Dermatologic Aspects of Fabry Disease

Paula C. Luna Paula Boggio Margarita Larralde About the authors

Abstract

Isolated angiokeratomas (AKs) are common cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse AKs should alert the physician to a possible diagnosis of Fabry disease (FD). Angiokeratomas often do not appear until adolescence or young adulthood. The number of lesions and the extension over the body increase progressively with time, so that generalization and mucosal involvement are frequent. Although rare, FD remains an important diagnosis to consider in patients with AKs, with or without familial history. Dermatologists must have a high index of suspicion, especially when skin features are associated with other earlier symptoms such as acroparesthesia, hypohidrosis, or heat intolerance. Once the diagnosis is established, prompt screening of family members should be performed. In all cases, a multidisciplinary team is necessary for the long-term follow-up and treatment.

Keywords
Fabry disease; angiokeratomas; lysosomal storage disorders

Introduction

Fabry disease (FD, also known as Anderson-Fabry disease or angiokeratoma corporis diffusum [ACD]) is a rare X-linked disease caused by the partial or complete deficiency of a lysosomal enzyme, α-galactosidase A (α-Gal A), responsible for the catabolism of neutral sphingolipids.11 Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288. These nonmetabolized substrates accumulate in the lysosomes of different cells (predominantly in the endothelial cells) along the whole organism. It is a multisystemic and progressive disease with a great clinical heterogenicity, with classical and mild late-onset phenotypes.22 Hauser, AC, Lorenz, M, Sunder-Plassmann, G. The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy. J Intern Med. 2004;255(6):629–636. It is highly penetrant in males, with a variable expressivity in females. It is a rare disease with calculated incidence of 1:40.000 for the classical variant. The skin harbors 1 cardinal symptom: angiokeratomas (AKs).

Dermatologic Manifestation

Angiokeratoma Corporis Diffusum

The term AKs describes a heterogenous group of lesions characterized by the presence of vascular hyperkeratotic papules. They are mainly divided into 2 groups: localized and generalized.11 Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288.

Localized AK includes AKs of Fordyce, AKs of Mibelli, solitary AK, naeviforme AK,33 Schiller, PI, Itin, PH. Angiokeratomas, an update. Dermatology. 1996;193(4):275–282.

4 Mittal, R, Aggarwal, A, Srivastava, G. Angiokeratoma circumscriptum: a case report and review of the literature. Int J Dermatol. 2005;44(12):1031–1034.
-55 O’Mahony, C, Franks, A, Llewellyn, R. Angiokeratomas€”when is a few too many? Int J STD AIDS. 2014;25(5):378–379. and AK of the tongue.66 Yaqoob, N, Ahsan, A, Ahmed, M. Angiokeratoma of tongue: a series of 14 cases. J Pak Med Assoc. 2006;56(6):285–287. These lesions show a distinct clinical appearance while sharing histopathologic findings described in Table 1.

Table 1
Different Types of Angiokeratomas.

Diffuse AKs are characterized by the presence of multiple lesions that affect more than 1 area of the skin. Although any region of the skin can be affected, lesions usually localize to the bathing suit area (from the umbilicus to the upper thighs); this phenotype is known as ACD. This type of AKs, previously considered a synonym of FD, has also been described in several other lysosomal storage diseases77 Fleming, C, Rennie, A, Fallowfield, M, McHenry, PM. Cutaneous manifestations of fucosidosis. Br J Dermatol. 1997;136(4):594–597.

8 Vargas-Diez, E, Chabas, A, Coll, MJ, Sánchez-Pérez, J, García-Díez, A, Fernández-Herrera, JM. Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria. Br J Dermatol. 2002;147(4):760–764.

9 Kanitakis, J, Allombert, C, Doebelin, B. Fucosidosis with angioqueratoma. Inmunohistochemical and electronmicroscopic study of a new case and literature review. J Cutan Pathol. 2005;32(7):506–511.

