Clinical Overview > Condition/ Syndrome > Familial hypocalciuric hypercalcaemia
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University of Queensland, Herston, Queensland, Australia
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University of Queensland, Herston, Queensland, Australia
Pathology Queensland, Australia
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Griffith University, Southport, Queensland, Australia
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Summary
Distinguishing primary hyperparathyroidism (PHPT) from familial hypocalciuric hypercalcaemia (FHH) can be challenging. Currently, 24-h urinary calcium is used to differentiate between the two conditions in vitamin D replete patients, with urinary calcium creatinine clearance ratio (UCCR) <0.01 suggestive of FHH and >0.02 supportive of PHPT. A 26-year-old Caucasian gentleman presented with recurrent mild hypercalcaemia and inappropriately normal parathyroid hormone (PTH) following previous parathyroidectomy 3 years prior. He had symptoms of fatigue and light-headedness. He did not have any other symptoms of hypercalcaemia. His previous evaluation appeared to be consistent with PHPT as evidenced by hypercalcaemia with inappropriately normal PTH and UCCR of 0.0118 (borderline low using guidelines of >0.01 consistent with PHPT). He underwent parathyroidectomy and three parathyroid glands were removed. His calcium briefly normalised after surgery, but rose again to pre-surgery levels within 3 months. Subsequently, he presented to our centre and repeated investigations showed 24-h urinary calcium of 4.6 mmol/day and UCCR of 0.0081 which prompted assessment for FHH. His calcium-sensing receptor (CASR) gene was sequenced and a rare inactivating variant was detected. This variant was described once previously in the literature. His mother was also confirmed to have mild hypercalcaemia with hypocalciuria and, on further enquiry, had the same CASR variant. The CASR variant was classified as likely pathogenic and is consistent with the diagnosis of FHH. This case highlights the challenges in differentiating FHH from PHPT. Accurate diagnosis is vital to prevent unnecessary surgical intervention in the FHH population and is not always straightforward.
Learning points:
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Distinguishing FHH from PHPT with co-existing vitamin D deficiency is difficult as this can mimic FHH. Therefore, ensure patients are vitamin D replete prior to performing 24-h urinary calcium collection.
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Individuals with borderline UCCR could have either FHH or PHPT. Consider performing CASR gene sequencing for UCCR between 0.01 and 0.02.
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Parathyroid imaging is not required for making the diagnosis of PHPT. It is performed when surgery is considered after confirming the diagnosis of PHPT.
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Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
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Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
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Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
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Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
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Hospital Universitario Cruces, UPV/EHU, Barakaldo, Spain
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Summary
Familial hypocalciuric hypercalcemia type I is an autosomal dominant disorder caused by heterozygous loss-of-function mutations in the CASR gene and is characterized by moderately elevated serum calcium concentrations, low urinary calcium excretion and inappropriately normal or mildly elevated parathyroid hormone (PTH) concentrations. We performed a clinical and genetic characterization of one patient suspected of familial hypocalciuric hypercalcemia type I. Patient presented persistent hypercalcemia with normal PTH and 25-hydroxyvitamin D levels. The CASR was screened for mutations by PCR followed by direct Sanger sequencing and, in order to detect large deletions or duplications, multiplex ligation-dependent probe amplification (MLPA) was used. One large deletion of 973 nucleotides in heterozygous state (c.1733-255_2450del) was detected. This is the first large deletion detected by the MLPA technique in the CASR gene.
Learning points:
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Molecular studies are important to confirm the differential diagnosis of FHH from primary hyperparathyroidism.
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Large deletions or duplications in the CASR gene can be detected by the MLPA technique.
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Understanding the functional impact of the mutations is critical for leading pharmacological research and could facilitate the therapy of patients.
Autonomous University of Barcelona, Barcelona, Spain
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Autonomous University of Barcelona, Barcelona, Spain
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Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
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Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, UPV-EHU, CIBERDEM, Cruces University Hospital, Barakaldo, Spain
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Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
Department of Pediatrics, Children’s University Hospital Vall Hebron, Barcelona, Spain
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Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
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Autonomous University of Barcelona, Barcelona, Spain
Centre for Biomedical Research Network on Rare Diseases (CIBERER), Madrid, Spain
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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:
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Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity.
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Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed.
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Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients.
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Treatment has been well tolerated and no side effects have been detected.
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Summary
A 22-year-old female student presented with a history of recurrent pancreatitis. The commonest causes of pancreatitis, including drugs, gallstones, corticosteroids, excess alcohol and hypertriglyceridaemia, were excluded. She was found to have an elevated serum calcium level that was considered to be the cause of her pancreatitis, with a detectable serum parathyroid hormone (PTH). An initial diagnosis of primary hyperparathyroidism was made. However, two neck explorations failed to reveal a parathyroid adenoma. She was referred to our unit three years later as her episodes of pancreatitis were becoming more frequent and her calcium level remained persistently elevated. Her investigations were as follows: elevated adjusted calcium level of 2.79 mmol/l (2.2–2.58), PTH level of 4.2 pmol/l (0.6–6.0), low 24 h urine calcium of 0.3 mmol/l and a urine calcium:creatinine ratio of <0.003. A clinical diagnosis of familial hypocalciuric hypercalcaemia (FHH) was made and confirmed on genetic testing that showed a c.1703 G>A mutation in the calcium-sensing receptor gene. Although the hypercalcaemia of FHH is usually without sequelae due to the generalised changes in calcium sensing, in the presence of this complication she was started on cinacalcet 30 mg daily. She had one further episode of pancreatitis with calcium levels ranging between 2.53 and 2.66 mmol/l. Her cinacalcet was gradually increased to 30 mg three times daily, maintaining her calcium levels in the range of 2.15–2.20 mmol/l. She has not had a further episode of pancreatitis for more than 2 years.
FHH is usually a benign condition with minimal complications from hypercalcaemia. Pancreatitis has been reported rarely, and no clear management strategy has been defined in these cases. Cinacalcet was successfully used in treating recurrent pancreatitis in a patient with FHH by maintaining calcium levels in the lower part of the reference range. Whether or not this is an effective long-term treatment remains yet to be seen.
Learning points
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FHH is an important differential diagnosis for hypercalcaemia.
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FHH can rarely cause pancreatitis.
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No clear strategy is available to help in the management of patients with pancreatitis due to FHH.
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Cinacalcet was effective in lowering serum calcium levels and reducing the frequency of pancreatitis in our patient with FHH.
