X-linked hypophosphatemia

XLH, X-linked vitamin D-resistant rickets, X-linked dominant hypophosphatemic rickets


X-linked hypophosphatemia (XLH, also called X-linked dominant hypophosphatemic rickets, X-linked vitamin d-resistant rickets ),is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. The prevalence of the disease is 1:20000. The leg deformity can be treated with Ilizarov frames and CHAOS surgery.

Symptoms - X-linked hypophosphatemia

XLH manifests during childhood with typical clinical features of rickets such as skeletal deformities (bowed legs, genu varum, rachitic rosary...), short stature, and bone pain. Cranial anomalies are observed due to thickness of parietal and frontal bones.Dental abnormalities (abscesses, cavities, abnormal enamal) are also observed in children and adults. In adults, mineralizing enthesopathy, osteophyte formation and osteoarthritis of the lower limbs  commonly occur and, in some rare cases, hearing loss has been observed. Hypotonia and muscle weakness are absent.

Causes - X-linked hypophosphatemia

LH is associated with a mutation in the PHEX gene sequence, located on the human X chromosome at location Xp22.2-p22.1. The PHEX protein regulates another protein called fibroblast growth factor 23 (produced from the FGF23 gene). Fibroblast growth factor 23 normally inhibits the kidneys' ability to reabsorb phosphate into the bloodstream. Gene mutations in PHEX prevent it from correctly regulating fibroblast growth factor 23. The resulting overactivity of FGF-23 reduces vitamin D 1α-hydroxylation and phosphate reabsorption by the kidneys, leading to hypophosphatemia and the related features of hereditary hypophosphatemic rickets. Also, in the absence of PHEX enzymatic activity, osteopontin- a mineralization-inhibiting secreted substrate protein found in the extracellular matrix of bonemay accumulate in the bone to contribute to the osteomalacia as shown in the mouse homolog (Hyp) of XLH. Biochemically, XLH is recognized by hypophosphatemia and inappropriately low level of calcitriol (1,25-(OH)2 vitamin D3). It also affects their equilibrium, only to the effect of their balance, which their knee/ankle joints are either farther outward or inward. A person affected by this disease usually cannot touch both knees and ankles together.

The disorder is inherited in an X-linked dominant manner. This means the defective gene responsible for the disorder (PHEX) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder. Males are normally hemizygous for the X chromosome, having only one copy. As a result, X-linked dominant disorders usually show higher expressivity in males than females.

As the X chromosome is one of the sex chromosomes (the other being the Y chromosome), X-linked inheritance is determined by the sex of the parent carrying a specific gene and can often seem complex. This is because, typically, females have two copies of the X-chromosome and males have only one copy. The difference between dominantand recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.

Prevention - X-linked hypophosphatemia

Not supplied.

Diagnosis - X-linked hypophosphatemia

Clinical findings

typical rickets/osteomalacia radiographic feautures:

  • Children: fraying and cupping of metaphyseal regions
  • Adults: pseudofactures and enthesopathies).

Biochemical findings

  • Hyperphosphaturia
  • Elevated circulating levels of FGF-23 associated with hypophosphatemia
  • Normal serum levels of parathyroid hormone and calcium
  • Increased or normal plasma levels of alkaline phosphatise
  • Normal plasma calcidiol concentration and inappropriately normal or low serum levels of calcitriol.

Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate.

Iliac bone biopsy

osteomalacia and hypomineralized periosteocytic lesions.

Molecular genetic testing

confirms the diagnosis

Prognosis - X-linked hypophosphatemia

Prognosis is good and skeletal deformities can be normalized with consistent treatment. but growth rates usually remain subnormal.

Treatment - X-linked hypophosphatemia

Oral phosphate, calcitriol, in the event of severe bowing, an osteotomy may be performed to correct the leg shape.

Resources - X-linked hypophosphatemia

Not supplied.
Orphan Therapies
by Scott Harwood