Mutational analysis of TAC and TACR3 in idiopathic central precocious puberty.

BACKGROUND: The genetic background of idiopathic central precocious puberty (ICPP) is not well understood, and is thought to arise from the effect of multiple genes. Familial ICPP have been reported suggesting the existence of monogenic causes of ICPP. The neurokinin B (NKB) system has recently been implicated in the regulation of the human reproductive axis. In humans, NKB and its receptor are encoded by the TAC3 and TACR3 genes, respectively. Mutations in these genes have been suggested to be causative for ICPP. METHODS: ICPP was defined by pubertal onset before 8 yrs of age in girls, and a pubertal LH response to GnRH testing. Twenty eight girls with ICPP were included in the study (age at diagnosis was 5.72±2.59; bone age, 6.12±2.81, height at the start of treatment, 0.90±1.48 SD). LHRH test was performed and was pubertal in all subjects (LH 20.35±32.37 mIU/ml; FSH 23.32±15.72 mIU/ml). The coding regions of TAC and TACR3 were sequenced. RESULTS: No rare variants were detected in TAC and TACR3 in the 28 subjects with ICPP. CONCLUSIONS: We confirmed that mutations in TAC and TACR3 are not a common cause for ICPP.

Hypomagnesemia with hypercalciuria and nephrocalcinosis: case report and a family study.

A 7-month-old male infant was referred for investigation after a documented febrile urinary tract infection. His past medical history was characterized by episodes of unexplained fever and mild dehydration. The ultrasound examination of his kidneys demonstrated bilateral diffuse medullary nephrocalcinosis. His serum and urine biochemistry revealed hypomagnesemia (0.4 mmol/l), hyperuricaemia (506 micromol/l), mildly increased iPTH (71 pg/ml) and hypercalciuria (16.0 mg/kg/day). The diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was confirmed by mutational analysis of the CLDN16 gene, encoding paracellin-1. Sequencing displayed a homozygous Leu151Phe exchange affecting the first extracellular loop of paracellin-1. There were eight family relatives who underwent biochemical analysis, renal ultrasound and genetic investigation for CLDN16 mutations. Five of them were found to be heterozygous for the Leu151Phe mutation. Two heterozygotes (the mother and the maternal grandfather) presented with hypercalciuria. The grandfather had a history of recurrent passage of calculi. These findings point to the role of heterozygous CLDN16 gene mutations in renal pathophysiology. In conclusion, patients suspected of having FHHNC should be screened for CLDN16 mutations, especially with respect to genetic counseling. In addition, heterozygotes at risk should be clinically assessed in order to prevent renal complications of hypercalciuria.