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Fabry Disease pp 259-274 | Cite as

Dermatological Manifestations of Fabry Disease

  • Catherine H. OrteuEmail author
Chapter

Abstract

The term ‘angiokeratoma corporis diffusum’ (ACD) has been used synonymously with Anderson-Fabry disease since its original description. Since the availability of effective therapy, the drive to identify patients has increased. As a result, we are becoming more aware of a broader spectrum in the cutaneous and systemic phenotype of the condition. Not all patients have widespread angiokeratomas. Macular (flat) angiomas without any overlying hyperkeratosis and papular- ‘cherry’ angiomas are also seen. Telangiectases may occur at sun exposed sites including the face and ‘V’ of the neck, more rarely they are present in unusual sites, such as flanks and elbow flexures. In addition to these cutaneous vascular lesions, skin signs include characteristic facial features, oedema and lymphoedema of the lower limbs, abnormalities of sweating and Raynaud’s phenomenon. Skin signs are an obvious, outward manifestation of disease and as such are important signs for diagnosis. They represent a significant source of morbidity, have a recognised impact on self-esteem and quality of life, and should be treated appropriately. Of particular interest, is whether the cutaneous phenotype may be helpful not only in making the diagnosis of Fabry disease, but also in assessing or predicting overall disease severity.

Keywords

Angiokeratoma Cherry angioma Cutaneous vascular lesions Fabry facial features Lymphoedema Hyperhidrosis Hypohidrosis Raynaud’s phenomenon 

Abbreviations

ACD

Angiokeratoma corporis diffusum

AK

Angiokeratoma

CVL

Cutaneous vascular lesions

ERT

Enzyme replacement therapy

FD

Fabry disease

FOS

Fabry outcome survey

LSD

Lysosomal storage disorders

MSSI

Mainz severity scoring index

SD

Standard deviation

TIA

Transient ischaemic attack

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

Notes

Acknowledgments

I would like to thank the patients for participating and allowing us to use their clinical photographs and Dr P Elliott for his helpful comments during the preparation of this manuscript.

