Introduction 

In the United Kingdom, there is a 6% risk of being affected by a rare disease within a person's lifetime and one example of an extremely rare disease is Fucosidosis. There are only 100 cases reported globally with 10 of these cases from the UK. Worldwide, those of Italian ancestry are most commonly affected.¹

Due to the rarity of the condition it is often undiagnosed and so it is important to understand the background of this disease and the variation of symptom severity in affected patients.² This condition presents with signs and symptoms such as mental and motor delay, seizures, impaired growth, skeletal system abnormalities, muscle spasticity, recurring respiratory infections, enlarged vital organs and symptoms relating to the skin. Skin symptoms are referred to as dermatological manifestations and the different types are detailed in this article.³

What is fucosidosis? 

Fucosidosis is a progressive genetic disease belonging to the class of lysosomal storage disorders. Lysosomal storage disorders are a group of 50 diseases where the body is unable to break down particular sugars that are found on protein and fat structures of cells in the body called oligosaccharides.³ This loss of function is due to a genetic mutations of lysosomes, which are the enzymes that carry out the role of breaking down these sugars. In the case of fucosidosis, the enzyme that loses its function is called alpha-L-fucosidase and the result of this is the buildup of oligosaccharides within cells leading to deposition in vital organs and cell death. The disorder is passed from parent to child in an autosomal recessive pattern which means that both parents need to pass a copy of the FUCA1 gene mutation that causes fucosidosis to the affected child.^4,5

As the amount of oligosaccharides/fucose-containing compounds builds up, the appearance of symptoms become more prominent.⁶ The same FUCA1 gene mutation can be split into two types based on when these symptoms appear; type 1 occurs in the first 3-18 months of life and it is characterised as a more severe form with symptoms primarily affecting neurological function leading to rapid decline. Type 2 follows a more milder course appearing at around 12 to 24 months and has specific ocular symptoms including twisted blood vessels in the eyeball and eyelid.^7,8

Dermatological manifestations

Although skin symptoms are not seen in all patients with fucosidosis, the presence of some type of skin abnormality has been documented in approximately 60% of patients. They are often widespread and include angiokeratomas, coarse facial features, hyperpigmentation, dry and thickened skin, recurrent skin infections and sweating abnormalities. The understanding of the cause behind these skin abnormalities is not clear, but studies suggest that the mutation of the 

FUCA1 can lead to the downregulation of genes relating to important functions of the development of the epidermis which is the outermost skin layer and the immune system.⁹

Angiokeratomas 

What are angiokeratomas?

Angiokeratomas are one of the hallmark skin lesions found in fucosidosis and are seen in around 51% of patients. They are especially common as the patient gets older, usually appearing on the skin by the age of 2. The specific type of angiokeratomas associated with fucosidosis is angiokeratoma corporis diffusum which can be described as wart-like growths seen in many other types of lysosomal storage diseases such as fabry disease, sialidosis and alpha-mannosidosis.¹⁰

Appearance 

Angiokeratomas appear as red or purple asymptomatic benign skin lesions that are raised and no more than 5 mm in diameter. They have either a smooth or rough surface. A dermoscopy (a skin surface microscope) will show angiokeratomas having ‘dark spots’ (dark lacunae) this is because the small blood vessels called capillaries on the uppermost skin layer dilate and get bigger. This is due to the deposits of oligosaccharides in lysosomes of endothelial, perithelial, and smooth muscle blood vessels cells and causing them to expand. 

Over the skin of the angiokeratomas there is also a ‘whitish veil’, a term to describe the lighter coloured layer of skin that is caused by increased levels of keratin, in the skin making the outer skin layer thicker.¹¹ Near the angiokeratomas, there may also be telangiectasia which are visible blood vessels and this may also appear without the angiokeratomas.⁹

Common locations and distribution on the body:

• Stomach
• Buttocks 
• External genitalia 
• Thighs¹²

Clinical significance and complications

It is usually an asymptomatic skin condition and tends to not be painful with an association with the type 2 milder form of fucosidosis. 

Complications may include: 

• Bleeding and discomfort 
• Thrombosis with inflammation¹¹

Other skin-related symptoms in fucosidosis

Coarse facial features:

Another dermatological sign ofucosidosis is the appearance of coarse facial features. This refers to the effects of thickened skin on the individual which over time can lead to: 

• Thickened lips, mouth, tongue and chin 
• A wide nose with nose flaring 
• Distinguishable brows and large jowls (sagging pads of skin that appears between the jawline and cheeks)¹²

These features create a characteristic rounded and heavy features which can resemble ‘gargoylism’ without the normal fine and sharp facial appearances and it becomes more noticeable as the individual gets older. Coarse facial features can occur with or without thickening of bony and subcutaneous tissues. Hair is another part of body that can be described as coarse in affected patients. Coarse hair is whereby the hair follicles will appear rough and thick in texture and will have a larger diameter than usual.¹³

Hyperpigmentation

Hyperpigmentation refers to darkening of the skin compared with the surrounding skin area. In fucosidosis, its distribution is patchy and widespread, however, the more common locations are areas like the elbows, armpits and knees that are continuously exposed to friction. The underlying cause of hyperpigmentation in this disease is unclear.¹⁴

Dry and thickened skin 

The accumulation of oligosaccharides disrupts the normal skin surface and can lead to dry skin which is known as xeroderma and thickened skin known as keratoderma which is responsible for the coarse facial features.¹

Recurrent skin infections:

The buildup of oligosaccharides and the presence of angiokeratomas compromises the skin barrier and means that people with fucosidosis are at a greater risk of skin infections including those of bacterial origin.¹

Abnormal sweating

Regulation of sweating can also be affected in fucosidosis with individuals sweating excessively and inappropriately due various temperature stimuli and additionally the sweat that they produce may also contain a high level of salt compared to normal.¹⁵

Summary 

Fucosidosis is a multisystem disease and the skin is one of the organs primarily affected. The severity of the symptoms is dependent on which type the individual is diagnosed with but due to its rarity and underdiagnosis, understanding of all of the symptoms in detail is important. It is a autosomal recessive genetic disorder that is caused by a mutation of the FUCA1 gene causing a loss of function of the lysosome called alpha-L-fucosidase leading to the buildup of oligosaccharides in various parts of the body including the skin.⁴  Dermatological symptoms include angiokeratomas, coarse facial features, hypopigmentation, dry and thickened skin, recurrent skin infections and sweating abnormalities.⁹ Angiokeratomas would be considered one of the hallmark features of this disease and is especially crucial to diagnose individuals over the age of 10 as it is seen more frequently as a patient gets older.¹¹ Coarse facial features are also more distinguishable as a child with fucosidosis gets older and its cause thickened skin.¹² The skin's ability to regulate sweating is also disrupted with individuals excessively sweating and having a high amount of salt in their sweat.¹⁵ Although the specialised paediatricians and neurologists are integral for diagnosis of fucosidosis, because of skin related symptoms a dermatologist may also be useful. There is no cure for fucosidosis and so the treatment is based on symptom relief and is often fatal with age of death being dependent on the type of fucosidosis and its complications. Research is still ongoing in this area like many other rare diseases and since 2023 there has been further work in bone marrow transplants in an effort to increase lysosomal activity.^1,2