Information on the following diseases can be found in the Related Disorders section of this report:

• Rickets, general
• Osteomalacia
• Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)
• Pseudovitamin D deficiency rickets (vitamin D-dependent rickets, type I)
• Fanconi's syndrome
• .

Symptoms of familial hypophosphatemia are usually first noticed after eighteen months of age. The symptoms of familial hypophosphatemia vary greatly from case to case. Abnormalities may include softening of bones (osteomalacia), an abnormal susceptibility to fractures, and/or abnormal bony extensions at the site of muscular attachments, which usually occur when the affected individual is older.

Infants with hypophosphatemic rickets may experience failure to grow at the expected rate. They may have an abnormally tall, narrow head (dolichocephaly). Affected individuals may have an abnormal "waddling" walk (gait) due to abnormalities in the hip joint, pain in the knees, and/or abnormally bowed legs (genu varus). In some cases, affected individuals may have knees that are too close together (knock knees or genu valgum). In addition, affected individuals often reach a shorter adult height than would otherwise be expected. Less frequently, narrowing of the spine (spinal stenosis) may occur. , abnormal side-to-side curvature of the spine (scoliosis), and/or a hip deformity in which the thighbone angles towards the center of the body (coxa vara) 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.

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. According to the medical literature, familial hypophosphatemia may also 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.

Investigators have determined that X-linked familial hypophosphatemia 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 disruptions in a functional PHEX protein result in hypophosphatemic rickets. 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.

Investigators have determined that autosomal dominant familial hypophosphatemia may be caused by disruption or changes (mutations) of the FGF23 (Fibroblast Growth Factor 23) gene located on the short arm (p) of chromosome 12 (12p13.3).

In familial hypophosphatemia, symptoms occur, at least in part, because of abnormal Vitamin D metabolism and impaired phosphate uptake in the kidneys. Vitamin D is needed to regulate calcium and phosphate levels in the body. If the blood levels of these minerals become abnormally low, bone mineralization becomes impaired, thereby weakening the bones. In addition, tiny tubes in the kidneys (renal tubules) that normally reabsorb salt, water, and several essential substances (e.g., glucose, amino acids, calcium, phosphorus) fail to properly reabsorb phosphorus, an important bone mineral. As a result, inadequate amounts of phosphorus are incorporated into the bones as they grow, leading to abnormal and bowed bones.

Familial hypophosphatemia 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. Familial hypophosphatemia 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. Familial hypophosphatemia is the most common form of heritable rickets in the United States.

Symptoms of the following disorders can be similar to familial hypophosphatemia. Comparisons may be useful for a differential diagnosis:

Rickets occurs because of vitamin-D deficiency, a condition that 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 basis. Onocogenic osteomalacia (OO), or tumor-induced rickets, is an acquired disorder resulting from the production of a phosphate-wasting substance from small tumors. This disorder is important to recognize as it can be entirely cured by removal of the tumor. Recently, it has been demonstrated that FGF23 may be an important mediator produced by tumors in OO (also known as tumor-induced osteomalacia or TIO). This is of great interest because mutations in the FGF23 gene cause the autosomal dominant form of hypophosphatemia, and blood levels of FGF23 are elevated in XLH.

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. The disorder should be treated differently from XLH.

Pseudovitamin D deficiency rickets (vitamin D-dependent rickets, type I) is 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 even earlier than familial hypophosphatemia. Blood levels of calcium are severely diminished in individuals with vitamin-D dependent rickets, although phosphate levels appear normal or only slightly deficient. 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 complicationg of too much secretion of a hormone called parathyroid hormone or PTH. Phosphate enhances the bone healing, but also does nto 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 may be successful in preventing spontaneous abscesses that are often associated with familial hypophosphatemia. Genetic counseling may be of benefit for affected individuals and their families.

Bone growth abnormalities associated with familial hypophosphatemia can be surgically removed in an attempt to prevent further shortening or deformities of affected arms or legs. More research is necessary before this procedure can be recommended for all but the most severe cases of familial hypophosphatemia.

In a study carried out by scientists in Australia among children with X-linked familial hypophosphatemia and using the enzyme calcitriol (1 alpha, 25 dihydroxyvitamin D3) and phosphate, a slight increase in height was noted along with the development of calcium deposits in the kidneys (nephrocalcinosis). These scientists recommend conservative use of calcitriol and careful observation of affected individuals to guard against serious kidney damage.

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