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Genodermatoses caused by genetic mosaicism


Genetic mosaicism is defined as the existence of at least two genetically distinct cell populations within one individual. Mosaic presentation of genetic disorders is common and is often particularly obvious in the skin, because there it will generate recognizable patterns. Recognizing those can frequently assist in establishing a diagnosis. In this review, we discuss the mechanisms that give rise to genetic mosaicism. We describe its most frequent cutaneous manifestations that are relevant to paediatric practice. While most mosaic genetic diseases are rare, it is important to recognize them so that patients and parents may receive appropriate genetic counselling. Moreover, recent developments are now resulting in novel, targeted treatments for such disorders that promise to considerably improve patients' lives.

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  1. 1.

    Aradhya S, Courtois G, Rajkovic A, Lewis RA, Levy M, Israel A, Nelson DL (2001) Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-gamma). Am J Hum Genet 68:765–771

  2. 2.

    Arnold AW, Bruckner-Tuderman L, Has C, Happle R (2012) Conradi-Hunermann-Happle syndrome in males versus MEND syndrome (male EBP disorder with neurological defects). Br J Dermatol 166:1309–1313

  3. 3.

    Baillie JK, Barnett MW, Upton KR, Gerhardt DJ, Richmond TA, De Sapio F, Brennan PM, Rizzu P, Smith S, Fell M, Talbot RT, Gustincich S, Freeman TC, Mattick JS, Hume DA, Heutink P, Carninci P, Jeddeloh JA, Faulkner GJ (2011) Somatic retrotransposition alters the genetic landscape of the human brain. Nature 479:534–537

  4. 4.

    Berlin AL, Paller AS, Chan LS (2002) Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol 47:169–187

  5. 5.

    Biesecker L (2006) The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet 14:1151–1157

  6. 6.

    Blaschko A (1901) Die Nervenverteilung in der Haut in ihrer Beziehung zu den Erkrankungen der Haut. Paper presented at VII Congress der Deutschen Dermatologischen Gesellschaft. Breslau, 28–30 May

  7. 7.

    Boente MC, Pizzi de Parra N, Larralde de Luna M, Bonet HB, Santos Munoz A, Parra V, Gramajo P, Moreno S, Asial RA (2000) Phacomatosis pigmentokeratotica: another epidermal nevus syndrome and a distinctive type of twin spotting. Eur J Dermatol 10:190–194

  8. 8.

    Boston BA, Mandel S, LaFranchi S, Bliziotes M (1994) Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing's syndrome and nodular adrenal hyperplasia. J Clin Endocrinol Metab 79:890–893

  9. 9.

    Canueto J, Giros M, Ciria S, Pi-Castan G, Artigas M, Garcia-Dorado J, Garcia-Patos V, Viros A, Vendrell T, Torrelo A, Hernandez-Martin A, Martin-Hernandez E, Garcia-Silva MT, Fernandez-Burriel M, Rosell J, Tejedor M, Martinez F, Valero J, Garcia JL, Sanchez-Tapia EM, Unamuno P, Gonzalez-Sarmiento R (2011) Clinical, molecular and biochemical characterization of nine spanish families with Conradi-Hunermann-Happle syndrome: New insights into CDPX2 with a comprehensive review of the literature. Br J Dermatol 166:830–838

  10. 10.

    Carnero A (2010) The PKB/AKT pathway in cancer. Curr Pharm Des 16:34–44

  11. 11.

    Cohen MM Jr, Hayden PW (1979) A newly recognized hamartomatous syndrome. Birth Defects Orig Artic Ser 15:291–296

  12. 12.

    Cohen MM Jr, Howell RE (1999) Etiology of fibrous dysplasia and McCune-Albright syndrome. Int J Oral Maxillofac Surg 28:366–371

  13. 13.

    Cohen MM Jr (2005) Proteus syndrome: an update. Am J Med Genet C: Semin Med Genet 137C:38–52

  14. 14.

