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

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.

Late-onset Fabry disease associated with angiokeratoma of Fordyce and multiple cherry angiomas.

Fabry disease (FD) is a lysosomal storage disorder. The prevalence and clinical spectrum is higher than previously thought. The average time between onset of symptoms and diagnosis is 10 years. Early identification of patients is essential to institute enzyme therapy and reduce morbidity. We report the case of a 76-year-old man, who presented with loss of consciousness following exertional chest pain. He was found to have tortuous corneal vessels, > 100 cherry angiomas on his trunk, and angiokeratomas on his scrotum. The latter were indistinguishable from angiokeratoma of Fordyce, a diagnosis reported in 15% of men over the age of 50 years, and generally ignored by them. The patient's α-galactosidase levels were low, and a mutation in exon 5 of the GLA gene was identified on DNA analysis, confirming the diagnosis of FD. This case highlights the importance of considering a diagnosis of FD in all male patients with angiokeratoma. It also raises the question of whether the presence of multiple cherry angiomas in patients with cardiac disease should raise the possible diagnosis of FD.

[Evaluation of patients with Fabry disease in Argentina]. / Evaluación de pacientes con enfermedad de Fabry en la Argentina.

Fabry disease is an X- linked lysosomal disorder due to deficient activity of the enzyme alpha galactosidase A which leads to multisystemic storage of globotriaosylceramide with neurologic, gastrointestinal, cardiac, renal, skin and ophtalmological involvement. Recent studies indicate that heterozygous females develop symptoms similar to the males, but comparative information regarding the relative frequency of clinical manifestations, age of onset and severity of the disorder between males and females with Fabry disease is not available in Argentina. We identified 59 symptomatic adult patients with Fabry disease: 32 males (mean age 34.8 years) and 27 females (mean age 46.6 years). Diagnosis was made by enzymatic analysis in males and by genetic studies in females. We compared the frequency and severity of the clinical manifestations in females and males with this disease. The most frequent manifestations were: acroparesthesias, angiokeratomas, hypohydrosis (all them were significantly more frequent in males than in females, as well as the severity of symptoms), and cornea verticillata. Proteinuria and ventricular hypertrophy were frequent findings both in males and females. There was a delayed latency between age at onset and age at diagnosis in our group: 14 years for men and 30 years for females. Fabry disease is an underdiagnosed and potentially fatal disorder that affects both sexes. The availability of enzyme replacement therapy should stimulate the identification of signs and symptoms suggestive of this disorder, to allow earlier diagnosis and treatment.

Angiokeratomas and treatment with enzyme replacement therapy in a patient with Fabry disease.

Angiokeratomas are the cutaneous hallmark of Fabry disease. Although it is well established that enzyme replacement therapy (ERT) prevents or slows the progression of disease on target organs in the majority of patients, the long-term effect of ERT on angiokeratomas remains unknown. We present a patient diagnosed with Fabry disease at age 11, with rapid progression of new angiokeratomas in typical regions before beginning treatment with ERT. To date, our patient has been treated with ERT for 10 years. During the treatment period, new angiokeratomas have not arisen nor have existing ones enlarged during puberty, adolescence, and early adulthood. Furthermore, partial regression of the angiokeratomas has occurred in association with regression of left ventricular hypertrophy and anhidrosis. Overall, this case suggests that long-term ERT could stop the progression of angiokeratomas and induce their partial regression but does not produce complete resolution. Importantly, regression of angiokeratomas might be a marker of systemic target-organ efficacy of ERT.

Case study: the surgical management of angiokeratoma resulting from radiotherapy for penile cancer.

Angiokeratoma is a rare, benign skin lesion and a recognised complication of radiation therapy. Here we describe a case of extensive angiokeratoma of the groin and external genitalia resulting from external beam radiation to that area in a patient with penile carcinoma. Furthermore, we outline the management of this problem by surgical reconstruction.

Angiokeratomas, not everything is Fabry disease.

INTRODUCTION: Angiokeratoma corporis diffusum are benign capillary malformations typically associated with Fabry disease and other lysosomal storage disorders. Only in a few cases they appear in healthy individuals. METHODS AND CASE: We carried out an exhaustive review of the literature on angiokeratomas and their main clinical, dermoscopy and histological features. Additionally, we reviewed the cases of healthy subjects illustrating the limitations of each case and comparing these results with our case. DISCUSSION: Angiokeratoma corporis diffusum is mostly related to Fabry disease and other lysosomal storage disorders. However, some cases may occur in apparently healthy individuals. Therefore, there is a increasing interest in its etiology, pathogenesis and clinical evaluation. CONCLUSION: This is an academic-clinical review on angiokeratomas and their main implications in daily dermatological practice. Additionally, we report the first case in the literature of angiokeratoma corporis diffusum in a healthy patient with up-to-date laboratory methods currently available. The clinician should remember that not all angiokeratoma corporis diffusum occurs with lysosomal storage disorders.

