Inherited rickets is often associated with growth retardation, bowing of the lower extremities, and poor dental development. X-linked dominant hypophosphatemic rickets, due to mutations in the PHEX gene, is the most common inherited form of the disorder. Both males and females are affected with the disease and male-to-male transmission is NOT observed. Few cases of dominant hypohosphatemic rickets are associated with mutation in the autosomal FGF23 gene. Rickets due to mutation in FGF23 demonstrates greater clinical variability due to incomplete penetrance and delayed onset. Male-to-male transmission of FGF23 mutation is possible. Rickets due to both PHEX and FGF23 is NOT responsive to treatment with Vitamin D. In contrast, Pseudovitamin D-deficiency rickets is an autosomal recessive condition due to mutations in the CYP27B1 gene and is responsive to treatment with Vitamin D. Another autosomal recessive form of rickets characterized by hypophosphatemia and osteomalacia, which is phenotypically similar to the more common X-linked form but is responsive to treatment with phosphate and vitamin D substitution, is caused by mutations in the DMP1 gene. Choosing which gene to analyze in a patient with inherited rickets should be based on family and/or medical history. For sporadic cases, analysis of PHEX should precede that of FGF23, as it is the most common cause of Vitamin D-resistant rickets.
Mutations in each of the four genes associated with hereditary rickets are identified by complete sequence analysis of entire coding region of the associated genes. In addition, PHEX analysis in females includes targeted array CGH analysis with exon-level resolution (ExonArrayDx) to evaluate for a deletion or duplication of one or more exons of this gene. The PHEX analysis requires a blood specimen (1-5ml in EDTA), while other tests can be performed on blood or buccal swabs (GeneDx kits only). Carrier detection in relatives and prenatal diagnosis is available once a mutation or deletion in a family has been defined.