Tetra-amelia syndrome (sometimes known as TETAMS) is a very rare disorder characterized by the absence of all four limbs. ("Tetra" is the Greek word for "four," and "amelia" refers to the failure of an arm or leg to develop before birth.)

This syndrome can also cause severe malformations of other parts of the body, including the nervous system, face, head, heart, skeleton, gastrointestinal system, urinary tract, and genitalia. The lungs are underdeveloped in many cases, which makes breathing difficult or impossible. Because children with tetra-amelia syndrome have such serious medical problems, most are stillborn or die shortly after birth.

There are two forms of tetra-amelia syndrome that have been described, and while the features overlap, they are distinguished by their signs and symptoms and genetic cause.

Tetra-amelia syndrome type 1 is typically characterized by severe gastrointestinal problems. These problems include an opening in the abdomen through which various abdominal organs can protrude (abdominal wall defect), abnormalities in the muscle (diaphragm) that separates the organs in the abdomen from those in the chest, and lack of an anal opening (imperforate anus). People with type 1 also tend to have frequent urinary tract problems, such as a lack of kidney development (renal agenesis).

Tetra-amelia syndrome type 2 is usually characterized by complete absence of both lungs. Affected individuals often have heart abnormalities, such as defects in the walls between the chambers of the heart (septal defects) or absence of the mitral valve, which connects the two left chambers of the heart. People with type 2 can also have facial abnormalities that include partial or complete fusion of the upper and lower eyelids, the bottom of the tongue attached to the floor of the mouth, or a small lower jaw (micrognathia).

Variants (also called mutations) in two genes have been found to cause tetra-amelia syndrome. Variants in the WNT3 gene cause tetra-amelia syndrome type 1 and variants in the RSPO2 gene cause tetra-amelia syndrome type 2.

The WNT3 gene is one of a family of WNT genes that are part of a process called Wnt signaling, which is involved in regulating cell growth and development before birth. The protein produced from the WNT3 gene is particularly involved in the formation of the limbs and neurological development.

The RSPO2 gene provides instructions for making a protein called R-spondin-2. The role of this protein is to increase Wnt signaling. Specifically, R-spondin-2, attaches (binds) to certain proteins on the surface of cells to turn off (inactivate) proteins that block Wnt signaling.

The variants in the WNT3 or RSPO2 gene that cause tetra-amelia syndrome likely prevent cells from producing any functional protein. As a result, Wnt signaling is impaired and normal limb formation is disrupted, which leads to the serious birth defects associated with tetra-amelia syndrome types 1 and 2.

In some affected individuals, the cause of tetra-amelia syndrome has not been determined. Researchers believe that unidentified mutations in WNT3, RSPO2, or other genes involved in limb development are probably responsible for the disorder in these cases.

Normal Function

The RSPO2 gene provides instructions for making a protein called R-spondin-2. R-spondin-2 plays a role in the Wnt signaling pathway, a series of steps that affect the way cells and tissues develop. Wnt signaling is important for cell division, attachment of cells to one another (adhesion), cell movement (migration), and many other cellular activities.

During early development, Wnt signaling plays a critical role in growth and development of the skeleton and other tissues. The role of R-spondin-2 is to increase Wnt signaling. Specifically, R-spondin-2 attaches (binds) to certain proteins on the surface of cells to turn off (inactivate) proteins that block the Wnt pathway.

Health Conditions Related to Genetic Changes

Tetra-amelia syndrome

Variants (also called mutations) in the RSPO2 gene have been found to cause tetra-amelia syndrome. This condition is very rare and characterized by the absence of all four limbs. RSPO2 gene variants cause a form of this condition known as tetra-amelia syndrome type 2 in which affected individuals typically have a complete absence of both lungs. Because children with this condition have such serious medical problems, most are stillborn or die shortly after birth.

In individuals with tetra-amelia syndrome, RSPO2 gene variants typically result in a complete lack of functional R-spondin-2 protein. As a result, the R-spondin-2 protein is not available on the cell surface to inactivate proteins that block the Wnt pathway, so this critical pathway is dysregulated. During early development, irregular Wnt signaling leads to poor development of the limbs, organs, and other tissues, resulting in the severe signs and symptoms of tetra-amelia syndrome type 2.

Cancers

Chromosomal rearrangements (translocations) involving the RSPO2 gene on chromosome 8 have been associated with certain types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In cancer cells, translocations can disrupt the region of chromosome 8 that contains the RSPO2 gene. Researchers have found a translocation between chromosome 8 and other chromosomes in several people with a cancer of the colon, stomach, lungs, liver, or prostate.

Increased activity (overexpression) of the RSPO2 gene has also been identified in different types of cancers, including cancer of the colon, stomach, breast, liver, and pancreas. The genetic changes involved in this overexpression are somatic. Research suggests that overexpression of the RSPO2 gene leads to increased Wnt signaling. As a result, cell growth and division are increased, which can lead to cancer.

Other Names for This Gene

• cristin2
• R-spondin family, member 2
• R-spondin-2

Normal Function

The WNT3 gene is part of a large family of WNT genes, which play critical roles in development before birth. WNT genes provide instructions for making proteins that participate in chemical signaling pathways in the body. These pathways control the activity of certain genes and regulate the interactions between cells during embryonic development.

Research in animals indicates that the protein produced from the WNT3 gene is critical for outgrowth of the limbs in the developing embryo. The WNT3 protein also appears to play an important role in determining the anterior-posterior axis (the imaginary line that runs from head to tail in animals) during the earliest stages of embryonic development. Additionally, the effects of mutations in the human WNT3 gene suggest that the protein may be involved in the normal formation of the facial features, head, heart, lungs, nervous system, skeleton, and genitalia.

Health Conditions Related to Genetic Changes

Tetra-amelia syndrome

A mutation in the WNT3 gene has been shown to cause tetra-amelia syndrome. This condition is very rare and characterized by the absence of all four limbs. The WNT3 gene variant causes a form of this condition known as tetra-amelia syndrome type 1. Because children with this condition have such serious medical problems, most are stillborn or die shortly after birth.

The WNT3 gene variant that causes tetra-amelia syndrome type 1, which occurs in both copies of the WNT3 gene in each cell, replaces one protein building block (amino acid) with a premature stop signal in the instructions for making the WNT3 protein. This variant is written as Gln83Ter or Q83X.

Researchers believe that the Gln83Ter variant results in the production of an abnormally short, nonfunctional version of the WNT3 protein. Loss of WNT3 protein activity disrupts normal limb formation before birth and leads to the other serious birth defects associated with tetra-amelia syndrome type 1.

Other Names for This Gene

• INT4
• Oncogene INT4
• Proto-oncogene protein Wnt-3
• wingless-type MMTV integration site family member 3
• wingless-type MMTV integration site family, member 3
• WNT-3 proto-oncogene protein
• WNT3_HUMAN

Genomic Location

Tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with tetra-amelia syndrome each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Tetra-amelia syndrome is a very rare condition that has been described in only a few families worldwide. Because this condition is so severe, the frequency is reported to be at least 30 times higher among stillbirths than among live births.