10 Kawachi, Y, Matsu-ura, K, Sakuraba, H, Otsuka, F. Angiokeratoma corporis diffusum associated with galactosialidosis. Dermatology. 1998;197(1):52–54.
-1111 Yasuike, R, Nakai, N, Komori, S, Katoh, N. Angiokeratoma corporis diffusum in the absence of metabolic disorders: a case report and mini-review of the published work. J Dermatol. 2013;40(8):668–669.(Table 2) and exceptionally in other systemic conditions.1212 Gil-Mateo, MP, Miquel, FJ, Velasco, AM, Pitarch, A, Fortea, JM, Aliaga, A. Widespread angiokeratomas and tuberous sclerosis. Br J Dermatol. 1996;135(2):280–282.

13 Shannon, PL, Ford, MJ. Angiokeratomas in juvenile dermatomyositis. Pediatr Dermatol. 1999;16(6):448–451.

14 Sodaifi, M, Aghaei, S, Monabati, A. Cutaneous variant of angiokeratoma corporis diffusum associated with angiokeratoma circumscriptum. Dermatol Online J, 2004;10(1):20.
-1515 Han, F, Wang, P, Li, Z. Angiokeratoma corporis diffusum in a patient with Hodgkin lymphoma: a new paraneoplastic skin manifestation? Br J Dermatol. 2013;168(6):1351–1353. The rare occurrence of the ACD phenotype with no underlying diseases or metabolic alterations has also been described. This type is known as idiopathic ACD or “ACD with no known underlying enzyme alteration.” The occurrence of cases of idiopathic ACD with a familiar trait raises the issue that there might be an unknown underlying genetic disease.1616 Fimiani, M, Mazzatenta, C, Rubegni, P, Andreassi, L. Idiopathic angiokeratoma corporis diffusum. Clin Exp Dermatol. 1997;22(4):205–206.

17 Laxmisha, C, Thappa, DM, Karthikeyan, K. Cutaneous variant of angiokeratoma corporis diffusum. Dermatol Online J. 2003;9(1):13.

18 Kelly, B, Kelly, E. Angiokeratoma corporis diffusum in a patient with no recognizable enzyme abnormalities. Arch Dermatol. 2006;142(5):615–618.
-1919 Lipsker, D, Kieffer, C, Nojavan, H, Doray, B, Cribier, B. Familial ACD with no recognizable enzyme abnormalities. Arch Dermatol. 2006;142(11):1509.

Table 2
Differential diagnosis of Angiokeratoma Corporis Diffusum.

Angiokeratomas in FD are found in a high percentage of patients: 90% of males and 75% of females.2020 MacDermot, KD, Holmes, A, Miners, AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750–760. In hemizygous patients, lesions began to appear around the age of 5 to 8 years, although at that age, they usually go unnoticed or misdiagnosed, mostly when they are isolated (Figure 1).2121 Ries, M., Gupta, S., Moore, DF. Pediatric Fabry disease. Pediatrics. 2005;115(3);e344–355.,2222 Choudhury, S, Meehan, S, Shin, HL. Fabry disease: an atypical presentation. Pediatr Dermatol. 2005;22(4):334–337. Lesions usually appear as minute, isolated red to black papules that do not blanch with pressure. As disease progresses, they tend to group and turn more verrucous. The most characteristic localization is the bathing trunk area (gluteal, genital and periumbilical areas, lower abdomen, and upper part of the thighs; Figures 2-4).2323 Mohrenschlager, M, Henkel, V, Ring, J. Fabry disease: more than angiokeratomas. Arch Dermatol. 2004;140(12):1526–1528.

