Oculofaciocardiodental syndrome

Oculofaciocardiodental (OFCD) syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-), and teeth (dental). 

The eye abnormalities associated with OFCD syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a high risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.

People with OFCD syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes, droopy eyelids (ptosis), and a nose with a high bridge and broad tip. Affected individuals may have a split (cleft) in their nose or in the roof of their mouth (cleft palate).

Heart defects are another common feature of OFCD syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).

Teeth with very large roots (radiculomegaly) are characteristic of OFCD syndrome. Additional dental abnormalities can include the delayed loss of primary (baby) teeth, missing or abnormally small teeth, delayed teething (dentition), misaligned teeth, and defective tooth enamel.

Individuals with OFCD syndrome can have additional features, such as skeletal abnormalities (typically affecting the toes), hearing loss, and intellectual disabilities. 

OFCD syndrome is very rare; the incidence is estimated to be less than 1 in 1 million people.

Variants (also called mutations) in the BCOR gene cause OFCD syndrome. The BCOR gene provides instructions for making a protein called the BCL6 corepressor. This protein helps regulate the activity of other genes. Specifically, the BCL6 corepressor appears to play an important role in regulating genes during early development, particularly those that are involved in the formation of the eye and other organs and tissues.

The variants in the BCOR gene that cause OFCD syndrome prevent the production of any functional BCL6 corepressor protein. As a result, gene regulation during development is disrupted, which impairs the normal development of the eyes and several other organs and tissues before birth.

OFCD syndrome is inherited in an X-linked dominant pattern. The BCOR gene is located on the X chromosome, which is one of the two sex chromosomes. In individuals who have two X chromosomes (typical for females), a variant in one of the two copies of the gene in each cell is sufficient to cause the disorder. As a result, some cells produce a normal amount of BCL6 corepressor protein and other cells produce none, leading to about half the normal amount of protein.

No individuals with only one X chromosome (typical for males) have been born with OFCD syndrome. A BCOR gene variant in the only copy of the gene would cause a complete lack of BCL6 corepressor protein, and this is thought to be lethal very early in development.