Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

canal (which holds the spinal cord) can be smaller than normal in patients with hypochondroplasia.

Genetic profile

Hypochondroplasia is caused by a mutation, or change, in the fibroblast growth factor receptor 3 gene (FGFR3) located on the short arm of chromosome 4.

FGFR (fibroblast growth factor receptor) genes provide the instruction for the formation of a cell receptor. Every cell in the body has an outer layer called a cell membrane that serves as a filter. Substances are transported into and out of the cells by receptors located on the surface of the cell membrane. Every cell has hundreds of different types of receptors. The fibroblast growth factor receptors transport fibroblast growth factor into a cell. Fibroblast growth factors play a role in the normal growth and development of bones. When the receptors for fibroblast growth factor do not work properly, the cells do not receive enough fibroblast growth factor and the result is abnormal growth and development of bones.

Approximately 70% of hypochondroplasia is caused by mutations in the FGFR3 gene. The genes (or gene) responsible for the other 30% of cases are not known. The FGFR3 gene is comprised of 2,520 bases. In a normal (non-mutated) gene, base number 1620 codes for the amino acid asparagine. In most individuals with hypochondroplasia, a mutation changes the asparagine to the amino acid lysine. Two specific mutations account for approximately 70% of hypochondroplasia. These small substitutions change the amino acid that affects the protein structure. Both of these small substitutions cause a change in the fibroblast growth factor receptor (FGFR) that affects the function of this receptor.

The remaining 30% of patients diagnosed with hypochondroplasia do not show FGFR3 gene mutations. It has not yet been made clear if these patients have a different gene abnormality, an unrecognized FGFR3 gene mutation, or are normal variants. Another possibility is that these individuals actually have another disorder in which short stature results.

Mutations in the FGFR3 gene are inherited in an autosomal dominant manner. All people have two FGFR3 genes—one from their father and one from their mother. In an autosomal dominant disorder, only one gene has to have a mutation for a person to have the disorder. An individual with hypochondroplasia has a 50% chance of passing the changed (mutated) gene to his or her offspring. An individual can inherit a mutated gene from one parent or the mutation can occur for the first time in that person. Mutations that arise for the first time in affected individuals are called de novo mutations. The causes of mutations are not known.

K E Y T E R M S

Fibroblast growth factor receptor gene—A type of gene that codes for a cell membrane receptor involved in normal bone growth and development.

Rhizomelic—Disproportionate shortening of the upper part of a limb compared to the lower part of the limb.

Demographics

Because hypochondroplasia has such a wide range of variability, many people mildly affected with hypochondroplasia may never be diagnosed. Thus, the true incidence of hypochondroplasia is unknown. No studies have been done to determine the incidence of hypochondroplasia but it is assumed to be a relatively common disorder with an incidence equal to achon- droplasia—one in 15,000 to one in 40,000.

Signs and symptoms

Individuals with hypochondroplasia have disproportionate short stature, limb abnormalities, and rhizomelic shortening of the limbs. Rhizomelic shortening of the limbs means that those segments of a limb closest to the body (the root of the limb) are more severely affected. In individuals with hypochondroplasia, the upper arms are shorter than the forearms and the upper leg (thigh) is shorter than the lower leg. In general, the upper limbs are more affected than the lower limbs in individuals with hypochondroplasia.

In addition to shortened limbs, individuals with hypochondroplasia have other characteristic limb differences such as a limited ability to rotate and extend their elbows. They can develop bowed legs, a finding that usually improves as they get older. Their hands and feet are short and broad, as are their fingers and toes. Their final adult height is usually 51-57 inches (130-145 cm). Their body habitus or shape is described as thick and stocky with a relatively long trunk. They may have lumbar lordosis (or curved back) giving them a swayed back appearance.

Diagnosis

The diagnosis of hypochondroplasia can be extremely difficult to make for a number of reasons. There is no one physical feature or x ray finding specific to hypochondroplasia and there is a great deal of overlap between individuals with hypochondroplasia and individ-

Hypochondroplasia

Hypochondroplasia

uals in the general population. Many of the physical findings of hypochondroplasia (short stature, bowed legs and a stocky build) are seen in individuals without hypochondroplasia. The same is true for the “typical” x ray findings. All of the possible x ray findings associated with hypochondroplasia can also be seen in unaffected individuals. There is no consensus on specific criteria necessary for diagnosis; however, it is usually made based on a combination of physical and x ray findings and is rarely made in infants.

DNA testing for hypochondroplasia is also complicated because testing will only detect 70% of the mutations that cause hypochondroplasia. DNA testing can be performed on blood samples from children or adults. If an individual is suspected of having hypochondroplasia and a mutation is detected, then the diagnosis is confirmed. If a mutation is not detected, then the diagnosis of hypochondroplasia has neither been confirmed nor ruled out. This individual could be one of the 30% of individuals with hypochondroplasia due to unknown mutations or he or she could have short stature due to another disorder.