24 Möhrenschlager, M, Braun-Falco, M, Ring, J, Abeck, D. Fabry disease: recognition and management of cutaneous manifestations. Am J Clin Dermatol. 2003;4(3):189–196.
-2525 Tokuriki, A, Kiyohara, T, Kumakiri, M. Electron-microscopy of cherry haemangioma in the early diagnosis of Fabry disease. Acta Derm Venereol. 2013;93(4):471–472. Isolated lesions might also be found over the chest, hands and feet, axillae, extensor surface of the arms, elbows (Figure 5), and along the spine (suggesting trauma might act as a trigger in some areas, the Köebner phenomenon).11 Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288. There seems not to be a correlation between the severity of the disease and the extension of the AKs, the mutation, or the amount of residual enzyme.2626 Kim, DH, Kim, SY, Im, M, Lee, Y, Seo, YJ, Lee, JH. A novel frameshift mutation of galactosidase-alpha in Fabry disease restricted to dermatologic manifestations. Ann Dermatol. 2013;25:95–98.

Figure 1
Few lesions over the scrotum of a young kid.
Figure 2
Lateral aspect of the thigh.
Figure 3
Few lesions over the penis of a severely affected patient.
Figure 4
Widespread keratotic lesions over the scrotum.
Figure 5
Lesions over the elbow (Köebner phenomenon).

Female patients show a great clinical heterogeneity; some may show a full-blown disease and AKs mainly in the bathing trunk area, such as male patients, whereas others show few scattered telangiectatic lesions.2727 Larralde, M, Boggio, P, Amartino, H, Chamoles, N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. 2004;140(12):1440–1446. Although the literature reports a low frequency of vulvar lesions, in our experience, they are not so infrequent but they might usually be subtle and easily missed (Figures 6 and 7). There are several differential diagnosis of AKs.2828 Zampetti, A., Orteu, CH., Antuzzi, D. Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol. 2012;166(4):712–720.

29 Guinovart, RM, Bielsa, I, Pintos-Morell, G, Ferrándiz, C. Fabry disease and the clinical spectrum of angiokeratomas. Actas Dermosifiliogr. 2013;104(3):261–263.
-3030 Möhrenschlager, M, Henkel, V, Ring, J, Angiokeratomas, Fabry disease and enzyme replacement therapy: still a challenge. Br J Dermatol. 2005;152(1):178–179. When lesions are few with a highly verrucous component, they can be misinterpreted as viral warts. Their vascular origin of these lesions may be confused with petechiae, cherry angiomas, capillary aneurisms, pyogenic granulomas, eruptive angiomas,3131 Della Giovanna, P . Del angioqueratoma a la enfermedad de Fabry. Dermatologia Argent. 2004;10(4):263–269. or even Schonlein-Henoch purpura.3232 Kim, JH, Han, DH, Park, MY. Fabry disease previously diagnosed as Henoch-Schonlein purpura. Korean J Intern Med. 2015;30(6):925–927. Dermoscopy might be useful to recognize AKs, showing a well-limited red to black lesion with grouped vascular lacunae and some hyperkeratosis.3333 Zaballos, P, Daufí, C, Puig, S. Dermoscopy of solitary angiokeratomas, a morphological study. Arch Dermatol. 2007;143(3):318–325. From a practical point of view when assessing patients with multiple AKs, the umbilicus should always be evaluated for lesions inside the navel, given their presence is highly evocative of FD (Figure 8). On the other hand, genitals should be completely evaluated both in males and females. Lesions over the dorsum of the penis (not only over the scrotum) might be a sign that help differentiate from the most common and benign Fordyce AK. In females, vulvar AKs might be easily unnoticed, as they are usually asymptomatic and most patient’s lesions are quite subtle. Rare reports of male adults with few lesions, but with suggestive personal or family history, have been previously published,3434 Corry, A, Feighery, C, Alderdice, D, Stewart, F, Walsh, M, Dolan, OM. A family with Fabry disease diagnosed by a single angiokeratoma. Dermatol Online J. 2011;17(4):5. raising the need to rule out FD even in patients with scattered cutaneous lesions in the correct clinical context. Under the light microscope, histopathologic findings are similar in all AKs, showing numerous dilated and congestive capillaries with thin walls in the papillary dermis underlying an epidermis that shows different degrees of acanthosis and orthokeratosis.3535 Weedon, D . Tumores de los anexos cutáneos. En Piel Patología de Weedon. Marbán Libros; 2002. Vol 2:735–736. Due to technical issues, the recognition of the lysosomal deposits in these types of biopsies is very difficult. It is worth mentioning that not all the lesions show hyperkeratosis, with some biopsies only revealing vascular dilation, more similar to cherry angiomas or telangiectasias.3636 Weidemann, F, Strotmann, JM, Breunig, F. Misleading terms in Anderson-Fabry disease. Eur J Clin Invest. 2008;38(3):191–196. For these reasons, further evaluation should be performed when other clinically significant signs are present. Characteristic electron-dense concentric or lamellar (zebra-like) inclusion bodies (with alternating light- and dark-staining bands) are evident under the electron microscope. These inclusion bodies can also be recognized in clinically normal skin.3737 Boggio, P, Luna, PC, Abad, ME, Larralde, M. Fabry disease. An Bras Dermatol. 2009;84(4):367–376.,2828 Zampetti, A., Orteu, CH., Antuzzi, D. Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol. 2012;166(4):712–720. They are especially evident in the eccrine sweat glands.

