Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism—lack of effect of cinacalcet |
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| Affiliation: | 1. Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul 34899, Turkey;2. Department of Neonatology, Marmara University, Pendik, Istanbul 34899, Turkey;3. Department of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec H3A 0G4, Canada;4. Calcium Research Laboratory and Hormones and Cancer Research Unit, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada;5. Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics, University of Toronto, Toronto, Ontario M5G IL5, Canada;1. Department of Cardiology, Saitama Medical University International Medical Center, Saitama, Japan;2. Department of Endocrinology and Diabetes, Saitama Medical University, Saitama, Japan;3. Department of Nuclear Medicine, Saitama Medical University International Medical Center, Saitama, Japan;4. Department of Cardiovascular Surgery, Saitama Medical University International Medical Center, Saitama, Japan;5. Department of Cardiovascular and Internal Medicine, Kanazawa University School of Medicine, Ishikawa, Japan;1. Division of Endocrinology, Diabetes and Metabolic Bone Diseases, Department of Medicine III, Dresden Technical University Medical Center, Germany;2. Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria;3. Vienna University of Technology, Austria;4. Krankenhaus der Barmherzigen Brüder, Vienna, Austria;5. Medical University of Vienna, Vienna, Austria;6. Harvard Medical School, Boston, USA;7. Center for Regenerative Therapies Dresden, Germany;8. University of Veterinary Medicine Vienna, Austria |
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| Abstract: | BackgroundNSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice.ObjectiveTo describe a case of NSHPT unresponsive to cinacalcet.Patient and ResultsA 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10–2.62), P: 0.83 mmol/l (1.55–2.64), PTH: 1096 pg/ml (9–52) and urinary Ca/Cr ratio: 0.5 mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5 mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion–frameshift mutation.ConclusionThe predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy. |
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