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Osteologie 2009; 18(04): 252-258
DOI: 10.1055/s-0037-1619908
Seltene Knochenerkrankungen
Schattauer GmbH

Hypophosphatasie – eine seltene Knochenstoffwechselerkrankung

Hypophosphatasia – a rare inborn error of bone metabolism
C. Beck
1   Pädiatrische Rheumatologie, Immunologie und Osteologie, Kinderklinik und Poliklinik, Universität Würzburg
,
H. Morbach
1   Pädiatrische Rheumatologie, Immunologie und Osteologie, Kinderklinik und Poliklinik, Universität Würzburg
,
C. Wirth
2   Klinik für Nuklearmedizin, Universität Würzburg
,
P. Schneider
3   Klinik für Neurochirurgie, Abteilung Pädiatrische Neurochirurgie, Universität Würzburg
,
H. Collmann
4   Orthopädisches Zentrum für Muskuloskelettale Forschung König-Ludwig Haus, Universität Würzburg
,
F. Jakob
5   Institut für Radiologie, Abteilung Pädiatrische Radiologie, Universität Würzburg
,
H. J. Girschick
1   Pädiatrische Rheumatologie, Immunologie und Osteologie, Kinderklinik und Poliklinik, Universität Würzburg
6   Vivantes Klinik für Kinder-und Jugendmedizin, Klinikum im Friedrichshain, Berlin
› Author Affiliations
Further Information

Publication History

eingereicht: 02 September 2009

angenommen: 10 September 2009

Publication Date:
30 December 2017 (online)

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Zusammenfassung

Die Hypophosphatasie (HP) ist eine seltene, meist autosomal rezessiv vererbte Erkrankung des Knochenstoffwechsels mit verminderter Aktivität der gewebeunspezifischen Alkalischen Phosphatase und konsekutiver Akkumulation von nicht abgebauten Stoffwechselprodukten. Sie ist charakterisiert durch eine generelle Störung der Knochenmineralisation mit nachfolgenden Knochendeformitäten, Frakturen und chronischer nicht-bakterieller Osteomyelitis. Weitere Symptome wie Nierenbeteiligung und Zahnveränderungen bzw. vorzeitiger Zahnverlust können auftreten. Kürzlich konnten wir zeigen, dass der klinische Phänotyp der infantiljuvenilen Form unter anderem durch Entzündung von Gelenken und Knochen beeinflusst wird. Akkumulierende Kalziumpyrophosphatkristalle scheinen hierbei von entscheidender Bedeutung zu sein. Zur Diagnosesicherung dienen laborchemische Analysen, humangenetische Tests sowie bildgebende Verfahren. Eine enge Anbindung an ein mit HP-Patienten erfahrenes Zentrum mit multidisziplinärer Betreuung ist von entscheidender Bedeutung. Da derzeit noch keine kurativen Therapien ausreichend evaluiert sind, stehen aktuell symptomatische Therapieansätze im Vordergrund der Behandlung.

Summary

Hypophosphatasia (HP) is an inborn error of bone metabolism transmitted predominantly as an autosomal-recessive trait. It is characterized by a reduced activity of the tissuenonspecific isoenzyme of alkaline phosphatase (TNSALP) and elevated concentrations of its substrates, including inorganic pyrophosphates. Calcium pyrophosphate crystals seem to be essentially involved in activating inflammatory signal transduction pathways via different receptors of the innate immune system. Clinical symptoms include defective bone mineralisation with bone deformities, fractures, chronic non-bacterial osteomyelitis, renal damage due to calcification, craniosynostosis and dental abnormalities with premature loss of dentition are further symptoms. Laboratory assays, genetic counselling and testing, and radiologic imaging can confirm the diagnosis. Because symptoms are highly variable in their clinical expression, patients should be followed by a HP-experienced multidisciplinary team. At the moment symptomatic support and treatment is most important because a more causative therapy, e. g. enzyme replacement therapy, is not yet available in Europe.

Schlüsselwörter

Hypophosphatasie - Knochenstoffwechsel - Alkalische Phosphatase - Kalziumpyrophosphatkristalle

Keywords

Hypophosphatasia - bone metabolism - alkaline phosphatase - calcium pyrophosphate crystals
 

