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'''Hypophosphatasia''' is a rare, and sometimes fatal metabolic bone disease.<ref>Whyte MP: Hypophosphatasia. In “The Metabolic and Molecular Bases of Disease,” 8th Ed., Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds; McGraw-Hill Book Company, New York pp 5313-5329, 2001.</ref> Clinical symptoms are heterogeneous ranging from the rapidly fatal perinatal variant, with profound skeletal hypomineralization and respiratory compromise to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 200 genetic mutations identified to date in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in milder forms. The prevalence of hypophosphatasia is not known. One study estimated the live birth incidence of severe forms to be 1:100,000.<ref>Fraser, D. Hypophosphatasia. Am J Med 22, 730-746, 1957.</ref>
'''Hypophosphatasia''' is a rare, and sometimes fatal metabolic bone disease.<ref name=Whyte01>{{cite book |author=Whyte MP |chapter=Hypophosphatasia |editor=Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B |title=The metabolic & molecular bases of inherited disease |publisher=McGraw-Hill |location=New York |year=2001 |pages=5313–29 |isbn=0-07-913035-6 |edition=8th |volume=4}}</ref> Clinical symptoms are heterogeneous ranging from the rapidly fatal perinatal variant, with profound skeletal hypomineralization and respiratory compromise to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 200 genetic mutations identified to date in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in milder forms. The prevalence of hypophosphatasia is not known. One study estimated the live birth incidence of severe forms to be 1:100,000.<ref name=Fraser57>{{cite journal |author=Fraser D |title=Hypophosphatasia |journal=Am. J. Med. |volume=22 |issue=5 |pages=730–46 |year=1957 |month=May |pmid=13410963 |url=http://linkinghub.elsevier.com/retrieve/pii/0002-9343(57)90124-9}}</ref>


== Clinical Symptoms ==
== Clinical Symptoms ==
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== Diagnosis ==
== Diagnosis ==
'''Dental Findings'''
'''Dental Findings'''
Often, one of the first symptoms of hypophosphatasia is early loss of deciduous (baby or primary teeth) with root intact.<ref>Orphanet J Rare Dis. 2009;10.1186/1750-1172-4-6,Published online</ref> Researchers have recently documented a positive correlation of dental abnormalities to clinical phenotype. Poor dentition is noted in adults.
Often, one of the first symptoms of hypophosphatasia is early loss of deciduous (baby or primary teeth) with root intact.<ref name=Reibel09/> Researchers have recently documented a positive correlation of dental abnormalities to clinical phenotype. Poor dentition is noted in adults.


'''Laboratory Testing'''
'''Laboratory Testing'''
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'''Radiography'''
'''Radiography'''
Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia, and can reveal the characteristic abnormalities found in other forms.<ref>Shohat M, Rimoin DL, Gruber HE, Lachman RS. (1991) Perinatal lethal hypophosphatasia: clinical, radiologic and morphologic findings. Pediatr Radiol, 21:421-427.</ref> Radiologic evidence of skeletal defects is found in nearly all patients and includes hypomineralization, rachitic changes, incomplete vertebrate ossification and occasionally, lateral bony spurs on the ulnae and fibulae. Availability of XRAYs are widespread.
Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia, and can reveal the characteristic abnormalities found in other forms.<ref>{{cite journal |author=Shohat M, Rimoin DL, Gruber HE, Lachman RS |title=Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings |journal=Pediatr Radiol |volume=21 |issue=6 |pages=421–7 |year=1991 |pmid=1749675 }}</ref> Radiologic evidence of skeletal defects is found in nearly all patients and includes hypomineralization, rachitic changes, incomplete vertebrate ossification and occasionally, lateral bony spurs on the ulnae and fibulae. Availability of XRAYs are widespread.


