that the best diagnostic approach to hyperparathyroid hypercalcemic patients suspected to have FHH is to screen the CASR and AP2S1 codon 15 for mutations. If the results are negative and there is still suspicion of an inherited condition (i.e. family history), then GNA11 should be examined.

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