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Hypophosphatasia is a inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Unlike other forms of rickets, Hypophosphatasia does not respond to treatment with vitamin D.
Infantile Hypophosphatasia: This is the most common form of the disorder, usually beginning before 6 months of age. It can be diagnosed before birth. In infants affected with Hypophosphatasia, defective bone hardening (mineralization) is often associated with increased pressure inside the skull which may result in bulging eyes (exophthalmos). There may be excessive levels of calcium in the blood (hypercalcemia) and urine (hypercalciuria). Calcium may accumulate in the little tubes of the kidneys, sometimes resulting in kidney failure. The bones usually become weak and bent, resembling Rickets. Bone abnormalities can be severe.
Childhood Hypophosphatasia: This form of the disorder usually begins after 6 months of age. It is characterized by premature loss of baby teeth, increased susceptibility to infections, and slowed growth. X-rays show irregularities in the tips (epiphyses) and shafts of the long bones. Spontaneous healing of Rickets- like (rachitic) bone changes may occur in this form of Hypophosphatasia.
Adult Hypophosphatasia: This form of Hypophosphatasia is quite rare. It is characterized by a history of Rickets symptoms and premature loss of baby teeth during childhood. The permanent teeth are often lost or extracted during early adulthood. The bones are less dense than normal and fractures tend to occur more often than in the general population.
Pseudohypophosphatasia: Patients with Pseudohypophosphatasia have all or many of the manifestations of Hypophosphatasia. However, blood concentrations of the enzyme alkaline phosphatase are normal.
The symptoms of Hypophosphatasia vary greatly from case to case.
The symptoms of Hypophosphatasia develop due to abnormally low levels of the enzyme alkaline phosphatase (ALP). The infantile and childhood forms of the disorder are inherited as autosomal recessive genetic traits. The adult form is inherited as an autosomal dominant genetic trait.
Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Hypophosphatasia is a rare disorder. The different forms of this disorder all affect males and females in equal numbers. It is believed that one in 100,000 infants may be affected by the more severe form of the disease. Approximately one in every 300 individuals in the United States are believed to carry the defective gene responsible for Hypophosphatasia.
Symptoms of the following disorders can be similar to Hypophosphatasia. Comparisons may be useful for a differential diagnosis:
Rickets Several forms of Rickets exist, all of which are characterized primarily by weakening of bones due to abnormal calcium metabolism as well as possible decreases of other substances in the body. Rickets may be either acquired or inherited. In cases caused by dietary deficiency of Vitamin D, a supplement to the diet can cure the disease when given before the bones are fully developed.
Hypophosphatemic Rickets is a rare genetic form of Rickets characterized by impaired transport of phosphate in the body, combined with diminished Vitamin-D metabolism in the kidneys. Additionally, calcium and phosphate are not absorbed properly in the intestines which can lead to softening of bones. Major symptoms include skeletal changes, weakness and slowed growth. Cases affecting females are usually less severe than those affecting males. One rare acquired form of this disorder may be associated with a benign tumor. (For more information on this disorder, choose "Hypophosphatemic Rickets" as your search term in the Rare Disease Database.)
Osteomalacia is a disorder characterized by gradual softening and bending of the bones. Pain may occur in various degrees of severity. Softening occurs because of deficient levels of calcium in bones due to diminished amounts of vitamin D or a kidney dysfunction. This illness is more common among women than men, and often begins during pregnancy. It can exist alone or in association with other disorders, such as Hypophosphatemic Rickets.
Pseudovitamin D Deficiency Rickets (Vitamin D-Dependent Rickets, Type I) is characterized by severe skeletal changes (such as bending of the bones) and weakness. Symptoms are caused by abnormal vitamin-D dependent metabolism. The disorder is inherited as an autosomal recessive trait. This type of Rickets often begins during early infancy. Blood levels of calcium are severely diminished in patients with Vitamin-D Dependent Rickets, although phosphate levels appear normal or only slightly deficient. Amino acids are lost in the urine due to a kidney dysfunction. Occasional muscle cramps may occur. Convulsions and abnormalities of the spine and pelvis may also develop.
Osteogenesis Imperfecta, or Brittle Bone Disease, is a group of hereditary connective tissue disorders characterized by unusual bone fragility and a tendency of bones to fracture easily. Traditionally, the disorder has been recognized in two forms. Osteogenesis Imperfecta Congenita is apparent at birth, while Osteogenesis Imperfecta Tarda manifests itself only later, usually at 3 or 4 years of age, and is a milder disorder. Osteogenesis is a relatively common birth defect, with an incidence in the United States of 1 in 20,000 to 50,000 births. (For more information on this disorder, choose "Osteogenesis Imperfecta"as your search term in the Rare Disease Database.)
Paget's Disease is a slowly progressive disorder of the skeletal system characterized by abnormally rapid bone formation and breakdown, leading to the development of bones that are dense but fragile. Some bones may also be bent. It usually affects middle-aged and elderly people and most frequently occurs in the spine, skull, pelvis, thighs and lower legs. (For more information on this disorder, choose "Paget Disease" as your search term in the Rare Disease Database.)
Hypophosphatasia can be diagnosed before birth because the unhardened (uncalcified) skull does not show up clearly in ultrasound pictures. This disorder can be distinguished from Anencephaly by analysis of the substance alpha-fetoprotein, which is normal in fetuses with Hypophosphatasia, and high in those with Anencephaly.
Treatment with Vitamin D and its breakdown products (metabolites) has not been successful in Hypophosphatasia and other forms of Vitamin-D resistant Rickets. Sustained oral phosphate supplements may be beneficial in some cases. Other treatment is symptomatic and supportive.
Genetic counseling is recommended for families of persons with Hypophosphatasia. For more information for parents and physicians dealing with Hypophosphatasia patients, please contact Dr. Michael Whyte listed in the Resource section.
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 National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, contact:
In November 2009, Enobia Pharma announced the initiation of a Phase II clinical study of ENB-0040, a bone-targeted enzyme replacement therapy under investigation for the treatment of hypophosphatasia. The six-month study will assess the safety, efficacy and pharmacokinetics of this ERT in children ages five to 12.
Enobia has also announced the launch of the Hypophosphatasia Impact Patient Survey (HIPS), an online questionnaire intended to better understand the burden of HPP on patients and their families. The survey is designed to document the disease history, medical history, functional disability, and quality of life in patients with HPP.
Information on both of the above is available on the company's website: www.enobia.com.
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The Metabolic Basis of Inherited Disease, 5th ed.: John B. Stanbury, et al.; Eds; McGraw Hill, 1983. Pp. 1497-1507.
Infantile Hypophosphatasia: Enzyme Replacement Therapy by Intravenous Infusion of Alkaline Phosphatase-Rich Plasma From Patients with Paget Bone Disease: M.P. Whyte et al.; Journal Pediatr (September 1982:101(3)). Pp. 379-386.
Enzyme Replacement Therapy for Infantile Hypophosphatasia Attempted by Intravenous Infusions of Alkaline Phosphatase-Rich Paget Plasma: Results in Three Additional Patients. M.P. Whyte et al.; Journal Pediatr (December 1984: 105(6)). Pp. 926-933.
Infantile Hypophosphatasia Diagnosed at 4 Months and Surviving at 2 Years: A. Albeggiani et al.; Helv Paediatr Acta (1982:37(1)). Pp. 49-58.
FROM THE INTERNET
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusik, Editor; Johns Hopkins University, Last Edit Date 7/24/96, Entry Number 241530.
Report last updated: 2009/11/23 00:00:00 GMT+0