In newborns X-rays readily distinguish perinatal HPP from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed. '''Tongues of radiolucency''' often protrude from the metaphyses into the bone shaft.
In newborns X-rays readily distinguish perinatal HPP from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed. '''Tongues of radiolucency''' often protrude from the metaphyses into the bone shaft.
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'''Genetic Analysis'''
'''Genetic Analysis'''
All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans ([[ALPL]]; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at http://www.sesep.uvsq.fr/database_hypo/Mutation.html. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression. There appears to be a correlation between genotype and phenotype in hypophosphatasia”.<ref>Zurutura et al. Hum Mol Gen, 8, 1039-46, 1999</ref> Mutation analysis is possible and available in 3 laboratories (as reported on www.genetest.org).
All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans ([[ALPL]]; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at http://www.sesep.uvsq.fr/database_hypo/Mutation.html. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression. There appears to be a correlation between genotype and phenotype in hypophosphatasia”.<ref>{{cite journal |author=Zurutuza L, Muller F, Gibrat JF, ''et al.'' |title=Correlations of genotype and phenotype in hypophosphatasia |journal=Hum. Mol. Genet. |volume=8 |issue=6 |pages=1039–46 |year=1999 |month=June |pmid=10332035 |url=http://hmg.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10332035}}</ref> Mutation analysis is possible and available in 3 laboratories (as reported on www.genetest.org).


== Inheritance ==
== Inheritance ==


Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern,<ref>Simon-Bouy B., Taillandier A., Fauvert D., BrunHeath I., Jean-Louis S., Armengod C.G., Bialer M.G., Mathieu M., Cousin J., Chitayat D., Liebelt J., Feldman B., Gerard-Blanluet M., Kortge-Jing S., King C., Laivuori H., Le Merrer M, Mehta S., Jern C., Sharif S., Prieur F., Gillessen-Kaesbach G., Zandl A., Mornet E. (2008) Hypophosphatasia: Molecular testing of 19 prenatal cases and discussion about genetic counseling. Prenat Diagn, 28;993-998.</ref> and by incomplete penetration of the trait.
Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern,<ref>{{cite journal |author=Simon-Bouy B, Taillandier A, Fauvert D, ''et al.'' |title=Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling |journal=Prenat. Diagn. |volume=28 |issue=11 |pages=993–8 |year=2008 |month=November |pmid=18925618 |doi=10.1002/pd.2088}}</ref> and by incomplete penetration of the trait.
HPP is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities.<ref>Fraser D. (1957) Hypophosphatasia. Am J Med 22:730-46.</ref> The prevalence of '''severe hypophosphatasia''' is estimated to be 1:100,000 in a population of largely Anglo Saxon origin. The frequency of '''mild HPP''' is more challenging to assess because the symptoms may escape notice, or be misdiagnosed. The highest incidence of HPP has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns manifests severe disease.<ref>Greenberg C.R., Taylor C.L.D., Haworth J.C., Seargeant L.E., Phillips S., Triggs-Raine B., Chodirker B.N. (1993) A homoallelic Gly317 β Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites. Genomics, 17;215-217.</ref> HPP is considered particularly rare in people of African ancestry in the U.S.<ref>Whyte M.P., Essmyer K., Geimer M., Mumm S. (2006) Homozygosity for TNSALP mutation 1348C>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. J Pediatr, 148:753-758.</ref>
HPP is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities.<ref name=Fraser57/> The prevalence of '''severe hypophosphatasia''' is estimated to be 1:100,000 in a population of largely Anglo Saxon origin. The frequency of '''mild HPP''' is more challenging to assess because the symptoms may escape notice, or be misdiagnosed. The highest incidence of HPP has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns manifests severe disease.<ref>{{cite journal |author=Greenberg CR, Taylor CL, Haworth JC, ''et al.'' |title=A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites |journal=Genomics |volume=17 |issue=1 |pages=215–7 |year=1993 |month=July |pmid=8406453 |doi=10.1006/geno.1993.1305 |url=http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(83)71305-4}}</ref> HPP is considered particularly rare in people of African ancestry in the U.S.<ref>{{cite journal |author=Whyte MP, Essmyer K, Geimer M, Mumm S |title=Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry |journal=J. Pediatr. |volume=148 |issue=6 |pages=753–8 |year=2006 |month=June |pmid=16769381 |doi=10.1016/j.jpeds.2006.01.031 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(06)00007-2}}</ref>