Figure 6
Multiple vulvar lesions.
Figure 7
Few vulvar lesions.
Figure 8
Umbilical papules.

Other Cutaneous Findings

Oral Manifestations

More than one-third of patients develop oral lesions. Angiokeratomas and telangiectasias can be found in the lips and intraorally,3838 Baccaglini, L, Schiffmann, R, Brennan, MT. Oral and craniofacial findings in Fabry’s disease: a report of 13 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92(4):415–4 specially in the anterior buccal mucosa. The tongue might also develop glossitis, fissures, and erythematous papillae. Xerostomia is a usual complain.

Raynaud Phenomenon

The presence of episodical color changes (pallor and cyanosis) on the acral extremities, mainly secondary to the exposure to cold and in the absence of lupus and scleroderma or antinuclear antibodies, has been recently described in up to 13% of patients with FD. Germain et al evaluated the presence of this symptom in 207 patients with FD reporting this phenomenon in 28 cases. This finding was noticed both in female and male patients and was independent of the mutation and the presence and amount of AKs, expanding the phenotype of vasculopathy observed in patients with FD.3939 Germain, D, Atanasiu, OI, Akrout-Marouene, J, Benistan, K. Raynaud’s phenomenon associated with Fabry disease. J Inherit Metab Dis. 2015;38(2):367–368.

Hypohidrosis or Anhidrosis

Hypohidrosis or anhidrosis is a frequent manifestation in hemizygous adults with FD (53%-93% of patients) and not so frequent in female patients (17%-28%).4040 Orteu, CH, Jansen, T, Lidove, O. Fabry disease and the skin: data from FOS, the Fabry outcome survey. Br J Dermatol. 2007;157(2):331–337.

41 Lidove, O, Jaussaud, R, Aractingi, S. Dermatological and soft-tissue manifestations of Fabry disease: characteristics and response to enzyme replacement therapy. In: Mehta, A, Beck, M, Sunder-Plassmann, G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, United Kingdom: Oxford PharmaGenesis; 2006;24:233–240.
-4242 Galanos, J, Nicholls, K, Grigg, L, Kiers, L, Crawford, A, Becker, G. Clinical features of Fabry's disease in Australian patients. Inter Med J. 2002;32(12):575–584. It usually starts early, during childhood or adolescence,4343 Jung, SE, Kim, YC. Hypohidrosis: an early clue in the diagnosis of Fabry disease. Clin Exp Dermatol. 2015;40(4):444–445. and leads to dry skin, heat intolerance, or fever of unknown origin, (due to the inability to sweat and eliminate heat transepidermically). The pathophysiology is thought to be due to the accumulation of nondegraded substances in the peripheric nerves and the endothelial deposits of the vessels surrounding the eccrine glands and the eccrine cells, as well as an abnormal autonomic nerve response.

