Primary localized cutaneous amyloidosis (PLCA) is a condition in which clumps of abnormal proteins called amyloids build up in the skin, specifically in the wave-like projections (dermal papillae) between the top two layers of skin (the dermis and the epidermis). The primary feature of PLCA is patches of skin with abnormal texture or color. The appearance of these patches defines three forms of the condition: lichen amyloidosis, macular amyloidosis, and nodular amyloidosis.

Lichen amyloidosis is characterized by severely itchy patches of thickened skin with multiple small bumps. The patches are scaly and reddish brown in color. These patches usually occur on the shins but can also occur on the forearms, other parts of the legs, and elsewhere on the body.

In macular amyloidosis, the patches are flat and dark brown. The coloring can have a lacy (reticulated) or rippled appearance, although it is often uniform. Macular amyloidosis patches are most commonly found on the upper back, but they can also occur on other parts of the torso or on the limbs. These patches are mildly itchy.

Nodular amyloidosis is characterized by firm, raised bumps (nodules) that are pink, red, or brown. These nodules often occur on the face, torso, limbs, or genitals and are typically not itchy.

In some affected individuals, the patches have characteristics of both lichen and macular amyloidosis. These cases are called biphasic amyloidosis.

In all forms of PLCA, the abnormal patches of skin usually arise in mid-adulthood. They can remain for months to years and may recur after disappearing, either at the same location or elsewhere. Very rarely, nodular amyloidosis progresses to a life-threatening condition called systemic amyloidosis, in which amyloid deposits accumulate in tissues and organs throughout the body.

PLCA can be caused by mutations in the OSMR or IL31RA gene. When caused by an OSMR gene mutation, the condition is classified as type 1, while an IL31RA gene mutation causes type 2. Mutations in either gene are likely involved in lichen and macular amyloidosis, which are thought to be related conditions that arise through similar disease mechanisms. The genetic basis of nodular amyloidosis is unknown.

The OSMR and IL31RA genes provide instructions for making parts (subunits) of the interleukin-31 (IL-31) receptor. The subunit produced from OSMR can also pair with a different protein to form the OSM receptor type II. Both receptors are embedded in the membrane of cells throughout the body. Each attaches to a particular protein, fitting together like a lock and its key. This attachment triggers a series of chemical signals inside the cell that directs certain cell functions.

OSM receptor type II interacts with a protein called oncostatin M (OSM). Signaling triggered by OSM appears to play a role in many body processes, including the development of blood cells, the maturation of cells to become certain cell types, an immune system response called inflammation, and the self-destruction (apoptosis) of cells. The IL-31 receptor interacts with IL-31, triggering signaling that promotes inflammation and itch (pruritus). OSMR gene mutations reduce signaling stimulated by OSM and IL-31, while IL31RA gene mutations impair only IL-31 signaling.

How PLCA develops is not completely understood. In lichen and macular amyloidosis, it is thought that scratching the itchy skin causes skin cells to undergo apoptosis, releasing proteins that abnormally clump together and form amyloids. The proteins that make up the amyloids are abnormal versions of proteins called keratins. The role of gene mutations in this process is still being determined. Because signaling triggered by IL-31 normally stimulates itching, it is unclear how a reduction of this signaling is involved in itchy skin. Also unclear is how reduced IL-31 signaling is related to apoptosis or amyloid formation. Researchers speculate that a reduction of signaling triggered by OSM may make cells more likely to undergo apoptosis, which may promote amyloid buildup.

In nodular amyloidosis, the amyloids are composed of abnormal versions of proteins called immunoglobulin light chains released from certain blood cells called plasma cells. However, it is unknown how this form of PLCA develops.

Many people with PLCA do not have a mutation in the OSMR or IL31RA gene. The cause of the condition in these cases is unknown.

Normal Function

The OSMR gene provides instructions for making a protein called oncostatin M receptor beta subunit (OSMRβ). This protein is one piece (subunit) of both the oncostatin M (OSM) receptor type II and the interleukin-31 (IL-31) receptor. These receptors are embedded in the cell membrane of many types of cells throughout the body. Each attaches to a particular protein, fitting together like a lock and its key. This attachment triggers a series of chemical signals inside the cell that directs certain cell functions.