Prenatal testing for hypochondroplasia can be performed using DNA technology. A sample of tissue from a fetus is obtained by either chorionic villus sampling (CVS) or by amniocentesis. Chorionic villus sampling is generally done between 10 and 12 weeks of pregnancy and amniocentesis is done between 16 and 18 weeks of pregnancy. Chorionic villus sampling involves removing a small amount of tissue from the developing placenta. The tissue in the placenta contains the same DNA as the fetus. Amniocentesis involves removing a small amount of fluid from around the fetus. This fluid contains some fetal skin cells. DNA can be isolated from these skin cells. The fetal DNA is then tested to determine if it contains either of the two mutations responsible for achondroplasia.

Prenatal DNA testing for hypochondroplasia is not routinely performed in low-risk pregnancies. This type of testing is generally limited to high-risk pregnancies, such as when one parent has hypochondroplasia. This testing can also only be performed if the mutation causing hypochondroplasia in the parent has been identified.

Treatment and management

There is no cure for hypochondroplasia. Because of the wide range of variability of this condition there is no consensus on the medical management of individuals with hypochondroplasia either. Individuals with more severe cases are the only individuals likely to need medical management. The recommendations for the medical management of individuals with achondroplasia have been outlined by the American Academy of Pediatrics’

Committee on Genetics and should be used as a guide for the management of individuals with severe hypochondroplasia. The potential medical complications of hypochondroplasia range from mild to moderate. Early intervention may avert some of the long-term consequences of these complications.

As children with hypochondroplasia develop, certain conditions and behaviors should be monitored. Their height, weight, and head circumference should be measured regularly and plotted on growth curves developed for children with achondroplasia as a guide. Neurologic problems such as lethargy, abnormal reflexes, or loss of muscle control should be seen by a neurologist to make sure that they are not experiencing compression of their spinal cord. Compression of the spinal cord is rare in individuals with hypochondroplasia but can occur because of the abnormal size of their spinal canal.

Children with hypochondroplasia should also be monitored for sleep apnea. Sleep apnea occurs when an individual stops breathing during sleep. This can occur for several reasons including obstruction of the throat by the tonsils and adenoids, spinal cord compression, and obesity. Individuals with hypochondroplasia are more prone to sleep apnea due to the changes in their spinal canal and foramen magnum. Treatment for sleep apnea depends on the cause of the sleep apnea. Obstructive sleep apnea is treated by surgically removing the tonsils and adenoids. Weight management may also play a role in the treatment of sleep apnea.

The bowed legs of children with hypochondroplasia usually improve as they get older and rarely require surgical intervention. Children with hypochondroplasia can often have an increased risk for middle ear infections which can be treated with oral antibiotics and the surgical placement of ear tubes.

Children with visible physical differences can have difficulties in school and socially. Support groups such as Little People of America can be a source of guidance on how to deal with these issues. It is important that children with hypochondroplasia not be limited in activities that pose no danger.

Two treatments have been used to try to increase the final adult height of individuals with hypochondropla- sia–limb-lengthening and growth hormone therapy. There are risks and benefits to both treatments and as of 2001, they are still considered experimental.

Limb-lengthening involves surgically attaching external rods to the long bones in the arms and legs. These rods run parallel to the bone on the outside of the body. Over a period of 18-24 months, the tension on these rods is increased which results in the lengthening of the underlying bone. This procedure is long, costly, and

has potential complications such as pain, infections, and nerve problems. Limb-lengthening can increase overall height by 12-14 in (30.5-35.6 cm). This is an elective surgery and individuals must decide for themselves if it would be of benefit to them. The optimal age to perform this surgery is not known.

Growth hormone therapy has been used to treat some children with hypochondroplasia. Originally there was doubt about the effectiveness of this treatment because children with hypochondroplasia are not growth hormone deficient. Studies have shown mixed results. Some children with hypochondroplasia show improvement in their growth rate and others do not. It is too early to say how effective this treatment is because the children involved in this study are still growing and have not reached their final adult height.

Prognosis

The prognosis for most people with hypochondroplasia is very good. In general, they have minimal medical problems, normal IQ, and most achieve success and have a long life regardless of their stature. The most serious medical barriers to an excellent prognosis are the neurologic complications that very rarely arise in hypochondroplasia, including mild mental retardation and spinal cord compression.

Successful social adaptation plays an important role in the ultimate success and happiness of an individual with hypochondroplasia. It is very important that the career and life choices of individuals with achondroplasia not be limited by preconceived ideas about their abilities.

Resources

ORGANIZATIONS

Human Growth Foundation. 997 Glen Cove Ave., Glen Head, NY 11545. (800) 451-6434. Fax: (516) 671-4055.http://www. hgf1@hgfound.org .

Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. (806) 737-8186 or (888) LPA2001. lpadatabase@juno.com. http://www.lpaonline

.org .