    Cohen MM Jr (2008) Segmental hemangioma: the misuse of a term. Am J Med Genet A 146A:672–673

  15. 15.

    de Sanctis L, Delmastro L, Russo MC, Matarazzo P, Lala R, de Sanctis C (2006) Genetics of McCune-Albright syndrome. J Pediatr Endocrinol Metab 19(Suppl 2):577–582

  16. 16.

    Derry JM, Gormally E, Means GD, Zhao W, Meindl A, Kelley RI, Boyd Y, Herman GE (1999) Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nat Genet 22:286–290

  17. 17.

    Di Lernia V (2007) Linear and whorled hypermelanosis. Pediatr Dermatol 24:205–210

  18. 18.

    Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C et al (2001) X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet 27:277–285

  19. 19.

    Donnai D, Read AP, McKeown C, Andrews T (1988) Hypomelanosis of Ito: a manifestation of mosaicism or chimerism. J Med Genet 25:809–818

  20. 20.

    Dumitrescu CE, Collins MT (2008) McCune-Albright syndrome. Orphanet J Rare Dis 3:12

  21. 21.

    Fiorillo L, Sinclair DB, O'Byrne ML, Krol AL (2003) Bilateral cerebrovascular accidents in incontinentia pigmenti. Pediatr Neurol 29:66–68

  22. 22.

    Furtado LV, Bayrak-Toydemir P, Hulinsky B, Damjanovich K, Carey JC, Rope AF (2010) A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation. Am J Med Genet A 152A:2838–2844

  23. 23.

    Garcia-Dorado J, de Unamuno P, Fernandez-Lopez E, Salazar Veloz J, Armijo M (1990) Incontinentia pigmenti: XXY male with a family history. Clin Genet 38:128–138

  24. 24.

    Georgakis GV, Younes A (2006) From Rapa Nui to rapamycin: targeting PI3K/Akt/mTOR for cancer therapy. Expert Rev Anticancer Ther 6:131–140

  25. 25.

    Hansen LK, Brandrup F, Rasmussen K (2003) Pigmentary mosaicism with mosaic chromosome 5p tetrasomy. Br J Dermatol 149:414–416

  26. 26.

    Happle R (1977) Genetic significance of Blaschko's lines. Z Hautkr 52:935–944

  27. 27.

    Happle R (1979) X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet 53:65–73

  28. 28.

    Happle R, Koch H, Lenz W (1980) The CHILD syndrome. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects. Eur J Pediatr 134:27–33

  29. 29.

    Happle R (1985) Lyonization and the lines of Blaschko. Hum Genet 70:200–206

  30. 30.

    Happle R (1986) The McCune-Albright syndrome: a lethal gene surviving by mosaicism. Clin Genet 29:321–324

  31. 31.

    Happle R (1990) Ptychotropism as a cutaneous feature of the CHILD syndrome. J Am Acad Dermatol 23:763–766

  32. 32.

    Happle R, Koopman R, Mier PD (1990) Hypothesis: vascular twin naevi and somatic recombination in man. Lancet 335:376–378

  33. 33.

    Happle R (1991) Allelic somatic mutations may explain vascular twin nevi. Hum Genet 86:321–322

  34. 34.

    Happle R (1999) Elattoproteus syndrome: delineation of an inverse form of Proteus syndrome. Am J Med Genet 84:25–28

  35. 35.

    Happle R (1999) Loss of heterozygosity in human skin. J Am Acad Dermatol 41:143–164

  36. 36.

    Happle R (2000) Phylloid hypomelanosis is closely related to mosaic trisomy 13. Eur J Dermatol 10:511–512

  37. 37.

    Happle R (2002) Dohi memorial lecture. New aspects of cutaneous mosaicism. J Dermatol 29:681–692

  38. 38.

    Happle R (2002) Transposable elements and the lines of Blaschko: a new perspective. Dermatology 204:4–7

  39. 39.

    Happle R (2003) Hypomorphic alleles within the EBP gene cause a phenotype quite different from Conradi-Hunermann-Happle syndrome. Am J Med Genet A 122:279, author reply 280

  40. 40.