References

  1. 1.
    Anderson W (1898) A case of angiokeratoma. Br J Dermatol 18:113–117CrossRefGoogle Scholar
  2. 2.
    Fabry J (1898) Ein Beitrag zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Dermatol Syph 43:187–200Google Scholar
  3. 3.
    Desnick RJ, Ioannou YA, Eng CM (2001) α-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet Al, Sly WS, Valk D (eds) The Metabolic and molecular basis of inherited disease, vol 3, 8th edn. McGraw Hill, New York, 3733–3774Google Scholar
  4. 4.
    Orteu CH, Jansen T, Lidove O et al (2007) Fabry disease and the skin: data from FOS the Fabry outcome survey. Br J Dermatol 157(2):331–337PubMedCrossRefGoogle Scholar
  5. 5.
    Dhoat S, Orteu CH, Navarro C, Lidove O, Jansen T, Clarke J (2009) Patients with Fabry disease with cutaneous vascular lesions have higher disease severity scores and more multisystem involvement: data from 1354 patients registered on FOS, the Fabry outcome survey. Br J Dermatol 161(Suppl 1):45Google Scholar
  6. 6.
    Braverman IM (1989) Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states. J Invest Dermatol 93(2 Suppl):2S–9SPubMedCrossRefGoogle Scholar
  7. 7.
    Navarro C, Teijeira S, Dominguez C et al (2006) Fabry disease: an ultrastructural comparative study of skin in hemizygous and heterozygous patients. Acta Neuropathol (Berl) 7:1–8Google Scholar
  8. 8.
    Ramaswami U, Whybra C, Parini R et al (2006) Clinical manifestations of Fabry disease in children: data from FOS – the Fabry Outcome Survey. Acta Paediatrica 95:86–92PubMedCrossRefGoogle Scholar
  9. 9.
    MacDermott KD, Holmes A, Miners AH (2001) Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 38:750–760CrossRefGoogle Scholar
  10. 10.
    MacDermott KD, Holmes A, Miners AH (2001) Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38:769–775CrossRefGoogle Scholar
  11. 11.
    Weidemann F, Strotmann JM, Breunig F et al (2008) Misleading terms in Anderson-Fabry disease. Eur J Clin Invest 38(3):191–196PubMedCrossRefGoogle Scholar
  12. 12.
    Fleming C, Rennie A, Fallowfield M, McHenry PM (1997) Cutaneous manifestations of fucosidosis. Br J Dermatol 136(4):594–597PubMedCrossRefGoogle Scholar
  13. 13.
    Kanzaki T, Yokota M, Irie F et al (1993) Aniokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity. Clincal, morphologic and biochemical studies. Arch Dermatol 129:460–465PubMedCrossRefGoogle Scholar
  14. 14.
    Rodriguez-Serna M, Botella-Estrada R, Chabas A et al (1996) Angiokeratoma corporis diffusum associated with beta-mannosidase deficiency. Arch Dermatol 132(10):1219–1222PubMedCrossRefGoogle Scholar
  15. 15.
    Paller SA (1987) Metabolic disorders characterized by angiokeratomas and neurologic dysfunction. Neurol clin 5(3):441–446PubMedGoogle Scholar
  16. 16.
    Albay D, Adler SG, Philipose J, Calescibetta CC, Romansky SG, Cohen AH (2005) Chloroquine-induced lipidosis mimicking Fabry disease. Mod Pathol 18(5):733–738PubMedCrossRefGoogle Scholar
  17. 17.
    Schiller PI, Itin PH (1996) Angiokeratomas: an update. Dermatology 193(4):275–282PubMedCrossRefGoogle Scholar
  18. 18.
    Orteu CH, Mehta AB, Dhoat S, Hughes DA (2009) Fabry disease and angiokeratoma corporis diffusum are not synonymous: cutaneous vascular lesions and facial features in 100 patients with Fabry disease. Br J Dermatol 161(Suppl 1):46Google Scholar
  19. 19.
    Plunkett A, Merlin K, Gill D, Zuo Y, Jolley D, Marks R (1999) The frequency of common nonmalignant skin conditions in adults in central Victoria, Australia. Int J Dermatol 38(12):901–908PubMedCrossRefGoogle Scholar
  20. 20.
    Eng CM, Banikazemi M, Gordon RE et al (2001) A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 68(3):711–722PubMedCrossRefGoogle Scholar
  21. 21.