MAGIC Foundation for Children’s Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 3624423. Fax: (708) 383-0899. mary@magicfoundation.org.http://www.magicfoundation.org/ghd.html .

WEBSITES

Human Growth Foundation. http://www.hgfound.org/ .

Little People of America: An Organization for People of Short Stature. http://www.lpaonline.org/lpa.html .

MAGIC Foundation for Children’s Growth.

http://www.magicfoundation.org .

Kathleen Fergus, MS

I Hypophosphatasia

Definition

Hypophosphatasia is an inherited bone disease whose clinical symptoms are highly variable, ranging from a profound lack of mineralization of bone with death occurring prior to delivery up to early loss of teeth in adulthood as the only sign. Still other affected individuals may have the characteristic biochemical abnormality but no outward clinical signs of the disorder. Hypophosphatasia is due to consistently low levels of an important enzyme in the body, alkaline phosphatase.

Description

The term hypophosphatasia was first coined in 1948 by a Canadian pediatrician, Dr. J.C. Rathbun. He used it to describe a male infant who developed and then died from severe rickets, weight loss, and seizures. Levels of the enzyme alkaline phosphatase were below normal in samples of blood and bone from this child.

Rickets is a condition resulting from a deficiency of vitamin D in children, causing inadequate strengthening of developing cartilage and newly formed bone. While this disorder shares many clinical characteristics with hypophosphatasia, the two conditions are separate and distinct. A major difference is that rickets are typically not lethal.

In 1953, the clinical features of hypophosphatasia were expanded to include not only abnormal mineralization of bone but also premature loss of the permanent teeth in adulthood. Since then, hypophosphatasia has been further divided into six different clinical forms. Each form is defined by the severity of the disease and the age at which symptoms first appear.

Alkaline phosphatase (ALP) is present in nearly all plants and animals. There are at least four different genes known to encode different forms of ALP in humans. Hypophosphatasia is due to a deficiency of the form of ALP that is particularly abundant in the liver, bones, and kidneys. This is often referred to as the tissue non-specific form of ALP, or TNSALP. This form of alkaline phosphatase is important in the mineralization, or hardening, of the bones of the skeleton as well as the teeth. Thus, abnormalities in either the production or function of this enzyme have a direct effect on the formation and strength of these parts of the body. In general, the more severe forms of hypophosphatasia are associated with lower serum TNSALP activity for that individual’s age.

Hypophosphatasia

Hypophosphatasia

Genetic profile

The first report of siblings affected with hypophosphatasia was published in 1950, providing supportive evidence that it is an inherited abnormality as opposed to one that is acquired. This is an important distinction, particularly since rickets alone is often due to a lack of vitamin D in a person’s diet. Good sources of vitamin D include fortified milk and sunlight. Rickets can therefore be an acquired medical problem.

Nearly all forms of hypophosphatasia are inherited as an autosomal recessive condition. In order to be affected, an individual must inherit two copies of a hypophosphatasia gene, or one copy from each carrier parent. Carriers have one normal gene and one hypophosphatasia gene and are typically asymptomatic. In some families, hypophosphatasia carriers have been found to have low to low-normal levels of TNSALP in their blood. As a general rule, however, it is difficult to detect carriers with biochemical tests due to the wide range of enzyme levels found among both carriers and non-carriers.

Two hypophosphatasia carriers face a risk of 25%, or a one in four chance, of both passing on the disease gene and having an affected child. On the other hand, there is a 75% chance that they will have an unaffected, normal child. These risks apply to each pregnancy.

In contrast, evidence suggests that some of the more mild adult forms of hypophosphatasia may be inherited as an autosomal dominant trait. In this mode of inheritance, a single copy of a hypophosphatasia gene can cause clinical abnormalities. An affected individual would consequently have a 50% risk of passing on the abnormal gene to each of his or her children.

The gene for TNSALP is located near the tip of the short arm of chromosome 1 at band 1p36.1-p34. Mutations in this gene are responsible for both the autosomal recessive and autosomal dominant forms of hypophosphatasia. Although it is not yet entirely clear how mutations in this gene cause impaired mineralization of bone, more recent work has shown that the type of mutation and its location within the gene each have an effect on the severity of disease. A wide range of mutations have been described to date. A common mutation for any form of hypophosphatasia has not yet been identified in most populations. Consequently, genetic analysis of TNSALP in most families requires extensive study of the entire gene.

Demographics

Hypophosphatasia has been described worldwide and is believed to occur in all races. The most severe form of the disease is estimated to occur in approxi-

mately one in every 100,000 liveborns. This corresponds to a carrier frequency of roughly one in every 200–300 individuals. The milder childhood and adult forms of hypophosphatasia are probably more common than the severe perinatal form.

Of note, hypophosphatasia is especially common among Mennonite families from Manitoba, Canada, where mating between blood relatives is not unusual. The frequency of severe disease in this population is approximately one in every 2,500 newborns with a corresponding carrier frequency of one in every 25. The number of mutations identified in this group is smaller than the general population.

