Years published: 1987, 1988, 1989, 1992, 1993, 1994, 1995, 2000, 2005, 2010, 2013, 2016, 2019, 2023
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 term that describes a group of rare inherited disorders characterized by impaired kidney conservation of phosphate and in some cases, altered vitamin D metabolism. In contrast, other forms of hypophosphatemia may result from inadequate dietary supply of phosphate or its poor absorption from the intestines. The chronic hypophosphatemia resulting from these impairments can lead to rickets, a childhood bone disease with characteristic bow deformities of the legs, growth plate abnormalities and progressive softening of the bone, referred to as osteomalacia. In children, growth rates may be impaired, frequently resulting in short stature. In adults, the growth plate is not present so that osteomalacia is the evident bone problem. Familial hypophosphatemia is most often inherited in an X-linked dominant manner; 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 bone fracture, arthritis or pain related to excess mineralization of tendons at the site of muscular attachments.
Infants may have an abnormally tall, narrow head (dolichocephaly), a relative enlargement of the front-to-back dimension (scaphocephaly) 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. Osteoarthritis-like features occur frequently in adults at earlier ages than would be otherwise expected.
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 others 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. Less frequently, affected individuals 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 in an X-linked dominant manner, however variant forms may be inherited in an autosomal dominant or recessive manner.
In contrast to most X-linked disorders which are recessive and primarily affect 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 hypophosphatemia (XLH) is caused by a change (variant or mutation) in the PHEX gene located on the X chromosome resulting in a variant type of PHEX protein. 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 there is impaired function of the PHEX protein, as occurs in XLH. FGF23 acts on the kidney and results in excessive urinary excretion of phosphate, but the mechanism by which elevated FGF23 levels occur in the setting of PHEX dysfunction is not understood.
Similarly, autosomal dominant hypophosphatemic rickets (ADHR) may be caused by specific variants of the FGF23 gene located on chromosome 12. These changes result in a variant type of FGF23 protein 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.
A second renal abnormality in XLH and ADHR is impaired activation of vitamin D. Active vitamin D formation is required for the body to maintain a normal handling of calcium, another mineral important to bones. Both of these abnormalities of kidney function (phosphate conservation and conservation of vitamin D activation) are due to 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 for XLH, 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 diagnosed far less frequently.
Tumor-induced osteomalacia (TIO) is an acquired hypophosphatemic disorder that may mimic the inherited hypophosphatemic disorders due to the resulting elevation in FGF23 hormone levels that occur. TIO tumors are usually small but produce excess amounts of FGF23. TIO is important to recognize as it can be entirely cured by removal of the tumor.
All of the above forms of hypophosphatemia have clinical features in common related to excess circulating FGF23 hormone
Familial hypophosphatemia (FH) is primarily considered a skeletal disease due to excess kidney losses of phosphate. The presentation may differ between various forms of the disease and by age. Children are brought to clinical attention with the signs and symptoms described above, including bowing of the legs, short stature and multiple dental abscesses. Such findings are then investigated with X-rays. In children, rachitic changes of the growth plate area of rapidly growing bones establish rickets as the primary skeletal issue and trigger further investigation. It is helpful for diagnosis if there is a likely pattern of inheritance of the disorder in the family history. The diagnosis of the most common form of FH, X-linked hypophosphatemia (XLH) and other forms of FGF23-dependent hypophosphatemia is typically confirmed when biochemical testing of blood and urine reveal a low serum phosphate level in the setting of normal serum calcium and 25-hydroxyvitamin D levels. The serum parathyroid hormone (PTH) level is usually normal or can be slightly elevated, and the alkaline phosphatase level is elevated, although usually not to the same degree as that observed in the setting of nutritional rickets. Finally, an assessment of the ability of the kidneys to retain phosphate should be performed to confirm suspected excessive renal phosphate losses. Other biochemical measures such as serum FGF23 and 1,25 dihydroxyvitamin D may provide supportive information for diagnosis. To determine the specific cause of FH, genetic testing can be performed.
Conventional treatment for XLH has historically consisted of using oral phosphate salts and activated forms of vitamin D such as calcitriol, given in a multiple daily dosing regimen. 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 assist with preventing the complications of excessive 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).
In 2018, burosumab (Crysvita), an antibody that inhibits FGF23 activity, was approved by the U. S. Food and Drug Administration (FDA) to treat adults and children ages one year and older with X-linked hypophosphatemia. Other international regulatory agencies have also approved its use. For children, burosumab is given by subcutaneous injection every 2 weeks, whereas adults are dosed every 4 weeks.
Covering teeth with sealants has been suggested as a preventive measure for the spontaneous abscesses associated with familial hypophosphatemia.
Genetic counseling is recommended for affected individuals and their families
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