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

• Paget's disease
• Familial expansile osteolysis
• Kenny-Caffey syndrome

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), decreased bone density (osteopenia), and muscle weakness. In some cases, affected individuals may develop deafness because of an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss).

Some individuals with hereditary hyperphosphatasia develop headaches or high blood pressure (hypertension). In rare cases, abnormal bluish discoloration of the whites of the eyes (blue sclera) may occur.

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 for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive 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. 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 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. (For more information on this disorder, choose "Paget" as your search term in the Rare Disease Database.) 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.

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. The clinical picture has some similarity to Paget’s disease. 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.)

Diagnosis
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, which may be detectable through blood and urine tests.

Treatment
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 may need to systematically and comprehensively plan an affected child’s treatment.

Individuals with hereditary hyperphosphatasia have been treated with drugs known as bisphosphonates and calcitonins. These drugs reduce bone turnover by inhibiting bone resorption.

According to the medical literature, treatment with these drugs has led to improvement of associated symptoms. Although studies assessing long-term effectiveness have not been conducted, two recent studies demonstrated that bisphosphonate therapy can suppress bone turnover and prevent malformations.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Researchers are studying the role of osteoprotegerin in the treatment of hereditary hyperphosphatasia. Initial results demonstrated significant benefit to affected individuals. Osteoprotegerin treatment resulted in reduced rate of bone turnover and increased bone mass. More research is necessary to determine the long term safety and effectiveness of this potential treatment for individuals with hereditary hyperphosphatasia.

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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

TEXTBOOKS
Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 17th ed. Elsevier Saunders. Philadelphia, PA; 2005:2344-5.

Kasper, DL, Fauci AS, Longo DL, et al., eds. Harrison’s Principles of Internal Medicine.
16th ed. McGraw-Hill Companies. New York, NY; 2005:2271.

Rimoin D, Connor JM, Pyeritz RP, Korf BR, eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:4135-6.

Gorlin RJ, Cohen MMJr, Hennekam RCM, eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:303.

JOURNAL ARTICLES
Cundy T, Davidson J, Rutland MD, Stewart C, DePaoli AM. Recombinant osteoprotegerin for juvenile Paget’s disease. N Engl J Med. 2005;353:918-23.

Janssens K, de Vernejoul MC, de Freitas F, Vanhoenacker F, Van Hul W. An intermediate form of juvenile Paget’s disease caused by a truncating TNFRSF11B mutation. Bone. 2005;23:542-8.

Cundy T, Wheadon L, King A. Treatment of idiopathic hyperphosphatasia with intensive bisphosphonate therapy. J Bone Miner Res. 2004;19:703-11.

Chong B, Hegde M, Fawkner M, et al. Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. J Bone Miner Res. 2003;18:2095-104.

Whyte MP, Obrecht SE, Patrick BS, et al. Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med. 2002;347:175-84.

Cundy T, Hedge M, Naot D, et al. A mutation in the gene TNFRSF11B encoding osteoprotegerin causes idiopathic hyperphosphatasia phenotype. Hum Mol Genet. 2002;11:2119-27.

Tuysuz B, Mercimek S, Ungur S, Deniz M. Calcitonin treatment in osteoclasia with hyperphosphatasia (juvenile Paget’s disease): radiographic changes after treatment. Pediatr Radiol. 1999;29:838-41.

Antoniades K, Karakasis D, Kapetanos G, Lasaridis N, Tzarou V. Chronic idiopathic hyperphosphatasemia. Case report. Oral Surg Oral Med Oral Pathol. 1993;76:200-4.

FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:239000; Last Update:03/30/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=239000 Accessed On: April 20, 2006.