Signs and symptoms

Each individual who has hypophosphatasia has clinical features derived from generalized impairment of skeletal mineralization. Six different clinical forms have been recognized. The prognosis associated with each form is dependent upon the severity of the disease and the age at which the condition is first recognized. Although affected individuals within a family tend to have similar abnormalities, it is possible to see clinical variability even between relatives.

Perinatal (lethal) hypophosphatasia

This is the most severe form of hypophosphatasia. Affected fetuses are often diagnosed during pregnancy with profound undermineralization of their bones. The limbs are typically shortened and abnormal. Bone fractures may be present. An excessive amount of amniotic fluid (polyhydramnios) during pregnancy is common. Many affected infants die prior to delivery, or are stillborn. Those who survive delivery are often irritable, have a high-pitched cry, and fail to gain weight. Respiratory failure is a common cause of death. This is usually due to deformities of the chest and associated underdevelopment of the lungs.

Infantile hypophosphatasia

Many infants with this form of the disease appear normal at birth and initially begin to develop normally. However, difficulties such as poor feeding and poor weight gain along with early clinical signs of rickets often begin before six months of age. Bony abnormalities of the chest as well as an increased susceptibility to fractures make affected infants more prone to developing pneumonia. Over 50% of affected children die during infancy, usually from severe respiratory failure. Those infants who do survive often suffer from episodes of recurrent vomiting and from abnormal kidney function due to excess loss of calcium from bone. Additionally,

they may develop a misshapen head due to early closure of specific bones of the skull. Spontaneous overall improvement in health has, however, also been reported.

Childhood hypophosphatasia

The most common clinical feature in this form of hypophosphatasia is loss of the primary (deciduous) teeth before the age of five. This premature loss is directly related to abnormal dental cementum. It is this structure that normally establishes the appropriate connection of the teeth to the jaw. In hypophosphatasia, it is frequently completely missing or present but either underdeveloped or abnormally developed.

Rickets is another feature commonly seen in this later onset form. Rickets frequently leads to delayed walking as a toddler, short stature, and a characteristic waddling gait. Other rachitic deformities may also be present such as bowed legs or enlargement of the wrists, knees, and ankles.

Adult hypophosphatasia

Most affected individuals are formally diagnosed in adulthood. However, a careful review of an individual’s health often reveals a childhood history of rickets and early loss of the primary teeth. This is typically followed by relatively good health during adolescence and young adulthood.

Dental and skeletal abnormalities, however, gradually recur. The age at their onset as well as their severity varies between individuals. Early loss or even extraction of the permanent teeth is common. Other skeletal abnormalities, however, are of greater concern. Osteomalacia is a common complaint. Osteomalacia is the adult form of rickets. It is characterized by increasing softness of the bones. This, in turn, leads to increased flexibility and fragility and causes deformities. Clinically, osteomalacia is typified by chronic pain in the feet due to recurrent, poorly healing stress fractures. Affected adults may also experience discomfort in their thighs and hips from painful thin zones of decalcification (pseudofractures) in the bones of the thigh.

Odontohypophosphatasia

The only clinical abnormality associated with this form of hypophosphatasia is dental disease. It may occur in children or adults. Neither rickets nor osteomalacia has been found to occur.

Pseudo-, or false, hypophosphatasia

This is an especially rare clinical form documented in only a few infants. The physical features all resemble

K E Y T E R M S

Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman’s abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Chorionic villus sampling (CVS)—A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother’s vagina or abdominal wall and a sample of cells is collected from around the fetus. These cells are then tested for chromosome abnormalities or other genetic diseases.

Enzyme—A protein that catalyzes a biochemical reaction or change without changing its own structure or function.

Rachitic—Pertaining to, or affected by, rickets. Examples of rachitic deformities include curved long bones with prominent ends, a prominent middle chest wall, or bony nodules at the inner ends of the ribs.

those seen in the infantile form of the disease. However, in contrast to all of the other forms of hypophosphatasia, the total alkaline phosphatase activity has been consistently normal or even increased in blood samples from the affected children. It is unclear what the exact biochemical or molecular abnormality is in these children.

Diagnosis

After birth, a diagnosis of hypophosphatasia is based on a combination of physical examination, x ray, and biochemical studies. X ray can be particularly helpful in differentiating between the more severe forms of hypophosphatasia (perinatal, infantile) and other inherited bone diseases. In the perinatal form, the skeleton generally appears completely undermineralized, occasionally absent. Bone fractures may be observed. The x- ray findings in the infantile form are similar to those seen in the perinatal form, but are usually much less severe.

Biochemical analysis may be performed on a routine blood sample. The serum may be used to determine the level of alkaline phosphatase activity. This usually represents TNSALP, and, in affected individuals, is generally low. However, it is important that the sample be obtained

Hypophosphatasia

Hypophosphatasia

and handled correctly in the laboratory so as not to interfere with the enzyme activity and raise the likelihood of an incorrect result. Also, the values from each individual should be interpreted carefully as variation normally occurs based on a person’s sex and his or her age.

