Severe hypocalcemia due to a de novo mutation in the fifth transmembrane domain of the calcium‐sensing receptor

The extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor, abundantly expressed in plasma membranes of parathyroid and kidney cells, where it regulates the secretion of parathyroid hormone (PTH) and urinary calcium excretion, respectively [Brown et al., 1993; Brown and MacLeod, 2001]. The CaR is also expressed in a variety of other cells seemingly not involved in systemic mineral ion homeostasis where its actions are poorly understood [Chattopadhyay et al., 1998]. Even small changes in circulating calcium concentration activate the CaR and inhibit the secretion of PTH from the parathyroid gland while decreasing resorption of filtered calcium in the renal cortical thick ascending limb of Henle. The physiologic importance of the CaR in regulating extracellular calcium homeostasis is emphasized by the identification of inactivating or activating mutations [Hofer and Brown, 2003]. The phenotypic consequences of loss of CaR function are hypercalcemia with hypocalciuria, while gain of CaR function is responsible for hypocalcemia and hypercalciuria. Since the first report [Pollak et al., 1993], more than 30 different activating mutations have been identified [Hu and Spiegel, 2003]. Activating mutations are responsible for a well-characterized disease, defined as autosomal dominant hypocalcemia (ADH). The clinical hallmarks of this condition are low serum calcium levels, high inorganic phosphate concentrations, and inappropriately low or undetectable serum PTH. Moreover, urinary calcium excretion is increased, frequently leading to nephrocalcinosis. The clinical presentation and the severity of the symptoms are extremely variable, even within family members carrying the same mutation [Hu et al., 2002]. We report on the first sporadic case of a young child carrying an activating mutation that alters the transmembrane domain of the CaR, leading to a severe form of ADH. The propositus is the second child of unrelatedparents. Thepatient (karyotype, 46 XY)wasborn at termbyCesarean. At 4 days of life, he presented with clonic movements of the extremities. Initial laboratory data revealed low serum total and ionized calcium concentrations: 1.7 mmol/L of total calcium (Ca) (normal range 1.9–2.6 mmol/L) and 0.86 mmol/L of ionized calcium (iCa) (normal range 1.05–1.48 mmol/L). The serum level of PTH was 1.9 pg/ml (normal range 12–72 pg/ml). Despite treatment with Ca gluconate i.v. and 25 hydroxyvitamin D (calcifediol), the patients had frequent episodes of hypocalcemia. Laboratory analyses showed low Ca (1.62 mmol/L) and iCa (0.80.9 mmol/L) levels, high serum phosphate concentration (3.3 mmol/L), and high urinary Ca/Creatinine ratio (0.7–0.8). PTH levels were persistently lower than normal. After discharge from the hospital (4 months of age), the patient was referred to our center. Calcium levels were persistently lower than normal (1.83 mmol/L), and serum phosphate (3.3 mmol/L) and urinary Ca/creatinine ratio (0.72) were high. Serum concentrations of magnesium were low (0.68 mmol/L). PTH serum levels were inappropriately low, according to serum calcium concentration. Renal ultrasound revealed signs of nephrocalcinosis. Computed tomography revealed basal ganglia calcifications. Ophthalmologic examination showed no alteration. The diagnosis of primary hypoparathyroidism was, therefore, made.