X-LINKED HYPOPHOSPHATEMIA Tom Gillespie Rinzin Dorjee Martin Kutti

X-LINKED DOMINANT HYPOPHOSPHATEMIC RICKETS, X- LINKED VITAMIN D-RESISTANT RICKETS OR HYPOPHOSPHATEMIC VITAMIN D-RESISTANT RICKETS (HPDR)  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).  Marked by bone distortions, nodular enlargements on the ends and sides of the bone, delayed closure of the fontanelles, muscle pain etc.  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

INFECTED CHILDREN

CAUSES 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 mutation results in altered (or missing) activity of the PHEX protein, which inactivates hormone-like substances (phosphatonins) that promote phosphate excretion.  The resulting excess excretion of phosphate impairs bone mineralization  Biochemically, XLH is recognized by hypophosphatemia and inappropriately low level of calcitriol  The disorder is inherited in an X-linked dominant manner.

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 - homozygous 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 due to the fact that, typically, females have two copies of the X-chromosome, while 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.

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

REFERENCES  1. Online 'Mendelian Inheritance in Man' (OMIM)  2. "Familial hypophosphatemic rickets caused by a large deletion in PHEX gene". European Journal of Endocrinology 161 (4): 647–651.  3. Carpenter TO (Apr 1997). "New perspectives on the biology and treatment of X-linked hypophosphatemic rickets".