The genetic abnormality that causes hypophosphatasia leads to an inactive form of TNSALP in most cases. As a result, the chemicals on which the enzyme would normally act begin to accumulate, or increase, in the blood and urine. This accumulation is what hastens the defective calcification of bone. In theory, these substances could be measured to establish a diagnosis of hypophosphatasia. Although none have yet been proven to alone be reliable in all situations, a few appear more promising than others. These include pyridoxal-5-phos- phate (PLP), phosphoethanolamine, or inorganic pyrophosphate. Abnormal (high) results lend further support to a diagnosis of hypophosphatasia when other clinical signs have also been recognized.

Prenatal diagnosis of hypophosphatasia has been successfully reported, although prior to the advent of molecular testing, it wasn’t always completely reliable. Prenatal testing has been most widely used for the detection of the perinatal lethal form of hypophosphatasia. In some cases, the severe bone abnormalities of this type have been missed with a standard mid-pregnancy ultrasound but subsequently identified at an ultrasound performed much later. While this may be due, in part, to inexperience of the person performing the ultrasound, the highly variable clinical nature of hypophosphatasia is also to blame. A fetal x ray may be performed as a fol- low-up to any suspicious prenatal ultrasound evaluation.

Both chorionic villus sampling (CVS) and amniocentesis have been performed but have also on occasion been complicated by technical factors. For example, cultured cells from either a villus or amniotic fluid sample may be used to determine ALP activity. Because there are four forms of ALP in humans, the TNSALP form, which is abnormal in hypophosphatasia, may not be directly analyzed. An accurate interpretation of test results may therefore not be possible.

Direct analysis of the TNSALP gene thus holds the greatest promise for accurate prenatal diagnosis. Many different TNSALP mutations have been identified; many have been found in individual families only. It is also not unusual for two carrier parents to each have a different mutation. Direct analysis is therefore only currently possible for those families who have had at least one affected child and whose mutations have already been determined. Either CVS or amniocentesis may be used in these families for mutation studies. Rapid prenatal diagnosis of hypophosphatasia in the context of a negative family history is difficult.

Treatment and management

For those families in whom the underlying mutations are unknown, the most reliable method of prenatal diagnosis for perinatal lethal hypophosphatasia includes a combination of either CVS or amniocentesis for biochemical studies as well as serial ultrasound evaluations during pregnancy. If a diagnosis is made with certainty relatively early in pregnancy, the expectant parents should be offered the option of pregnancy termination.

As of 2001, there is no established, effective medical therapy for any form of hypophosphatasia. Care is mainly directed toward the prevention or correction of disease-related complications. Expert dental care is highly recommended for those individuals with dental abnormalities. Physical therapy and orthopedic management are important in the care and treatment of bone complications such as fractures. Young children with the infantile form should also be monitored carefully for increasing pressure within the head from early fusion of the bones of the skull. Traditional treatments for rickets or osteomalacia, such as vitamin D or other mineral supplements, should be avoided as these bone symptoms represent only one component of an inherited, rather than acquired, complex medical problem.

Prognosis

The prognosis associated with hypophosphatasia is directly related to the severity of the disease. In general, those individuals with the most severe skeletal abnormalities tend to do much worse than those with only mild clinical symptoms. Hence, infants who are diagnosed either during pregnancy or who have significant bone deformities at birth generally die within the first few days or weeks of life. These infants may also be stillborn. The prognosis associated with the infantile form of hypophosphatasia is variable: while over half of affected infants die during their first year due to serious breathing abnormalities, others spontaneously improve and may do well. Childhood disease is associated with skeletal deformities in some cases. Symptoms may improve, however, during adolescence only to occasionally reappear in adulthood. Finally, adult-onset hypophosphatasia is associated with ongoing, orthopedic problems once skeletal symptoms begin. Women, in particular, may notice increased bone loss and fractures after menopause.

Resources

BOOKS

Whyte, Michael P. “Hypophosphatasia.” In, The Metabolic and Molecular Bases of Inherited Disease. 7th Edition. Edited by Charles R. Scriver, Arthur L. Beaudet, William S. Sly, and David Valle. New York: McGraw-Hill, Inc., 1995, pp. 4095-4110.

PERIODICALS

Deeb, A. A., S. N. Bruce, A. A. M. Morris, and T. D. Cheetham. “Infantile hypophosphatasia: disappointing results of treatment.” Acta Pediatrica 89, no. 6 (June 2000):730-33.

Gehring, B., E. Mornet, H. Plath, M. Hansmann, P. Bartmann, and R. E. Brenner. “Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family.” Clinical Genetics 56, no. 4 (October 1999): 313-17.