== Treatment ==
== Treatment ==
There are no approved therapies for HPP today. Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions as necessary.<ref>Whyte MP: Hypophosphatasia. In “The Metabolic and Molecular Bases of Disease,” 8th Ed., Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds; McGraw-Hill Book Company, New York pp 5313-5329, 2001.</ref>
There are no approved therapies for HPP today. Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions as necessary.<ref name=Whyte01/>
• Hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. This should be done carefully so as not to increase the skeletal demineralization that results from the disease itself,<ref>Barcia J.P., Strife C.F., Langman C.B. (1997) Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. J Pediatr,130: 825.</ref>
• Hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. This should be done carefully so as not to increase the skeletal demineralization that results from the disease itself,<ref>{{cite journal |author=Barcia JP, Strife CF, Langman CB |title=Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization |journal=J. Pediatr. |volume=130 |issue=5 |pages=825–8 |year=1997 |month=May |pmid=9152296 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3476(97)80029-7}}</ref>
. Vitamin D sterols and mineral supplements traditionally used for rickets or osteomalacia should not be used unless there is a deficiency, as blood levels of calcium ions (Ca2+), inorganic phosphate (Pi) and vitamin D metabolites usually are not reduced.<ref>Opshaug O., Maurseth K., Howlid H., Aksnes .L, Aarskog D. (1982) Vitamin D metabolism in hypophosphatasia. Acta Paediatr Scand, 71(3):517-21.</ref>
. Vitamin D sterols and mineral supplements traditionally used for rickets or osteomalacia should not be used unless there is a deficiency, as blood levels of calcium ions (Ca2+), inorganic phosphate (Pi) and vitamin D metabolites usually are not reduced.<ref>{{cite journal |author=Opshaug O, Maurseth K, Howlid H, Aksnes L, Aarskog D |title=Vitamin D metabolism in hypophosphatasia |journal=Acta Paediatr Scand |volume=71 |issue=3 |pages=517–21 |year=1982 |month=May |pmid=6291316 }}</ref>
• Craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infants<ref>Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H. (2009) Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst. 25(2):217-23.</ref>
• Craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infants<ref>{{cite journal |author=Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H |title=Neurosurgical aspects of childhood hypophosphatasia |journal=Childs Nerv Syst |volume=25 |issue=2 |pages=217–23 |year=2009 |month=February |pmid=18769927 |doi=10.1007/s00381-008-0708-3}}</ref>
• Bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. Fractures and corrective osteotomies (bone cutting) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. A load-sharing intramedullary nail on rod has been shown to be the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult HPP patients<ref>Coe J.D., Murphy W.A., Whyte M.P. (1986) Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am, 68:981-990.</ref>
• Bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. Fractures and corrective osteotomies (bone cutting) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. A load-sharing intramedullary nail on rod has been shown to be the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult HPP patients<ref>{{cite journal |author=Coe JD, Murphy WA, Whyte MP |title=Management of femoral fractures and pseudofractures in adult hypophosphatasia |journal=J Bone Joint Surg Am |volume=68 |issue=7 |pages=981–90 |year=1986 |month=September |pmid=3745261 }}</ref>
• Dental problems: Children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. Dentures may ultimately be needed. Dentists should carefully monitor patients’ dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease<ref>Reibel A., Maniere M., Class F., Droz D., Alembik Y., Mornet E., Bloch-Zupan A. (2009) Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet J Rare Dis, 4:6.</ref>
• Dental problems: Children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. Dentures may ultimately be needed. Dentists should carefully monitor patients’ dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease<ref name=Reibel09>{{cite journal |author=Reibel A, Manière MC, Clauss F, ''et al.'' |title=Orodental phenotype and genotype findings in all subtypes of hypophosphatasia |journal=Orphanet J Rare Dis |volume=4 |pages=6 |year=2009 |pmid=19232125 |pmc=2654544 |doi=10.1186/1750-1172-4-6 |url=http://www.ojrd.com/content/4//6}}</ref>
• Physical Impairments and Pain: Rickets and bone weakness associated with HPP can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. Nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance<ref>Girschick H.J., Seyberth H.W., Huppertz H.I. (1999) Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone, 25:603-7.</ref>
