NORD gratefully acknowledges Thomas O. Carpenter, MD, Pediatric Endocrinology, Yale University School of Medicine, for assistance in the preparation of this report.
Familial hypophosphatemia is a rare inherited disorder characterized by impaired transport of phosphate and often altered vitamin-D metabolism in the kidneys. In addition, phosphate may not be well-absorbed in the intestines. The hypophosphatemia resulting from these impairments can lead to a skeletal defect called osteomalacia, which can be considered a softening of bones. Familial hypophosphatemia also results in rickets, a childhood bone disease with characteristic bow deformities of the legs, as well as growth plate abnormalities and progressive softening of the bone as occurs in osteomalacia. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. In children, growth rates may be slower than normal, frequently resulting in short stature. Familial hypophosphatemia is most often inherited as an X-linked trait. However, autosomal dominant and recessive forms of familial hypophosphatemia occur.
Signs and symptoms of familial hypophosphatemia vary greatly, and are usually first noticed after eighteen months of age. Children often present with progressive bow deformities, short stature, and can develop bone pain. Adults may complain of osteomalacia-related pain, propensity to fracture, arthritis, or pain attributable to abnormal mineralization at the site of muscular attachments.
Infants may have an abnormally tall, narrow head (dolichocephaly), or abnormally early fusion of the skull bones (craniosynostosis). Toddlers may have an abnormal “waddling” walk (gait) due to abnormally bowed legs (genu varus). In some cases, the knees are bent inwards such that they are too close together (knock knees or genu valgum). Hip deformities in which the thighbone angles towards the center of the body (coxa vara) may occur. Affected individuals often reach a shorter adult height than would otherwise be expected. In older adults, narrowing of the spine (spinal stenosis), and abnormal side-to-side curvature of the spine (scoliosis) may occur.
Symptoms such as weakness and intermittent muscle cramps may also occur, although this is not a usual finding in childhood. Cases of familial hypophosphatemia may range from mild to severe. Some cases may have no noticeable symptoms while other cases may be marked by pain and/or stiffness of the back, hips, and shoulders possibly limiting mobility. In later adulthood calcification of tendons and ligaments, and the development of bone spurs or bony protrusions can further limit mobility and cause pain.
Dental problems such as decay and abscesses or late eruption of teeth may develop in individuals with familial hypophosphatemia. In addition, affected individuals may experience enamel defects and an increased frequency of cavities (caries). In some cases, hearing impairment due to malformation of the inner ears (sensorineural hearing loss) may also be present.
In most cases, familial hypophosphatemia is inherited as a dominant X-linked trait, however variant forms may be inherited as an autosomal dominant or recessive trait.
In contrast to most X-linked disorders, which are recessive, X-linked dominant disorders are evident in a female with one normal X chromosome and one affected X chromosome.
X-linked familial hypophosphatemia (XLH) is caused by disruption or changes (mutations) of the PHEX gene located on the short arm (p) of the X chromosome (Xp22.2-22.1).* The PHEX protein is a member of an enzyme family of proteins, but at present it is not clear why the loss of a functional PHEX protein results in hypophosphatemic rickets. Individuals with XLH have been found to have elevated circulating levels of a novel growth factor called FGF23, and this factor has been shown to act on the kidney to result in excessive urinary excretion of phosphate. The mechanism by which the elevated FGF23 levels occur in the setting of PHEX dysfunction is also not understood.
* [Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”. Chromosomes are further subdivided into bands that are numbered. For example, “chromosome Xp22.2-22.1” refers to bands 22.2 through 22.1 on the short arm of chromosome X.]
Similarly, autosomal dominant familial hypophosphatemia (ADHR) may be caused by specific changes (mutations) of the FGF23 (Fibroblast Growth Factor 23) gene located on the short arm (p) of chromosome 12 (12p13.3). These changes result in a variant type of FGF23 that persists for longer than normal periods of time in the body, and can result in elevated FGF23 blood levels.
In familial hypophosphatemia, symptoms occur, at least in part, because of an impaired ability of the kidneys to retain phosphate. If the blood levels of phosphate become abnormally low, bone mineralization becomes impaired, thereby weakening the bones and leading to osteomalacia and bowed bones.
In addition there is a second renal abnormality in XLH and ADHR related to the activation of vitamin D. Active vitamin D formation is required for the body to maintain a normal handling of calcium, another important mineral important to bones. Both of these abnormalities of kidney function that of phosphate conservation and of vitamin D activation are mediated by the high levels of circulating FGF23.
XLH may affect males and females in equal numbers. Cases affecting males have been said to be more severe than those affecting females, but this issue is controversial as a great variation in degree of severity exists. XLH occurs in one in 10,000 to 20,000 individuals. More recent estimates suggest that the figure may be as high as one in 20,000. XLH is the most common form of heritable rickets in the United States. The related disorder, ADHR, is encountered far less frequently.
Treatment of familial hypophosphatemia is symptomatic and supportive. Treatment consists of providing phosphate as well as an activated vitamin-D metabolite such as calcitriol. This treatment must be carefully monitored to prevent excess blood or urinary calcium levels. Vitamin-D compounds do not cure the disorder completely, but help the body retain phosphate and help with preventing the complications of too much secretion of a hormone called parathyroid hormone or PTH. Phosphate enhances the bone healing, but also does not completely cure the disease.
Treatment of affected individuals with this combination of vitamin D and phosphate may result in several side effects, including calcium deposits in the kidneys (nephrocalcinosis), excess levels of calcium in the blood (hypercalcemia), and excess levels of calcium in the urine (hypercalciuria).
Covering teeth with sealants has been suggested as a preventive measure for the spontaneous abscesses associated with familial hypophosphatemia. Genetic counseling may be of benefit for affected individuals and their families.
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