    Thurberg BL, Randolph Byers H, Granter SR, Phelps RG, Gordon RE, O’Callaghan M (2004) Monitoring the 3-year efficacy of enzyme replacement therapy in fabry disease by repeated skin biopsies. J Invest Dermatol 122(4):900–908PubMedCrossRefGoogle Scholar
  22. 22.
    Ross BS, Levine VJ, Ashinoff R (1997) Laser treatment of acquired vascular lesions. Dermatol Clin 15(3):385–396PubMedCrossRefGoogle Scholar
  23. 23.
    Morais P, Santos AL, Baudrier T, Mota AV, Oliveira JP, Azevedo F (2008) Angiokeratomas of Fabry successfully treated with intense pulsed light. J Cosmet Laser Ther 10(4):218–222PubMedCrossRefGoogle Scholar
  24. 24.
    Pfirrmann G, Raulin C, Karsai S (2009) Angiokeratoma of the lower extremities: successful treatment with a dual-wavelength laser system (595 and 1064 nm). J Eur Acad Dermatol Venereol 23(2):186–187PubMedCrossRefGoogle Scholar
  25. 25.
    Ozdemir M, Baysal I, Engin B, Ozdemir S (2009) Treatment of angiokeratoma of Fordyce with long-pulse neodymium-doped yttrium aluminium garnet laser. Dermatol Surg 35(1):92–97PubMedCrossRefGoogle Scholar
  26. 26.
    Bechara FG, Jansen T, Wilmert M, Altmeyer P, Hoffmann K (2004) Angiokeratoma Fordyce of the glans penis: combined treatment with erbium: YAG and 532 nm KTP (frequency doubled neodynium: YAG) laser. J Dermatol 31(11):943–945PubMedGoogle Scholar
  27. 27.
    Ries M, Moore DF, Robinson CJ et al (2006) Quantitative dysmorphology assessment in Fabry disease. Genet Med 8(2):96–101PubMedCrossRefGoogle Scholar
  28. 28.
    Cox-Brinkman J, Vedder A, Hollak C et al (2007) Three-dimensional face shape in Fabry disease. Eur J Hum Genet 15(5):535–542PubMedCrossRefGoogle Scholar
  29. 29.
    Freeman RG (1977) A pathologic basis for the cutaneous papules of mucopolysaccharidosisII (The Hunter syndrome). J Cutan Pathol 4:318–328PubMedCrossRefGoogle Scholar
  30. 30.
    Galan-Gomez E, Guerrero-Rico A, Caceres-Marzal C et al (2008) Early response to idursulfase treatment in a 3 year-old boy affected of Hunter syndrome. Eur J Med Genet 51(3):268–271PubMedCrossRefGoogle Scholar
  31. 31.
    Richfield L, Orteu CH, Fox N et al (2005) Fabry disease, changes in typical facial features in response to enzyme replacement therapy with agalsidase alpha. Acta Paediatr Suppl 447:122Google Scholar
  32. 32.
    Suter LG, Murabito JM, Felson DT, Fraenkel L (2005) The incidence and natural history of Raynaud’s phenomenon in the community. Arthritis Rheum 52(4):1259–1263PubMedCrossRefGoogle Scholar
  33. 33.
    Brand FN, Larson MG, Kannel WB, McGuirk JM (1997) The occurrence of Raynaud’s phenomenon in a general population: the Framingham Study. Vasc Med 2(4):296–301PubMedGoogle Scholar
  34. 34.
    Cooke JP, Marshall JM (2005) Mechanisms of Raynaud’s disease. Vasc Med 10(4):293–307PubMedCrossRefGoogle Scholar
  35. 35.
    Cherkas LF, Williams FM, Carter L et al (2007) Heritability of Raynaud’s phenomenon and vascular responsiveness to cold: a study of adult females twins. Arthritis Rheum 57(3):524–528PubMedCrossRefGoogle Scholar
  36. 36.
    Wasik JS, Simon RW, Meier T, Steinmann B, Amann-Vesti BR (2009) Nailfold capillaroscopy: specific features in Fabry disease. Clin Hemorheol Microcirc 42(2):99–106PubMedGoogle Scholar
  37. 37.
    Pope JE (2007) The diagnosis and treatment of Raynaud’s phenomenon. Drugs 67(4):517–525PubMedCrossRefGoogle Scholar
  38. 38.
    Coleiro B, Marshall SE, Denton CP et al (2001) Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxford) 40(9):1038–1043CrossRefGoogle Scholar
  39. 39.
    Rockson SG (2008) Diagnosis and management of lymphatic vascular disease. J Am Coll Cardiol 52(10):799–806PubMedCrossRefGoogle Scholar
  40. 40.
