|55 Kenosia Avenue
Danbury, CT 06810
Toll Free: 1.800.999.6673
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
Copyright 1987, 1988, 1989, 1992, 1993, 1994, 1995, 2000, 2005, 2010, 2013
NORD is very grateful to 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.
Symptoms of the following disorders can be similar to familial hypophosphatemia. Comparisons may be useful for a differential diagnosis:
Rickets may also occur because of vitamin-D deficiency, which in turn, reduces the availability to the body of dietary calcium. Calcium is an important mineral for the formation of normal bone tissue. Vitamin-D deficiency can occur at any time of life and may be treated with vitamin D. In infancy or childhood, contributing factors are usually nutritional, sometimes in combination with a lack of sunlight exposure. Malabsorption syndromes in which the intestines do not adequately absorb nutrients from foods may also be a factor. Major symptoms of this type of rickets include bowed legs, bone pain or tenderness, restlessness, and slow growth. This disorder occurs in the United States but is most frequent in other areas of the world. Calcium deficiency may also be a contributing factor in the development of nutritional rickets.
Osteomalacia in adults may also arise from the same nutritional deficiency. Onocogenic or tumor-induced osteomalacia (OO or TIO), and tumor-induced rickets, are acquired disorders resulting from the production of a phosphate-wasting substance (usually FGF23) from small tumors. OO or TIO is important to recognize as it can be entirely cured by removal of the tumor. These forms of hypophosphatemia all have clinical features in common that are related to an accumulation of circulating FGF23 levels.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare bone disorder characterized by symptoms associated with hypophosphatemic rickets, including muscle weakness, short stature, skeletal deformities, and bone pain. The disorder is inherited as an autosomal recessive trait. There may be a tendency for the kidneys to develop calcifications or even renal stones. In contrast to XLH, the disorder is not due to elevations in FGF23 levels, but loss of function in a specific transporter protein in the kidney (NaPi-IIc) which acts to retain phosphate. HHRH should be treated differently from XLH, because it does not have the vitamin D abnormalities that are present in the FGF23-mediated forms of hypophosphatemia.
Pseudovitamin D deficiency rickets (vitamin D-dependent rickets, type I) is usually characterized by more severe skeletal changes and weakness than those of familial hypophosphatemia. This disorder is caused by abnormal vitamin D metabolism and is inherited as an autosomal recessive trait. This type of rickets may be evident at even earlier ages than occurs with familial hypophosphatemia. Blood levels of calcium are usually reduced in individuals with vitamin-D dependent rickets, although phosphate levels may be normal or mildly decreased. Intermittent muscle cramps may occur. Additional symptoms may include muscle weakness, bowed legs, dental abnormalities, convulsions, and abnormalities of the spine and pelvis. Hereditary resistance to vitamin D (vitamin D dependent rickets, type II) may present in an identical manner. This is a rare autosomal recessive disorder that is caused by mutations in an important protein in the body called the vitamin D receptor (VDR), which is required for vitamin D to work properly.
Fanconi's syndrome is characterized by kidney dysfunction and bone abnormalities similar to those of familial hypophosphatemia. Excess kidney losses of a variety of substances in addition to phosphate may occur. These include amino acids (bicarbonate), glucose, potassium, and uric acid. This disorder may be acquired or inherited.is thought to be inherited through a recessive gene. Bone symptoms include rickets in children and softening of bones (osteomalacia) in adults. Fanconi's syndrome may be associated with a variety of inherited metabolic disorders such as cystinosis, Lowe's syndrome, tyrosinemia, hereditary fructose intolerance, Wilson's disease, or galactosemia.
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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Bergwitz C, Jüppner H. FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol. 2012;728:41-64.
Gattineni J, Baum M. Genetic disorders of phosphate regulation. Pediatr Nephrol. 2012;27(9):1477-87.
Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Min Res. 26:1381-1388, 2011.
Pettifor JM. What's new in hypophosphataemic rickets? Eur J Pediatr. 2008;167(5):493-9.
Bielesz B, et al. Renal phosphate loss in hereditary and acquired disorders of bone mineralization. Bone. 2004;35(6):1229-39.
Rowe PS. The wrickkened pathways of FGF23, MEPE aand PHEX. Critical Reviews in Oral Biology & Medicine. 2004;15(5):264-81.
Holm IA, et al. Familial hypophosphatemia and related disorders. In: Pediatric Bone; Biology & Diseases. Glorieux FH, et a., eds. San Diego, CA: Academic Press. 2003. 603-31.
Jan de Beur SM, Levine MA. Molecular pathogenesis of hypophosphatemic rickets. J Clin Endocrin. & Metabl. 2002;87(6):2467-73.
DiMeglio LA. Econs MJ. Hypophosphatemic rickets. Reviews in Endocrine & Metabolic Disorders. 2001; 2(2):165-73.
Garg RK, et al., Hypophosphatemic rickets: easy to diagnose, difficult to treat. Indian J Pediatr. 1999;66:849-57.
Goodman JR, et al., Dental problems associated with hypophosphatemic vitamin D resistant rickets. Int J Paediatr Dent. 1998;8:19-28.
Carpenter TO. Primary disorders of phosphate metabolism. In: WWW.ENDOTEXT.ORG, version of September 20, 2010, (Ed: DeGroot L; Section Ed: Singer F), published by MDTEXT.COM, INC, S. Dartmouth, MA. Available at: http://www.endotext.org/parathyroid/parathyroid10/parathyroidframe10.htm Accessed:January 29, 2013.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Available at: http://www.ncbi.nlm.nih.gov/omim Entry No:307800; Last Update:5/24/11. Entry No:193100; Last Update:10/4/10. Entry No:241520; Last Update:9/27/12. Entry No:241530; Last Update:11/29/12. Accessed January 29, 2013.
Report last updated: 2013/02/27 00:00:00 GMT+0