  • Literatur

  • 1 Akahoshi T, Murakami Y, Kitasato H. Recent advances in crystal-induced acute inflammation. Curr Opin Rheumatol 2007; 19 (02) 146-150.
    CrossrefPubMedGoogle Scholar
  • 2 Baumgartner-Sigl S, Haberlandt E, Mumm S. et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone 2007; 40 (06) 1655-1661.
    CrossrefPubMedGoogle Scholar
  • 3 Beck C, Morbach H, Richl P. et al. How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases?. Rheumatol Int 2008; 29 (03) 229-238.
    PubMedGoogle Scholar
  • 4 Beck C, Morbach H, Stenzel M. et al. Hypophosphatasie. Klin Padiatr 2009; (221) 1-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Chuck AJ, Pattrick MG, Hamilton E. et al. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis 1989; 48 (07) 571-576.
    CrossrefPubMedGoogle Scholar
  • 6 Collmann H, Mornet E, Gattenlohner S. et al. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst 2008; 25: 217-223.
    PubMedGoogle Scholar
  • 7 Dayer JM, Evequoz V, Zavadil-Grob C. et al. Effect of synthetic calcium pyrophosphate and hydroxyapatite crystals on the interaction of human blood mononuclear cells with chondrocytes, synovial cells, and fibroblasts. Arthritis Rheum 1987; 30 (12) 1372-1381.
    CrossrefPubMedGoogle Scholar
  • 8 Drenth JP, van der Meer JW. The inflammasome - a linebacker of innate defense. N Engl J Med 2006; 355 (07) 730-732.
    CrossrefPubMedGoogle Scholar
  • 9 Fauvert D, Brun-Heath I, Lia-Baldini AS. et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygocity for severe and moderate alleles. BMC Med Genet 2009; 06 (10) 51.
    Google Scholar
  • 10 Fedde KN, Whyte MP. Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5’-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Am J Hum Genet 1990; 47 (05) 767-775.
    PubMedGoogle Scholar
  • 11 Girschick HJ, Huppertz HI, Harmsen D. et al. Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 1999; 30 (01) 59-65.
    CrossrefPubMedGoogle Scholar
  • 12 Girschick HJ, Mornet E, Beer M. et al. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr 2007; 07: 3.
    CrossrefPubMedGoogle Scholar
  • 13 Girschick HJ, Raab P, Surbaum S. et al. Chronic nonbacterial osteomyelitis in children. Ann Rheum Dis 2005; 64 (02) 279-285.
    CrossrefPubMedGoogle Scholar
  • 14 Girschick HJ, Schneider P, Haubitz I. et al. Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia. Orphanet J Rare Dis 2006; 01: 24.
    CrossrefPubMedGoogle Scholar
  • 15 Girschick HJ, Seyberth HW, Huppertz HI. Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone 1999; 25 (05) 603-607.
    CrossrefPubMedGoogle Scholar
  • 16 Girschick HJ, Zimmer C, Klaus G. et al. Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated?. Nat Clin Pract Rheumatol 2007; 03 (12) 733-738.
    Google Scholar
  • 17 Hallegua DS, Weisman MH. Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases. Ann Rheum Dis 2002; 61 (11) 960-967.
    CrossrefPubMedGoogle Scholar
  • 18 Hessle L, Johnson KA, Anderson HC. et al. Tissuenonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A 2002; 99 (14) 9445-9449.
    CrossrefPubMedGoogle Scholar
  • 19 Jones AC, Chuck AJ, Arie EA. et al. Diseases associated with calcium pyrophosphate deposition disease. Semin Arthritis Rheum 1992; 22 (03) 188-202.
    CrossrefPubMedGoogle Scholar
  • 20 Liu-Bryan R, Liote F. Monosodium urate and calcium pyrophosphate dihydrate (CPPD) crystals, inflammation, and cellular signaling. Joint Bone Spine 2005; 72 (04) 295-302.
    CrossrefPubMedGoogle Scholar
  • 21 Mariathasan S, Monack DM. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 2007; 07 (01) 31-40.
    CrossrefPubMedGoogle Scholar
  • 22 Martinon F, Petrilli V, Mayor A. et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440 (7081): 237-241.
    CrossrefPubMedGoogle Scholar
  • 23 Millan JL, Narisawa S, Lemire I. et al. Enzyme Replacement Therapy for Murine Hypophosphatasia. J Bone Miner Res 2008; 23 (06) 777-787.
    CrossrefPubMedGoogle Scholar
  • 24 Mornet E. Hypophosphatasia. Orphanet J Rare Dis 2007; 02: 40.
    CrossrefPubMedGoogle Scholar
  • 25 Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003; 425 (6957): 516-521.
    CrossrefPubMedGoogle Scholar
  • 26 Shohat M, Rimoin DL, Gruber HE, Lachman RS. Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings. Pediatr Radiol 1991; 21 (06) 421-427.
    CrossrefPubMedGoogle Scholar
  • 27 van den Bos T, Handoko G, Niehof A. et al. Cementum and dentin in hypophosphatasia. J Dent Res 2005; 84 (11) 1021-1025.
    CrossrefPubMedGoogle Scholar
  • 28 Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly S. eds. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill; 1995: 4095-4111.
    Google Scholar
  • 29 Whyte MP, Landt M, Ryan LM. et al. Alkaline phosphatase: placental and tissue-nonspecific isoenzymes hydrolyze phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5’-phosphate. Substrate accumulation in carriers of hypophosphatasia corrects during pregnancy. J Clin Invest 1995; 95 (04) 1440-1445.
    PubMedGoogle Scholar