Hypophosphatemia is a group of inherited disorders in which there is abnormally low levels of the substance phosphate in the blood, leading to softening of the bones. This condition can result in rickets, a childhood disease in which soft and weak bones can lead to the development of bone deformities. While there is no cure, treatment can prevent the bone changes and allow proper growth of bones.
Bone is one of the strongest tissues of the human body. As the main component of the adult skeleton, it provides support for movement, protects the brain and organs of the chest from injury, and contains the bone marrow, where blood cells are formed. Bone is made up of several components, including a substance called hydroxyapatite. Hydroxyapatite is made of calcium and phosphate and is partially responsible for the strength of bone.
Because of the importance of hydroxyapatite, the strength of bone is dependent on the proper levels of calcium and phosphate within the body. A lack of calcium or phosphate in the diet or a failure in maintaining proper levels of calcium or phosphate in the blood can lead to abnormalities of bone growth. Another factor required for proper development of bone is vitamin D. Vitamin D is either obtained through foods in the diet, or is made by the body in response to sunlight exposure. Vitamin D is converted to another substance within the body called calcitriol. Calcitriol promotes bone development by helping to absorb calcium and phosphate from the diet and by preventing the loss of calcium and phosphate in the urine.
Hypophosphatemia is a group of inherited disorders in which there is abnormally low phosphate levels in the blood because large amounts of phosphate exit the body through the urine. In some forms of the disease there may also be problems in the conversion of vitamin D to calcitriol. Research suggests that inherited hypophosphatemia syndromes result from an abnormality in the way the kidney handles phosphate. Normally, the kidney prevents phosphate from leaving the body in the urine, but in hypophosphatemia, an abnormality in the way the kidney handles phosphate leads to large losses of phosphate in the urine. This results in abnormally low levels of phosphate in the blood, leading to poor hydroxyapatite formation and soft bones. Insufficient levels of phosphate for bone formation results in rickets, a childhood condition in which there is abnormal bone development, growth, and repair (when this occurs in adults, it is called osteomalacia). Inherited hypophosphatemia was first described by R. W. Winters in 1958 and has been referred to in the past as vitamin D-resistant rickets or familial hypophosphatemic rickets.
Hypophosphatemia is a group of conditions that can be inherited or passed on in a family. The different types of hypophosphatemia have different causes, patterns of inheritance, and symptoms.
The most common and widely studied form of hypophosphatemia is hereditary hypophosphatemia type I, also known as X-linked hypophosphatemia (XLH). The abnormality in XLH is in a gene called PHEX. It is not known precisely how this gene affects phosphate handling by the kidney. Changes in other genes have been shown to cause hypophosphatemia, but the mechanism is similarly unclear. While most occurrences of hypophosphatemia are passed from parent to child, there are several examples of new genetic changes arising in a child with no relatives with hypophosphatemia.
There are different patterns of inheritance in different forms of hypophosphatemia, including autosomal dominant inheritance and X-linked dominant inheritance. In autosomal dominant inheritance, only one abnormal
X-linked dominant inheritance is similar to autosomal dominant inheritance in that only one abnormal gene is needed to display the disease. However, in X-linked dominant inheritance, the genetic abnormality is located on the X chromosome. Females have two X chromosomes, whereas males only have one X chromosome. Females have a 50% chance of passing the abnormal gene on to either a son or a daughter, as the mother always contributes one X chromosome to a child. On the other hand, males with the abnormal X chromosome will always pass the abnormal gene to a daughter (the father will contribute the abnormal X chromosome), but never to a son (the father will contribute a normal Y chromosome, and not the abnormal X chromosome)
Hypophosphatemia has been estimated to be present in between one in 10,000 and one in 100,000 people, but one in 20,000 people is the most widely quoted figure. It is not known whether this disease is present equally among different geographical areas and ethnic groups. The first reports of the condition found hypophosphatemia in a Bedouin (nomadic Arab) tribe.
Signs and symptoms
Major symptoms of hypophosphatemia include poor growth, bone pain, abnormally bowed legs, weakness, tooth abscesses and sometimes listlessness and irritability in infants and young children. Although the disease affects all bones, the legs are more severely affected than the arms, ribs, or pelvis. The bowed legs are often noted by 12 months of age, and the altered growth increases in severity as the child grows older. Because of poor hydroxyapatite formation, people may experience fractures, and abnormal healing follows, further contributing to growth abnormalities. As a result of poor bone development and poor healing, people with hypophosphatemia often have short stature and may have a waddling walk. Other, less common manifestations of hypophosphatemia include high blood pressure and hearing loss or deafness.
While most symptoms are the same in the different types of hypophosphatemia, there may be small changes in the severity and age at which the person will experience the symptoms.
If there is no family history of hypophosphatemia, diagnosis is usually guided by physical exam. Obvious bow leg deformities will lead to x rays of the legs and knees, which will show characteristic bone abnormalities. Other studies of bone strength using radioactive tracer materials can be used, or a bone biopsy (surgical excision of a small portion of bone for inspection with a microscope) can be performed to confirm that there is less hydroxyapatite than normal.
Laboratory tests aid in determining the cause of poor bone growth and rickets. In XLH, the serum phosphorus is low and the levels of serum calcium and calcitriol are low or sometimes normal. However, urine levels of phosphate are high, indicating that phosphate is being lost in the urine and that the kidney is not reabsorbing the phosphate properly. Another laboratory finding in XLH is the presence of increased alkaline phosphatase, a enzyme that breaks down bone. However, alkaline phosphatase is often elevated in growing children compared to normal adult values. Other forms of hypophosphatemia may have other variations in laboratory findings, including normal calcitriol levels or high levels of calcium in the urine and can be used to distinguish between the different types of hypophosphatemia.
Treatment and management
There is no cure, but medical and surgical treatment can greatly improve the outcome of people with hypophosphatemia. Goals of treatment include improvement in growth, reduction in severity of bone disease, bowed legs, and activity limitations, and minimizing the complications that may develop from the treatment itself.
Medical treatment is directed toward increasing the blood phosphate levels by using phosphate salts and calcitriol, both given by mouth. However, phosphate may have to be given five times a day because it is rapidly lost in the urine, and phosphate often causes diarrhea. Despite these drawbacks, the response to the medications is very good, and bowed legs may straighten over several years of growth. Scientific studies are also being performed to determine if growth hormone can help in achieving normal growth and height development.
Health care providers are able to monitor the person's ability to take the medication by checking the phosphate levels in the urine and the blood. It is recommended that these tests be performed in small children every three months to determine if they are receiving adequate amounts of phosphate. Later, the monitoring can be decreased to every four to six months. It is also recommended that childhood x rays of the knee be performed every one to two years to see whether medication changes are needed.
Some problems may result from the medications used to treat hypophosphatemia. High levels of calcium can build up in the bloodstream causing problems with the kidneys and the parathyroid (a gland in the neck). Because of these problems, routine calcium measurements and kidney ultrasound studies should be performed to determine if additional medications should be added or changes in medications should be made.
Treatment with medication is sometimes not enough to reverse the bone abnormalities. In cases such as these, surgery can be performed to reshape or even lengthen the bones.
With early diagnosis and treatment, the prognosis for people with hypophosphatemia is excellent. Adult heights of 170 cm may be achievable, compared to 130-165 cm without treatment. While some degree of abnormal bone growth may always be detectable, people with hypophosphatemia will generally live normal lifespans.
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Oren Traub, MD, PhD