Angiokeratoma: decision-making aid for the diagnosis of Fabry disease

Abstract

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: Data from individual patients and family studies

“…As that woman also manifested angiokeratoma(s?) and albuminuria, GLA p.(Arg118Cys) was considered pathogenic, but the investigators did not provide histopathological evidence of FD cardiomyopathy or nephropathy, and the clinical observation of angiokeratoma(s) is inconclusive, since the presence of isolated or a few scattered angiokeratomas is not uncommon in otherwise healthy individuals [45]. In contrast to these results, the GLA p.(Arg118Cys) variant was not identified in any of 279 male patients with HCM screened for FD in a French case-finding study [38], neither in any of 508 non-selected patients (328 males, 64.6%) with HCM screened for FD in a Spanish case-finding study [46], using plasma α-Gal activity as the screening method; however, it is of note that three unrelated men in this cohort were hemizygous for the GLA Tyr313 allele.…”

Mutation identification of Fabry disease in families with other lysosomal storage disorders

“…Cryptogenic early-onset stroke and multiple sclerosis can be erroneously diagnosed in patients recognized to be suffering from FD later in life (16). Angiokeratomas are skin lesions also described in other LSDs, including sialidosis, galactosialidosis, adult form of gangliosidosis GM1, aspartylglucosaminuria (AGA) and fucosidosis, this latter disease being known to affect other members of the same family (18). Since 2001, as a consequence of the availability of the specific ERT, screening for FD has been extended to patients with LVH and to patients with history of early stroke, apparently without other risk factors, and this has increased the diagnosis of FD (17).…”

Anderson-Fabry, the Histrionic Disease: From Genetics to Clinical Management

“…38 Angiokeratoma is another early feature of AFD. 39 Small purple skin lesions may be present in children and tend to increase in size and number with age. They can be found typically on the lower back, thighs, genital areas, umbilicus and sometimes on mucosae ( Figure 3).…”