Advertisement

Der Pathologe

, Volume 39, Issue 2, pp 146–153 | Cite as

Die aktivierende GNAS-Mutation

Eine Bestandsaufnahme bei der Fibrösen Dysplasie, der ihr assoziierten Syndrome sowie weiterer skelettaler und extraskelettaler Läsionen
  • H. Ostertag
  • S. Glombitza
Schwerpunkt: Knorpel, Knochen, Chorda – Molekulare Pathologie
  • 242 Downloads

Zusammenfassung

Die Fibröse Dysplasie ist eine konnatale, aber nicht erbliche, benigne Skelettveränderung, die isoliert in monostotischer oder polyostotischer Form oder syndromal mit extraskelettalen Veränderungen als McCune-Albright-Syndrom oder assoziiert mit Myxomen der Skelettmuskulatur als Mazabraud-Syndrom auftritt.

Der Nachweis wiederkehrender chromosomaler Veränderungen lässt vermuten, dass es sich um eine Neoplasie und nicht um eine Knochendysplasie handelt. Ursächlich ist allen Formen eine aktivierende Mutation des GNAS-Gens, die in fast allen Herden nachzuweisen ist.

Die Forschung zu Auswirkungen dieser Mutation hat in den letzten Jahren wesentliche Fortschritte in der Erklärung dieser bisher nur deskriptiv verstandenen Krankheitsbilder erzielt und auch ihre bessere diagnostische Abgrenzung gegenüber anderen fibroossären Skelettläsionen ermöglicht. Aktuelle Erkenntnisse lassen vermuten, dass diese Mutation bei weiteren extraskelettalen Neoplasien ebenfalls eine Rolle spielt.

Schlüsselwörter

Chromosomenaberration Mutation Myxom Fibröse Dysplasie GNAS Mazabraud McCune Albright 

The activating GNAS mutation

A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions

Abstract

Fibrous dysplasia of bone is a connatal but not hereditary disease with monostotic or polyostotic manifestations and may be associated either with the extraskeletal disease McCune-Albright syndrome or with myxoma of the skeletal muscle, termed Mazabraud syndrome.

The confirmation of recurrent chromosomal aberrations may lead to the conclusion that fibrous dysplasia is a neoplasia rather than a dysplastic skeletal disease.

The primary cause of all forms of the described diseases is the activating GNAS mutation, which is detectable in almost all lesions. Research into the impact of this mutation has increased the understanding of these up to now solely descriptively defined diseases and also allowed easier discrimination of various fibro-osseous skeletal lesions. Current insights suggest that this mutation may also play a pivotal role in other extraskeletal neoplasias.

Keywords

Chromosomal aberration Mutation Myxoma Fibrous Dysplasia GNAS Mazabraud McCune Albright 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

