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 some people, phosphate may not be well-absorbed in the intestines. The hypophosphatemia resulting from these impairments can lead to a skeletal defect called osteomalacia, or 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 impaired, 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 at about eighteen months of age. Children often present with progressive bow or knock-knee deformities, and/or short stature. Bone pain often develops when the child is actively engaged in physical activities. Adults may complain of osteomalacia-related pain, propensity to fracture, arthritis, or pain attributable to excess mineralization of tendons 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 patients, 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 individuals may have no noticeable symptoms while other patients 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. Affected individuals may less frequently develop enamel defects and an increased frequency of cavities (caries). In some affected individuals, hearing impairment due to malformation of the inner ears (sensorineural hearing loss) may also be present.
In most individuals, familial hypophosphatemia is inherited as an X-linked dominant trait, however variant forms may be inherited as an autosomal dominant or recessive trait.
In contrast to most X-linked disorders, which are recessive, primarily affecting males (in which the only X chromosome is affected), X-linked dominant disorders also occur in heterozygous females (with only one affected X chromosome and one normal 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 it is not precisely clear what the cellular function of PHEX is. The bone cells that express PHEX also secrete an important hormone called FGF23, which is produced in increased amounts when the PHEX protein loses its function, as occurs in XLH. 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 affects both males and females. In some families it has been anecdotally observed that females may have less severe features of the disease than males. However such a great variation in degree of severity exists overall, that it is not clear that this is always the case. The most widely cited estimated prevalence of XLH is one in 20,000 individuals. XLH is the most common form of heritable rickets in the United States. The related disorders, ADHR and ARHR, are encountered far less frequently.
Treatment of familial hypophosphatemia includes provision of supplemental phosphate salts and activated forms of vitamin D, such as calcitriol. Symptomatic and supportive measures are important as well. The usual medication regimen must be carefully monitored to prevent excess blood or urinary calcium levels. The approach does not completely cure the disorder. The vitamin D compounds help with phosphate balance and also assist with preventing the complications of too much secretion of parathyroid hormone (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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