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NORD is very grateful to Prof. Tim Cundy, Department of Medicine, Faculty of Medical & Health Sciences, University of Auckland, New Zealand, for assistance in the preparation of this report.
Hereditary hyperphosphatasia is a rare genetic bone disorder (osteopathy) that becomes apparent during infancy or early childhood. Affected individuals develop progressive skeletal malformations especially in the long bones of the arms and legs. Skeletal malformations in the legs may cause problems walking and may eventually result in short stature. Additional symptoms include pain, fractures of affected bones, and muscle weakness. Because the biochemical and radiographic findings of hereditary hyperphosphatasia are similar to those of adult Paget's disease, a focal skeletal disorder of abnormal bone destruction and reformation, the disorder is sometimes referred to as juvenile Paget's disease. However, despite these similarities, the two disorders are distinct. Hereditary hyperphosphatasia is inherited as an autosomal recessive trait.
The severity of symptoms associated with hereditary hyperphosphatasia varies from case to case. Symptoms usually become apparent during infancy or early childhood usually between 2 and 3 years of age. Most individuals develop widening and bowing of the long bones of the legs eventually resulting in problems walking and short stature. Thickening of the upper domelike portion of the skull (calvaria) is another common finding.
Additional symptoms include pain, fractures of affected bones, abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and muscle weakness. Deafness is common - it arises because of an impaired ability of the auditory nerves to transmit input to the brain (sensorineural hearing loss).
Ocular manifestations including optic nerve pallor, angioid streaks and retinal neovacularization may become evident in long-term survivors. Aneurysms of the internal carotid arteries have also been described.
Laboratory findings include greatly elevated bone turnover markers (such as plasma alkaline phosphatase) and decreased bone density.
Hereditary hyperphosphatasia is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from both the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal 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 two carrier parents to both pass the defective gene and therefore have an affected child is 25% with each pregnancy. The risk of a child being a carrier like the parents is 50% with each pregnancy. The chance for a child of receiving normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that about two-thirds of cases of hereditary hyperphosphatasia are caused by changes or disruptions (mutations) of the TNFRSF11B gene located on the long arm (q) of chromosome 8 (8q24). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 11p13" refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The human skeleton is living tissue that is constantly changing (remodeling). The symptoms of hereditary hyperphosphatasia occur because of markedly increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down (bone resorption) and then reforms. If the loss of bone is greater than the rate of new bone formation, complications occur. Bone turnover involves cells that assist bone resorption (osteoclasts) and cells that assist bone formation (osteoblasts). The interaction between osteoclasts and osteoblasts determines how bone reforms. The interaction is a complex process that involves many factors including a protein called osteoprotegerin.
Mutations affecting the TNFRSF11B gene result in deficiency of osteoprotegerin, which normally acts as a brake on bone resorption by regulating the activity of osteoclasts. Individuals with hereditary hyperphosphatasia have a deficiency of osteoprotegerin, which results in an increased rate of bone turnover.
Hereditary hyperphosphatasia affects males and females in equal numbers. Like all recessive disorders it is more common in countries where within-family marriage is commonly practiced. More than 50 cases have been described since the disorder was first reported in the medical literature in 1956.
Symptoms of the following disorders can be similar to those of hereditary hyperphosphatasia. Comparisons may be useful for a differential diagnosis.
Paget's disease is a slowly progressive focal disease of the skeletal system characterized by abnormally rapid bone breakdown and formation, leading to the development of bones that are dense but fragile. The major symptom is bone pain. It usually affects middle-aged and elderly people: children are not affected. The disease most frequently occurs in the spine, skull, pelvis, thighs and lower legs. Most cases are asymptomatic or mild.
Symptoms are often vague and may be hard to distinguish from those of many other bone diseases. Bowed long bones and frequent fractures are caused by abnormally soft bones. Enlargement of the head, headaches, sensation of heat, deep dull pain in the bones and hearing loss may also occur. About a third of patients with Paget's disease have a family history of the disorder, and in about half of these cases, familial Paget's disease is associated with mutations in the SQSTM1 gene. (For more information on this disorder, choose "Paget" as your search term in the Rare Disease Database)
Familial expansile osteolysis, also known as McCabe disease, is an extremely rare genetic bone disorder also osteoclastic overactivity (osteolysis). Affected individuals experience painful bone deformities, early loss of teeth, increased susceptibility to fractures, and hearing loss. Familial expansile osteolysis results from activating mutations in the TNFRSF11A gene and is inherited as an autosomal dominant trait.
Kenny-Caffey syndrome is an extremely rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of Kenny-Caffey syndrome is short stature. Mental abilities are rarely affected. Individuals with Kenny-Caffey syndrome may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hpoparathyroidism). In most cases, Kenny-Caffey syndrome is inherited as an autosomal dominant trait. Other cases are inherited as an autosomal recessive trait, linked to the TBCE gene. (For more information on this disorder, choose "Kenny Caffey" as your search term in the Rare Disease Database.)
Benign hyperphosphatasia is a biochemical finding unaccompanied by skeletal changes.
A diagnosis of hereditary hyperphosphatasia is made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of x-rays tests that reveal distinct radiographic findings. Affected individuals also have elevated levels of serum alkaline phosphatase and other biochemical markers of bone turnover, detectable through blood and urine tests.
The treatment of hereditary hyperphosphatasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat skeletal malformations (orthopedic surgeon), specialists who asses and treat hearing problems (audiologists), and other healthcare professionals need to systematically and comprehensively plan an affected child's treatment.
Individuals with hereditary hyperphosphatasia have been treated with drugs known as bisphosphonates.. These drugs reduce bone turnover by inhibiting bone resorption.
According to the medical literature, treatment with these drugs has led to improvement of bone-associated symptoms. Although studies assessing long-term effectiveness have not been conducted, recent studies have suggested that bisphosphonate therapy can suppress bone turnover and prevent malformations. These drugs probably do not affect the ocular and vascular manifestations. In theory, the novel drug, denosumab, that directly targets the effects of osteoprotegerin deficiency might be better in this regard, although its effectiveness has not yet been reported in the medical literature.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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:
Contact for more information about this condition:
Prof. Tim Cundy
Department of Medicine Faculty of Medical & Health Sciences
University of Auckland, New Zealand
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Report last updated: 2013/02/27 00:00:00 GMT+0