Test Directory

Hypophosphatemic rickets, autosomal dominant

Hypophosphatemic rickets, autosomal dominant (ADHR; MIM 193100) is a disorder characterized by a highly variable phenotype with renal phosphate wasting and incomplete penetrance. Patients may be grouped by the age of onset. Childhood onset is characterized by short stature, rickets, growth retardation and lower limb abnormalities. Those with adult onset have generalized weakness and pseudofractures. Additional findings may also include tooth abscesses, bone pain and osteomalacia. Laboratory findings are hypophosphatemia, increased serum alkaline phosphatase, normocalcemia, normal serum parathyroid hormone and inappropriately normal serum 1,25-dihydroxyvitamin D3. ADHR is caused by mutations in the fibroblast growth factor 23 (FGF23) gene.

Hypophosphatemic rickets, X-linked dominant

 Hypophosphatemic rickets, X-linked dominant (XLH; MIM 307800) is also known as X-linked hypophosphatemia. This disorder is considered to represent the most common form of heritable rickets or osteomalacia. It is characterized by short stature resulting from growth retardation, bowing of the lower extremities with the onset of weight bearing, curvatures of the femur, tibia and fibula, frontal bossing, dolichocephaly, calcification of tendons, ligaments and joint capsules, hypomineralized teeth with recurrent abscesses, bone and joint pain, and osteoarthritis with pseudofractures in adults. Laboratory findings include: hypophosphatemia due to renal phosphate wasting, increased serum alkaline phosphatase, normal to low normal serum calcium, inappropriately normal to low normal 1,25-dihydroxyvitamine D3 and normal to mildly increased PTH. This disorder has been linked to the PHEX gene. To date more than 150 discrete mutations have described in PHEX.

Vitamin D-dependent rickets, type I

Vitamin D-dependent rickets, type I (VDDR I; MIM 264700) is an autosomal recessive disorder due to defects in the CYP27B1 gene. This gene encodes a component of 25-hydroxyvitamin D3-1-alpha-hydroxylase, the enzyme responsible for the hydroxylation of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, the most active form of vitamin D. Children with vitamin D-dependent rickets have typical findings associated with the malabsorption of calcium. These include: Failure to thrive, growth retardation, hypotonia, delayed motor development, possible seizures and skeletal findings associated with rickets. Rickets is characterized by increased fractures, enlargement of the costochondral junctions (rachitic ribs), delayed opacification of the epiphyses, widened distorted epiphyses, sparse bone trabeculae, frayed irregular metaphyses, bowed legs and curving of the femurs, tibia and fibula, frontal bossing, widened sutures and deformed rib cage with pigeon breast. Laboratory findings include hypocalcemia, hypophosphatemia, low serum 1,25-hydroxyvitamin D3 and features of secondary hyperparathyroidism. Adults with this disorder may display osteomalacia.

Hypophosphatemic rickets, autosomal recessive

Hypophosphatemic rickets, autosomal recessive, 1 (ARHR1; MIM 241520) is caused by mutations in the dentin matrix acidic phosphoprotein 1 gene (DMP1) and hypophosphatemic rickets, autosomal recessive, 2 (ARHR2; MIM 613312) is caused by mutations in the ectonucleotide pyrophosphatase / phosphodiesterase 1 gene (ENPP1). DMP1 is a highly acidic, serine rich protein critical for osteocyte maturation. Several loss of function mutations have been described in DMP1. ENPP1 is a transmembrane glycoprotein regulating soft tissue calcification and bone and joint cartilage mineralization via generation of pyrophosphate (PPi). PPi is a physiological inhibitor of hydroxyapatite crystal formation and a suppressor of chondrogenesis. Loss of function mutations have also been described in ENPP1. Mutations in ENPP1 also cause generalized arterial calcification of infancy 1 (GACI1; MIM 208000). In at least one instance, the identical homozygous ENPP1 mutation has been shown to cause hypophosphatemic rickets in a father and generalized arterial calcification of infancy in his son. The clinical, biochemical and morphological findings in autosomal recessive hypophosphatemic rickets are similar to those associated with X-linked dominant and autosomal dominant hypophosphatemic rickets. Autosomal recessive hypophosphatemic rickets is a vitamin D resistant infantile rickets caused by early fusion of cranial sutures, bone deformities, deafness, renal phosphate wasting and elevated plasma FGF23.