Endocrine Abstracts

Hypophosphatemic rickets is a genetically heterogeneous disorder of defective renal phosphate transport and vitamin D metabolism with an X-linked dominant (XLHR), autosomal-dominant (ADHR) or autosomal-recessive (ARHR) pattern of inheritance. Germline mutations in the PHEX gene are associated with the X-linked form which affects both males and females. The autosomal dominant form is characterised by mutations in the FGF23 gene and the autosomal recessive form by mutations in the DMP1 (ARHR type 1) or ENPP1 (ARHR type 2) genes. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive disorder associated with mutations in the SLC34A3 gene. Our laboratory has offered testing for PHEX gene mutations since 2002 and has recently extended this service to include all the genes listed above. Test methodology involves direct sequencing for all genes and dosage analysis by MLPA for the PHEX gene. A total of 181 index cases have been referred for testing. The mutation detection rate is 61% for the PHEX gene, increasing to 88% for cases with a family history and 13% for FGF23. Three patients with SLC34A3 or ENPP1 mutations have been identified. Inactivating mutations in ENPP1 can cause arterial calcifications and it is therefore important to distinguish these patients to ensure an appropriate treatment regime. In total a genetic diagnosis has been obtained for 76% of probands referred for testing. Identifying the genetic aetiology confirms the clinical subtype, provides prognostic information and accurate estimation of the recurrence risk. Genetic testing early in life for at-risk individuals enables early diagnosis and prompt treatment to avoid irreversible bone deformities.