A novel mutation in the calcium sensing receptor gene in a neonate with severe hyperparathyroidism. .

Parathyroid hormone (PTH) is the major calciotropic hormone in the body. PTH secretion is increased by hypocalcaemia, through interaction of ionized calcium with calcium sensing receptors (CASR) (8). Neonatal severe Hyperparathyroidism (NSHPT) is a life-threatening condition with severe hypercalcemia, hypotonia, bone demineralization, respiratory distress, failure to thrive, feeding difficulties, vomiting, skeletal abnormalities, kidney stones, hypertension and hypercalciuria (7,8). NSHPT is a rare autosomal dominant disease associated with an inactivating homozygous mutation of the CASR. CASR is a G-protein-coupled receptor found in the cell membranes in the parathyroid glands. It plays a key role in calcium homeostasis, activates phospholipase C when there is an increase in calcemia, and decreases PTH secretion (1,3). CASR is also expressed in other tissues, including bone marrow, brain, intestine and kidney. Activation of the parathyroid CASR by extracellular ionized calcium inhibits secretion of PTH, while in the distal renal tubule cells receptor activation leads to enhanced urinary excretion of calcium (10). We here present a newborn case of NSHPT with a novel mutation which has never been described before neither as a mutation nor as a polymorphism, and discuss the treatment in relation to the defined mutation.A-3500 g-male newborn with 40 weeks gestation was bom to a 41-year-old mother by normal vaginal delivery after an uneventful pregnancy. On the postnatal 6th day he was brought to the regional hospital for hypoactivity, difficulty in sucking and poor oral intake.Although his physical examination was unremarkable, biochemical analysis showed severe hypercalcemia (29.8 mg/dl) (N; 8.6-10.2 mg/ dl) with hypophosphatemia (2.1 mg/dl) (N; 3.5-7J mg/dl) and normal serum alkaline phosphatase (ALP) activity (224 U/L) (N; He was diagnosed as severe hyperparathyroidism and referred to our hospital after control of hypercalcemia with intravenous biphosphanate (Pamidronat) (Aredia, Novartis Pharma, Switzerland). He was admitted to our neonatal intensive care unit (NICU) on the postnatal 1 llh day with a Ca level of 14.2 mg/dl. The physical examination was recorded as normal except his cachectic appearance. His weight, length and head circumference were 2775 g (10-25 p), 51 cm (75-90 p) and 34 cm (50-75p), respectively. Family history revealed second degree consanguinity between parents and the patient was the youngest of nine siblings. There was no history of another hypercalcemie case in his family.The follow-up of the patient for Ca and PTH levels are shown in Figures 1-2. X-rays showed no signs of calcification but mild bone resorption in the extremities. Although cranial ultrasonography (USG) was normal, abdominal USG revealed renal echogenity secondary to nephrolithiasis. Parathyroid and thyroid USG was unrevealing.Genomic DNA was extracted from the patient and his mothers and sequencing analysis for the six coding exons and junctions for intron/ exon was conducted. Genetic evaluation was performed at The University Hospital of Limoges, France. Homozygous p.MlLys point mutation ( c.242T>A) was detected in the patient and both of the parents were heterozygote for the mutation.The patient was given pamidronate treatment on the postnatal 7th and 8lh days of life at a dose of 0.5 mg/kg/d to control hypercalcemia which was persistent to hydration and fiirosemide treatments at the regional hospital. Patient showed a stable normocalcemic period at upper margins until the postnatal 33th day when Ca level was 14.1 mg/dl and cinacalcet (Mimpara, Eczacibaci, Turkey) treatment at a dose of 0.5 mg/ kg/d was started, and increased to 3 mg/kg/d. The patient was given a single intravenous pamidronate at a dose of 0. …