Angiokeratomas

Cottle, 1879; Mibelli, 1889; Fordyce 1896; Fabry 1915; Crow 1980; Ramsay 1988; Anderson 1898; Fabry 1898; Durand 1966; Wenger 1986; Jenner & Pollitt 1967

• Angiokeratoma

The umbrella term angiokeratoma describes a heterogeneous entity of congenital or acquired haemangiomas or vascular ectasias. The hyperkeratosis presumed by the name is, however, not always present and thus not alone decisive for the clinic. A uniform aetiology is also lacking. Histologically, everything from capillary to cavernous haemangioma to a mixed picture can be seen. The vulvar or scrotal variant (angiokeratoma scroti et vulvae) is a vascular ectasia. Angiokeratomas can also occur as a dermatological symptom in various underlying diseases

• Angiokeratoma Mibelli:
  • Affected are mainly cold-intolerant, vagotonic female patients with a predisposition to acrocyanosis and chilblains
  • First manifestation usually between the ages of 10 and 15 years.
  • Females usually develop the disease later than males.
• Angiokeratoma scroti et vulvae (Fordyce) :
  • Frequently occurring in older age
  • Lesions of the vulva may be favoured by varicosis, haemorrhoids, oral contraception or increased venous pressure during pregnancy.
• Angiokeratoma circumscriptum:
  • Mostly women are affected. m:f = 1:3.
  • Mostly congenital skin lesion, rarely develops in childhood.
  • Frequently occurring together with nevus flammeus, veinctasia and osteohypertrophy as a symptom of a complex venous malformation.
  • If applicable, it is a minimal variant of verrucous angioma.
• Acral pseudolymphomatous angiokeratomas of childhood:
  • Rare. Few case reports exist.
  • Peak between 3-17 years of age. Rarely first manifestation in adulthood.
• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency):
  • Incidence: 1/3,100 live births, 1:40,000 individuals.
  • Skin manifestation in about 70% of patients.
  • First manifestation in childhood or adolescence, in the late-onset variant from the age of 45.
• Fucosidosis:
  • Very rare.
  • Manifestation in 1-3 years of age.
  • Incidence unclear.
• Beta-mannosidosis:
  • Very rare.
• Aspartylglucosaminuria:
  • Excessively occurring in Finland.
  • Sporadically described in Central Europe or North America.
  • Manifestation in childhood.

The umbrella term angiokeratoma is used to describe multiple clinical pictures:

• Angiokeratoma mibelli
• Angiokeratoma scroti et vulvae (Fordyce)
• Solitary angiokeratoma
• Multiple (non-syndromal) angiokeratomas (Calzavara-Pinton)
• Angiokeratoma circumscriptum
• Acral pseudolymphomatous angiokeratomas of childhood

Angiokeratomas are also seen in the following underlying diseases:

• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency)
• Fucosidosis
• Beta-mannosidosis
• Aspartylglucosaminuria

