|Classification and external resources|
X-linked hypophosphatemia (XLH), also called X-linked dominant hypophosphatemic rickets, X-linked vitamin d-resistant rickets or hypophosphatemic vitamin d-resistant rickets (HPDR), 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.
Cause and Genetics
XLH 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 this protein reduces 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 bone — may 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 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).
- Online 'Mendelian Inheritance in Man' (OMIM) 307800"HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR". 23 May 2011.
- Saito, T.; Nishii, Y.; Yasuda, T.; Ito, N.; Suzuki, H.; Igarashi, T.; Fukumoto, S.; Fujita, T. (Oct 2009). "Familial hypophosphatemic rickets caused by a large deletion in PHEX gene". European Journal of Endocrinology 161 (4): 647–651. doi:10.1530/EJE-09-0261. PMID 19581284.
- Carpenter TO (Apr 1997). "New perspectives on the biology and treatment of X-linked hypophosphatemic rickets". Pediatr. Clin. North Am. 44 (2): 443–466. doi:10.1016/S0031-3955(05)70485-5. PMID 9130929.
- 300550"PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED; PHEX". 18 April 2011.
- Sodek, J; et al (2000). "Osteopontin". Critical Reviews in Oral Biology and Medicine 11 (3): 279–303. doi:10.1177/10454411000110030101. PMID 11021631.
- McKee, MD; et al (2005). "Hierarchies of extracellular matrix and mineral organization in bone of the craniofacial complex and skeleton". Cells Tissues Organs 181 (3–4): 176–188. doi:10.1159/000091379. PMID 16612083.
- Barros, NMT; et al (2013). "Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia". Journal of Bone and Mineral Research 28 (3): 688–699. doi:10.1002/jbmr.1766. PMID 22991293.
- Imel, E. A.; DiMeglio, L. A.; Hui, S. L.; Carpenter, T. O.; Econs, M. J. (15 February 2010). "Treatment of X-Linked Hypophosphatemia with Calcitriol and Phosphate Increases Circulating Fibroblast Growth Factor 23 Concentrations". Journal of Clinical Endocrinology & Metabolism 95 (4): 1846–1850. doi:10.1210/jc.2009-1671. PMC 2853995. PMID 20157195.
- 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