What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloidosis of Skin
• Amyloidosis-Associated Skin Disease
• Skin Amyloidosis

What is Cutaneous Amyloidosis? (Definition/Background Information)

• Amyloidosis is a group of disorders in which the ‘amyloid protein’ builds up in many organs and tissues of the body. The term “amyloid” is used for protein molecules of any type that stick together owing to misfolding (through incorrect formation of the proteins)
• These protein aggregates are abnormally-formed and arranged into fibrils (slender fibers). An amyloid build-up can occur locally in only one organ, or may occur throughout the body. The deposition of amyloid proteins in the dermis layer of skin leads to Cutaneous Amyloidosis
  • The dermis is the inner structural layer of skin, comprised of collagen, elastin and other molecules, and containing the blood vessels, nerves, sweat glands, and hair follicles
  • The dermis lies beneath the epidermis and is also known as the “true skin”
• Amyloidosis is divided into 5 major subtypes, namely:
  • AL amyloidosis that occurs when bone marrow produces too much amyloid protein, creating light (L) chains
  • AA amyloidosis, when amyloid proteins build up secondary to a chronic disease
  • Hereditary amyloidosis: It is an inherited form of the disease; the amyloid build-up primarily affects the kidneys and nerves
  • Wild-type ATTR amyloidosis: This form leads to amyloid protein deposits in elderly adults, particularly in the heart and tendons
  • Dialysis-related amyloidosis: This occurs in individuals who have undergone dialysis for a long time. The amyloid protein tends to get deposited in the tendons and joints
• Cutaneous Amyloidosis may occur as primary localized form (localized primary Cutaneous Amyloidosis or LPCA) or be associated with systemic AA, AL, and hereditary subtypes of amyloidosis. This condition generally affects older men and women
• Cutaneous Amyloidosis can affect the face, back, arms, legs, and genitals, with symptoms of scaly skins, raised spots (papules) and nodules, which may be itchy
• Based on the appearance of the lesions, localized primary Cutaneous Amyloidosis may be classified as macular, lichen and nodular types. Women are more vulnerable to the macular type of localized primary Cutaneous Amyloidosis
• Cutaneous Amyloidosis is treated with medication and through the surgical removal of amyloid deposits from the body. There is a likelihood of recurrence of the skin condition even after treatment

Who gets Cutaneous Amyloidosis? (Age and Sex Distribution)

• Cutaneous Amyloidosis occurs worldwide in adults; both males and females are affected
• The macular type of localized primary Cutaneous Amyloidosis is more common in individuals of Asian, South American, and Middle Eastern descent, and is more common in women than men
• The lichen type of localized primary disease is more common in individuals of Chinese descent and occurs more frequently in men

What are the Risk Factors for Cutaneous Amyloidosis? (Predisposing Factors)

The following are some known risk factors for developing Cutaneous Amyloidosis:

• Advancing age
• Physical trauma
• A family history of amyloidosis
• Any condition that affects the antibody-producing cells in the body, including benign monoclonal gammopathy, malignant lymphoma, and multiple myeloma
• Chronic inflammatory conditions such as
  • Arthritis, including rheumatoid arthritis, juvenile inflammatory arthritis, psoriatic arthritis and ankylosing spondylitis
  • Inflammatory bowel disease (IBD) such as ulcerative colitis
• Chronic infections, including
  • Tuberculosis
  • Leprosy
  • Bronchiectasis
  • Osteomyelitis
  • Skin infections (especially in drug abusers, who use needles to inject themselves)
  • Chronic infection in skin with burns
  • Chronic kidney infections (pyelonephritis)
  • Whipple’s disease
• Uncontrolled diabetes
• Infectious diseases such as HIV/AIDS
• Cystic fibrosis; individuals with this condition are prone to repeat infections
• Certain cancers such as Hodgkin’s lymphoma and renal cell carcinoma
• Family history of certain hereditary disorders that may include:
  • Familial Mediterranean fever (FMF)
  • Tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS)
  • Hyperimmunoglobulin D syndrome and periodic fever syndrome (HIDS)
  • Cryopyrin-associated periodic syndrome (CAPS)
  • Majeed syndrome
  • Sjögren's syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Cutaneous Amyloidosis? (Etiology)

Cutaneous Amyloidosis of the primary localized form is caused by mutation(s) in the OSMR or IL31RA genes.

