Which are the causes of X-linked Hypophosphatemia (XLH)?

X-linked hypophosphatemia (XLH) is a rare genetic disorder that affects the bones and teeth. It is caused by mutations in the PHEX gene, which is located on the X chromosome. This means that the condition primarily affects males, as they have only one X chromosome, while females have two and can compensate for the mutation.

The PHEX gene provides instructions for producing an enzyme called phosphate-regulating endopeptidase homolog X-linked (PHEX). This enzyme plays a crucial role in regulating the levels of phosphate in the body. Phosphate is essential for the development and maintenance of bones and teeth.

In XLH, the mutations in the PHEX gene lead to reduced or absent activity of the PHEX enzyme. As a result, phosphate levels in the blood become abnormally low, a condition known as hypophosphatemia. This disrupts the normal process of bone mineralization, leading to skeletal abnormalities and impairments in growth.

XLH is an X-linked disorder, meaning that the mutated gene is located on the X chromosome. Males have one X chromosome and one Y chromosome, while females have two X chromosomes. Since the PHEX gene is located on the X chromosome, males are more severely affected by XLH because they have only one copy of the gene. Females, on the other hand, have a second, unaffected copy of the gene on their other X chromosome, which can partially compensate for the mutation.

XLH is typically inherited in an X-linked dominant manner. This means that if a mother carries the mutated gene, there is a 50% chance of passing it on to each of her children, regardless of their gender. However, the severity of the condition can vary even among affected individuals within the same family.

While XLH is primarily caused by genetic mutations, there have been rare cases where the condition occurs sporadically without a family history of the disorder. In these cases, the exact cause is unknown, and it is believed to be due to de novo mutations that arise spontaneously during early development.

In conclusion, X-linked hypophosphatemia is caused by mutations in the PHEX gene, leading to reduced or absent activity of the PHEX enzyme. This results in low phosphate levels in the blood, affecting bone mineralization and causing skeletal abnormalities. The condition is primarily inherited in an X-linked dominant manner, with males being more severely affected due to having only one X chromosome. While the exact cause of sporadic cases is unknown, they are believed to be caused by de novo mutations.