Lymphedema

Lymphedema of the lower legs is another cutaneous finding in some patients with FD. It is thought to be due to the direct deposit of sphingolipids in lymphatic vessels with a fragmentation of the microlymphatic net (as demonstrated by Amann-Vesti et al by fluorescence microlymphography).4444 Amann-Vesti, BR, Glitzelmann, G, Widmer, U, Bosshard, NU, Steinmann, B, Koppensteiner, R. Severe lymphatic microangiopathy in Fabry disease. Lymphat Res Biol. 2003;1(3):185–189.

Hair Alterations

Hypotrichosis and sparse, fine facial hair have been typically described in patients with FD. It seems to be more accentuated in the lower legs. One report of “hard and thick scalp hair” failed to demonstrate the deposit of sphingolipids in the hair bulb, but suggested that the hair alterations could be due to the indirect effect of the microvessel disturbances and a secondary micronutrient deficiency.4545 Tabata, H, Yamakage, A, Yamazaki, S. Hair abnormality of Fabry disease. Int J Dermatol. 1996;35:576–378.

Facial Features

Although facial dysmorphism is usually important in most lysosomal storage disorders, facial features in patients with FD have been historically considered unrevealing.4646 Cox-Brinkman, J, Vedder, A, Hollak, C. Three-dimensional face shape in Fabry disease. Eur J Hum Genet. 2007;15(5):535–542. More recent evaluation of patients has allowed the recognition of certain minor facial abnormalities such as periorbital fullness, prominent lobules of the ears, bushy eyebrows, recessed forehead, pronounced nasal angle, generous nose/bulbous nasal tip, full lips, coarse features, and prognathism, among others,4747 Ries, M, Moore, DF, Robinson, CJ. Quantitative dysmorphology assessment in Fabry disease. Genet Med. 2006;8(2):96–101. in both male and female patients with FD.

Other Skin Findings in Histopathology

The skin is a very accessible organ where to perform a biopsy if we compare it with other sites such as the kidney or heart. Repeated skin biopsies performed in patients in 1 trial performed by Thurberg et al4848 Thurberg, B, Byers, R, Granter, S, Phelps, R, Gordon, RE, O’Callaghan, M. Monitoring the 3-year efficacy of enzyme replacement therapy in Fabry disease by repeated skin biopsies. J Invest Dermatol. 2004;122(4):900–908. allowed the assessment of enzyme replacement therapy (ERT) effects (agalsidase-β 1 mg/kg every 2 weeks) in the substrate clearance of the superficial capillary endothelium, showing an excellent response.

Diagnosis

A thorough discussion of the diagnostic methods of FD is beyond the scope of this article, but some points are worth mentioning. Definite diagnosis requires the demonstration of low α-Gal A activity in plasma, serum or leukocytes, and in dried blood spots on the filter paper.2727 Larralde, M, Boggio, P, Amartino, H, Chamoles, N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. 2004;140(12):1440–1446.,4949 Desnick, RJ, Brady, R, Barranger, J. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338–346.,5050 Linthorst, G, De Rie, M, Tjiam, K, Aerts, J, Dingemans, KP, Hollak, CE. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol. 2004;150(3):575–577. As female patients have variable enzymatic activities, with a great amount of patients showing normal activity, the diagnosis should be confirmed with the detection of the pathogenic mutation.5151 Ries, M, Schiffmann, R. Fabry disease: angiokeratoma, biomarker and the effect of enzyme replacement therapy on kidney function. Arch Dermatol. 2005;141(7):904–905.

