Hypophosphatasia 

  • Author: Horacio Plotkin, MD, FAAP; Chief Editor: Bruce Buehler, MD   more...
 
Updated: May 15, 2012
 

Background

Initially recognized by Rathbun in 1948, hypophosphatasia is a rare inborn error of metabolism caused by mutations in the gene encoding tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).[1] TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. Alterations in the TNSALP gene lead to low alkaline phosphatase activity levels and ultimately to rickets, osteomalacia, or both, which characterize this disorder. Incidence has been estimated at 1 case per 100,000 live births. Clinical presentation varies widely, from death in utero to cases in which pathologic fractures first present in adulthood.

At least 6 clinical forms of hypophosphatasia have been reported, although form assignment is often challenging as the age when skeletal lesions are discovered determines the type, and less severe bone lesions may be missed for years, until a radiograph is obtained for chronic pain or a pathological fracture. Because hypophosphatasia is often misdiagnosed, patients considered to have an adult form may have had signs of the disease earlier in life but were not diagnosed with hypophosphatasia.

The types include perinatal (lethal), infantile, childhood, and adult. Two other forms include odontohypophosphatasia (no clinical changes in long bones are present, only biochemical and dental manifestations) and pseudohypophosphatasia. The latter is clinically indistinguishable from infantile hypophosphatasia, but serum alkaline phosphatase (ALP) activity is normal. Pseudohypophosphatasia has been suggested as a possible consequence of a mutant TNSALP gene that still has activity in vitro but not in vivo. Conversely, in these patients, phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal-5'-phosphate (PLP) levels are elevated in serum and urine despite normal or elevated alkaline phosphatase activity levels.

Patients may present with varying signs and symptoms, history, and inheritance patterns. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is variable. Analysis of the TNSALP gene aids prenatal diagnosis. Compound heterozygosity and autosomal dominant mutations in the TNSALP gene may cause childhood and adult hypophosphatasia. At least 2 mutations occur in specific populations and are lethal when homozygous: c.1559delT affects Japanese patients and gly317asp is found in a Canadian Mennonite population.

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Pathophysiology

Alkaline phosphatase is present as 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. TNSALP is known to cleave the phosphate-containing substrates PLP, PEA, and PPi, which are all extracellular substrates. The TNSALP gene is located on chromosome 1p36.1 and consists of 12 exons distributed over 50 kb. More than 250 distinct mutations have been described for this gene, the vast majority (79%) of which are missense mutations.

Patients with hypophosphatasia have low alkaline phosphatase activity levels, which leads to increased PPi, an inhibitor of hydroxyapatite crystal formation. The increase in PPi causes defects in calcium and phosphate balance.

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Epidemiology

Frequency

United States

Incidence of the severe form is believed to be approximately 1 case per 100,000 live births.[2] In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns.

International

International incidence is unknown.

Mortality/Morbidity

The most severe cases are lethal. The mortality rate in infants with hypophosphatasia is 50% in patients who manifest within 6 months of birth. The most common cause of death in infants with hypophosphatasia is respiratory complications. Individuals with less severe disease can reach adulthood, although often with significantly increased morbidity. Children with hypophosphatasia often have rachitic deformities, and adults may have increased morbidity from poorly healing stress fractures and may be severely affected and not able to ambulate. Commonly, patients experience premature loss of dentition. Patients may also present with nephrocalcinosis, neurological damage secondary to vitamin B-6–respondent seizures, increased intracranial pressure secondary to craniosynostosis, and joint problems secondary to calcium deposits. Adults may present with severe mobility impairment (about 23% require the use of a wheelchair; about 25% require the use of a walking device).

Race

Hypophosphatasia occurs in all races.

Sex

Males and females are equally affected.

Age

Hypophosphatasia affects all age groups; however, the severity of the disease in general varies with age, from a lethal disorder in neonates to a less severe condition in some adults, although adults can experience significant morbidity.

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Contributor Information and Disclosures
Author

Horacio Plotkin, MD, FAAP  Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska School of Medicine

Horacio Plotkin, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics

Disclosure: Enobia Pharma Salary Management position

Coauthor(s)

George A Anadiotis, DO  Consulting Staff, Division of Clinical and Biochemical Genetics, Department of Pediatric Rehabilitation and Development, Emmanuel Children's Hospital

George A Anadiotis, DO is a member of the following medical societies: American Medical Association and American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

James Bowman, MD  Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Leonard G Feld, MD, PhD, MMM, FAAP  Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

Daniel Rauch, MD, FAAP  Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine

Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine

Disclosure: Baxter Honoraria Consulting

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References
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  6. Rauch F, Greenberg C, Whyte MP, et al. The Bone Tissue Defect in Children with Hypophosphatasia: Histomorphometric Study. Proceedings of the 33 Annual ASBMR Meeting. 2011.

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  8. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. Mar 8 2012;366(10):904-13. [Medline].

  9. Kishnani PS, Rockman CR, Whyte MP et al. Hypophosphatasia: Enzyme Replacement Therapy (ENB-0040) Decreases TNSALP Substrate Accumulation and Improves Functional Outcome in Affected Adolescents and Adults. Proceedings of American College of Medical Genetics. 2012;303.

  10. Gagnon C, Sims NA, Mumm S, et al. Lack of Sustained Response to Teriparatide in a Patient with Adult Hypophosphatasia. J Clin Endocrinol Metab. 2010;Epub:[Medline].

  11. Cahill RA, Wenkert D, Perlman SA, et al. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. Aug 2007;92:2923-30. [Medline].

  12. Plecko B, Stockler S. Vitamin B6 dependent seizures. Can J Neurol Sci. 2009;36:S73-7. [Medline].

  13. van den Bos T, Handoko G, Niehof A, et al. Cementum and dentin in hypophosphatasia. J Dent Res. Nov 2005;84(11):1021-5. [Medline].

  14. Whyte MP. Enzyme defects and the skeleton. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. 7th ed. 2008:454-455.

  15. Whyte MP. Hypophosphatasia. In: The metabolic & molecular bases of inherited disease. 8th ed. 2001:5313-29.

  16. Whyte MP, Kurtzberg J, McAlister WH, et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res. Apr 2003;18(4):624-36. [Medline].

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