H. Ostertag und S. Glombitza geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Albright F, Butler AM, Hampton AO, Smith P (1937) Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. N Engl J Med 216(17):727–746.  https://doi.org/10.1056/NEJM193704292161701 CrossRefGoogle Scholar
  2. 2.
    Benhamou J, Gensburger D, Messiaen C, Chapurlat R (2016) Prognostic factors from an epidemiologic evaluation of fibrous dysplasia of bone in a modern cohort. The FRANCEDYS study. J Bone Miner Res 31(12):2167–2172.  https://doi.org/10.1002/jbmr.2894 CrossRefPubMedGoogle Scholar
  3. 3.
    Carney JA, Young WF, Stratakis CA (2011) Primary bimorphic adrenocortical disease. Cause of hypercortisolism in McCune-Albright syndrome. Am J Surg Pathol 35(9):1311–1326.  https://doi.org/10.1097/PAS.0b013e31821ec4ce CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Carter JM, Inwards CY, Jin L, Evers B, Wenger DE, Oliveira AM, Fritchie KJ (2014) Activating GNAS mutations in parosteal osteosarcoma. Am J Surg Pathol 38(3):402–409.  https://doi.org/10.1097/PAS.0000000000000144 CrossRefPubMedGoogle Scholar
  5. 5.
    Chapurlat RD, Orcel P (2008) Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract Res Clin Rheumatol 22(1):55–69.  https://doi.org/10.1016/j.berh.2007.11.004 CrossRefPubMedGoogle Scholar
  6. 6.
    Dal Cin P, Sciot R, Brys P, de Wever I, Dorfman H, Fletcher CD, Jonsson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, van den Berghe H, Vanni R, Willen H (2000) Recurrent chromosome aberrations in fibrous dysplasia of the bone. A report of the CHAMP study group. Cancer Genet Cytogenet 122(1):30–32.  https://doi.org/10.1016/S0165-4608(00)00270-3 CrossRefGoogle Scholar
  7. 7.
    Deel C, Hassell L (2016) Liposclerosing myxofibrous tumor. A review. Arch Pathol Lab Med 140(5):473–476.  https://doi.org/10.5858/2014-0503-RS CrossRefPubMedGoogle Scholar
  8. 8.
    Demicco EG, Deshpande V, Nielsen GP, Kattapuram SV, Rosenberg AE (2010) Well-differentiated osteosarcoma of the jaw bones. A clinicopathologic study of 15 cases. Am J Surg Pathol 34(11):1647–1655.  https://doi.org/10.1097/PAS.0b013e3181f7dac6 PubMedGoogle Scholar
  9. 9.
    DiCaprio MR, Enneking WF (2005) Fibrous dysplasia. Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am 87(8):1848–1864.  https://doi.org/10.2106/JBJS.D.02942 PubMedGoogle Scholar
  10. 10.
    Dreizin D, Glen C, Jose J (2012) Mazabraud syndrome. Am J Orthop (Belle Mead, NJ) 41(7):332–335Google Scholar
  11. 11.
    Fletcher CDM, Bridge JA, Hagendoorn PCW, Mertens F (2013) WHO classification of tumours of soft tissue and bone. Fibrous dysplasia, 4. Aufl. International Agency for Research on Cancer, Lyon, S 352–353Google Scholar
  12. 12.
    Freyschmidt J (2016) Skeletterkrankungen. Klinisch-radiologische Diagnose und Differentialdiagnose, 4. Aufl. Springer, Heidelberg, Berlin, HeidelbergGoogle Scholar
  13. 13.
    Freyschmidt J, Ostertag HM, Jundt G (2010) Knochentumoren mit Kiefertumoren. Klinik · Radiologie · Pathologie, 3. Aufl. Springer, Berlin Heidelberg, Berlin, HeidelbergCrossRefGoogle Scholar
  14. 14.
    Gaujoux S, Salenave S, Ronot M, Rangheard A‑S, Cros J, Belghiti J, Sauvanet A, Ruszniewski P, Chanson P (2014) Hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome. J Clin Endocrinol Metab 99(1):E97–E101.  https://doi.org/10.1210/jc.2013-1823 CrossRefPubMedGoogle Scholar
  15. 15.
    Happle R (1986) The McCune-Albright syndrome. A lethal gene surviving by mosaicism. Clin Genet 29(4):321–324CrossRefPubMedGoogle Scholar
  16. 16.
    Hart ES, Kelly MH, Brillante B, Chen CC, Ziran N, Lee JS, Feuillan P, Leet AI, Kushner H, Robey PG, Collins MT (2007) Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J Bone Miner Res 22(9):1468–1474.  https://doi.org/10.1359/jbmr.070511 CrossRefPubMedGoogle Scholar