Treatment

The many different debilitating symptoms of FD demand a multidisciplinary evaluation that involves the primary caregiver, as well as experienced nephrologists, cardiologists, dermatologists, and neurologists.11 Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288.,5252 Consenso de Médicos de AADELFA y GADYTEF, Neumann, P., Antongiovanni, N., Fainboim, A. Guidelines for diagnosis, monitoring and treatment of Fabry disease. Medicina (B Aires). 2013;73(5):482–494.

53 Politei, JM, Cabrera, G, Amartino, H. Fabry disease in Argentina: an evaluation of patients enrolled in the Fabry Registry. Int J Clin Pract. 2013;67(1):66–72.
-5454 Eng, MC, Germain, DP, Banikazemi, M. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539–548.

A specific treatment (ERT) is available for eligible patients and has shown to be safe and effective.5555 Banikazemi, M, Bultas, J, Waldek, S. Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146(2):77–86.,5656 Thurberg, BL, Rennke, H, Colvin, RB. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 2002;62(6):1933–1946. It will be discussed in-depth elsewhere in this supplement.

The nonspecific treatment of cutaneous lesions includes different types of destructive measures such as cryotherapy, electrocoagulation, or excisional surgery. However, the treatment of choice is laser therapy (neodymium YAG, pulsed dye, KTP 532 nm, copper, argon, candela V, or beam laser).11 Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288.,5757 Morais, P, Santos, AL, Baudrier, T, Mota, AV, Oliveira, JP, Azevedo, F. Angiokeratomas of Fabry successfully treated with intense pulsed light. J Cosmet Laser Ther. 2008;10(4):218–222.,5858 Lapins, J, Emtestam, L, Marcusson, JA. Angiokeratomas in Fabry’s disease and Fordyce’s disease: successful treatment with copper vapour laser. Acta Derm Venereol. 1993;73(2):133–135. It should be taken into account that lesions may continue appearing even under specific treatment in some patients, so a palliative measure should be offered when cutaneous manifestations show an impact in the quality of life.

