Ellis-van Creveld syndrome is an inherited disorder of bone growth that results in very short stature (dwarfism). People with this condition have particularly short forearms and lower legs and a narrow chest with short ribs. Ellis-van Creveld syndrome is also characterized by the presence of extra fingers and toes (polydactyly), malformed fingernails and toenails, and dental abnormalities. More than half of affected individuals are born with a heart defect, which can cause serious or life-threatening health problems.

The features of Ellis-van Creveld syndrome overlap with those of another, milder condition called Weyers acrofacial dysostosis. Like Ellis-van Creveld syndrome, Weyers acrofacial dysostosis involves tooth and nail abnormalities, although affected individuals have less pronounced short stature and typically do not have heart defects. The two conditions are caused by mutations in the same genes.

In most parts of the world, Ellis-van Creveld syndrome occurs in 1 in 60,000 to 200,000 newborns. It is difficult to estimate the exact prevalence because the disorder is very rare in the general population. This condition is much more common in the Old Order Amish population of Lancaster County, Pennsylvania, and in the Indigenous (native) population of Western Australia.

Ellis-van Creveld syndrome can be caused by mutations in the EVC or EVC2 gene. Little is known about the function of these genes, although they appear to play important roles in cell-to-cell signaling during development. In particular, the proteins produced from the EVC and EVC2 genes are thought to help regulate the Sonic Hedgehog signaling pathway. This pathway plays roles in cell growth, cell specialization, and the normal shaping (patterning) of many parts of the body.

The mutations that cause Ellis-van Creveld syndrome result in the production of an abnormally small, nonfunctional version of the EVC or EVC2 protein. It is unclear how the defective proteins lead to the specific signs and symptoms of this condition. Studies suggest that they prevent normal Sonic Hedgehog signaling in the developing embryo, disrupting the formation and growth of the bones, teeth, and other parts of the body.

Together, mutations in the EVC and EVC2 genes account for more than half of all cases of Ellis-van Creveld syndrome. The cause of the remaining cases is unknown.

Normal Function

The EVC gene provides instructions for making a protein whose function is unclear. However, it appears to be important for normal growth and development, particularly the development of bones and teeth. The EVC protein is found in primary cilia, which are microscopic, finger-like projections that stick out from the surface of cells and are involved in signaling pathways that transmit information between cells. In particular, the EVC protein is thought to help regulate a signaling pathway known as Sonic Hedgehog, which plays roles in cell growth, cell specialization, and the normal shaping (patterning) of many parts of the body.

EVC and another gene, EVC2, are located very close together on chromosome 4. Researchers believe that the two genes may have related functions and that their activity may be coordinated.

Health Conditions Related to Genetic Changes

Ellis-van Creveld syndrome

More than 25 mutations in the EVC gene have been reported to cause Ellis-van Creveld syndrome, an inherited disorder characterized by dwarfism, abnormal nails and teeth, and heart defects. The mutations that cause this condition occur in both copies of the EVC gene in each cell. These genetic changes disrupt the normal function of the EVC protein or lead to the production of an abnormally small, nonfunctional version of the protein. Although it is unclear how the loss of this protein's function underlies the signs and symptoms of Ellis-van Creveld syndrome, researchers believe that it may prevent normal Sonic Hedgehog signaling in the developing embryo. Problems with this signaling pathway may ultimately lead to the abnormal bone growth and heart defects seen with this condition.

Weyers acrofacial dysostosis

At least one mutation in the EVC gene has been found to cause the characteristic features of Weyers acrofacial dysostosis, affecting the development of the teeth, nails, and bones. The signs and symptoms of Weyers acrofacial dysostosis are similar to, but typically milder than, those of Ellis-van Creveld syndrome.

The EVC gene mutation that causes Weyers acrofacial dysostosis occurs in one copy of the gene in each cell. It changes a single protein building block (amino acid) in the EVC protein, replacing the amino acid serine with the amino acid proline at position 307 (written as Ser307Pro). It is unclear how this genetic change leads to the specific features of Weyers acrofacial dysostosis. Studies suggest that the abnormal protein interferes with Sonic Hedgehog signaling in the developing embryo, disrupting the normal formation and growth of the teeth, nails, and bones.

Other Names for This Gene

• DWF-1
• Ellis van Creveld protein
• Ellis van Creveld syndrome
• Ellis van Creveld syndrome protein
• EVC1
• EVC_HUMAN
• EVCL

Genomic Location

Normal Function

The EVC2 gene provides instructions for making a protein whose function is unknown. However, it appears to be important for normal growth and development, particularly the development of bones and teeth. The EVC2 protein is found in primary cilia, which are microscopic, finger-like projections that stick out from the surface of cells and are involved in signaling pathways that transmit information between cells. In particular, the EVC2 protein is thought to help regulate a signaling pathway known as Sonic Hedgehog, which plays roles in cell growth, cell specialization, and the normal shaping (patterning) of many parts of the body.

EVC2 and another gene, EVC, are located very close together on chromosome 4. Researchers believe that the two genes may have related functions and that their activity may be coordinated.

Health Conditions Related to Genetic Changes

Ellis-van Creveld syndrome

More than 30 mutations in the EVC2 gene have been found to cause Ellis-van Creveld syndrome, an inherited disorder characterized by dwarfism, abnormal nails and teeth, and heart defects. The mutations that cause this condition occur in both copies of the EVC2 gene in each cell. Most of the genetic changes lead to the production of an abnormally small, nonfunctional version of the EVC2 protein. Although it is unclear how the loss of this protein's function underlies the signs and symptoms of Ellis-van Creveld syndrome, researchers believe that it may prevent normal Sonic Hedgehog signaling in the developing embryo. Problems with this signaling pathway may ultimately lead to the abnormal bone growth and heart defects seen with this condition.

Weyers acrofacial dysostosis

At least three mutations in the EVC2 gene have been found to cause Weyers acrofacial dysostosis, a condition that affects the development of the teeth, nails, and bones. Its signs and symptoms are similar to, but typically milder than, those of Ellis-van Creveld syndrome.

The mutations that cause Weyers acrofacial dysostosis occur in one copy of the EVC2 gene in each cell. Each mutation changes a single protein building block (amino acid) near the end of the EVC2 protein. These mutations probably result in the production of an abnormally short, malfunctioning version of the protein. It is unclear how the defective protein leads to the specific features of Weyers acrofacial dysostosis. Studies suggest that it interferes with Sonic Hedgehog signaling in the developing embryo, disrupting the normal formation and growth of the teeth, nails, and bones.

Other Names for This Gene

• Ellis van Creveld syndrome 2
• Ellis van Creveld syndrome 2 (limbin)
• LBN
• LBN_HUMAN
• limbin

Genomic Location

This condition 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.