    Moffatt CJ, Franks PJ, Doherty DC et al (2003) Lymphoedema: an underestimated health problem. QJM 96(10):731–738PubMedCrossRefGoogle Scholar
  41. 41.
    Chabas A, Coll MJ, Aparicio M, Rodriguez Diaz E (1994) Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J Inhert Metab Dis 17(6):724–731CrossRefGoogle Scholar
  42. 42.
    Lozano F, Garcia-Talavera R, Gomez-Alonso A (1988) An unusual cause of lymphoedema–confirmed by isotopic lymphangiography. Eur J Vasc Surg 2(2):129–131PubMedCrossRefGoogle Scholar
  43. 43.
    Gemignani F, Pietrini V, Tagliavini F et al (1979) Fabry’s disease with familial lymphedema of the lower limbs. Case report and family study. Eur Neurol 18(2):84–90PubMedCrossRefGoogle Scholar
  44. 44.
    Jansen T, Bechara FG, Orteu CH, Altmeyer P, Mehta A, Beck M (2005) The significance of lymphoedema in Fabry Disease. Acta Paediatr Suppl 447:117Google Scholar
  45. 45.
    Amann-Vesti BR, Gitzelmann G, Widmer U, Bosshard NU, Steinmann B, Koppensteiner R (2003) Severe Lymphatic micrangiopathy in Fabry disease. Lymphat Res Biol 1(3):185–189PubMedCrossRefGoogle Scholar
  46. 46.
    Gitzelmann G, Widmer U, Bosshard NU, Steinmann B, Koppensteiner R, Amann-Vesti BR (2006) Lymphoedema in Fabry disease: pathology and therapeutic perspectives. Acta Pardiatr Suppl 451:122Google Scholar
  47. 47.
    Lohela M, Bry M, Tammela T, Alitalo K (2009) VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 21(2):154–165PubMedCrossRefGoogle Scholar
  48. 48.
    Albuquerque RJ, Hayashi T, Cho WG et al (2009 Sep) Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 15(9):1023–1030Google Scholar
  49. 49.
    Jin da P, An A, Liu J, Nakamura K, Rockson SG (2009) Therapeutic responses to exogenous VEGF-C administration in experimental lymphedema: immunohistochemical and molecular characterization. Lymphat Res Biol 7(1):47–57PubMedCrossRefGoogle Scholar
  50. 50.
    Larralde M, Boggio P, Amartino H, Chamoles N (2004) Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol 140(12):1440–1446PubMedCrossRefGoogle Scholar
  51. 51.
    Cable WJ, Kolodny EH, Adams RD (1982) Fabry disease, impaired autonomic function. Neurology 32:498–502PubMedCrossRefGoogle Scholar
  52. 52.
    Shelley ED, Shelley WB, Kurczynski TW (1995) Painful fingers, heat intolerance, telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol 12:215–219PubMedCrossRefGoogle Scholar
  53. 53.
    Hilz MJ, Brys M, Marthol H, Stemper B, Dutsch M (2004) Enzyme replacement therapy improves function of C-adelta-, and Abeta-nerve fibers in Fabry neuropathy. Neurology 62(7):1066–1072PubMedCrossRefGoogle Scholar
  54. 54.
    Schiffmann R, Floeter MLK, Dambrosia JM et al (2003) Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve 28(6):703–710PubMedCrossRefGoogle Scholar
  55. 55.
    Lidove O, Ramaswami U, Jaussaud R et al (2006) Hyperhidrosis: a new and often early symptom in Fabry disease. International experience and data from the Fabry Outcome Survey. Int J Clin Pract 60(9):1053–1059PubMedCrossRefGoogle Scholar
  56. 56.
    Strutton DR, Kowalski JW, Glaser DA, Stang PE (2004) US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol 51(2):241–248PubMedCrossRefGoogle Scholar
  57. 57.
    Ram R, Lowe NJ, Yamauchi PS (2007) Current and emerging therapeutic modalities for hyperhidrosis, part 1: conservative and non-invasive treatments. Cutis 79(3):211–217PubMedGoogle Scholar
  58. 58.
    Ram R, Lowe NJ, Yamauchi PS (2007) Current and emerging therapeutic modalities for hyperhidrosis, part 2: moderately invasive and invasive procedures. Cutis 79(4):281–288PubMedGoogle Scholar

Copyright information

© Springer Netherlands 2010

Authors and Affiliations

  1. 1.Department of DermatologyRoyal Free HospitalLondonUK

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