Hypophosphatemic rickets is an X-linked dominant inherited bone disorder, characterized by renal phosphate wasting, inappropriately normal to low vitamin D serum levels and severe skeletal and dental defects from early childhood. Inactivating mutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X-chromosome) have been identified as the underlying cause, although the pathomechanism is unknown. The PHEX gene encodes a membrane-bound metalloprotease that is expressed mainly in bone and teeth, but not in the kidney.
We screened 31 patients with suspected XLH by direct sequencing of PCR amplified genomic DNA. In 17 patients (55%) 14 different inactivating mutations in the PHEX gene were identified. The mutations detected include missense, nonsense, splice site and frameshift mutations. In one family a deletion of exon 22 was found. Twelve of these mutations are novel mutations. Among our patients there were four families with hypophosphatemia with pedigrees of two or more consecutive generations, most cases, however, are sporadic. In one of the families, hypophosphatemic rickets was found in four generations. The two year old index patient showed deformities of the lower extremities and low serum phosphate levels which normalized under therapy (phosphate substitution, Vitamin D). Her mother needed surgical corrections of the lower extremities at the age of 13, while the grandmother showed a less severe phenotype. From the grandmothers father severe deformities and a complete loss of mobility are reported. Molecular genetic testing revealed a double mutation in the index patient: Two novel missense mutations were detected, the substitution of cysteine 59 by serine in exon 2 and replacement of alanine 363 by valine in exon 10.
In conclusion, confirmation of the diagnosis of hypophosphatemic rickets by molecular genetic testing has important implications for the clinical management of the patient and affected family members.
01 - 05 Apr 2006
European Society of Endocrinology