[Molecular pathology and clinical manifestations of Fabry disease]. / A Fabry-kór molekuláris patológiája és klinikai megjelenési formái.

Fabry disease is a rare, progressive lysosomal storage disorder caused by mutation in the GAL gene and an impaired function of the alpha-galactosidase A enzyme. The enzymatic defect results in the progressive accumulation of glycosphingolipids in endothelial cells, smooth muscle cells, leucocytes and fibroblasts leading to organ damage in the skin, eye, nervous system, kidney and heart. Major clinical manifestations include acroparesthesis, angiokeratoma, corneal opacities, vascular diseases of the heart, kidney, and the central nervous system. Enzyme replacement therapy has recently become available for the treatment of Fabry patients. In this review the authors describe clinical features of Fabry disease in 31 Hungarian patients. At the time of this analysis the database consisted of 31 cases (15 males, 16 females) of whom 5 have died (4 males, 1 female). The most common disease-specific manifestation was angiokeratoma in males, and eye symptoms in females. 25% of female subjects were symptom free. Genotyping was performed in all cases and disease-causing mutations were found in all families. Three new mutations were identified. Twelve patients (8 males and 4 females) are currently receiving enzyme replacement therapy.

Clinical and molecular characterization of an extended family with Fabry disease.

OBJECTIVE: To characterize clinical manifestations, biochemical changes, mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA), and functional capability of mutant protein. MATERIAL AND METHOD: Seventeen subjects from a family with a newly diagnosed patient with Fabry disease were enrolled in the present study. In each individual, clinical history, physical examination, leukocyte enzyme activity of alpha-Gal A, and mutation analysis were performed. Those with a mutation were further investigated by ophthalmological and audiological evaluations, electrocardiography, echocardiogram, urinalysis, and blood tests to determine renal insufficiency. Expression study of the mutant protein was performed using a Pichia pastoris expression system. RESULTS: Four affected males and five symptomatic female carriers were identified. Clinical manifestations included severe neuropathic pain, acroparesthesia, hypo-/hyper-hidrosis, frequent syncope, ischemic stroke, cardiac hypertrophy, corneal dystrophy and cart-wheel cataract, high frequency sensorineural hearing loss, periorbital edema and subcutaneous edema over hands and interphalangeal joints. None had angiokeratoma or renal symptoms. The authors identified a novel mutation, p.L106R, in the GLA gene. Recombinant expression of the mutant protein gave little or no enzyme activity compared to the normal protein. CONCLUSION: There were intrafamilial clinical variabilities, but consistent findings of the absence of angiokeratoma and renal symptoms, which could represent a unique feature of this particular mutation.

The impact of fever/hyperthermia in the diagnosis of Fabry: A retrospective analysis.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A enzyme, which leads to the accumulation of its substrate, the globotriaosylceramide or Gb3, in many organs and tissues. Main clinical manifestations of FD are neuropathic pain, angiokeratomas, proteinuria and renal failure, left ventricular hypertrophy and stroke. Fever is also a possible symptom at the onset of the disease during childhood and adolescence, but it is frequently misdiagnosed, causing a delay in FD diagnosis. METHODS: We retrospectively analysed the medical records in our series of 58 Fabry patients, focusing on the proportion of patients who exhibited fever as the main symptom at the onset of FD in order to evaluate the diagnostic delay in these patients. FINDINGS: In our series, we found a significant proportion of patients with a history of fevers at the beginning of their medical history (20.7%; 12/58). 83% of patients with fever also exhibited acroparesthesias (10/12). Inflammatory markers were elevated in few of those cases (2/12). The mean diagnostic delay was 15.6±SD 12.8years. INTERPRETATION: Fever emerged to be common as part of the FD clinical spectrum and it significantly contributed to the diagnostic delay encountered with this rare disease. Furthermore, our retrospective analysis indicated that FD patients commonly exhibit episodes of fever in association with other symptoms suggestive of FD (such as episodic pain crisis, acroparesthesias, hypo/anhydrosis, heat intolerance, fatigue and gastrointestinal distress). A careful analysis of the medical history in patients suffering fever could lead to an early and correct FD diagnosis. We believe that fever/hyperthermia, acroparesthesias and angiokeratoma should be considered for inclusion in the algorithm for Intermittent Fever of Unknown Origin (FUO) in order to improve the recognition of FD.

Argon laser therapy of vulvar angiokeratoma.

A 25-year-old woman with Noonan syndrome presented with painful, bleeding lesions of the vulva and perineum. The histologic diagnosis was angiokeratoma. Chronic increased central venous pressure from the patient's underlying cardiac disease was felt to be etiologic. The Argon laser was used for ablation, with minimal blood loss despite the extreme vascularity of these lesions.

Fabry disease: recognition and management of cutaneous manifestations.