• Physical Impairments and Pain: Rickets and bone weakness associated with HPP can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. Nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance<ref>{{cite journal |author=Girschick HJ, Seyberth HW, Huppertz HI |title=Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs |journal=Bone |volume=25 |issue=5 |pages=603–7 |year=1999 |month=November |pmid=10574582 |url=http://linkinghub.elsevier.com/retrieve/pii/S8756-3282(99)00203-3}}</ref>
Investigational use of more directed treatments has been limited.
Investigational use of more directed treatments has been limited.
• Bisphosphonate (pyrophosphate synthetic analog) in one infant had no discernible effect on the skeleton, and the infant’s disease progressed until death at 14 months of age<ref>Deeb AA, Bruce SN, Morris AA, Cheetham TD. (2000) Infantile hypophosphatasia: disappointing results of treatment. Acta Paediatr. 89(6):730-3.</ref>
• Bisphosphonate (pyrophosphate synthetic analog) in one infant had no discernible effect on the skeleton, and the infant’s disease progressed until death at 14 months of age<ref>{{cite journal |author=Deeb AA, Bruce SN, Morris AA, Cheetham TD |title=Infantile hypophosphatasia: disappointing results of treatment |journal=Acta Paediatr. |volume=89 |issue=6 |pages=730–3 |year=2000 |month=June |pmid=10914973 |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0803-5253&date=2000&volume=89&issue=6&spage=730}}</ref>
• Bone marrow cell transplantation in two severely-affected infants produced radiographic and clinical improvement, although the mechanism of efficacy is not fully understood and significant morbidity persisted<ref>Whyte MP, Kurtzberg J, McAlister WH, Mumm S, Podgornik MN, Coburn SP, Ryan LM, Miller CR, Gottesman GS, Smith AK, Douville J, Waters-Pick B, Armstrong RD, Martin PL. (2003) Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res.18(4):624-36.</ref><ref>Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, Mumm S, Whyte MP. (2007) Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. 92(8):2923-30.</ref>
• Bone marrow cell transplantation in two severely-affected infants produced radiographic and clinical improvement, although the mechanism of efficacy is not fully understood and significant morbidity persisted<ref>{{cite journal |author=Whyte MP, Kurtzberg J, McAlister WH, ''et al.'' |title=Marrow cell transplantation for infantile hypophosphatasia |journal=J. Bone Miner. Res. |volume=18 |issue=4 |pages=624–36 |year=2003 |month=April |pmid=12674323 |doi=10.1359/jbmr.2003.18.4.624}}</ref><ref>{{cite journal |author=Cahill RA, Wenkert D, Perlman SA, ''et al.'' |title=Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts |journal=J. Clin. Endocrinol. Metab. |volume=92 |issue=8 |pages=2923–30 |year=2007 |month=August |pmid=17519318 |doi=10.1210/jc.2006-2131 |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=17519318}}</ref>
• Enzyme replacement therapy with normal or ALP-rich serum from patients with Paget’s bone disease was not beneficial<ref>Whyte MP, Valdes R Jr, Ryan LM, McAlister WH. (1982) Infantile hypophosphatasia: enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease. J Pediatr. 101(3):379-86.</ref><ref>Whyte MP, McAlister WH, Patton LS, Magill HL, Fallon MD, Lorentz WB Jr, Herrod HG. (1984) Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusion of alkaline phosphatase-rich Paget plasma: results in three additional patients. J Pediatr. 105(6):926-33.</ref>
• Enzyme replacement therapy with normal or ALP-rich serum from patients with Paget’s bone disease was not beneficial<ref>{{cite journal |author=Whyte MP, Valdes R, Ryan LM, McAlister WH |title=Infantile hypophosphatasia: enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease |journal=J. Pediatr. |volume=101 |issue=3 |pages=379–86 |year=1982 |month=September |pmid=7108657 }}</ref><ref>{{cite journal |author=Whyte MP, McAlister WH, Patton LS, ''et al.'' |title=Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients |journal=J. Pediatr. |volume=105 |issue=6 |pages=926–33 |year=1984 |month=December |pmid=6502342 }}</ref>
• Phase 2 clinical trials of bone targeted enzyme replacement therapy have been completed for the treatment of hypophosphatasia in infants and juveniles, a phase 2 study in adults is ongoing.<ref>http://www.clinicaltrials.gov</ref><ref>http://www.enobia.com</ref>
• Phase 2 clinical trials of bone targeted enzyme replacement therapy have been completed for the treatment of hypophosphatasia in infants and juveniles, a phase 2 study in adults is ongoing.<ref>http://www.clinicaltrials.gov</ref><ref>http://www.enobia.com</ref>