• Angiokeratoma Mibelli:
  • Rare, autosomal-dominant hereditary condition with variable penetrance, particularly affecting females.
• Angiokeratoma scroti et vulvae (Fordyce):
  • Unclear.
  • Varicoceles and the associated increased venous pressure are discussed as triggers.
  • Strictly speaking, the term angiokeratoma is not applicable here, since it is a matter of vascular ectasia, as can be observed in other localisations.
• Solitary angiokeratoma:
  • Not conclusively established as a distinct entity.
  • Perhaps monotopic variant of angiokeratoma circumscriptum.
• Angiokeratoma circumscriptum:
  • Capillary or capillary-lymphatic malformation.
  • Possible autosomal dominant inherited disorder, RASA1 or KRIT1 are discussed.
• Acral pseudolymphomatous angiokeratomas of childhood:
  • Hitherto unknown.
  • A traumatic genesis is possible.
  • A clear assignment to angiokeratomas is uncertain.
• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency):
  • X-linked recessive lysosomal storage disease.
  • Deficiency of the enzyme galactosidase-A in the lysosomes due to mutation of the alpha-galactosidase A gene (alpha GAL) located at gene locus Xq22, with resulting defect in glycosphingolipid metabolism.
  • Vascular endothelial accumulation of glycosphingolipids, especially globotriaosylceramides and galabiosylceramides, occurs
  • Deposition can also be observed to a lesser extent in other body cells such as perithelial or muscle cells.
  • Women often show later and less pronounced symptoms due to their genetic mosaic, as the X chromosome is non-functional in some body cells, but switched on in others.
• Fucosidosis:
  • Rare, autosomal recessive inherited disease involving the absence of the enzyme alpha-L-fucosidase localised in the lysosomes, resulting in reduced breakdown of oligosaccharides.
  • Mutation of the FUCA gene on chromosome 1p34.
• Beta-mannosidosis:
  • Autosomal recessive inherited condition with almost complete absence of the lysosomal enzyme beta-mannosidase due to a mutation at gene locus 4q22-25.
• Aspartylglucosaminuria:
  • Autosomal recessive inherited dysfunction of aspartyl glucosaminidase localised to 4q32-q33 with consecutive lysosomal storage disease (sphingolipidosis). This leads to the deposition of glycoproteins in the lysosomes of cells of the vascular intima as well as neuronal cells.

