Blepharocheilodontic (BCD) syndrome is a disorder that is present at birth. It mainly affects the eyelids (blepharo-), upper lip (-cheilo-), and teeth (-dontic).

People with BCD syndrome have lower eyelids that turn out so that the inner surface is exposed (ectropion). The outside of the lower lid may sag away from the eye (euryblepharon), and the eyelids may not be able to close completely (lagophthalmia). There can be extra eyelashes (distichiasis) on the upper eyelids, ranging from a few extra eyelashes to a full extra set. These eyelashes do not grow along the edge of the eyelid with the normal lashes, but out of its inner lining. When the abnormal eyelashes touch the eyeball, they can cause damage to the clear covering of the eye (cornea). Affected individuals may also have widely spaced eyes (hypertelorism), a flat face, and a high forehead.

Other features of BCD syndrome usually include openings on both sides of the upper lip (bilateral cleft lip) and an opening in the roof of the mouth (cleft palate). Affected individuals may have fewer teeth than normal (oligodontia) and their teeth are often smaller than usual and cone-shaped. The dental abnormalities affect both primary teeth (sometimes called "baby teeth") and secondary (permanent) teeth. Other frequent features include sparse, fine hair and abnormal nails.

Occasionally people with BCD syndrome have additional features, including an obstruction of the anal opening (imperforate anus); malformation or absence of the butterfly-shaped gland in the lower neck called the thyroid, resulting in lack of thyroid gland function; or fused fingers or toes (syndactyly). Very rarely, affected individuals have incompletely formed arms or legs (limb reduction defects) or a spinal cord abnormality known as spina bifida.

BCD syndrome is caused by mutations in the CDH1 or CTNND1 gene. These genes provide instructions for making proteins called epithelial cadherin (E-cadherin) and p120-catenin, respectively. The E-cadherin protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body, including the inside of the eyelids and mouth. This protein is involved in the attachment of cells to one another (cell adhesion). The p120-catenin protein helps keep E-cadherin in its proper place in the cell membrane, preventing it from being taken into the cell and broken down prematurely. Interactions between the two proteins are also important for other cell processes that are involved in the development of the head and face (craniofacial development), including the eyelids and teeth.

While the specific effects of the CDH1 gene mutations that cause BCD syndrome are not well understood, researchers suggest that the mutations may result in an E-cadherin protein that is unstable and quickly broken down. CTNND1 gene mutations reduce or eliminate the production or function of p120-catenin, so E-cadherin is broken down prematurely. A shortage of these proteins disrupts normal development, especially craniofacial development, which is thought to underlie the features of BCD syndrome.

Normal Function

The CDH1 gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body, such as the inside of the eyelids and mouth. E-cadherin belongs to a family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized tissues. Another protein called p120-catenin, produced from the CTNND1 gene, helps keep E-cadherin in its proper place in the cell membrane, preventing it from being taken into the cell through a process called endocytosis and broken down prematurely.

E-cadherin is one of the best-understood cadherin proteins. In addition to its role in cell adhesion, E-cadherin is involved in transmitting chemical signals within cells, controlling cell maturation and movement, and regulating the activity of certain genes. Interactions between the E-cadherin and p120-catenin proteins, in particular, are thought to be important for normal development of the head and face (craniofacial development), including the eyelids and teeth. E-cadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Breast cancer

Inherited mutations in the CDH1 gene increase a woman's risk of developing a form of breast cancer that begins in the milk-producing glands (lobular breast cancer). In many cases, this increased risk occurs as part of an inherited cancer disorder called hereditary diffuse gastric cancer (HDGC) (described below). Inherited mutations in the CDH1 gene are thought to account for only a small fraction of all breast cancer cases.

CDH1 gene mutations also occur commonly in lobular breast cancers in women without a family history of the disease. These genetic changes, known as somatic mutations, are not inherited. Somatic gene mutations are acquired during a person's lifetime and occur only in certain cells in the breast. Some of these genetic changes occur within the gene itself, while others turn off (inactivate) a region of nearby DNA that controls the gene's activity. Researchers believe that the resulting loss of E-cadherin protein may allow breast cells to grow and divide unchecked, leading to a cancerous tumor. A lack of this protein, which is critical for cell adhesion, may also make it easier for cancer cells to detach from a primary tumor and spread (metastasize) to other parts of the body.

Hereditary diffuse gastric cancer

More than 120 inherited mutations in the CDH1 gene have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). People with CDH1 gene mutations associated with HDGC have a 56 to 70 percent chance of developing stomach (gastric) cancer in their lifetimes. Women with these mutations also have a 40 to 50 percent chance of developing lobular breast cancer (described above). People with HDGC caused by CDH1 gene mutations are born with one mutated copy of the gene in each cell. An additional mutation that impairs the normal copy of the CDH1 gene is needed for cancer to develop. This mutation is a somatic mutation and is present only in cells that give rise to cancer.

