An overlooked cutaneous manifestation of Fabry disease: Lower‐extremity ulcers

Abstract

Dear Editors, Fabry disease (FD) is an X-linked recessive disorder characterised by decreased activity of alpha-galactosidase A enzyme and results in lysosomal accumulations of neutral glycosphingolipids and globotriaosylceramide GL-3. It is a multi-systemic disease with different clinical presentations depending on the partial or complete loss of alphagalactosidase A activity. A wide spectrum of organs, including the skin, the eye, the kidney, the heart, the brain, and the peripheral nervous system, can be involved. Among all these organs, cutaneous findings such as hypo/hyperhidrosis, angiokeratomas, and telengiectasias are well-known manifestations of FD. Here, we report a case of FD with lower-extremity ulcers, and we would like to emphasise this rare cutaneous manifestation that might be easily overlooked. Lower-extremity ulcers seen in the course of FD should be taken into account in the differential diagnosis. A 39-year-old man presented to our dermatology clinic with multiple foot ulcers for 2 years. He reported that cold was one of the trigging factors for the development of ulcers and that the ulcers healed after winter. On dermatological examination, 5 to 10 relatively shallow, scattered ulcers were found on the dorsal and plantar sides of the toes on both feet. The diameters of the largest ulcers were approximately 2 cm and were located on the plantar surfaces of both the big toes (Figure 1). Four years ago, he had been diagnosed with FD and was started on enzyme replacement therapy. He also had left ventricular hypertrophy, mild mitral insufficiency, proteinuria, and anaemia related to FD. Other cutaneous findings, such as hypohydrosis, telengiectasias on the nose and multiple angiokeratomas distributed over the lower trunk and abdomen, were noted on dermatological examination (Figure 2). For differential diagnosis of lower-extremity ulcers, a skin biopsy was performed. Histopathological examination did not show any characteristic features of vasculitis, but it demonstrated ulceration, epidermal ischaemic changes, and chronic mixed-cell infiltration in the upper dermis. Laboratory parameters for vasculitis, including complement 3, complement 4, antinuclear antibody, extractable nuclear antibody, perinuclear antineutrophilic cytoplasmic antibody, and cytoplasmic antineutrophilic cytoplasmic antibody, were found at normal levels. In addition, the diagnosis of diabetic foot ulcer was ruled out by normal fasting blood glucose and haemoglobin A1c levels. Doppler ultrasonography to check for any vascular insufficiency of the arteriolar and venous system did not show any abnormalities. Based on this medical history and clinical findings, a diagnosis of FD-related lower-extremity ulcers was made. In the literature, there are a few case reports about FDrelated lower-extremity ulcers. It is not clear which pathogenetic mechanisms play roles in the development of these ulcers. Okada et al. reported a patient with multiple leg ulcers that were refractory to enzyme replacement therapy, and they were able to show venous reflux and varices on the leg venography of their patient. They identified lysosomal deposition of glycosphingolipid as a zebra body in vascular smooth muscle cells and a few accumulations in the vascular endothelium on electron micrograph of the venous biopsy. Unlike our Doppler ultrasonography findings, their venography and electron microscopy findings supported a baseline vascular insufficiency in the aetiology of the ulcers. Nakai et al suggest that lamellar electron-dense inclusion bodies in both the endothelial cells and the pericytes of the dermal blood vessels may lead to vascular permeability and stasis ulcers in FD. Unlike their hypothesis, the absence of pedal or ankle oedema in our patient and the unusual localisation of the ulcers on the toes, other than the expected localisations for venous ulcers, suggest that a different mechanism might be responsible in the development of the cutaneous ulcers in our patient. It is well known that thromboembolic events are more common among individuals with FD. Cerebrovascular disease resulting primarily from multifocal small vessel involvement and thrombosis have been reported. Likewise, ischaemic changes observed on the histopathological examination in our patient are in concordance with thromboembolic micro-occlusion theory. Received: 18 February 2019 Accepted: 20 February 2019