    Happle R (2004) Gustav Schimmelpenning and the syndrome bearing his name. Dermatology 209:84–87

  41. 41.

    Happle R (2006) X-chromosome inactivation: role in skin disease expression. Acta Paediatr Suppl 95:16–23

  42. 42.

    Happle R (2011) A novel X-linked phenotype caused by hypomorphic EBP mutations. Am J Med Genet A 155A:1770–1771, author reply 1772

  43. 43.

    Hartmann A, Hofmann UB, Hoehn H, Broecker EB, Hamm H (2004) Postnatal confirmation of prenatally diagnosed trisomy 20 mosaicism in a patient with linear and whorled nevoid hypermelanosis. Pediatr Dermatol 21:636–641

  44. 44.

    Hellemans J, Coucke PJ, Giedion A, De Paepe A, Kramer P, Beemer F, Mortier GR (2003) Homozygous mutations in IHH cause acrocapitofemoral dysplasia, an autosomal recessive disorder with cone-shaped epiphyses in hands and hips. Am J Hum Genet 72:1040–1046

  45. 45.

    Hoffman WH, Jueppner HW, Deyoung BR, O'Dorisio MS, Given KS (2005) Elevated fibroblast growth factor-23 in hypophosphatemic linear nevus sebaceous syndrome. Am J Med Genet A 134:233–236

  46. 46.

    Holmstrom G, Thoren K (2000) Ocular manifestations of incontinentia pigmenti. Acta Ophthalmol Scand 78:348–353

  47. 47.

    Hummel M, Cunningham D, Mullett CJ, Kelley RI, Herman GE (2003) Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene. Am J Med Genet A 122A:246–251

  48. 48.

    Ihara C, Shimatsu A, Murabe H, Kataoka K, Kondo C, Nakao K (1996) Growth hormone-secreting pituitary adenoma associated with multiple bone cysts, skin pigmentation and aortitis syndrome. J Endocrinol Investig 19:753–757

  49. 49.

    Ippolito E, Bray EW, Corsi A, De Maio F, Exner UG, Robey PG, Grill F, Lala R, Massobrio M, Pinggera O, Riminucci M, Snela S, Zambakidis C, Bianco P (2003) Natural history and treatment of fibrous dysplasia of bone: a multicenter clinicopathologic study promoted by the European Pediatric Orthopaedic Society. J Pediatr Orthop B 12:155–177

  50. 50.

    Jean-Baptiste S, O'Toole EA, Chen M, Guitart J, Paller A, Chan LS (2002) Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti. Clin Exp Immunol 127:470–478

  51. 51.

    Kaplan I, Metzker A, Calderon S (1993) Epidermal nevus syndrome with maxillary involvement. Int J Oral Maxillofac Surg 22:298–300

  52. 52.

    Kargul B, Alcan T, Kabalay U, Atasu M (2001) Hypohidrotic ectodermal dysplasia: dental, clinical, genetic and dermatoglyphic findings of three cases. J Clin Pediatr Dent 26:5–12

  53. 53.

    Kenwrick S, Woffendin H, Jakins T, Shuttleworth SG, Mayer E, Greenhalgh L, Whittaker J, Rugolotto S, Bardaro T, Esposito T, D'Urso M, Soli F, Turco A, Smahi A, Hamel-Teillac D, Lyonnet S, Bonnefont JP, Munnich A, Aradhya S, Kashork CD, Shaffer LG, Nelson DL, Levy M, Lewis RA (2001) Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome. Am J Hum Genet 69:1210–1217

  54. 54.

    Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, Chen EY, Ezer S, Saarialho-Kere U, de la Chapelle A, Schlessinger D (1996) X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 13:409–416

  55. 55.

    Klaassens M, Blom EW, Schrander JJ, Ris-Stalpers C, Nieuwenhuijzen Kruseman AC, van Steensel MA, Schrander-Stumpel CT (2010) Unique skin changes in a case of Albright hereditary osteodystrophy caused by a rare GNAS1 mutation. Br J Dermatol 162:690–694

  56. 56.