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== Further reading ==
== Further reading ==
* {{cite journal |author=Rathbun JC |title=Hypophosphatasia; a new developmental anomaly |journal=Am J Dis Child |volume=75 |issue=6 |pages=822–31 |year=1948 |month=June |pmid=18110134 |doi= |url=}}
* {{cite journal |author=Rathbun JC |title=Hypophosphatasia; a new developmental anomaly |journal=Am J Dis Child |volume=75 |issue=6 |pages=822–31 |year=1948 |month=June |pmid=18110134 }}


== External links ==
== External links ==
*{{cite journal |author=Mornet E, Nunes ME |title=Hypophosphatasia |url=http://www.ncbi.nlm.nih.gov/books/NBK1150/ |editor=Pagon RA, Bird TD, Dolan CR, Stephens K |journal=GeneReviews |publisher=University of Washington |location=Seattle WA |year=2007 }}
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hops GeneReview/NIH/UW entry on Hypophosphatasia]
* [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=146300 Adult Hypophosphatasia]
*{{OMIM|146300|Adult Hypophosphatasia}}
* [http://www.hypophosphatasie.com Hypophosphatasie Europe]
* [http://www.hypophosphatasie.com Hypophosphatasie Europe]
* [http://www.hpp-ev.de Hypophosphatasie Deutschland E.V.]
* [http://www.hpp-ev.de Hypophosphatasie Deutschland E.V.]

Revision as of 22:55, 4 March 2011

Hypophosphatasia
SpecialtyEndocrinology Edit this on Wikidata

Hypophosphatasia is a rare, and sometimes fatal metabolic bone disease.[1] Clinical symptoms are heterogeneous ranging from the rapidly fatal perinatal variant, with profound skeletal hypomineralization and respiratory compromise to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 200 genetic mutations identified to date in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in milder forms. The prevalence of hypophosphatasia is not known. One study estimated the live birth incidence of severe forms to be 1:100,000.[2]

Clinical Symptoms

There is a remarkable heterogeneity in symptom presentation depending largely on age at initial presentation, ranging from death in utero to relatively simple problems with dentition in adult life. Although several clinical sub-types of the disease have been characterized based on the age at which skeletal lesions are discovered, the disease is best understood as a single continuous spectrum of severity.

In the perinatal period, Hypophosphatasia is the most pernicious form of hypophosphatasia. It is expressed in utero as profound hypomineralization that results in caput membraneceum, deformed or shortened limbs during gestation and at birth and rapid death due to respiratory failure. Stillbirth is not uncommon and long-term survival is rare. Neonates who manage to survive several days or weeks suffer increasing respiratory compromise due to rachitic chest disease and hypoplastic lungs, and ultimately, respiratory failure. Epilepsy (seizures) can occur and prove lethal (vide infra). Excessive osteoid may encroach on the marrow space and result in myelophthisic anemia. In radiographic examinations, perinatal hypophosphatasia is readily distinguished from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, giving areas of the unossified calvaruim the illusion that cranial sutures are widely separated when they are in fact functionally closed. Another unusual radiographic feature is bony spurs that protrude laterally from the midshafts of the ulnae and fibulae. Despite the considerable patient-to-patient variability and the diversity of radiographic findings, the X-ray can be considered diagnostic.