• Angiokeratoma Mibelli:
  • Initially dark to grey-red, macular, progressively blue, papular excoriations.
  • Facially firm, yellowish, verrucous surface.
  • Pinhead- to lentil-sized.
  • Symmetrical, loose sowing.
  • Accompanied by acrocyanosis and frostbite.
  • Rarely ulceration of the tips of the fingers or toes.
• Angiokeratoma scroti et vulvae (Fordyce):
  • Isolated or multiple circumscribed extension of blood vessels with scrotal or vulvar localisation, rarely also occurring on the glans penis, with disseminated character or along the corona glandis in groups.
  • Papules or vesicles with mostly smooth surface. Rarely, this also presents as warty or scaly. Erosions are possible.
  • Initially bright, in the course deep red, blue-red or black-red colouring.
  • Pinhead- to lentil-sized.
  • There may be bleeding or oozing of the skin symptoms.
  • No growth progression.
  • May be associated with thrombophlebitis, varicocele or inguinal hernia.
• Solitary angiokeratoma:
  • Solitary fielded papule or nodule.
  • 0.2 - 1cm in size.
  • Initially bright red colouring and soft texture, increasing dark red to black colouring as it progresses and marked increase in hardness accompanied by the formation of a hyperkeratotic surface.
  • Local thrombosis may lead to a sudden change in colour or increase in size.
• Angiokeratoma circumscriptum:
  • Mostly occurring unilaterally on the extremities, solitary or multiple, solitary or confluent, bright to purplish-red plaque or nodules.
  • In the case of thrombosis, a blue, black-red or black colouring is also seen within the angiokeratoma itself.
  • Surface verrucous-keratotic or smooth.
  • Solitic excoriations are usually only a few centimetres in size, but in confluence they can be as large as the palm of the hand and rarely include entire extremities.
  • A linear arrangement is possible.
  • Without further symptomatology.
• Acral pseudolymphomatous angiokeratomas of childhood:
  • Multiple occurrences of solitary or grouped, reddish-livid papules ranging in size from 0.1 - 0.3 cm.
  • A slight scaling can often be seen.
• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency):
  • In childhood, there is initial diffuse pain, paresthesias of the extremities with onset on the soles of the feet and palms of the hands, angiokeratomas and hypohidrosis
  • In 70% of patients, the integument is affected. Here, multiple purplish-red to black-blue papules or macules appear, which are symmetrically distributed and have a size of 1-3mm. They may confluence. Hyperkeratosis may occur. They cannot be removed diascopically. The skin symptoms can be very discrete, especially in women. Particular attention should be paid to the nail fold. Tuft-like branching may be the precursor of an angiokeratoma. Perioral telangiectasia is typical for Fabry disease
  • In the course of the disease, cardiac insufficiency occurs in the context of hypertrophic cardiomyopathy, conduction disorders, renal insufficiency accompanied by hypertension as well as cerebro-vascular and myocardial insults or angina pectoris
  • In 80%, there is a cornea verticillata, in which swirl-shaped, yellow-brown lines clouding the cornea can be seen. The deposits are subepithelial. Aneurysms of the retinal vessels and an ampullary deformation of the veins are seen on ophthalmoscopic examination
  • Neurological abnormalities include, in addition to the early onset of paraesthesia, a temperature-dependent pain exacerbation in the extremities (acroparaesthesia), which shows a clear regression from the age of 30. In addition, there are headaches, paresis and intracranial haemorrhages
  • Episodic vasospasm of the acras, similar to Raynaud's syndrome is possible.
  • Peripheral oedema and/or lymphoedema may be present.
  • The gastrointestinal tract, lungs and musculoskeletal system may also be affected. This is manifested by symptoms such as pain, vomiting, diarrhoea, dyspnoea, chronic cough, wheezing or osteopenia.
  • Diminished body hair has been described in some cases.
  • There is debate about classic facial features in men affected by Fabry disease. These include bushy eyebrows, broad forehead and broad bridge of the nose as well as thick lips, prominent earlobes or prognathism.
• Fucosidosis:
  • There are 3 types according to the dominant clinic, although symptoms of the other types may also be present:
    • Type I: Primarily neurologically dominated clinic.
    • Type II: Primarily skeletal involvement.
    • Type III: Cutaneous manifestation with angiokeratomas.
  • Angiokeratomas develop mainly between the ages of 10 and 20 (< 10 years in 33%, < 20 years in 85%)
  • Other cutaneous abnormalities may include xerosis cutis, thin skin, acrocyanosis and nevus anemicus
  • Facial dysmorphia, organomegaly, dystosis multiplex, neurological disorders with mental retardation, corneal opacities, retinal vascular changes, and growth disturbances occur.
  • Excessive sinus and lung infections.
• Beta-mannosidosis:
  • Angiokeratomas as a cutaneous symptom.
  • Other symptoms include: increased infections esp. pyoderma, mental retardation, hearing loss, facial dysmorphia, skeletal deformities, and hepatospelonomegaly.
• Aspartylglucosaminuria:
  • Cutaneous manifestation in the setting of cutis laxa, acne, photosensitivity and generally thickened skin. Angiokeratomas occur only rarely.
  • Already in childhood, the patient develops dementia.
  • Further symptoms are short stature, coarse facial features, hernias, recurrent airway infections and arthritides.

