Background
Angiokeratoma corporis diffusum is the cutaneous hallmark of Fabry disease, an X-linked inherited disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A. Decreased or absent enzyme activity causes uncleaved glycosphingolipids to accumulate in various cell types, particularly in the vascular endothelium, smooth muscle cells, and pericytes, causing ischemia and infarction of tissues. Progressive accumulation of glycosphingolipids accounts for the associated clinical abnormalities of skin, eye, kidney, heart, brain, and peripheral nervous system. The Fabry disease gene is now known as the GLA gene, which stands for alpha-galactosidase. More than 370 GLA gene mutations have been cloned, all with a cytogenetic location of Xq22, located between base pairs 100,539,452 and 100,549,606. [1]
Angiokeratomas in Fabry disease typically appear in childhood or adolescence and present as small red-to-black papules that most commonly affect the bathing trunk area (buttocks, groin, umbilicus, upper thighs), although almost any area of the body can be involved. A high index of suspicion for Fabry disease should be noted, especially when angiokeratomas are seen with other earlier symptoms of the disease (acroparesthesia, hypohidrosis, or heat intolerance).
Angiokeratoma corporis diffusum is not unique to Fabry disease and has also been documented in several other rare lysosomal storage disorders such as fucosidosis, sialidosis, GM1 gangliosidosis, galactosialidosis, beta-mannosidosis, Kanzaki disease, and aspartylglucosaminuria. [2]
Additionally, angiokeratoma corporis diffusum has been described in individuals without any metabolic disease or any identified enzyme defect. [3, 4, 5]
Nucleoside sequencing of the entire GLA gene has enabled theoretical treatment of Fabry disease using recombinant technology.
Pathophysiology
Deficiency or absence of alpha-galactosidase A (α-GAL A) activity as a result of gene mutations in the GLA gene (Xq21.3-q22) leads to lysosomal accumulation of neutral glycosphingolipids, most notably globotriaosylceramide (G3b). These glycosphingolipids accumulate in many different types of cells. The most affected are the vascular endothelium and smooth muscle cells. Deposition of glycosphingolipids can be attributed to both endogenous production and diffusion of material from the circulation. As a result of the lack of this lysosomal enzyme that breaks down the glycolipid, persons with Fabry disease have 3-10 times the normal amount in their serum.
Glycosphingolipid deposits in lysosomes of endothelial, perithelial, and smooth muscle cells of blood vessels cause swelling into the blood vessel lumen. In so doing, the vessels are narrowed and reactively expand, which leads to ischemia and infarction of affected tissue. This process in the cutaneous endothelium causes angiokeratomas.
Accumulation of Gb3 in autonomic ganglia; dorsal root ganglia; renal glomerular, tubular, and interstitial cells; cardiac muscle cells; vascular smooth muscle cells; vascular and lymphatic endothelial cells in the cornea; valvular fibrocytes; and cardiac conduction fibers may lead to the myriad other manifestations of the disease.
Fabry disease is transmitted in an X-linked recessive pattern. The GLA gene is located at band Xq22. More than 370 gene mutations have been identified in people with Fabry disease. Most of these mutations are de novo, occurring in individuals or in a small number of families. Similar to other entities with this inheritance pattern, hemizygous males are most severely affected. Females are carriers of the disease and have diminished levels of alpha-galactosidase. Owing to random X inactivation, females may present with varying degrees of disease severity.
Persons with Fabry disease who have type AB or B blood also accumulate blood group B glycosphingolipids (those with alpha-galactosyl–terminated residues) and can have more severe Fabry disease (related to greater body substrate mass) than patients with blood group A. This is because these blood groups have two additional terminal alpha-galactosyl moieties.
Researchers found increased serum levels of vascular endothelial growth factor-A (VEGF-A), an endothelial cell mitogen, in 35 patients with angiokeratoma corporis diffusum (Fabry disease) versus matched controls, suggesting VEGF-A might be involved with vascular damage in angiokeratoma corporis diffusum (Fabry disease); however, additional research is needed to clarify the significance of this finding. [6]
Molho-Pessach et al, [7] in 2007, reported a 36-year-old Arab woman with beta-mannosidosis who presented with intellectual disability and multiple angiokeratomas with a novel null mutation involving a G→A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X).