The Infantile subtype is described with Hypophosphatasia presents in the first 6 months of life. Postnatal development often appears normal until the onset of poor feeding and inadequate weight gain, and clinical manifestations of rickets are recognized. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often “functional” craniosynostosis; and if the patient survives infancy, these sutures can permanently fuse. Oftentimes, a flail chest from rib fractures, rachitic deformity, etc. leads to respiratory compromise and pneumonia. Hypercalcemia and hypercalcenuria are also common and may explain the nephrocalcinosis, renal compromise, and episodes of recurrent vomiting. Radiographic features are striking though generally less severe than those found in perinatal hypophosphatasia. In some newly diagnosed patients an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears, which suggests the occurrence of abrupt metabolic change. In addition, serial radiography studies may demonstrate the persistence of impaired skeletal mineralization (i.e. rickets) and reveal gradual generalized demineralization. Mortality is estimated to be 50% in the first year of life.

In childhood Hypophosphatasia’s clinical expression is extremely variable. As a result of aplasia, hypoplasia, or dysplasia of dental cementum, premature loss of deciduous teeth (i.e. before the age of 5) occurs. Frequently, incisors are shed first; occasionally almost the entire primary dentition is exfoliated prematurely. Dental radiographs sometimes show the enlarged pulp chambers and root canals characteristic of the “shell teeth” of rickets. Patients may also experience delayed walking, a characteristic waddling gait, complain of stiffness and pain, and have an appendicular muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show rachitic deformities and characteristic bony defects near the ends of major long bones (i.e. “tongues” of radiolucency projecting from the rachitic growth plate into the metaphsysis). Growth retardation, frequent fractures and osteopenia are common. In severely affected infants and young children it is not uncommon, despite the appearance of widely “open” fontanels on radiographic studies, for functional synostosis of cranial sutures to occur. The illusion of “open” fontanels results from large areas of hypomineralized calvarium. Subsequently true premature bony fusion of cranial sutures may elevate intracranial pressure.

In adult years, Hypophosphatasia can present during middle age. Frequently, there is a history of rickets, premature loss of deciduous teeth, or early loss of adult dentition followed by relatively good health. Osteomalacia manifests in painful feet resulting from recurrent poorly healing metatarsal stress fractures, and discomfort in the thighs or hips due to femoral pseudofractures which, when they appear in radiographic study, are distinguished from most other types of osteomalacia (which occur medially) by their location in the lateral cortices of the proximal femora. Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional overt attacks of arthritis (pseudogout), which appears to be the result of elevated endogenous inorganic pyrophosphate (PPi) levels. These patients may also suffer articular cartilage degeneration and pyrophosphate arthropathy. Radiographs may reveal pseudofractures in the lateral cortices of the proximal femora, stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis.

Odontohypophosphatasia is present when dental disease is the only clinical abnormality and radiographic and/or histologic studies reveal no evidence of rickets or osteomalacia. Although hereditary leukocyte abnormalities and other disorders usually account for this condition, odontohypophosphatasia may explain some “early-onset periodontitis” cases.

Causes

The metabolic basis of hypophosphatasia stems from a molecular defect in the gene encoding tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an ectoenzyme tethered to the outer surface of osteoblast and chondrocyte cell membranes. TNSALP normally hydrolyzes several substances, including inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP) a major form of vitamin B6.

When TSNALP is low, inorganic pyrophosphate (PPi) accumulates extracellularly and potently inhibits formation of hydroxyapatite (mineralization) causing rickets in infants and children and osteomalacia (soft bones) in adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP for PL to cross over the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, deposition of calcium pyrophosphate dehydrate (CPPD) crystals in the joint can cause pseudogout.

Diagnosis

Dental Findings Often, one of the first symptoms of hypophosphatasia is early loss of deciduous (baby or primary teeth) with root intact.[3] Researchers have recently documented a positive correlation of dental abnormalities to clinical phenotype. Poor dentition is noted in adults.

Laboratory Testing The pathognomonic symptom is subnormal serum activity of alkaline phosphatase (ALP). In general, clinical severity mirrors the degree of enzyme deficiency. The most sensitive substrate marker for hypophosphatasia is an increased pyridoxal 5’-phosphate (PLP) plasma level, which often correlates with disease severity. And, although it remains only a research technique, quantitation of urinary inorganic pyrophosphate (PPi) levels, which are elevated in most hypophosphatasia patients, has been reported to accurately detect carriers. In addition, increased urinary levels of phosphoethanolamine (PEA) are observed in most patients. Availability of the age-adjusted serum ALP test is widespread and included on many CHEM20 panels.