• Angiokeratoma Mibelli:
  • Clinical
  • Family history
• Angiokeratoma scroti et vulvae (Fordyce):
  • Clinical
  • If necessary, histological confirmation of diagnosis
• Solitary angiokeratoma:
  • Clinic
• Angiokeratoma circumscriptum:
  • Clinic
• Acral pseudolymphomatous angiokeratomas of childhood:
  • Clinic
• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency):
  • Anamnesis:
    • Inquire about temperature elevation on physical exertion and increased sensitivity to change in ambient temperature as signs of hypohidrosis.
  • Clinic
  • Eye examination by slit lamp
  • Laboratory:
    • Determine globotriaosylceramide (Gb3) in blood and urine
    • Supplementary α-galactosidase A activity can be determined in leukocytes, serum and/or tear fluid
    • In hemizygotes, evidence of absent or very low enzyme activity
    • In heterozygous women, there may be only slightly impaired enzyme function. However, this does not exclude a clinic, since in female patients it is always also a genetic mosaic with affected and healthy cells
    • Polymorphisms without disease value are possible.
  • Urine and urine sediment:
    • Microhaematuria (already occurring in childhood)
    • Proteinuria
    • Isosthenuria
    • Maltese cross (sediment)
  • Capillary microscopy
    • Tufted branching in 2 to 5 loops of visible capillaries
    • Moderate plexus visibility (plexus score 2 according to Maricq)
    • Similar picture to collagenosis
    • This examination can provide an indication of systemic vascular changes, which do not necessarily have to be accompanied by lipid deposition.
  • Bone marrow biopsy (macrophage changes)
  • Renal biopsy, if necessary
  • Molecular genetic analysis
  • Pränatal diagnostics:
    • Chorionic villus biopsy in 10th-12th SSW
    • Amniocentesis in 15th-18th SSW
• Fucosidosis:
  • Clinical
  • Salt concentration in sweat is elevated.
  • Oligosaccharide analysis of urine. (For a definitive diagnosis, the enzyme deficiency must still be proven.)
  • The enzyme deficiency is detected in cell cultures of fibroblasts and leucocytes.
  • No differentiation from Fabry disease is possible by light microscopy.
  • Pränatal diagnosis:
    • Chorion villus biopsy in 10th-12th SSW
    • Amniocentesis in 15th-18th SSW.
• Beta-mannosidosis:
  • Clinical
  • Serum ß-mannosidosis level
  • Elevated urinary mannosyl(1-4)-N-acetylglucosamine and heparan sulphate.
• Aspartylglucosaminuria:
  • Clinical
  • Bone marrow aspiration to detect vacuolated lymphocytes and memory cells.

• Angiokeratoma Mibelli:
  • Acra, esp. dorsum of hand, dorsal and lateral side of fingers and toes.
  • External lower quadrant of the mamma.
  • Incurrence on elbows and knees may occasionally be observed.
• Angiokeratoma scroti et vulvae (Fordyce) :
  • Vulva
  • Scrotum
  • Rarely glans penis
  • Occurrence along superficial vessels
• Solitary angiokeratoma:
  • Mostly lower extremity
• Angiokeratoma circumscriptum:
  • Frequently lower extremity
  • Rare strain
  • Mostly unilateral localisation
• Acral pseudolymphomatous angiokeratomas of childhood:
  • The acras (hands and feet) are particularly affected
  • Rarely, the skin change occurs on the back, chest or lower legs.
• Angiokeratoma corporis diffusum (Fabry disease - alpha galactosidase deficiency):
  • Navel region as a leading symptom
  • Perioral, without other involvement of the facial skin
  • Otherwise gluteal, genital, scrotum, trunk
  • Rarely, there is manifestation in the extremities or involvement of the oral mucosa and conjunctiva
• Fucosidosis:
  • Torso
  • Lower extremities
  • Oral

Death of the patient in the context of lysosomal septicemia.

None possible.

• Angiokeratoma Mibelli:
  • Slow progression without malignant potential.
• Angiokeratoma scroti et vulvae (Fordyce) :
  • No growth tendency or malignant potential.
• Angiokeratoma circumscriptum:
  • Growth in size over years
  • No regression
  • Surface bleeding after minor trauma and thrombosis as possible complications.
• Acral pseudolymphomatous angiokeratomas of childhood:
  • Gut-like
  • Years of persistence with possible spontaneous remission
• Angiokeratoma corporis diffusum (Fabry disease - alpha-galactosidase deficiency):
  • Untreated infauste prognosis with a life expectancy of 30 to 50 years.
  • In late-onset variants, there is a normal life expectancy.
  • Women have a better prognosis than men due to the X-linked recessive disease.
  • With enzyme replacement therapy, at least a stagnation of the disease course as well as a regression of acroparaesthesias and thus an improvement of the quality of life can be achieved. There is evidence of improvement in cardiac and renal activity.
  • Renal insufficiency from the 2nd to 4th year of life.
• Fucosidosis:
  • Due to lack of treatment option with poor prognosis and high mortality after 20 years of age.