Hereditary Hyperphosphatasia

Hereditary Hyperphosphatasia

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Hereditary Hyperphosphatasia is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • familial idiopathic hyperphosphatasia
  • familial osteoectasia
  • hyperostosis corticalis deformans juvenilis
  • juvenile Paget's disease
  • chronic congenital idiopathic hyperphosphatasemia

Disorder Subdivisions

  • None

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Standard Therapies

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, 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 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.

Investigational Therapies

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



For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/



Contact for more information about this condition:

Prof. Tim Cundy

Department of Medicine Faculty of Medical & Health Sciences

University of Auckland, New Zealand

t.cundy@auckland.ac.nz

References

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.



Tau C, Mautalen C, Casco C, Alvarez V, Rubinstein M, Chronic idiopathic hyperphosphatasia: normalization of bone turnover with cyclical intravenous pamidronate therapy Bone 2004; 35 210-6.



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.



INTERNET

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:239000; Last Update:1/13/11. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=239000 Accessed: January 23, 2013.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



NIH/Osteoporosis and Related Bone Diseases National Resource Center

2 AMS Circle

Bethesda, MD 20892-3676

USA

Tel: (301)495-4484

Fax: (301)718-6366

Tel: (877)226-4267

TDD: (301)565-2966

Email: NIHBoneInfo@mail.nih.gov

Internet: http://www.bones.nih.gov



NIH/National Institute on Deafness and Other Communication Disorders

31 Center Drive, MSC 2320

Communication Avenue

Bethesda, MD 20892-3456

Tel: (301)402-0900

Fax: (301)907-8830

Tel: (800)241-1044

TDD: (800)241-1105

Email: nidcdinfo@nidcd.nih.gov

Internet: http://www.nidcd.nih.gov



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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