Funding

  • The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

  • 1
    Larralde, M, Luna, PC. Chapter 136: Fabry disease. In: Goldsmith, W, Gilchrest, K, Paller, AS, Leffell, DJ, eds. Fitzpatrick's Dermatology in General Medicine. 7th ed. Mc Graw Hill Medical Publishing Division; 2007:1281–1288.
  • 2
    Hauser, AC, Lorenz, M, Sunder-Plassmann, G. The expanding clinical spectrum of Anderson-Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy. J Intern Med. 2004;255(6):629–636.
  • 3
    Schiller, PI, Itin, PH. Angiokeratomas, an update. Dermatology. 1996;193(4):275–282.
  • 4
    Mittal, R, Aggarwal, A, Srivastava, G. Angiokeratoma circumscriptum: a case report and review of the literature. Int J Dermatol. 2005;44(12):1031–1034.
  • 5
    O’Mahony, C, Franks, A, Llewellyn, R. Angiokeratomas€”when is a few too many? Int J STD AIDS. 2014;25(5):378–379.
  • 6
    Yaqoob, N, Ahsan, A, Ahmed, M. Angiokeratoma of tongue: a series of 14 cases. J Pak Med Assoc. 2006;56(6):285–287.
  • 7
    Fleming, C, Rennie, A, Fallowfield, M, McHenry, PM. Cutaneous manifestations of fucosidosis. Br J Dermatol. 1997;136(4):594–597.
  • 8
    Vargas-Diez, E, Chabas, A, Coll, MJ, Sánchez-Pérez, J, García-Díez, A, Fernández-Herrera, JM. Angiokeratoma corporis diffusum in a Spanish patient with aspartylglucosaminuria. Br J Dermatol. 2002;147(4):760–764.
  • 9
    Kanitakis, J, Allombert, C, Doebelin, B. Fucosidosis with angioqueratoma. Inmunohistochemical and electronmicroscopic study of a new case and literature review. J Cutan Pathol. 2005;32(7):506–511.
  • 10
    Kawachi, Y, Matsu-ura, K, Sakuraba, H, Otsuka, F. Angiokeratoma corporis diffusum associated with galactosialidosis. Dermatology. 1998;197(1):52–54.
  • 11
    Yasuike, R, Nakai, N, Komori, S, Katoh, N. Angiokeratoma corporis diffusum in the absence of metabolic disorders: a case report and mini-review of the published work. J Dermatol. 2013;40(8):668–669.
  • 12
    Gil-Mateo, MP, Miquel, FJ, Velasco, AM, Pitarch, A, Fortea, JM, Aliaga, A. Widespread angiokeratomas and tuberous sclerosis. Br J Dermatol. 1996;135(2):280–282.
  • 13
    Shannon, PL, Ford, MJ. Angiokeratomas in juvenile dermatomyositis. Pediatr Dermatol. 1999;16(6):448–451.
  • 14
    Sodaifi, M, Aghaei, S, Monabati, A. Cutaneous variant of angiokeratoma corporis diffusum associated with angiokeratoma circumscriptum. Dermatol Online J, 2004;10(1):20.
  • 15
    Han, F, Wang, P, Li, Z. Angiokeratoma corporis diffusum in a patient with Hodgkin lymphoma: a new paraneoplastic skin manifestation? Br J Dermatol. 2013;168(6):1351–1353.
  • 16
    Fimiani, M, Mazzatenta, C, Rubegni, P, Andreassi, L. Idiopathic angiokeratoma corporis diffusum. Clin Exp Dermatol. 1997;22(4):205–206.
  • 17
    Laxmisha, C, Thappa, DM, Karthikeyan, K. Cutaneous variant of angiokeratoma corporis diffusum. Dermatol Online J. 2003;9(1):13.
  • 18
    Kelly, B, Kelly, E. Angiokeratoma corporis diffusum in a patient with no recognizable enzyme abnormalities. Arch Dermatol. 2006;142(5):615–618.
  • 19
    Lipsker, D, Kieffer, C, Nojavan, H, Doray, B, Cribier, B. Familial ACD with no recognizable enzyme abnormalities. Arch Dermatol. 2006;142(11):1509.
  • 20
    MacDermot, KD, Holmes, A, Miners, AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750–760.
  • 21
    Ries, M., Gupta, S., Moore, DF. Pediatric Fabry disease. Pediatrics. 2005;115(3);e344–355.
  • 22
    Choudhury, S, Meehan, S, Shin, HL. Fabry disease: an atypical presentation. Pediatr Dermatol. 2005;22(4):334–337.
  • 23
    Mohrenschlager, M, Henkel, V, Ring, J. Fabry disease: more than angiokeratomas. Arch Dermatol. 2004;140(12):1526–1528.
  • 24
    Möhrenschlager, M, Braun-Falco, M, Ring, J, Abeck, D. Fabry disease: recognition and management of cutaneous manifestations. Am J Clin Dermatol. 2003;4(3):189–196.
  • 25
    Tokuriki, A, Kiyohara, T, Kumakiri, M. Electron-microscopy of cherry haemangioma in the early diagnosis of Fabry disease. Acta Derm Venereol. 2013;93(4):471–472.
  • 26
    Kim, DH, Kim, SY, Im, M, Lee, Y, Seo, YJ, Lee, JH. A novel frameshift mutation of galactosidase-alpha in Fabry disease restricted to dermatologic manifestations. Ann Dermatol. 2013;25:95–98.
  • 27
    Larralde, M, Boggio, P, Amartino, H, Chamoles, N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. 2004;140(12):1440–1446.
  • 28
    Zampetti, A., Orteu, CH., Antuzzi, D. Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol. 2012;166(4):712–720.
  • 29
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Publication Dates

  • Publication in this collection
    30 May 2019
  • Date of issue
    2016

History

  • Received
    13 Feb 2016
  • Reviewed
    14 Apr 2016
  • Accepted
    30 May 2016
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br