  17. 17.
    Henschen F (1926) Ein Fall von Ostitis fibrosa mit multiplen Tumoren in der umgebenden Muskulatur. Verh Dtsch Ges Pathol 21:93–97Google Scholar
  18. 18.
    Jasnau S, Meyer U, Potratz J, Jundt G, Kevric M, Joos UK, Jürgens H, Bielack SS (2008) Craniofacial osteosarcoma: experience of the cooperative German-Austrian-Swiss osteosarcoma study group. Oral Oncol 44(3):286–294.  https://doi.org/10.1016/j.oraloncology.2007.03.001 CrossRefPubMedGoogle Scholar
  19. 19.
    Kitagawa Y, Ishihara Y, Hayashi M, Kim Y, Fujii N, Ito H (2011) Mazabraud syndrome associated with McCune-Albright syndrome. J Orthop Sci 16(1):129–132.  https://doi.org/10.1007/s00776-010-0004-4 CrossRefPubMedGoogle Scholar
  20. 20.
    Kransdorf MJ, Murphey MD, Sweet DE (1999) Liposclerosing myxofibrous tumor. A radiologic-pathologic-distinct fibroosseous lesion of bone with a marked predilection for the intertrochanteric region of the femur. Radiology 212(3):693–698.  https://doi.org/10.1148/radiology.212.3.r99se40693 CrossRefPubMedGoogle Scholar
  21. 21.
    Kuznetsov SA, Cherman N, Riminucci M, Collins MT, Robey PG, Bianco P (2008) Age-dependent demise of GNAS-mutated skeletal stem cells and “normalization” of fibrous dysplasia of bone. J Bone Miner Res 23(11):1731–1740.  https://doi.org/10.1359/jbmr.080609 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lee SE, Lee EH, Park H, Sung J‑Y, Lee HW, Kang SY, Seo S, Kim BH, Lee H, Seo AN, Ahn G, Choi Y‑L (2012) The diagnostic utility of the GNAS mutation in patients with fibrous dysplasia. Meta-analysis of 168 sporadic cases. Hum Pathol 43(8):1234–1242.  https://doi.org/10.1016/j.humpath.2011.09.012 CrossRefPubMedGoogle Scholar
  23. 23.
    Lee SH, Jung SH, Kim T‑M, Rhee J‑K, Park H‑C, Kim MS, Kim SS, An CH, Lee SH, Chung Y‑J (2017) Whole-exome sequencing identified mutational profiles of high-grade colon adenomas. Oncotarget 8(4):6579–6588.  https://doi.org/10.18632/oncotarget.14172 CrossRefPubMedGoogle Scholar
  24. 24.
    Lichtenstein L (1938) Polyostotic fibrous dyplasia. Arch Surg 36:874–898CrossRefGoogle Scholar
  25. 25.
    Lichtenstein L, Jaffe HL (1942) Fibrous dyplasia of bone. A condition affecting one, several or many bones, the graver cases of which may present abnormal pigmentation of skin, premature sexual development, hyperthyroidism or still other extraskeletal abnormalities. Arch Pathol Lab Med 33:777–816Google Scholar
  26. 26.
    Mantovani G, Lania AG, Spada A (2010) GNAS imprinting and pituitary tumors. Mol Cell Endocrinol 326(1–2):15–18.  https://doi.org/10.1016/j.mce.2010.04.009 CrossRefPubMedGoogle Scholar
  27. 27.
    Mazabraud A, Semat P, Roze R (1967) A propos de l’association de fibromyxomes des tissus mous à la dysplasie fibreuse des os. Presse Med 75(44):2223–2228PubMedGoogle Scholar
  28. 28.
    McCune DJ, Bruch H (1937) Osteodystrophia fibrosa. Report of a case in which the condition was combined with precocious puberty; pathologic pigmentation of the skin and hyperthyroidism. Am J Dis Child 54:806–848CrossRefGoogle Scholar
  29. 29.
    Okamoto S, Hisaoka M, Meis-Kindblom JM, Kindblom L‑G, Hashimoto H (2002) Juxta-articular myxoma and intramuscular myxoma are two distinct entities. Activating Gs alpha mutation at Arg 201 codon does not occur in juxta-articular myxoma. Virchows Arch 440(1):12–15CrossRefPubMedGoogle Scholar
  30. 30.
    Pittman ME, Rao R, Hruban RH (2017) Classification, morphology, molecular pathogenesis, and outcome of premalignant lesions of the pancreas. Arch Pathol Lab Med 141(12):1606–1614.  https://doi.org/10.5858/arpa.2016-0426-RA CrossRefPubMedGoogle Scholar