• In most cases, these mutations are spontaneous
• These gene mutations may also be inherited. Both autosomal dominant and autosomal recessive patterns of inheritance are known

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive mode of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

The primary form of Cutaneous Amyloidosis may also be caused by physical trauma, or occur in certain disorders, such as Sjögren's syndrome.

• In addition, Cutaneous Amyloidosis can occur as part of systemic AA, AL, and hereditary subtypes of amyloidosis
• In both cases, abnormal proteins are generated that undergo misfolding to form amyloid proteins
• The amyloid proteins get deposited in the dermis layer of skin, which is the thick layer of tissue under the outer skin (or epidermis)
• The deposition of amyloid particles in skin can cause papules, patches, and nodules on skin

What are the Signs and Symptoms of Cutaneous Amyloidosis?

The signs and symptoms of Cutaneous Amyloidosis may vary in type and severity among the affected individuals. The skin on the limbs, back, trunk, face and genitals may be affected. The following signs and symptoms of Cutaneous Amyloidosis may be noted:

• Small, red blood spots on skin
• Round or irregularly shaped flat spots that may be red, purple, or blue in color
• Raised spots (papules) or plaques near eyelids, neck and genital area
• Dark skin patches, which may be distributed symmetrically on the body
• Skin rashes; nodules on skin
• Itching
• Infection due to scratching
• Brittle nails
• Loss of hair in patches across the skin

Cutaneous Amyloidosis, particularly the primary localized type, may present with a set of associated symptoms, based on the different subtypes.

The lichen form (most common) may result in:

• Rashes on the legs, feet, and arms
• Raised red or brown spots, which may be scaly
• Formation of plaques by spreading and coalescing of skin papules
• The rashes may be extremely itchy

The macular form may result in:

• Red or gray spots, which may coalesce to become larger patches
• The lesions may be distributed symmetrically on the body
• Occurs more on the shoulder blades, chest, and arms

The nodular form (nodular localized primary Cutaneous Amyloidosis or NLPCA) may result in:

• Presence of one or many firm nodules
• They may be pink or reddish brown in color
• The nodules may appear on the face, limbs and genitals

If Cutaneous Amyloidosis occurs as part of systemic amyloidosis, there may be additional symptoms, depending on the tissues and organs affected, such as given below:

• Fatigue
• Shortness of breath. This, fatigue and swelling of the ankles and legs result from heart pump failure from amyloid infiltrating the heart
• Swollen tongue (macroglossia)
• Swelling in the ankles and legs
• Unintended weight loss
• Pain in hands and feet
• Joint pain
• Bruising around the eyes: This can be seemingly spontaneous, or result from coughing, vomiting, or simply having the head in a low position for some time. It is sometimes the first sign of systemic amyloidosis
• Eyes that appear puffy
• Tingling sensation; numbness
• Anemia
• Carpal tunnel syndrome (resulting in weak grip)
• Bleeding disorders; problems with proper clotting of blood

How is Cutaneous Amyloidosis Diagnosed?

The diagnosis of Cutaneous Amyloidosis may include general tests to ascertain the subtype of amyloidosis (and its underlying cause), as well as specific tests to assess damage to the skin.

