X-Linked Hypophosphatemia: Featuring PHEX Genetics

Introduction

X-linked Hypophosphatemia is an uncommon genetic disorder that is characterized by low levels of blood phosphate as a result of abnormal processing by the kidney. Loss of phosphate through urine (phosphate washing ) occurs. This leads to weak and soft bones (rickets). The condition is mostly diagnosed in childhood and is characterized by short stature, bent legs, dental pain, and bone pain. Hearing and mobility may also be affected. The condition is very rare and affects 1 in 20,000 people.

The condition is also referred to as:

• X-linked Rickets.

• Phosphate Diabetes.

• Vitamin-D-resistant rickets.

• Hypophosphatemic rickets.

The condition is also referred to as vitamin-D-resistant rickets, as it resembles symptoms of vitamin D deficiency but does not respond to treatment with vitamin D supplementation.

What Are the Causes of X-Linked Hypophosphatemia?

Phosphorous is a mineral that is present in the teeth and bones and plays a role in bone repair. It is an essential mineral for growth and development. X-linked Hypophosphatemia (XLH) is caused by a genetic mutation in the PHEX gene on the X chromosome. This gene is responsible for phosphate regulation in the body. As a result of this change, the kidneys become unable to process phosphorous properly.

The condition also results in increased formation of fibroblast growth factor 23. This, in turn, blocks the kidney’s ability to process phosphorous. As a result, too much phosphorous is lost through urine, a condition called phosphate wasting.

There are different causes for rickets, with XLH being one of them. The condition is inherited and is passed down from parent to child. In some 20 percent of cases, the condition is not linked to any family history.

The condition has an X-linked dominant inheritance pattern. Females have a pair of X-chromosomes, while males have one Y chromosome and one X chromosome. Female offspring inherit one X chromosome from the mother and one from the father. Male offspring inherit one X chromosome from the mother and one Y chromosome from the father. If the father has an X-linked mutation, all his female children are affected, but the male child is unaffected. If the mother has the X-linked mutation, there will be a 50 percent chance that her child will be affected (male or female).

What Are the Symptoms of X-Linked Hypophosphatemia?

Symptoms can start in infancy or childhood. The age at which symptoms appear varies. The disease's severity varies from one person to another. As phosphorous is essential for bone growth and development, the affected children grow slowly and usually have short statures.

The childhood symptoms include

• Muscle and bone pain.

• Short stature.

• Abnormal tooth development.

• A delayed ability to stand up at the appropriate developmental stage.

• A delayed ability to walk at the appropriate developmental stage.

• Bowed legs.

• Soft and weak bones (rickets).

Some symptoms are mild and are recognized only in adulthood.

These include:

• Muscle weakness.

• Abnormal walking pattern.

• Hearing loss.

• Joint pain.

• Chronic fractures.

• Fatigue.

• Swollen ankles and wrists.

• Calcification of tendon.

• Knee osteoarthritis.

• Disorders in ligaments and tendons.

• Bending of long bones.

Undiagnosed fractures found on X-rays, bone pain, and tender joints are mostly the initial signs of XLH.

How Is X-Linked Hypophosphatemia Diagnosed?

If XLH or any other type of rickets is suspected, the healthcare professional takes the following steps:

• Thoroughly evaluate the medical history to analyze the occurrence of symptoms.

• Inquire about the familial history of the condition.

• Physical examination.

• Blood tests help evaluate low blood phosphorous levels and high fibroblast growth factor 23 levels.

• Elevation of alkaline phosphatase levels in children.

• Parathyroid hormone levels are normal or slightly elevated.

• Normal serum calcium levels.

• 25-hydroxyvitamin D levels are normal.

• Imaging studies help in evaluating bone density. Radiologic studies show a widening of metaphysis in children. In some cases, the beading of ribs due to poor skeletal mineralization is seen.

• Molecular genetic testing to evaluate the inheritance pattern.

What Is the Differential Diagnosis of X-Linked Hypophosphatemia?

• ADHR (AD Hypophosphatemic Rickets) - ADHR is much rarer when compared to XLH, and phosphate wasting resolves later in life.

• Tumor-Induced Osteomalacia- Though it can occur at any age, most of those with the condition are adults.

• AR Hypophosphatemic Rickets- This is an extremely rare condition.

• McCune-Albright Syndrome- It is similar to hypophosphatemic rickets but is characterized by cafe au lait lesions.

• Fanconi Syndrome- This condition also presents with renal phosphate loss. But it is characterized by bicarbonaturia, glycosuria, and aminoaciduria.

• Nutritional Form of Rickets - The skeletal changes of nutritional and hereditary forms of rickets are difficult to distinguish. But vitamin D-deficient rickets is linked with low levels of 25-hydroxyvitamin D in serum, and serum calcium levels may be low or normal.

• Raine Syndrome - Raine syndrome also presents with hypophosphatemia, and a severe form of the condition is neonatal lethal.

What Are the Treatment Options of X-Linked Hypophosphatemia?

Pharmacological Treatment:

• Pharmacological treatment mainly aims at correcting bone deformities and pain management. In children, treatment is initiated at diagnosis and continues until long bone growth is completed.

• Oral phosphate and calcitriol are administered three to five times daily.

• Different treatment regimens are followed, including high-dose and low-dose regimens. Dose adjustments are made based on therapeutic success and complications.

• In adults, treatment is done in individuals with upcoming orthopedic surgery, skeletal pain, recurrent pseudofractures, etc. The usual dose of calcitriol is .5 to 0.75 micrograms daily for adults.

Orthopedic Treatment:

• In cases of lower extremity malalignment due to persistent lower limb bowing, orthopedic intervention may be required even after pharmacological treatment.

• The surgical treatment options for older children and adults include distraction osteogenesis by external fixation, acute correction by intramedullary nailing, and internal fixation with intramedullary nailing.

Dental Treatment:

The affected are susceptible to recurrent dental abscesses, so good oral hygiene maintenance and regular dental care are important.

Conclusion

X-linked Hypophosphatemia is a rare disorder, mostly inherited through an autosomal dominant pattern. The age of onset is usually infancy or childhood, and the symptoms and disease severity vary from one individual to another. Bowed legs, bone pain, muscle weakness, and other symptoms characterize the condition. The blood phosphorous levels are low in such cases. Treatment options include pharmacological management and orthopedic interventions.