Radiography Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia, and can reveal the characteristic abnormalities found in other forms.[4] Radiologic evidence of skeletal defects is found in nearly all patients and includes hypomineralization, rachitic changes, incomplete vertebrate ossification and occasionally, lateral bony spurs on the ulnae and fibulae. Availability of XRAYs are widespread.

In newborns X-rays readily distinguish perinatal HPP from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed. Tongues of radiolucency often protrude from the metaphyses into the bone shaft.

In infants, radiographic features of infantile HPP are striking though generally less severe than those found in perinatal HPP. In some newly-diagnosed patients, an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears suggesting an abrupt metabolic change has occurred. Serial radiography studies may reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis and gradual generalized demineralization.

In adults, x-rays may reveal bilateral femoral pseudofractures in the lateral subtrochanteric diaphysis. These psuedofractures may remain for years or worsen, but they may not heal until they break completely or the patient receives intramedullary fixation. These patients may also experience recurrent metatarsal fractures.

Genetic Analysis All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at http://www.sesep.uvsq.fr/database_hypo/Mutation.html. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression. There appears to be a correlation between genotype and phenotype in hypophosphatasia”.[5] Mutation analysis is possible and available in 3 laboratories (as reported on www.genetest.org).

Inheritance

Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern,[6] and by incomplete penetration of the trait.

HPP is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities.[2] The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo Saxon origin. The frequency of mild HPP is more challenging to assess because the symptoms may escape notice, or be misdiagnosed. The highest incidence of HPP has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns manifests severe disease.[7] HPP is considered particularly rare in people of African ancestry in the U.S.[8]

Treatment

There are no approved therapies for HPP today. Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions as necessary.[1] • Hypercalcemia in infants may require restriction of dietary calcium or administration of calciuretics. This should be done carefully so as not to increase the skeletal demineralization that results from the disease itself,[9] . Vitamin D sterols and mineral supplements traditionally used for rickets or osteomalacia should not be used unless there is a deficiency, as blood levels of calcium ions (Ca2+), inorganic phosphate (Pi) and vitamin D metabolites usually are not reduced.[10] • Craniosynostosis, the premature closure of skull sutures, may cause intracranial hypertension and may require neurosurgical intervention to avoid brain damage in infants[11] • Bony deformities and fractures are complicated by the lack of mineralization and impaired skeletal growth in these patients. Fractures and corrective osteotomies (bone cutting) can heal, but healing may be delayed and require prolonged casting or stabilization with orthopedic hardware. A load-sharing intramedullary nail on rod has been shown to be the best surgical treatment for complete fractures, symptomatic pseudofractures, and progressive asymptomatic pseudofractures in adult HPP patients[12] • Dental problems: Children particularly benefit from skilled dental care, as early tooth loss can cause malnutrition and inhibit speech development. Dentures may ultimately be needed. Dentists should carefully monitor patients’ dental hygiene and use prophylactic programs to avoid deteriorating health and periodontal disease[3] • Physical Impairments and Pain: Rickets and bone weakness associated with HPP can restrict or eliminate ambulation, impair functional endurance, and diminish ability to perform activities of daily living. Nonsteroidal anti-inflammatory drugs may improve pain-associated physical impairment and can help improve walking distance[13] Investigational use of more directed treatments has been limited. • Bisphosphonate (pyrophosphate synthetic analog) in one infant had no discernible effect on the skeleton, and the infant’s disease progressed until death at 14 months of age[14] • Bone marrow cell transplantation in two severely-affected infants produced radiographic and clinical improvement, although the mechanism of efficacy is not fully understood and significant morbidity persisted[15][16] • Enzyme replacement therapy with normal or ALP-rich serum from patients with Paget’s bone disease was not beneficial[17][18] • Phase 2 clinical trials of bone targeted enzyme replacement therapy have been completed for the treatment of hypophosphatasia in infants and juveniles, a phase 2 study in adults is ongoing.[19][20]