    Konig A, Happle R, Bornholdt D, Engel H, Grzeschik KH (2000) Mutations in the NSDHL gene, encoding a 3beta-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am J Med Genet 90:339–346

  57. 57.

    Konig A, Skrzypek J, Loffler H, Oeffner F, Grzeschik KH, Happle R (2010) Donor dominance cures CHILD nevus. Dermatology 220:340–345

  58. 58.

    Krum SA, Chang J, Miranda-Carboni G, Wang CY (2010) Novel functions for NFkappaB: inhibition of bone formation. Nat Rev Rheumatol 6:607–611

  59. 59.

    Kurban M, Abbas O, Ghosn S, Kibbi AG (2010) Late evolution of giant verruciform xanthoma in the setting of CHILD syndrome. Pediatr Dermatol 27:551–553

  60. 60.

    Lania A, Mantovani G, Spada A (2001) G protein mutations in endocrine diseases. Eur J Endocrinol/Eur Fed Endocr Soc 145:543–559

  61. 61.

    Legendre CM, Charpentier-Cote C, Drouin R, Bouffard C (2011) Neurofibromatosis type 1 and the “elephant man's” disease: the confusion persists: an ethnographic study. PLoS One 6:e16409

  62. 62.

    Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C (1995) A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82:803–814

  63. 63.

    Libow LF (1993) Phakomatosis pigmentovascularis type IIIb. J Am Acad Dermatol 29:305–307

  64. 64.

    Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J et al (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365:611–619

  65. 65.

    Lumbroso S, Paris F, Sultan C (2004) Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome—a European Collaborative Study. J Clin Endocrinol Metab 89:2107–2113

  66. 66.

    Maingay-de Groof F, Lequin MH, Roofthooft DW, Oranje AP, de Coo IF, Bok LA, van der Spek PJ, Mancini GM, Govaert PP (2008) Extensive cerebral infarction in the newborn due to incontinentia pigmenti. Eur J Paediatr Neurol 12:284–289

  67. 67.

    Malvehy J, Palou J, Mascaro JM (1998) Painful subungual tumour in incontinentia pigmenti. Response to treatment with etretinate. Br J Dermatol 138:554–555

  68. 68.

    Mastorakos G, Mitsiades NS, Doufas AG, Koutras DA (1997) Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities sixty years after the first report. Thyroid 7:433–439

  69. 69.

    Migeon BR (1998) Non-random X chromosome inactivation in mammalian cells. Cytogenet Cell Genet 80:142–148

  70. 70.

    Milunsky JM, Maher TA, Metzenberg AB (2003) Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP. Am J Med Genet 116:249–254

  71. 71.

    Moody MN, Landau JM, Goldberg LH (2012) Nevus sebaceous revisited. Pediatr Dermatol 29:15–23

  72. 72.

    Moreira AI, Ferreira G, Santos M, Baptista A, Ferreira EO (2010) Epidermal nevus syndrome associated with hypophosphatemic rickets. Dermatol Online J 16:14

  73. 73.

    Mustonen T, Ilmonen M, Pummila M, Kangas AT, Laurikkala J, Jaatinen R, Pispa J, Gaide O, Schneider P, Thesleff I, Mikkola ML (2004) Ectodysplasin A1 promotes placodal cell fate during early morphogenesis of ectodermal appendages. Development 131:4907–4919

  74. 74.

    Oduber CE, van der Horst CM, Hennekam RC (2008) Klippel-Trenaunay syndrome: diagnostic criteria and hypothesis on etiology. Ann Plast Surg 60:217–223

  75. 75.

    Oduber CE, van der Horst CM, Sillevis Smitt JH, Smeulders MJ, Mendiratta V, Harper JI, van Steensel MA, Hennekam RC (2011) A proposal for classification of entities combining vascular malformations and deregulated growth. Eur J Med Genet 54:262–271

  76. 76.

    Oji V, Tadini G, Akiyama M, Blanchet Bardon C, Bodemer C, Bourrat E, Coudiere P et al (2010) Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol 63:607–641

  77. 77.

