Hyaline fibromatosis syndrome is a disorder in which a clear (hyaline) substance abnormally accumulates in body tissues. This disorder affects many areas of the body, including the skin, joints, bones, and internal organs. The severity of the signs and symptoms of hyaline fibromatosis syndrome fall along a spectrum. In more severe cases (previously diagnosed as infantile systemic hyalinosis), signs and symptoms are present at birth or begin within the first few months of life and can be life-threatening. In milder cases (previously diagnosed as juvenile hyaline fibromatosis), signs and symptoms begin in childhood and affect fewer body systems.

One of the main features of hyaline fibromatosis syndrome is the growth of noncancerous masses of tissue (nodules) under the skin, very commonly on the scalp. In more severely affected individuals, nodules also grow in the muscles and internal organs, causing pain and complications. Some severely affected individuals develop a condition called protein-losing enteropathy due to the formation of nodules in their intestines. This condition results in severe diarrhea, failure to gain weight and grow at the expected rate, and general wasting and weight loss (cachexia).

Another common feature of hyaline fibromatosis syndrome is painful skin bumps that frequently appear on the hands, neck, scalp, ears, and nose. They can also develop in joint creases and the genital region. These skin bumps are described as white or pink and pearly. They may be large or small and often increase in number over time.

In some affected individuals, especially those with more severe signs and symptoms, the skin covering joints, such as the ankles, wrists, elbows, and finger joints, is unusually dark (hyperpigmented). Hyaline fibromatosis syndrome is also characterized by overgrowth of the gums (gingival hypertrophy), and some affected individuals have thickened skin.

Joint stiffness and pain are common in hyaline fibromatosis syndrome, and many affected individuals develop joint deformities called contractures that limit movement. By adulthood, some people with the condition require a wheelchair for mobility. Bone abnormalities can also occur in hyaline fibromatosis syndrome.

Although individuals with hyaline fibromatosis syndrome have severe physical limitations, mental development is typically normal. People with milder signs and symptoms live into adulthood, while the most severely affected individuals often do not survive beyond early childhood due to chronic diarrhea and recurrent infections.

Hyaline fibromatosis syndrome is caused by mutations in a gene called ANTXR2. This gene provides instructions for making a protein that is found at the surface of many types of cells. The ANTXR2 protein is believed to interact with components of the extracellular matrix, which is the lattice of proteins and other molecules outside the cell. This matrix strengthens and supports connective tissues, such as skin, bone, cartilage, tendons, and ligaments. The ANTXR2 protein may play a role in the structure of the extracellular matrix. The nature of the hyaline substance that builds up in hyaline fibromatosis syndrome is unknown, but it likely contains extracellular matrix proteins, among other materials.

Mutations in the ANTXR2 gene are thought to result in production of an ANTXR2 protein that is unable to get to the surface of cells or that has impaired ability to interact with extracellular matrix components. It is unclear what effect these mutations have in cells and tissues. Researchers suspect that gene mutations disrupt the formation of the extracellular matrix, allowing a hyaline substance to leak through and build up in various body tissues. Alternatively, the mutations could impair the breakdown of excess extracellular matrix proteins, which then accumulate in tissues and lead to the signs and symptoms of hyaline fibromatosis syndrome.

Researchers are unsure why the severity of hyaline fibromatosis syndrome varies among affected individuals. Some studies have indicated that the severity of the condition may be linked to where in the gene the mutation occurs.

Normal Function

The ANTXR2 gene provides instructions for making a protein that is found at the surface of many types of cells. The ANTXR2 protein is believed to interact with components of the extracellular matrix, which is the lattice of proteins and other molecules outside the cell. This matrix strengthens and supports connective tissues, such as skin, bone, cartilage, tendons, and ligaments.

The ANTXR2 protein is involved in the formation of tiny blood vessels (capillaries). It may also be important for maintaining the structure of basement membranes, which are thin, sheet-like extracellular matrix structures that separate and support cells in many connective tissues. Research suggests that the ANTXR2 protein aids in the breakdown of at least one type of extracellular matrix protein, ensuring the correct balance of proteins is maintained for normal functioning of muscles and connective tissues.

The ANTXR2 protein also acts as a receptor for the toxin that causes anthrax, allowing the toxin to attach to cells and trigger disease.

Health Conditions Related to Genetic Changes

Hyaline fibromatosis syndrome

More than 45 mutations in the ANTXR2 gene have been found to cause hyaline fibromatosis syndrome, a painful condition characterized by accumulation of a clear (hyaline) substance in different tissues in the body. The nature of the hyaline substance is unknown, but it likely contains extracellular matrix proteins, among other materials. Buildup of this material can cause firm lumps of noncancerous tissue (nodules) under the skin and in internal organs, joint deformities called contractures that restrict movement, and overgrowth of the gums. The severity of the signs and symptoms falls along a spectrum. The most severely affected individuals have severe diarrhea and recurrent infections and usually do not survive beyond early childhood. Individuals at the milder end of the spectrum typically survive into adulthood.

Some ANTXR2 gene mutations reduce or eliminate the amount of ANTXR2 protein at the surface of cells. Others are thought to impair the protein's ability to interact with extracellular matrix components. It is unclear what effect these mutations have in cells and tissues. Researchers suspect that gene mutations disrupt the formation of basement membranes, allowing a hyaline substance to leak through and build up in various body tissues. Alternatively, the mutations could impair the breakdown of excess extracellular matrix proteins, which then accumulate in tissues and lead to the signs and symptoms of hyaline fibromatosis syndrome.

It is unclear why the severity of hyaline fibromatosis syndrome varies among affected individuals. Some studies have indicated that the severity of the condition may be linked to where in the gene the mutation occurs.

Other Names for This Gene

• anthrax toxin receptor 2
• ANTR2_HUMAN
• capillary morphogenesis protein 2
• CMG-2
• CMG2
• FLJ31074
• ISH
• JHF
• MGC111533
• MGC45856

Genomic Location

Hyaline fibromatosis syndrome is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not be a carrier.

Once an at-risk sibling of an affected person is known to be unaffected, the chance for that sibling to be a carrier is about 67% (2 in 3).

If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies may be available. The use of prenatal ultrasound for detecting HFS is unclear, but in a pregnancy at risk, detecting decreased fetal activity and contractures could suggest recurrence. Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

People with a family history of HFS are encouraged to speak with a genetic counselor or other genetics professional.

Hyaline fibromatosis syndrome is a rare condition. Its prevalence is unknown.