  31. 31.
    Pollandt K, Engels C, Kaiser E, Werner M, Delling G (2001) Gsalpha gene mutations in monostotic fibrous dysplasia of bone and fibrous dysplasia-like low-grade central osteosarcoma. Virchows Arch 439(2):170–175CrossRefPubMedGoogle Scholar
  32. 32.
    Ragsdale BD (1993) Polymorphic fibroosseous lesions of bone. An almost site-specific diagnostic problem of the proximal femur. Hum Pathol 24(5):505–512CrossRefPubMedGoogle Scholar
  33. 33.
    Ramaswamy G, Kim H, Zhang D, Lounev V, Wu JY, Choi Y, Kaplan FS, Pignolo RJ, Shore EM (2017) Gsα controls cortical bone quality by regulating osteoclast differentiation via cAMP/PKA and β‑catenin pathways. Sci Rep 7:45140.  https://doi.org/10.1038/srep45140 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Regard JB, Cherman N, Palmer D, Kuznetsov SA, Celi FS, Guettier J‑M, Chen M, Bhattacharyya N, Wess J, Coughlin SR, Weinstein LS, Collins MT, Robey PG, Yang Y (2011) Wnt/beta-catenin signaling is differentially regulated by Galpha proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci USA 108(50):20101–20106.  https://doi.org/10.1073/pnas.1114656108 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Remoli C, Michienzi S, Sacchetti B, Di Consiglio A, Cersosimo S, Spica E, Robey PG, Holmbeck K, Cumano A, Boyde A, Davis G, Saggio I, Riminucci M, Bianco P (2015) Osteoblast-specific expression of the fibrous dysplasia (FD)-causing mutation Gsalpha(R201C) produces a high bone mass phenotype but does not reproduce FD in the mouse. J Bone Miner Res 30(6):1030–1043.  https://doi.org/10.1002/jbmr.2425 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Riminucci M, Fisher LW, Shenker A, Spiegel AM, Bianco P, Gehron Robey P (1997) Fibrous dysplasia of bone in the McCune-Albright syndrome. Abnormalities in bone formation. Am J Pathol 151(6):1587–1600PubMedPubMedCentralGoogle Scholar
  37. 37.
    Riminucci M, Liu B, Corsi A, Shenker A, Spiegel AM, Robey PG, Bianco P (1999) The histopathology of fibrous dysplasia of bone in patients with activating mutations of the Gs alpha gene. Site-specific patterns and recurrent histological hallmarks. J Pathol 187(2):249–258. https://doi.org/10.1002/(SICI)1096-9896(199901)187:2<249::AID-PATH222>3.0.CO;2‑JCrossRefPubMedGoogle Scholar
  38. 38.
    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Waguespack S, Gupta A, Hannon T, Econs MJ, Bianco P, Gehron Robey P (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 112(5):683–692.  https://doi.org/10.1172/JCI18399 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Riminucci M, Saggio I, Robey PG, Bianco P (2006) Fibrous dysplasia as a stem cell disease. J Bone Miner Res 21(Suppl 2):125–131.  https://doi.org/10.1359/jbmr.06s224 CrossRefGoogle Scholar
  40. 40.
    Riminucci M, Remoli C, Robey PG, Bianco P (2015) Stem cells and bone diseases. New tools, new perspective. Bone 70:55–61.  https://doi.org/10.1016/j.bone.2014.09.009 CrossRefPubMedGoogle Scholar
  41. 41.
    Ritterhouse LL, Vivero M, Mino-Kenudson M, Sholl LM, Iafrate AJ, Nardi V, Dong F (2017) GNAS mutations in primary mucinous and non-mucinous lung adenocarcinomas. Mod Pathol 30(12):1720–1727.  https://doi.org/10.1038/modpathol.2017.88 CrossRefPubMedGoogle Scholar
  42. 42.