ORGANIZATIONS

MAGIC Foundation for Children’s Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 3624423. Fax: (708) 383-0899. mary@magicfoundation.org.http://www.magicfoundation.org/ghd.html .

National Institutes of Health, Osteoporosis and Related Bone Diseases. National Resource Center, 1232 22nd Street NW, Washington, DC 20037-1292. Fax: (202) 223-0344.http://www.osteo.org/hypoph.html .

WEBSITES

OMIM—Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nih.gov/omim .

Terri A. Knutel, MS, CGC

I Hypophosphatemia

Definition

Hypophosphatemia is a group of inherited disorders in which there is abnormally low levels of the substance phosphate in the blood, leading to softening of the bones. This condition can result in rickets, a childhood disease in which soft and weak bones can lead to the development of bone deformities. While there is no cure, treatment can prevent the bone changes and allow proper growth of bones.

Description

Bone is one of the strongest tissues of the human body. As the main component of the adult skeleton, it provides support for movement, protects the brain and organs of the chest from injury, and contains the bone marrow, where blood cells are formed. Bone is made up of several components, including a substance called hydroxyapatite. Hydroxyapatite is made of calcium and phosphate and is partially responsible for the strength of bone.

Because of the importance of hydroxyapatite, the strength of bone is dependent on the proper levels of calcium and phosphate within the body. A lack of calcium or phosphate in the diet or a failure in maintaining proper

levels of calcium or phosphate in the blood can lead to abnormalities of bone growth. Another factor required for proper development of bone is vitamin D. Vitamin D is either obtained through foods in the diet, or is made by the body in response to sunlight exposure. Vitamin D is converted to another substance within the body called calcitriol. Calcitriol promotes bone development by helping to absorb calcium and phosphate from the diet and by preventing the loss of calcium and phosphate in the urine.

Hypophosphatemia is a group of inherited disorders in which there is abnormally low phosphate levels in the blood because large amounts of phosphate exit the body through the urine. In some forms of the disease there may also be problems in the conversion of vitamin D to calcitriol. Research suggests that inherited hypophosphatemia syndromes result from an abnormality in the way the kidney handles phosphate. Normally, the kidney prevents phosphate from leaving the body in the urine, but in hypophosphatemia, an abnormality in the way the kidney handles phosphate leads to large losses of phosphate in the urine. This results in abnormally low levels of phosphate in the blood, leading to poor hydroxyapatite formation and soft bones. Insufficient levels of phosphate for bone formation results in rickets, a childhood condition in which there is abnormal bone development, growth, and repair (when this occurs in adults, it is called osteomalacia). Inherited hypophosphatemia was first described by R. W. Winters in 1958 and has been referred to in the past as vitamin D-resistant rickets or familial hypophosphatemic rickets.

Genetic profile

Hypophosphatemia is a group of conditions that can be inherited or passed on in a family. The different types of hypophosphatemia have different causes, patterns of inheritance, and symptoms.

The most common and widely studied form of hypophosphatemia is hereditary hypophosphatemia type I, also known as X-linked hypophosphatemia (XLH). The abnormality in XLH is in a gene called PHEX. It is not known precisely how this gene affects phosphate handling by the kidney. Changes in other genes have been shown to cause hypophosphatemia, but the mechanism is similarly unclear. While most occurrences of hypophosphatemia are passed from parent to child, there are several examples of new genetic changes arising in a child with no relatives with hypophosphatemia.

There are different patterns of inheritance in different forms of hypophosphatemia, including autosomal dominant inheritance and X-linked dominant inheritance. In autosomal dominant inheritance, only one abnormal

Hypophosphatemia

Hypophosphatemia

K E Y T E R M S

Biopsy—The surgical removal and microscopic examination of living tissue for diagnostic purposes.

Calcitriol—A substance that assists in bone growth by helping to maintain calcium and phosphate levels in the blood. Vitamin D is converted into this substance by the body.

Calcium—One of the elements that make up the hydroxyapatite crystals found in bone.

Hydroxyapatite—A mineral that gives bone its rigid structure and strength. It is primarily composed of calcium and phosphate.

Hypophosphatemia—The state of having abnormally low levels of phosphate in the bloodstream.

Osteomalacia—The adult form of rickets, a lack of proper mineralization of bone.

Parathyroid glands—A pair of glands adjacent to the thyroid gland that primarily regulate blood calcium levels.

Phosphate—A substance composed of the elements phosphorus and oxygen that contributes to the hydroxyapatite crystals found in normal bones.

Rickets—A childhood disease caused by vitamin D deficiency, resulting in soft and malformed bones.

gene is needed to display the disease, and the chance of passing the gene to offspring is 50%.

