X-linked hypophosphatemic rickets (XLH), also known as Familial hypophosphatemic rickets, or vitamin D-resistant rickets is a rare genetic disorder characterized by low levels of the mineral phosphorus in the blood. Unlike rickets, which occurs from a nutritional deficiency of vitamin D, XLH does not respond to vitamin D intake. Children with XLH develop leg bowing, short stature and tooth abscesses. The involved gene has recently been localized to the X chromosome.
It is estimated that one in 20,000 children has XLH in the US. XLH is a hereditary condition. It is not contagious or preventable. XLH is an X-linked dominant condition occurring mostly in males. Women with XLH are less severely affected. Females with XLH have a 50% risk of transmitting the condition to their children. Males with XLH will transmit the disorder only to their daughters. They cannot transmit the XLH to their sons because boys receive their X chromosome from their mothers. Most affected children will have a family history of XLH symptoms. However, approximately one third of children with XLH did not receive the defective gene from their parents, instead spontaneous mutation of the gene occurred.
Signs and Symptoms
Infants with XLH develop normally. Bowing of the bones does not occur until children reach walking age and begin to bear weight. While mild bowing of the legs is common in healthy toddlers and resolves with growth, in XLH the deformity continues to progress. Legs are more severely affected than arms. Children may waddle when walking or refuse to stand or walk. They may develop an exaggerated forward curvature of the lower spine to compensate for the leg bowing. Abnormal shaping of the skull may also occur. Infrequently this may cause crowding of the brain. Narrowing of the spinal canal can also develop and cause back and leg pain. Calcium deposits in tendons and ligaments can appear at various ages. Bone and joint pain are common. Short stature resulting from poor bone growth and bone deformity is a hallmark of XLH. Left untreated, adults will not grow to more than 130-165 cm (4 foot 3 inches to 5 foot 5 inches) tall. Tooth development is delayed and abscesses occur commonly due to under-mineralization of the tooth pulp, which results in expansion of the pulp and diminishes the barrier to oral bacteria. While hearing loss occurs commonly, intellectual development is usually normal. Seizures do not occur. In contrast to vitamin D-deficient rickets, in XLH, muscle weakness does not occur unless phosphate levels drop severely.
As bone is formed from calcium and phosphate, inadequate phosphate levels lead to poor bone mineralization and bowing or bending of the bones. Vitamin D and other hormones influence the levels of calcium and phosphate in the body. Vitamin D is activated in the kidney and increases the absorption of calcium and phosphate from the intestines. In XLH, phosphate levels in the blood are low due to inability of the kidneys to reabsorb phosphate from the urine and due to inadequate levels of activated vitamin D.
XLH has been localized to a gene on the X chromosome called PHEX (Phosphate regulating gene with Homologies to Endopeptidases on the X chromosome). Mutation of the PHEX gene results in decreased ability of the kidneys to reabsorb phosphate and convert inactive vitamin D to the active form.
XLH is diagnosed by physical examination, blood and urine testing and radiography. Starting at 6-10 months of age, blood phosphate levels are low and urine phosphate levels are high. Blood calcium levels are normal or slightly low. Urine calcium excretion is normal. In affected children, alkaline phosphatase, an indicator of bone breakdown, is elevated. Vitamin D levels are normal instead of being elevated in response to low phosphate. Levels of parathyroid hormone, a hormone involved in regulation of calcium, are normal to slightly elevated. X-rays of the wrists, knees, ankles and long bones show the typical findings of rickets as early as 1 year of age. These findings include increased bone volume, but low bone mineral content.
Currently no molecular testing is available to confirm the diagnosis of XLH. DNA analysis is possible in large families with many affected members. If the mutated gene is identified, prenatal testing of the unborn child and parent is possible.
Presently, there is no cure for XLH. Early treatment can minimize bone deformity and maximize growth. The goal of therapy is to achieve bone mineralization and prevent soft tissue calcification. Oral phosphate supplements are necessary to replace phosphate loss in the urine. The most common side effect of phosphate therapy is diarrhea, which often resolves with time. In addition, vitamin D supplementation is necessary to increase calcium and phosphate absorption in the intestines and help heal bones. The usual vitamin D preparations are no longer used because very high doses are required and toxicity from high blood calcium frequently occurs. Instead, calcitriol, the active form of vitamin D, is prescribed. Healing of the bones occurs within 2 months of starting therapy. Therapy improves bone mineralization and growth. However, calcium deposition (nephrocalcinosis) in the kidneys is a common side effect. In fact, 50% of properly treated patients will develop this problem within 3 to 4 years of beginning therapy. Fortunately, these calcium deposits do not appear to progress to kidney failure. More serious but infrequent complications of therapy include calcifications in the eye and heart. A kidney specialist must closely monitor calcium and phosphate levels in the urine and blood and perform periodic kidney ultrasounds to adjust medication doses. Two other medications, amiloride and hydrochlorothiazide, may help increase calcium reabsorption in the kidneys, reduce the risk of renal stones and counteract bone calcium loss.
Even with therapy, dental abscesses occur. Periodic dental procedures and close follow-ups with a dentist are required. Surgery by an orthopedic surgeon experienced in procedures in children with XLH can realign extremely distorted leg curvature. However, surgery cannot be performed until the bones have healed. Skull deformity may require helmet use and/or surgical intervention. Properly treated children may still not achieve average height. Growth hormone to improve stature is an expensive option. Recently, leg-lengthening procedures have been tried in a few patients.
Normal life span can be expected in affected individuals. Once the rickets is completely healed, activity is no longer restricted. Until then, children should not engage in contact sports, as fractures can occur.
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A very comprehensive article on this disorder.
Carpenter TO (April 1997). New perspectives on the biology and treatment of X-linked hypophosphatemic rickets. Pediatric Clinics North America, 44(2): 443-66.
Author unknown (2004) Familial Hypophosphatemia (Vitamin D Resistant Rickets, X-Linked Hypophosphatemia, In: Behrman RE, Kliegman RM, Jenson HB (eds) Nelson Textbook of Pediatrics, 17th ed, Elsevier, p. 2345-2347.