    Saggio I, Remoli C, Spica E, Cersosimo S, Sacchetti B, Robey PG, Holmbeck K, Cumano A, Boyde A, Bianco P, Riminucci M (2014) Constitutive expression of GsαR201C in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J Bone Miner Res 29(11):2357–2368.  https://doi.org/10.1002/jbmr.2267 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Salenave S, Boyce AM, Collins MT, Chanson P (2014) Acromegaly and McCune-Albright syndrome. J Clin Endocrinol Metab 99(6):1955–1969.  https://doi.org/10.1210/jc.2013-3826 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Salinas-Souza C, de Andrea C, Bihl M, Kovac M, Pillay N, Forshew T, Gutteridge A, Ye H, Amary MF, Tirabosco R, Toledo SRC, Baumhoer D, Flanagan AM (2015) GNAS mutations are not detected in parosteal and low-grade central osteosarcomas. Mod Pathol 28(10):1336–1342.  https://doi.org/10.1038/modpathol.2015.91 CrossRefPubMedGoogle Scholar
  45. 45.
    Salpea P, Stratakis CA (2014) Carney complex and McCune Albright syndrome. An overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol 386(1–2):85–91.  https://doi.org/10.1016/j.mce.2013.08.022 CrossRefPubMedGoogle Scholar
  46. 46.
    Schwarze M, Weber M‑A, Mechtersheimer G, Lehner B, Renker EK (2017) Mazabraud- und McCune-Albright-Syndrom in Assoziation. Ein Fall zweier sehr seltener tumororthopädischer Entitäten. Orthopäde 46(9):776–780.  https://doi.org/10.1007/s00132-017-3399-1 CrossRefPubMedGoogle Scholar
  47. 47.
    Shi R‑R, Li X‑F, Zhang R, Chen Y, Li T‑J (2013) GNAS mutational analysis in differentiating fibrous dysplasia and ossifying fibroma of the jaw. Mod Pathol 26(8):1023–1031.  https://doi.org/10.1038/modpathol.2013.31 CrossRefPubMedGoogle Scholar
  48. 48.
    Singhi AD, Davison JM, Choudry HA, Pingpank JF, Ahrendt SA, Holtzman MP, Zureikat AH, Zeh HJ, Ramalingam L, Mantha G, Nikiforova M, Bartlett DL, Pai RK (2014) GNAS is frequently mutated in both low-grade and high-grade disseminated appendiceal mucinous neoplasms but does not affect survival. Hum Pathol 45(8):1737–1743.  https://doi.org/10.1016/j.humpath.2014.04.018 CrossRefPubMedGoogle Scholar
  49. 49.
    Tabareau-Delalande F, Collin C, Larousserie F, Bouvier C, Gomez-Brouchet A, Aubert S, Guinebretière J‑M, Decouvelaere A‑V, de Muret A, Pagès J‑C, de Pinieux G (2015) Comments on Carter et al’s “activating GNAS mutations in parosteal osteosarcoma”. Am J Surg Pathol 39(7):1010–1013.  https://doi.org/10.1097/PAS.0000000000000461 CrossRefPubMedGoogle Scholar
  50. 50.
    Tsai J‑H, Yuan R‑H, Chen Y‑L, Liau J‑Y, Jeng Y‑M (2013) GNAS is frequently mutated in a specific subgroup of intraductal papillary neoplasms of the bile duct. Am J Surg Pathol 37(12):1862–1870.  https://doi.org/10.1097/PAS.0b013e3182986bb5 CrossRefPubMedGoogle Scholar
  51. 51.
    Tsourdi E, Hamann C, Hofbauer LC (2013) Skeletal and soft tissue involvement in Mazabraud syndrome. J Clin Endocrinol Metab 98(8):E1381–E1382.  https://doi.org/10.1210/jc.2013-2186 CrossRefPubMedGoogle Scholar
  52. 52.
    Turan S, Bastepe M (2015) GNAS spectrum of disorders. Curr Osteoporos Rep 13(3):146–158.  https://doi.org/10.1007/s11914-015-0268-x CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Voytek TM, Ro JY, Edeiken J, Ayala AG (1995) Fibrous dysplasia and cemento-ossifying fibroma. A histologic spectrum. Am J Surg Pathol 19(7):775–781CrossRefPubMedGoogle Scholar
  54. 54.
    Zauber P, Marotta S, Sabbath-Solitare M (2015) GNAS mutations are associated with mucin production in low-grade appendiceal mucinous neoplasms, villous adenomas, and carcinomas. Hum Pathol 46(2):339.  https://doi.org/10.1016/j.humpath.2014.09.017 CrossRefPubMedGoogle Scholar
  55. 55.
    Zreik RT, Littrell LA, Jin L, Oliveira AM, Fritchie KJ (2017) Malignant transformation of polyostotic fibrous dysplasia with aberrant keratin expression. Hum Pathol 62:170–174.  https://doi.org/10.1016/j.humpath.2016.09.030 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Pathologisches InstitutKlinikum Region HannoverHannoverDeutschland

Personalised recommendations