X-linked dominant inheritance is similar to autosomal dominant inheritance in that only one abnormal gene is needed to display the disease. However, in X-linked dominant inheritance, the genetic abnormality is located on the X chromosome. Females have two X chromosomes, whereas males only have one X chromosome. Females have a 50% chance of passing the abnormal gene on to either a son or a daughter, as the mother always contributes one X chromosome to a child. On the other hand, males with the abnormal X chromosome will always pass the abnormal gene to a daughter (the father will contribute the abnormal X chromosome), but never to a son (the father will contribute a normal Y chromosome, and not the abnormal X chromosome)

Demographics

Hypophosphatemia has been estimated to be present in between one in 10,000 and one in 100,000 people, but

one in 20,000 people is the most widely quoted figure. It is not known whether this disease is present equally among different geographical areas and ethnic groups. The first reports of the condition found hypophosphatemia in a Bedouin (nomadic Arab) tribe.

Signs and symptoms

Major symptoms of hypophosphatemia include poor growth, bone pain, abnormally bowed legs, weakness, tooth abscesses and sometimes listlessness and irritability in infants and young children. Although the disease affects all bones, the legs are more severely affected than the arms, ribs, or pelvis. The bowed legs are often noted by 12 months of age, and the altered growth increases in severity as the child grows older. Because of poor hydroxyapatite formation, people may experience fractures, and abnormal healing follows, further contributing to growth abnormalities. As a result of poor bone development and poor healing, people with hypophosphatemia often have short stature and may have a waddling walk. Other, less common manifestations of hypophosphatemia include high blood pressure and hearing loss or deafness.

While most symptoms are the same in the different types of hypophosphatemia, there may be small changes in the severity and age at which the person will experience the symptoms.

Diagnosis

If there is no family history of hypophosphatemia, diagnosis is usually guided by physical exam. Obvious bow leg deformities will lead to x rays of the legs and knees, which will show characteristic bone abnormalities. Other studies of bone strength using radioactive tracer materials can be used, or a bone biopsy (surgical excision of a small portion of bone for inspection with a microscope) can be performed to confirm that there is less hydroxyapatite than normal.

Laboratory tests aid in determining the cause of poor bone growth and rickets. In XLH, the serum phosphorus is low and the levels of serum calcium and calcitriol are low or sometimes normal. However, urine levels of phosphate are high, indicating that phosphate is being lost in the urine and that the kidney is not reabsorbing the phosphate properly. Another laboratory finding in XLH is the presence of increased alkaline phosphatase, a enzyme that breaks down bone. However, alkaline phosphatase is often elevated in growing children compared to normal adult values. Other forms of hypophosphatemia may have other variations in laboratory findings, including normal calcitriol levels or high levels of calcium in the urine and can be used to distinguish between the different types of hypophosphatemia.

Treatment and management

There is no cure, but medical and surgical treatment can greatly improve the outcome of people with hypophosphatemia. Goals of treatment include improvement in growth, reduction in severity of bone disease, bowed legs, and activity limitations, and minimizing the complications that may develop from the treatment itself.

Medical treatment is directed toward increasing the blood phosphate levels by using phosphate salts and calcitriol, both given by mouth. However, phosphate may have to be given five times a day because it is rapidly lost in the urine, and phosphate often causes diarrhea. Despite these drawbacks, the response to the medications is very good, and bowed legs may straighten over several years of growth. Scientific studies are also being performed to determine if growth hormone can help in achieving normal growth and height development.

Health care providers are able to monitor the person’s ability to take the medication by checking the phosphate levels in the urine and the blood. It is recommended that these tests be performed in small children every three months to determine if they are receiving adequate amounts of phosphate. Later, the monitoring can be decreased to every four to six months. It is also recommended that childhood x rays of the knee be performed every one to two years to see whether medication changes are needed.

Some problems may result from the medications used to treat hypophosphatemia. High levels of calcium can build up in the bloodstream causing problems with the kidneys and the parathyroid (a gland in the neck). Because of these problems, routine calcium measurements and kidney ultrasound studies should be performed to determine if additional medications should be added or changes in medications should be made.

Treatment with medication is sometimes not enough to reverse the bone abnormalities. In cases such as these, surgery can be performed to reshape or even lengthen the bones.

Prognosis

With early diagnosis and treatment, the prognosis for people with hypophosphatemia is excellent. Adult heights of 170 cm may be achievable, compared to 130165 cm without treatment. While some degree of abnormal bone growth may always be detectable, people with hypophosphatemia will generally live normal lifespans.

Resources

BOOKS

Brenner, B. M., ed. Brenner and Rector’s The Kidney. Philadelphia: W.B. Saunders, 2000.

Behrman, R. E., ed. “Familial Hypophosphatemia.” In Nelson Textbook of Pediatrics. Philadelphia: W.B. Saunders, 2000, pp. 2136-2137.

Goldman, L., ed. “Osteomalacia and Rickets.” In Cecil Textbook of Medicine. Philadelphia: W.B. Saunders, 2000, pp. 1391-1398.

Wilson, J. D., ed. “Rickets and Osteomalacia.” In Williams Textbook of Endocrinology. Philadelphia: W.B. Saunders, 1998, pp. 1228-1230.

