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88 Sangüeza and Requena / Pathology of Vascular Skin Lesions Fig. 13. Angiokeratomas of Fordyce involving the vulva of an elderly woman. Fig. 14. Angiokeratomas of Mibelli in the inner border of the left hand. disorders, but there is also an idiopathic form that presents with no other associated anomalies. Among the different diseases associated with angiokeratoma corporis diffusum, Fabry’s disease is the most common. Fabry’s disease is a rare error of the metabolism that results in a deficiency of the lysosomal enzyme hydrolase a-galactosi-dase A. It is transmitted as an X-linked recessive trait. The gene responsible for the coding of a-galactosidase A has been localized to the middle of the long arm of the X chromo-some. As an X-linked disease, Fabry’s disease exclusively affects males; females may be asymptomatic carriers and may have corneal dystrophic changes that can be detected by slit-lamp examination (18,19). As a consequence of the enzymatic defect, glycosphingolipids, predominantly trihexosylceramide, accumulate within the lysosomes of endothelial cells, fibroblasts, pericytes, and smooth muscle fibers of the dermis. There is also an accumulation of this material in other organs including ganglion cells, nerves, cornea, heart, and kidney, resulting in cardiac, renal, ocular, and neurologic abnormalities (20). Angiokeratomas of Fabry’s disease usually appear shortly before puberty. They are small, punctate, dark red papules, some of them less than 1 mm, mainly located in the lower part of abdomen, genitalia, buttocks, and thighs in a bathing-trunk distribution (Figs. 15, 16, and 17). A frequent and asymptomatic finding is the so-called cornea verticillata, which is a super-ficial corneal dystrophy. This finding is of diagnostic importance for the detection of mild cases and female carriers. Other cutaneous manifestations include dry skin, anhidrosis, hyperthermic crises (21), and acroparaesthesiae secondary to capillary changes in the nail matrix (22). In rare instances patients with Fabry’s disease may also present with concur- Chapter 6 / Cutaneous Lesions with Dilations 89 Fig. 15. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. Multiple small red papules involving the left flank. rent Klippel-Trenaunay-Weber syndrome (23). Patients with Fabry’s disease who are devoid of cutaneous lesions have been reported (24). Angiokeratoma corporis diffusum is not exclusive to Fabry’s disease and has also been described in association with other rare inherited lysosomal storage diseases such as fucosidosis type II (25,26), galactosidosis type II (27), Kanzaki’s disease or deficiency of a-N-acetylgalactosaminidase (28–30), aspartylglycosaminuria (31), sialidosis type II (32), adult-onset GM1 gangliosidosis (33), and b-mannosidase deficiency (34–36). By the same token, rare cases of angiokeratoma corporis diffusum have been described in patients without metabolic anomalies (37–40). In some of these patients the angiokeratomas were multiple and presented in a zosteriform distribution (41). These angiokeratomas have been described in patients with cutaneous and cerebral hemangio-mas (42), tuberous sclerosis (43), blue rubber bleb nevus syndrome (44), and juvenile dermatomyositis (45). In a recent report, angiokeratoma corporis diffusum not associated with metabolic disease was described in a three-generation family with autosomal dominant transmis-sion. Some of the affected patients showed arteriovenous shunts with hypertrophy of the affected limb (46). HISTOPATHOLOGIC FEATURES Histopathologically, all variants of angiokeratomas are identical under a conventional microscope. Common features of all angiokeratomas include the presence of dilated thin- 90 Sangüeza and Requena / Pathology of Vascular Skin Lesions Fig. 16. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. (A) Lesions of angiokeratoma involved the dorsum of the foot. (B) Close-up view shows that small red papules are also present in the spaces among the toes. Fig. 17.Angiokeratoma corporis diffusum in a patient with Fabry’s disease with small red papules on the buttocks. walled blood vessels lined by a layer of endothelial cells in the papillary dermis and a variable degree of hyperkeratosis (1). Occasionally, angiokeratomas may be seen over-lying deep vascular malformations (47). Hyperkeratosis is usually absent in Fordyce’s angiokeratomas and in angiokeratoma corporis diffusum (Fabry’s disease). Ultrastruc- Chapter 6 / Cutaneous Lesions with Dilations 91 tural studies have demonstrated quantitative alterations of cytoplasmic organelles within the endothelial cells (48). In patients with Fabry’s disease, there is vacuolization of the cytoplasm of the endot-helial cells of the arterioles and smooth muscle cells of the arrector pili. The presence of these vacuoles may be a clue to the specific diagnosis in sections stained with hematoxy-lin and eosin. However, in most cases the amount of glycolipid in the skin is small, making it extremely difficult, if not impossible, to identify them in routinely prepared sections. Special stains such as Sudan black B (49) and PAS (50) highlight the presence of glycolipid deposits within the vacuoles in patients with Fabry’s disease and related disorders (Fig. 18). The lipid material is double refractile, which can be demonstrated by means of polariscopic examination of unfixed, or formalin-fixed frozen sections. Depos-its of glycolipids in patients with Fabry’s disease are not restricted to the lesions of angiokeratoma but may also be seen in skin that appears to be normal (51). Electron microscopy examination of the skin in Fabry’s disease shows large, electrodense lipid deposits in endothelial cells, pericytes, fibroblasts, arrector pili muscles, and secretory, ductal, and myoepithelial cells of the eccrine glands (52). These deposits show a charac-teristic lamellar structure(53–58), not seen in other types of angiokeratomas or in lesions of angiokeratoma corporis diffusum with no enzymatic anomalies (38–45). Other ultra-structural findings in patients with Fabry’s disease consist of intersecting short, crescent-shaped, tightly packed membranes in the endothelial cells of the small cutaneous blood vessels (59) and cytoplasmic vacuoles in the epithelial cells of the eccrine glands (60). TREATMENT Small angiokeratomas may be managed by diathermy, electrodessication and curet-tage, or cryotherapy with liquid nitrogen. Good cosmetic results have been reported with laser therapy (61–67). For larger lesions the preferred treatment is surgical excision if treatment is required. Recombinant human a-galactosidase A replacement therapy has been demonstrated to be safe and efficient in reversing the chief clinical manifestations in patients with Fabry’s disease (68). References 1. Imperial R, Helwig EB. Angiokeratoma: a clinicopathological study. Arch Dermatol 1967;95:166–75. 2. Kumar MV, Thappa DM, Shanmugam S, Ratnakar C. Angiokeratoma circumscriptum of the oral cavity. Acta Derm Venereol 1988;78:472. 3. Foucar E, Mason WV. Angiokeratoma circumscriptum following damage to underlying vasculature. Arch Dermatol 1986;122:245–6. 4. Goldman L, Gibson SH, Richfield DF. Thrombotic angiokeratoma circumscriptum simulating mela-noma. Arch Dermatol 1981;117:138–9. 5. Imperial R, Helwig EB. Angiokeratoma of the scrotum (Fordyce type). J Urol 1967;98:379–87. 6. Agger P, Osmundsen PE. Angiokeratoma of the scrotum (Fordyce). Acta Derm Venereol 1970;50:221–4. 7. Patrizi A, Neri I, Trevisi P, Landi C, Bardazzi F. Congenital angiokeratoma of Fordyce. J Eur Acad Dermatol Venereol 1998;10:195–6. 8. Bisceglia M, Carosi I, Castelvetere M, Nurgo R. Angiocheratomi multipli dello scroto, “tipo Fordyce.” Su un cado ad insorgenza iatrogena. Pathologica 1998;90:46–50. 9. Carrasco L, Izquierdo MJ, Fariña MC, Martín L, Moreno C, Requena L. Strawberry glans penis: a rare manifestation of angiokeratomas involving the glands penis. Br J Dermatol 2000;142:1256–7. 10. Novick NL. Angiokeratoma vulvae. J Am Acad Dermatol 1985;12:561–3. 11. Clark JR, Wheelock JB. Angiokeratoma of the vulva. A case report. J Reprod Med 1988;33:473–4. 12. Cohen PR, Young AW Jr, Tovell HM. Angiokeratoma of the vulva: diagnosis and review of the litera- ture. Obstet Gynecol Surv 1989;44:339–46. 92 Sangüeza and Requena / Pathology of Vascular Skin Lesions ... - tailieumienphi.vn
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