OSM receptor type II interacts with a protein called oncostatin M (OSM). Signaling triggered by OSM was first recognized to block the growth of cancerous cells and appears to play a role in many other body processes, including the development of blood cells, the maturation of cells to become certain cell types, and an immune system response called inflammation. The signaling may also block the self-destruction (apoptosis) of cells.

The IL-31 receptor interacts with a protein called IL-31. Signaling triggered by IL-31 is involved in inflammation and stimulating itching (pruritus), although its role is not completely understood.

Health Conditions Related to Genetic Changes

Primary localized cutaneous amyloidosis

At least 13 mutations in the OSMR gene have been found to cause primary localized cutaneous amyloidosis (PLCA) type 1, an itchy skin condition in which clumps of abnormal proteins called amyloids build up in the skin. These mutations change single protein building blocks (amino acids) in OSMRβ. Most alter a region of the protein thought to interact with the other subunit of the OSM receptor type II or the IL-31 receptor and may impair formation of these receptors.

OSMR gene mutations reduce the chemical signals triggered by OSM and IL-31. Researchers speculate that this reduced signaling may make cells more likely to undergo apoptosis. Some studies suggest that apoptosis of skin cells releases abnormal proteins that form amyloids. It has been suggested that apoptosis is triggered by scratching the itchy skin, but the role of OSMR gene changes in skin itching is not clear.

Other Names for This Gene

• IL-31 receptor subunit beta
• IL-31R subunit beta
• IL-31R-beta
• IL-31RB
• interleukin-31 receptor subunit beta
• oncostatin-M specific receptor beta subunit
• OSMRB
• PLCA1

Genomic Location

Normal Function

The IL31RA gene provides instructions for making a protein called interleukin-31 receptor alpha subunit (IL-31RA). This protein is one piece (subunit) of the IL-31 receptor, which is embedded in the cell membrane of many types of cells throughout the body.

At the cell surface, the IL-31 receptor interacts with a protein called interleukin 31 (IL-31). The receptor and IL-31 fit together like a lock and its key, triggering a series of chemical signals inside the cell. These signals stimulate itching (pruritus) and an immune system response called inflammation, although the mechanism is not completely understood.

Health Conditions Related to Genetic Changes

Primary localized cutaneous amyloidosis

At least one mutation in the IL31RA gene has been found to cause primary localized cutaneous amyloidosis (PLCA) type 2, an itchy skin condition in which clumps of abnormal proteins called amyloids build up in the skin. This mutation changes a single protein building block (amino acid) in IL-31RA, replacing the amino acid serine with the amino acid phenylalanine at protein position 521 (written as Ser521Phe or S521F). This change occurs in a region of the protein thought to interact with the other subunit of the IL-31 receptor and may impair the receptor's formation.

The IL31RA gene mutation that causes PLCA reduces the chemical signals triggered by IL-31. While IL-31 signaling plays a role in itching, it is unclear how a reduction of this signaling is involved in itchy skin or the buildup of amyloids in PLCA.

Other Names for This Gene

• class I cytokine receptor
• CRL
• CRL3
• cytokine receptor-like 3
• GLM-R
• GLMR
• gp130-like monocyte receptor
• GPL
• hGLM-R
• IL-31 receptor subunit alpha
• IL-31R subunit alpha
• IL-31RA
• PLCA2
• PRO21384
• soluble type I cytokine receptor CRL3
• zcytoR17

Genomic Location

In most cases, PLCA is not inherited and occurs in people with no history of the condition in their family.

When the condition runs in families, it is usually inherited in an autosomal dominant pattern, which means one copy of the altered OSMR or IL31RA gene in each cell is sufficient to cause the disorder. In these cases, the affected person has one parent with the condition.

Rarely, when caused by a mutation in the OSMR gene, PLCA is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

PLCA occurs worldwide, most commonly in Southeast Asia and South America. The prevalence of the condition is unknown.