The following methods may be employed for an accurate diagnosis of Amyloidosis of Skin:

• A thorough physical examination
• Evaluation of personal and family medical history
• Assessment of the presenting signs and symptoms
• Blood tests to assess the following:
  • Complete blood count (CBC)
  • “Freelite assay”, a measurement of light chain immunoglobulins
  • Immunoglobulin by immunofixation electrophoresis
  • Liver enzymes
• Urine tests to check function of kidneys
• Electrocardiography and echocardiography for checking heart functions
• Imaging tests to assess amyloid deposits in the body/organs, and to assess damage to the organs, tissues, and bones, which include:
  • X-ray of the affected region
  • Ultrasound imaging
  • Computed tomography scanning
  • Magnetic resonance imaging
• Serum amyloid protein (SAP) scintigraphy scan: In this procedure, a small amount of radiolabeled (radioactive iodine) SAP is introduced through injection into the body. After several hours, individuals are scanned with a whole body gamma scanner to check for amyloid deposits in the tissues and organs. Individuals undergoing this procedure ingest potassium iodide before and after the procedure, to prevent the thyroid glands from absorbing the radioactive iodine
• Tissue biopsy: A biopsy of affected skin area is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis. In case of Amyloidosis,
  • Immunohistochemical analysis of tissue samples using anti-AA serum may be performed, to identify the type of amyloidosis an individual has
  • Biopsy of affected tissue, such as organ tissue, bone, muscle or fat, may be necessary
  • Amyloid deposit from affected tissue is detected using a staining procedure. When stained with Congo red stain, the amyloid protein deposits appear green under a special type of microscope (polarizing microscope)
• Bone marrow aspiration for checking the type of abnormal immunoglobulin light chains
• Molecular genetic testing to check for mutation(s) in genes known to cause various types of amyloidosis
• Molecular testing to check the type of proteins in amyloid deposits through mass spectrophotometry

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Cutaneous Amyloidosis?

The potential complications of Cutaneous Amyloidosis include:

• Intense itching that may affect one’s quality of life
• Disfigurement due to lesions and scratching
• Increased risk of skin secondary infections from scratching
• Progression of nodular primary localized Cutaneous Amyloidosis to systemic amyloidosis

How is Cutaneous Amyloidosis Treated?

The following are some treatment options for Cutaneous Amyloidosis:

• Medication to control itching (such as topical steroids)
• Antibiotics for skin infection
• Phototherapy, or the use of artificial UV light to modulate overactive immune cells
• Removal of amyloid deposits via the following procedures:
  • Dermabrasion
  • Laser vaporization
• Removal of nodules may involve additional methods such as:
  • Delivering corticosteroids inside the lesions through injection
  • Cryotherapy, which is the use of extremely cold temperatures to freeze (treat) tissue
  • Curettage and electrodessication, or the removal of lesion with a small device known as a curette under local anesthesia
  • Surgery

Cutaneous Amyloidosis may occur in isolation in the primary localized form, and or in association with involvement of many other organs as part of systemic amyloidosis. Therefore, additional treatments to treat the condition and any underlying cause are often necessary.

How can Cutaneous Amyloidosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Cutaneous Amyloidosis
• Seeking prompt medical attention for pre-existing conditions that can lead to systemic amyloidosis, which consequently causes Cutaneous Amyloidosis is advisable
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Cutaneous Amyloidosis? (Outcomes/Resolutions)

• The prognosis of Cutaneous Amyloidosis is determined by a number of factors, such as the extent of disease, overall health of the affected individual, and his/her response to treatment
• Even though it may be possible to remove skin lesions caused by the condition, there is a likelihood that the lesions will recur
• In about 7% of individuals with the nodular form of primary localized Cutaneous Amyloidosis, the disease may progress to become systemic amyloidosis

Additional and Relevant Useful Information for Cutaneous Amyloidosis:

• Approximately, 30 different proteins with a tendency to form amyloids have been identified. These are known as precursor proteins or amyloidogenic proteins
• The misfolding of proteins can occur due to a number of reasons, including aberrant formation, improper breakdown, or accumulation beyond a critical concentration in serum