Etiology
A defect in the activity of alpha-galactosidase, a lysosomal enzyme, results in the insidious storage of neutral glycosphingolipids, most notably globotriaosylceramide (G3b). Angiokeratoma corporis diffusum is inherited in an X-linked recessive pattern.
Epidemiology
Frequency
Angiokeratoma corporis diffusum (Fabry disease) is rare. The incidence of Fabry disease has been estimated at 1 case in 40,000 to 1 case in 117,000 live births. These numbers may be underestimates, as milder variants of the disease are not always diagnosed. [8]
In an analysis of data from the Fabry Outcome Survey database of 714 patients, 66% of males and 36% of females with Fabry disease presented with angiokeratomas. Skin manifestations of Fabry disease are associated with more severe systemic disease. [9]
Race
There is no known predilection of Fabry disease for any specific race or ethnicity.
Sex
Because angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease, only men are fully afflicted. Heterozygous women, in addition to transmitting the condition, may develop symptoms.
Age
In males, signs and symptoms of angiokeratoma corporis diffusum (Fabry disease) begin in late childhood or adolescence. By age 20-29 years, most affected men experience the full brunt of the disease. Heterozygous women first note symptoms by age 20 years to early 30 years. The median cumulative survival of hemizygous men with Fabry disease is 50 years, compared with 70 years for females.
Prognosis
Fabry disease can be divided into a classic phenotype, seen in patients without residual enzyme activity, or into milder nonclassic variants, seen in patients with some residual enzyme activity. Classic Fabry disease has long-term complications such as hypertrophic cardiomyopathy, cardiac arrhythmias, renal failure, and stroke. Nonclassic Fabry disease has a more variable disease course in which patients are less severely affected and symptoms may be limited to a single organ.
In the past, renal failure was the major cause of death in men with Fabry disease. The increased availability of renal replacement therapy (long-term dialysis or kidney transplantation) over the past several decades has extended the lifespan of Fabry patients. Consequently, mortality from renal failure has decreased, and cardiovascular disease is now the most common cause of death among Fabry patients. [8, 10]
Based on a 2009 study using data from 2848 patients in the Fabry Registry, life expectancy of Fabry males was 58 years, compared with 75 years in the general US population. Life expectancy in Fabry females was 75 years, compared with 80 years in the general US population. Patients in the Registry who died from Fabry disease were diagnosed with the disease at a later age, which likely allowed the disease to progress, contributing to their earlier deaths. [8] Enzyme replacement therapy slows the progression of disease, but its exact impact on life expectancy still needs to be studied.
Heterozygous women have a longer lifespan with the disease because if they develop renal and cardiac symptoms, they do so later in life. Heterozygous females develop angiokeratomas and cataracts and experience a milder clinical course.
A variety of clinical findings occur in female carriers. The scope is vast and ranges from asymptomatic carriers to carriers with fully expressed Fabry disease. Asymptomatic corneal dystrophy occurs in approximately 70% of carriers. This is an indication of the carrier state. Approximately 30% of female carries have angiokeratomas, with less than 10% having paresthesias. A 2004 study by Larralde et al [11] of obligate female carriers found significant disease manifestations in 20 of 60 women. Another study performed on 20 carriers of Fabry disease showed that each woman had some symptom of Fabry disease, with a wide scope of manifestations. Larralde et al [11] concluded that Fabry disease might be designated a storage disease transmitted as an X-linked–dominant, not X-linked–recessive, disease.
Hormonal function and fertility rates are normal in both male and female Anderson-Fabry patients compared with controls.
Patient Education
Genetic counseling is urged. Both affected men and heterozygous women can transmit the gene. Sons of affected men are free of the gene, but daughters can pass the gene to future generations. In the offspring of heterozygous women, 50% of male children may have the disease and 50% of female children may become carriers.
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Angiokeratomas are commonly observed as dense cluster of lesions on the flank and private areas.
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Angiokeratoma is the small punctate reddish-to-bluish angiectases on the umbilicus.
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Corneal verticillata, commonly seen in patients with Fabry disease, detectable by slit lamp examination
