X-linked hypophosphatemia

X-linked hypophosphatemia (XLH), also called X-linked dominant hypophosphatemic rickets, X-linked vitamin d-resistant rickets or hypophosphatemic vitamin d-resistant rickets (HPDR),^[1] 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.^[2] The prevalence of the disease is 1:20000.^[3] The leg deformity can be treated with Ilizarov frames and CHAOS surgery.

Cause and Genetics

X-linked dominant inheritance works differently depending upon whether the mother (left image) or father (right image) is the carrier of a gene that causes a disease or disorder

XLH is associated with a mutation in the PHEX gene sequence, located on the human X chromosome at location Xp22.2-p22.1.^[1][2][4] The mutation results in altered (or missing) activity of the PHEX protein, which inactivates hormone-like substances (phosphatonins) that regulate phosphate excretion; the resulting excess excretion of phosphate impairs bone mineralization (osteomalacia). Also, in the absence of PHEX enzymatic activity, osteopontin^[5] — a mineralization-inhibiting secreted substrate protein found in the extracellular matrix of bone^[6] — may accumulate in the bone to contribute to the osteomalacia as shown in the mouse homolog (Hyp) of XLH.^[7] 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.^[1][2] 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 gender 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 dominant and recessive inheritance patterns also plays a role in determining the chances of a child inheriting an X-linked disorder from their parentage.

Difference in male to female

An affected male males legs bow outwards (ankles touch, but not the knees), causing the identification of the disease to be at a later age than in females. Females legs bow inwards (knees touch, but not the ankles).

Treatment

Oral phosphate,^[8] calcitriol,^[8] And, in the event of severe bowing, an Osteotomy may be performed to correct the leg shape.^{[citation needed]}

See also

• hypophosphatemia

References

External links

• 00754 at CHORUS
• Hypophosphatemic rickets; XLH; Hypophosphatemia, vitamin D-resistant rickets at NIH's Office of Rare Diseases
• The PHEXdb - a database of nucleotide variation in the PHEX gene
• The XLH Network Inc. - a worldwide patient support organization