PERIODICALS

Carpenter, T. O. “New perspectives on the biology and treatment of X-linked hypophosphatemic rickets.” Pediatric Clinics of North America 44 (April 1997): 443-466.

Subramanian R., and R. Khardori. “Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment.” Medicine 79 (January 2000): 1-8.

WEBSITES

National Center for Biotechnology Information, National Library of Medicine. OMIM—Online Mendelian Inheritance in Man. http://www3.ncbi.nlm.nih.gov/ htbin-post/Omim .

XLH Network.

http://georgia.ncl.ac.uk/VitaminD/vitamind.html .

Oren Traub, MD, PhD

Hypophosphatemic rickets see

Hypophosphatemia

I Hypospadias and epispadias

Definition

Hypospadias is a congenital defect, primarily of males, in which the urethra opens on the underside (ventrum) of the penis. The corresponding defect in females is an opening of the urethra into the vagina and is rare.

Epispadias (also called bladder exstrophy) is a congenital defect of males in which the urethra opens on the upper surface (dorsum) of the penis. The corresponding defect in females is a fissure in the upper wall of the urethra and is quite rare.

Description

In a male, the external opening of the urinary tract (external meatus) is normally located at the tip of the penis. In a female, it is normally located between the clitoris and the vagina.

In males with hypospadias, the urethra opens on the inferior surface or underside of the penis. In females with

epispadias and Hypospadias

Hypospadias and epispadias

K E Y T E R M S

Bladder—This is the organ that stores urine after it flows out of the kidneys and through the ureters.

Circumcision—The surgical removal of the foreskin of the penis.

Continence—Normal function of the urinary bladder and urethra, allowing fluid flow during urination and completely stopping flow at other times.

External meatus—The external opening through which urine and seminal fluid (in males only) leave the body.

Genital tract—The organs involved in reproduction. In a male, they include the penis, testicles, prostate and various tubular structures to transport seminal fluid and sperm. In a female, they include the clitoris, vagina, cervix, uterus, fallopian tubes and ovaries.

Urethra—The tubular portion of the urinary tract connecting the bladder and external meatus through which urine passes. In males, seminal fluid and sperm also pass through the urethra.

hypospadias, the urethra opens into the cavity of the vagina.

In males with epispadias, the urethra opens on the superior surface or upper side of the penis. In females with epispadias, there is a crack or fissure in the wall of the urethra and out of the body through an opening in the skin above the clitoris.

During the embryological development of males, a groove of tissue folds inward and then fuses to form a tube that becomes the urethra. Hypospadias occurs when the tube does not form or does not fuse completely. Epispadias is due to a defect in the tissue that folds inward to form the urethra.

During the development of a female, similar processes occur to form the urethra. The problem is usually insufficient length of the tube that becomes the urethra. As a result, the urethra opens in an abnormal location, resulting in a hypospadias. Occasionally, fissures form in the bladder. These may extend to the surface of the abdomen and fuse with the adjacent skin. This is most often identified as a defect in the bladder although it is technically an epispadias.

Hypospadias in males generally occur alone. Female hypospadias may be associated with abnormalities of the genital tract, since the urinary and genital tracts are formed in the same embryonic process.

Because it represents incomplete development of the penis, some experts think that insufficient male hormone may be responsible for hypospadias.

Genetic profile

Hypospadias and epispadias are congenital defects of the urinary tract. This means that they occur during intrauterine development. There is no genetic basis for the defects. Specific causes for hypospadias are not known. This means that blood relatives do not have increased chances of developing them.

Demographics

In males, the incidence of hypospadias is approximately one per 250 to 300 live births. Epispadias is much less common, having an incidence of about one per 100,000 live male births.

In females, hypospadias is much less common than in males. It appears about once in every 500,000 live female births. Epispadias is even rarer. Reliable estimates of the prevalence of epispadias in females are not available. Epispadias in females is often diagnosed and recorded as a bladder anomaly.

Signs and symptoms

Hypospadias is usually not associated with other defects of the penis or urethra. In males, it can occur at any site along the underside of the penis. In females, the urethra exits the body in an abnormal location. This is usually due to inadequate length of the urethra.

Epispadias is associated with bladder abnormalities. In females, the front wall of the bladder does not fuse or close. The bladder fissure may extend to the external abdominal wall. In such a rare case, the front of the pelvis is also widely separated. In males, the bladder fissure extends into the urethra and simply becomes an opening somewhere along the upper surface of the penis.

Hypospadias is associated with difficulty in assigning gender to babies. This occurs when gender is not obvious at birth because of deformities in the sex organs.

Diagnosis

Male external urinary tract defects are discovered at birth during the first detailed examination of the newborn. Female urethral defects may not be discovered for some time due to the difficulty in viewing the infant vagina.

Treatment and management

Surgery is the treatment of choice for both hypospadias and epispadias. All surgical repairs should be under-