See also

References

  1. ^ a b Whyte MP (2001). "Hypophosphatasia". In Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (ed.). The metabolic & molecular bases of inherited disease. Vol. 4 (8th ed.). New York: McGraw-Hill. pp. 5313–29. ISBN 0-07-913035-6.{{cite book}}: CS1 maint: multiple names: editors list (link)
  2. ^ a b Fraser D (1957). "Hypophosphatasia". Am. J. Med. 22 (5): 730–46. PMID 13410963. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ a b Reibel A, Manière MC, Clauss F; et al. (2009). "Orodental phenotype and genotype findings in all subtypes of hypophosphatasia". Orphanet J Rare Dis. 4: 6. doi:10.1186/1750-1172-4-6. PMC 2654544. PMID 19232125. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  4. ^ Shohat M, Rimoin DL, Gruber HE, Lachman RS (1991). "Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings". Pediatr Radiol. 21 (6): 421–7. PMID 1749675.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Zurutuza L, Muller F, Gibrat JF; et al. (1999). "Correlations of genotype and phenotype in hypophosphatasia". Hum. Mol. Genet. 8 (6): 1039–46. PMID 10332035. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Simon-Bouy B, Taillandier A, Fauvert D; et al. (2008). "Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling". Prenat. Diagn. 28 (11): 993–8. doi:10.1002/pd.2088. PMID 18925618. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Greenberg CR, Taylor CL, Haworth JC; et al. (1993). "A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites". Genomics. 17 (1): 215–7. doi:10.1006/geno.1993.1305. PMID 8406453. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Whyte MP, Essmyer K, Geimer M, Mumm S (2006). "Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry". J. Pediatr. 148 (6): 753–8. doi:10.1016/j.jpeds.2006.01.031. PMID 16769381. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Barcia JP, Strife CF, Langman CB (1997). "Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization". J. Pediatr. 130 (5): 825–8. PMID 9152296. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Opshaug O, Maurseth K, Howlid H, Aksnes L, Aarskog D (1982). "Vitamin D metabolism in hypophosphatasia". Acta Paediatr Scand. 71 (3): 517–21. PMID 6291316. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H (2009). "Neurosurgical aspects of childhood hypophosphatasia". Childs Nerv Syst. 25 (2): 217–23. doi:10.1007/s00381-008-0708-3. PMID 18769927. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Coe JD, Murphy WA, Whyte MP (1986). "Management of femoral fractures and pseudofractures in adult hypophosphatasia". J Bone Joint Surg Am. 68 (7): 981–90. PMID 3745261. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Girschick HJ, Seyberth HW, Huppertz HI (1999). "Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs". Bone. 25 (5): 603–7. PMID 10574582. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Deeb AA, Bruce SN, Morris AA, Cheetham TD (2000). "Infantile hypophosphatasia: disappointing results of treatment". Acta Paediatr. 89 (6): 730–3. PMID 10914973. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Whyte MP, Kurtzberg J, McAlister WH; et al. (2003). "Marrow cell transplantation for infantile hypophosphatasia". J. Bone Miner. Res. 18 (4): 624–36. doi:10.1359/jbmr.2003.18.4.624. PMID 12674323. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Cahill RA, Wenkert D, Perlman SA; et al. (2007). "Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts". J. Clin. Endocrinol. Metab. 92 (8): 2923–30. doi:10.1210/jc.2006-2131. PMID 17519318. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Whyte MP, Valdes R, Ryan LM, McAlister WH (1982). "Infantile hypophosphatasia: enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease". J. Pediatr. 101 (3): 379–86. PMID 7108657. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Whyte MP, McAlister WH, Patton LS; et al. (1984). "Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients". J. Pediatr. 105 (6): 926–33. PMID 6502342. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ http://www.clinicaltrials.gov
  20. ^ http://www.enobia.com

Further reading

  • Rathbun JC (1948). "Hypophosphatasia; a new developmental anomaly". Am J Dis Child. 75 (6): 822–31. PMID 18110134. {{cite journal}}: Unknown parameter |month= ignored (help)

External links

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