Terminal osseous dysplasia

Terminal osseous dysplasia is a rare genetic disorder characterized by skeletal abnormalities and specific skin changes, occurring exclusively in females.

Overview

Terminal osseous dysplasia is a disorder primarily involving skeletal abnormalities and certain skin changes. It is a member of a group of related conditions called otopalatodigital spectrum disorders. In general, these disorders involve hearing loss caused by malformations in tiny bones in the ears (ossicles), problems in the development of the roof of the mouth (palate), and skeletal abnormalities involving the fingers or toes (digits), although not every condition in the spectrum has all of these features.

This condition occurs only in females; males with the condition do not survive to birth.

Symptoms

The skeletal and skin manifestations of terminal osseous dysplasia include:

• Camptodactyly: Permanently bent fingers and toes.
• Skeletal underdevelopment: Hypoplasia, shortening, or fusion of the bones in the wrists and hands.
• Bone abnormalities: Abnormalities in the outer layer of bone (cortex) in other parts of the skeleton, bowed arms or legs, or shorter stature than peers.
• Skin changes: Dark patches of skin on the face, often near the temples.
• Fibromas: Benign tumors on the fingers or toes in infants, which may reappear after removal but tend to resolve in childhood.
• Other signs: Extra oral frenulae (tissue connecting lips to gums), widely spaced eyes, hair loss, and potential cardiac septal defects.

Causes

Terminal osseous dysplasia is caused by a mutation in the FLNA gene. This gene provides instructions for producing the protein filamin A, which helps build the cytoskeleton that gives structure to cells and allows them to change shape, move, and interact with neighboring cells. The mutation alters the blueprint for filamin A, resulting in an abnormally short protein that cannot interact with other molecules normally, disrupting skeletal development and cell growth.

Inheritance

This condition is inherited in an X-linked dominant pattern. Because the FLNA gene is on the X chromosome, a mutation in one copy is sufficient to cause the disorder in females. In males, who have only one X chromosome, the mutation is lethal early in development. In females, skewed X-inactivation allows for the expression of the normal copy of the FLNA gene in most cells, which is believed to be why affected females survive to birth.