X-linked hypophosphatemic (XLH) rickets is a rare genetic disorder related to low levels of phosphate in the blood, termed hypophosphatemia. Phosphate is a mineral that is essential for bone and teeth formation, helping nerves function and helping with muscle contraction.
XLH is the most common form of rickets that runs in families, with an incidence of about 1 in 20,000 newborns. Affected children experience slow growth and are shorter than their peers. As stated in the title of the condition, these children develop rickets which is a term used to describe the various bony abnormalities that result from low phosphate levels. The most noticeable of these bony abnormalities is severe bowing of the knees. If untreated, the condition worsens with time.
Genetics
Researchers have described the genetic pattern of inheritance for XLH in detail. The condition is “X-linked,” meaning that the mutated gene is carried on the X chromosome and males are more likely to be afflicted in families who carry the gene.
An affected male passes the gene variant to all of his daughters and none of his sons, while an affected female passes the variant to 50 percent of her offspring. Given that males possess an X and Y chromosome they are more likely to be affected, while females (with 2 X chromosomes) are less likely to be affected. The gene responsible has been identified as the PHEX gene, which plays an important role in preserving phosphate balance in the body. Mutations in the PHEX gene impair the kidney’s ability to reabsorb phosphate into the bloodstream. Thus, too much phosphate gets excreted through the kidneys and the body becomes depleted of its phosphate stores.
Signs/Symptoms
Signs of XLH typically manifest in the first two years of life when leg bowing (outward curving of the lower extremities) becomes apparent with the onset of weight bearing. Other signs/symptoms include: impaired growth, bone tenderness, muscle weakness, dental abscesses, increased tendency for fractures, muscle spasms, wrist widening, hearing loss and kidney stones.
Diagnosis/Testing
The diagnosis of XLH is based on clinical findings, imaging, blood work and family history. The clinical findings that prompt consideration of XLH are described in the Signs/symptoms section above. X-rays may show bony abnormalities of the upper extremities, lower extremities and sometimes ribs. Occasionally, X-rays may reveal bone fractures. Kidney ultrasound may reveal kidney stones, a complication of this condition. Blood work typically reveals low levels of phosphorous, and high levels of alkaline phosphatase. Blood calcium levels and Vitamin D 25 (OH) levels are typically normal. Finally, a pivotal clue to the diagnosis is a calculation based on blood work and urine studies to determine if the kidneys are appropriately reabsorbing phosphate. If suspicion for XLH is high, your doctor may order molecular genetic testing for the PHEX gene. Additionally, if the PHEX variant has been identified in the family, genetic testing may be suggested for family members, especially newborns at risk in order to ensure early treatment for optimal outcome.
Additional testing to evaluate manifestations of disease: kidney function testing, kidney ultrasound, hormone levels related to phosphate balance.
Treatment
Treatment of XLH focuses on the correction of phosphate levels in the blood and oral vitamin D therapy to ensure adequate bone growth and development. If diagnosed early, pain and leg bowing typically improve with frequent oral administration of phosphate and high-dose calcitriol (active form of vitamin D) therapy. Children are generally treated from the time of diagnosis to the cessation of long bone growth. Good oral hygiene with flossing and regular dental follow-up is encouraged to prevent dental abscesses.
For patients on phosphate and calcitriol therapy, the following surveillance examinations are required:
- Blood work: regular monitoring of phosphate, calcium, kidney function, alkaline phosphatase and parathyroid hormone level
- Urine studies: calcium, phosphate and creatinine
- X-rays: lower extremity X-rays to assess skeletal response to therapy
- Ultrasound: yearly kidney ultrasounds to assess for kidney stones
- Dental examinations: at least two times per year
Outlook
Long-term outcomes of patients with XLH are largely dependent on proper commitment to phosphate and vitamin D therapy. Untreated XLH is associated with growth limitation and bony abnormalities, whereas treatment with oral phosphate and Vitamin D therapy may improve growth. Height velocity commonly increases during the initial year of therapy. Despite improvement in growth with treatment, correction is limited and typical adult height is usually not met. Leg deformities may correct spontaneously, alleviating the need for surgery, however this is not always the case. If leg deformities worsen and impair the child’s ability to ambulate, orthopedic surgery consultation may be sought to evaluate surgical options.
Other secondary complications of XLH which may arise despite therapy include kidney stones, high blood pressure, dental infections/abscesses and electrolyte abnormalities. Therefore, children with XLH require close monitoring and care by a nephrologist who can assist families with proper monitoring and treatment of this condition.