    Pacheco TR, Levy M, Collyer JC, de Parra NP, Parra CA, Garay M, Aprea G, Moreno S, Mancini AJ, Paller AS (2006) Incontinentia pigmenti in male patients. J Am Acad Dermatol 55:251–255

  78. 78.

    Paller AS, van Steensel MA, Rodriguez-Martin M, Sorrell J, Heath C, Crumrine D, van Geel M, Cabrera AN, Elias PM (2011) Pathogenesis-based therapy reverses cutaneous abnormalities in an inherited disorder of distal cholesterol metabolism. J Investig Dermatol 131:2242–2248

  79. 79.

    Park JM, Kim DS, Kim J, Lee MG, Oh SH (2009) Epibulbar complex choristoma and hemimegalencephaly in linear sebaceous naevus syndrome. Clin Exp Dermatol 34:e686–e689

  80. 80.

    Siemens HW (1929) Die Melanosis corii degenerativa, eine neue Pigmentdermatose. Arch Derm Syph 382

  81. 81.

    Singal A, Dhaliwal U, Bhattacharya SN, Rohatgi J, Singh N (2001) Complex ocular choristomas in linear nevus sebaceus syndrome: a report of two cases. J Dermatol 28:259–264

  82. 82.

    Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israel A et al (2000) Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405:466–472

  83. 83.

    Steijlen PM, van Geel M, Vreeburg M, Marcus-Soekarman D, Spaapen LJ, Castelijns FC, Willemsen M, van Steensel MA (2007) Novel EBP gene mutations in Conradi-Hunermann-Happle syndrome. Br J Dermatol 157:1225–1229

  84. 84.

    Stern C, Tokunaga C (1971) On cell lethals in Drosophila. Proc Natl Acad Sci U S A 68:329–331

  85. 85.

    Taieb A, Boralevi F (2007) Hypermelanoses of the newborn and of the infant. Dermatol Clin 25:327–336, viii

  86. 86.

    Tibbles JA, Cohen MM Jr (1986) The Proteus syndrome: the Elephant Man diagnosed. Br Med J 293:683–685

  87. 87.

    Verghese S, Newlin A, Miller M, Burton BK (1999) Mosaic trisomy 7 in a patient with pigmentary abnormalities. Am J Med Genet 87:371–374

  88. 88.

    Vreeburg M, van Geel M, van den Heuij LG, Steijlen PM, van Steensel MA (2011) Focal dermal hypoplasia in a male patient due to mosaicism for a novel PORCN single nucleotide deletion. J Eur Acad Dermatol Venereol 25:592–595

  89. 89.

    Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM (1991) Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695

  90. 90.

    Weinstein LS, Liu J, Sakamoto A, Xie T, Chen M (2004) Minireview: GNAS: normal and abnormal functions. Endocrinology 145:5459–5464

  91. 91.

    Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E (1983) The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140:5–12

  92. 92.

    Wiley JE, Madigan M, Christie JD, Smith AW (2002) Dispermic chimerism with two abnormal cell lines, 47, XY, +21 and 47, XX, +12. Am J Med Genet 107:64–66

  93. 93.

    Wolvius EB, de Lange J, Smeets EE, van der Wal KG, van den Akker HP (2006) Noonan-like/multiple giant cell lesion syndrome: report of a case and review of the literature. J Oral Maxillofac Surg 64:1289–1292

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The outpatient clinic depends on the outstanding support by Ms. Y. Detisch, genetics nurse. We acknowledge Dr. Marcus-Soekarman for her enthusiastic and unwavering support and participation. MvS is partly supported by grants from the Dutch Cancer Society (KWF UM2009-4352), the Association for International Cancer Research (11-0687) and the Annadal Foundation (AU11.1068).

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Correspondence to M. A. M. van Steensel.

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Vreeburg, M., van Steensel, M.A.M. Genodermatoses caused by genetic mosaicism. Eur J Pediatr 171, 1725–1735 (2012).

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  • Genetic mosaicism
  • X-linked
  • Lethal gene
  • Blaschko line