Fabry disease (angiokeratoma corporis diffusum universale) is a rare, X chromosome-linked lysosomal storage disease. The deficient enzyme, alpha-galactosidase A (alpha-gal A), is responsible for the accumulation of neutral glycosphingolipids within vascular endothelial lysosomes of various organs, including skin, kidneys, heart, and brain. The disease manifests primarily in affected hemizygous men and to some extent in heterozygous women ('carriers'). The diagnosis of Fabry disease is made in hemizygous males after the detection of the presence of angiokeratomas, irregularities in sweating, edema, scant body hair, painful sensations, and of cardiovascular, gastrointestinal, renal, ophthalmologic, phlebologic, and respiratory involvement. A deficiency of alpha-gal A in serum, leukocytes, tears, tissue specimens, or cultured skin fibroblasts further supports the diagnosis in male patients. Since heterozygous women show angiokeratomas in only about 30% of cases and may have alpha-gal A levels within normal range, genetic analysis is recommended. Current treatment of angiokeratomas of Fabry disease is based mainly on the use of laser systems, including variable pulse width 532nm Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) laser, 578nm copper vapor laser, and flashlamp-pumped dye laser. When cutaneous and mucous glands are affected, restrictions may be required with regard to the time spent in a warm climate and the amount time spent working or on sporting activities, and may necessitate the use of topical and systemic antiperspirant agents, and topical application of artificial lacrimal fluid and saliva, respectively. For the future, new treatment modalities, including enzyme replacement therapy, substrate deprivation strategies, and gene therapy offer extraordinary options for the cutaneous and visceral lesions in patients with Fabry disease.

Oral and craniofacial findings in Fabry's disease: a report of 13 patients.

OBJECTIVE: Fabry's disease is an X-linked metabolic disease caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. The purpose of this study was to assess oral and craniofacial findings in a cohort of patients with Fabry's disease to facilitate recognition of this condition and early treatment of its manifestations. STUDY DESIGN: This is a case series describing oral and craniofacial findings of 13 male patients diagnosed with Fabry's disease. Data were collected by means of a standardized questionnaire, clinical examination, panoramic and cephalometric radiographs, and magnetic resonance imaging. RESULTS: A variety of abnormalities are described, including an increased prevalence of cysts/pseudocysts of the maxillary sinuses (PCMs) and the presence of maxillary prognathism. CONCLUSION: Given the high prevalence of oral and dental abnormalities, we recommend a thorough stomatologic evaluation of these patients.

Fabry's disease presenting as syncope, angiokeratomas, and spoke-like cataracts in a young man: discussion of the differential diagnosis.

A 44-year-old male with a remote history of skin lesions and cataracts presented with subacute onset of syncope. The presentation and the differential diagnosis in this case of Fabry's disease are discussed. The pathophysiology, diagnosis, clinical manifestations, and treatment of this disorder are discussed, with a review of the literature. Fludrocortisone acetate therapy resulted in a reduction in the patient's syncopal event frequency. Serum enzymatic assay and skin biopsy are useful in the diagnosis of Fabry's disease. We advocate a conservative approach to the oculocutaneous symptoms and suggest appropriate interventions for the renovascular and autonomic nervous system complications of this disorder.

[Angiokeratoma and fucosidosis. Immunohistochemical and ultrastructural study]. / Angiokératomes et fucosidose. Etude immunohistochimique et ultrastructurale.

INTRODUCTION: Angiokeratoma can lead to diagnoses other than Fabry's disease. We report a case of angiokeratoma in a child with fucosidosis. CASE REPORT: A 7-year-old child with psychomotor retardation presented angiokeratoma located on the penis. Uptake of type I Ulex Europaeus Agglutinin antilectin antiserum was intense in the endothelial structure. This antibody is specific for alpha-L-fucose residues which were thus found in large quantities in the vacuoles of the ultrastructure. The patient also had a major deficiency in leukocyte, serum and fibroblast alpha-fucosidase. COMMENTS: This is a typical case of fucosidosis, a rare hereditary disease with autosomal recessive transmission due to generalized deficiency in alpha-L-fucosidase. Diffuse angiokeratosis should suggest, other than Fabry's disease, fucosidase and other enzyme deficiencies including sialidase, GM1 gangliosidase as well as Kanzaki's disease.

Angiokeratomas - When is a few too many?

Many patients have a few scattered angiokeratoma and we reassure them that this it is normal; however, if they are numerous, Fabry disease should be considered and the family history should be checked.

Cutaneous complications of Anderson-Fabry disease.

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a defect in the α-galactosidase A gene, which leads to the deficiency of the hydrolytic enzyme α-galactosidase A. The consequent inability to catabolize glycosphingolipids causes progressive accumulation of globotriaosylceramide in the vascular endothelium throughout the body. Fatalities in the classical phenotype may usually occur as a consequence of cerebral, cardiac or renal disease. Dermatological manifestations are a relevant feature of Fabry disease and include angiokeratomas, telangiectasiae, lymphedema, anhidrosis or hypohidrosis and pseudo-acromegalic facial appearance. The actual causal treatment for Fabry disease is the enzyme replacement therapy. Dermatologists have a key role, since cutaneous manifestations may lead to the diagnosis. This may help an early therapeutic intervention, reducing both morbidity and mortality.