The mutations that cause HDGC often lead to the production of an abnormally short, nonfunctional version of the E-cadherin protein or lead to the production of a protein with an altered structure. The loss of normal E-cadherin prevents it from acting as a tumor suppressor, contributing to the uncontrollable growth and division of cells. A lack of E-cadherin impairs cell adhesion, increasing the likelihood that cancer cells will invade the stomach wall and small clusters of cancer cells will metastasize into nearby tissues. In combination, the inherited and somatic mutations lead to a lack of functional E-cadherin and result in HDGC.

Blepharocheilodontic syndrome

At least five inherited CDH1 gene mutations have been identified in people with blepharocheilodontic (BCD) syndrome. This disorder is present at birth and causes abnormalities mainly affecting the eyelids and mouth, including openings on both sides of the upper lip (bilateral cleft lip) and an opening in the roof of the mouth (cleft palate). CDH1 gene mutations that cause BCD syndrome are thought to result in an abnormal E-cadherin protein that is quickly broken down. A shortage of E-cadherin protein impairs the interaction between E-cadherin and p120-catenin and affects craniofacial development, leading to the features of BCD syndrome. Despite the association of CDH1 gene mutations with increased cancer risk (see below), it is unclear whether people with BCD syndrome are at increased risk of developing cancer.

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Prostate cancer

MedlinePlus Genetics provides information about Prostate cancer

Other cancers

Somatic CDH1 gene mutations are also associated with an increased risk of other cancers, including cancers of the lining of the uterus (endometrium) or the ovaries in women, and prostate cancer in men. These CDH1 gene mutations are thought to result in a nonfunctional E-cadherin protein. A loss of functional E-cadherin in these cells prevents tumor suppression and cell adhesion, leading to rapid cell growth and metastasis.

In addition, a specific inherited variation in the CDH1 gene is thought to increase the risk of prostate cancer. It is unclear why CDH1 gene mutations increase the risk of cancer in certain tissues and not in others.

Other disorders

Individuals with inherited CDH1 gene mutations may have cleft lip, cleft palate, or both (orofacial clefting) without the other signs and symptoms of BCD syndrome and with or without a family history of HDGC (both described above). The CDH1 gene mutations in these individuals are thought to alter the E-cadherin protein and impair normal craniofacial development, leading to orofacial clefting. It is unknown why some people with orofacial clefting caused by CDH1 gene mutations have additional signs and symptoms while others do not.

Other Names for This Gene

• Arc-1
• CADH1_HUMAN
• cadherin 1, E-cadherin (epithelial)
• cadherin 1, type 1
• cadherin 1, type 1, E-cadherin (epithelial)
• calcium-dependent adhesion protein, epithelial
• CAM 120/80
• CD324
• CDHE
• cell-CAM 120/80
• E-cadherin
• ECAD
• LCAM
• liver cell adhesion molecule
• UVO
• uvomorulin

Genomic Location

Normal Function

The CTNND1 gene provides instructions for making a protein called p120-catenin, also known as delta 1 catenin. This protein and others in the catenin family interact with proteins from another family called cadherins. Catenins and cadherins form protein complexes that help cells stick to neighboring cells (cell adhesion) to form organized tissues. In addition to their role in cell adhesion, catenin and cadherin interactions help transmit chemical signals within cells, control cell maturation and movement, and regulate the activity of certain genes.

The p120-catenin protein interacts with a protein called E-cadherin, which is produced from the CDH1 gene. The E-cadherin protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body, including the inside of the eyelids and the mouth. The p120-catenin protein helps keep E-cadherin in its proper place in the cell membrane, preventing it from being taken into the cell through a process called endocytosis and broken down prematurely. Interactions between the two proteins are also important for other cell processes that are involved in the development of the head and face (craniofacial development), including the eyelids and teeth.

Health Conditions Related to Genetic Changes

Blepharocheilodontic syndrome

At least three CTNND1 gene mutations have been identified in people with blepharocheilodontic (BCD) syndrome, a disorder that is present at birth and causes abnormalities mainly affecting the eyelids and mouth. These mutations are thought to prevent the production of the p120-catenin protein or result in an unstable protein that quickly breaks down. A shortage of p120-catenin protein allows E-cadherin to be taken into the cell and destroyed too quickly by endocytosis. A shortage of these proteins disrupts normal development, especially craniofacial development, which is thought to underlie the features of BCD syndrome.

Other Names for This Gene

• cadherin-associated Src substrate
• CAS
• catenin (cadherin-associated protein), delta 1
• CTNND
• delta catenin
• KIAA0384
• p120
• p120 catenin
• p120(CAS)
• p120(CTN)
• P120CAS
• P120CTN

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

BCD syndrome is a rare disorder; its prevalence is unknown. At least 50 affected individuals have been described in the medical literature.