Liebenberg syndrome is a condition that involves abnormal development of the arms, resulting in characteristic arm malformations that can vary in severity. In people with this condition, bones and other tissues in the elbows, forearms, wrists, and hands have characteristics of related structures in the lower limbs. For example, bones in the elbows are abnormally shaped, which affects mobility of the joints. The stiff elbows function more like knees, unable to rotate as freely as elbows normally do. Bones in the wrists are joined together (fused), forming structures that resemble those in the ankles and heels and causing permanent bending of the hand toward the thumb (radial deviation). The bones in the hands (metacarpals) are longer than normal, and the fingers are short (brachydactyly), similar to the proportions of bones found in the feet. In addition, muscles and tendons that are typically found only in the hands and not in the feet are missing in people with Liebenberg syndrome. Affected individuals also have joint deformities (contractures) that limit movement of the elbows, wrists, and hands. Development of the lower limbs is normal in people with this condition.

Individuals with Liebenberg syndrome have no other health problems related to this condition, and life expectancy is normal.

Liebenberg syndrome is caused by genetic changes near the PITX1 gene. The protein produced from this gene plays a critical role in lower limb development by controlling the activity of other genes involved in limb development, directing the shape and structure of bones and other tissues in the legs and feet.

The genetic changes involved in Liebenberg syndrome delete, insert, or rearrange genetic material near the PITX1 gene. These changes affect regions of DNA known as regulatory elements, which help turn on or turn off genes (known as enhancers or repressors, respectively). They control when and where certain genes are active. The mutations that cause Liebenberg syndrome are thought to relocate enhancers that normally promote the activity of genes involved in upper limb development to be near the PITX1 gene, where they can promote its activity. Alternatively, the mutations may remove repressors that normally turn off the PITX1 gene during upper limb development. As a result, the PITX1 gene is abnormally active during development of the upper limbs. Because the PITX1 protein normally directs lower limb structure, bones, muscles, and tendons in the arms and hands develop more like those in the legs and feet, leading to the features of Liebenberg syndrome.

Normal Function

The PITX1 gene provides instructions for making a protein that plays a critical role in development of the lower limbs. The PITX1 protein is found primarily in the developing legs and feet. The protein acts as a transcription factor, which is a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Specifically, PITX1 regulates the activity of genes to direct the shape and structure of tissues in the lower limbs, including the bones, muscles, and tendons (the bands of tissue that connect muscles to bones).

The PITX1 protein is also found in the developing pituitary gland, which is a hormone-producing gland located at the base of the brain, and in an embryonic structure called the branchial arch. The PITX1 protein may play a role in formation of the pituitary gland and tissues derived from the branchial arch, such as the roof of the mouth, the jaw, and parts of the inner ear.

Health Conditions Related to Genetic Changes

Liebenberg syndrome

Changes in the DNA near the PITX1 gene cause Liebenberg syndrome, a rare condition characterized by abnormal development of the arms, resulting in short fingers (brachydactyly), joint deformities called contractures that limit movement of the elbows and wrists, and other bone and muscle abnormalities. These genetic changes delete, insert, or rearrange genetic material near the PITX1 gene; at least five such mutations have been identified in affected individuals. These changes affect regions of DNA known as regulatory elements, which help turn on or turn off genes (known as enhancers or repressors, respectively). They control when and where certain genes are active. The mutations that cause Liebenberg syndrome likely relocate enhancers that promote the activity of genes involved in upper limb development to be near the PITX1 gene. Alternatively, mutations may remove repressors that normally turn off the PITX1 gene during upper limb development. As a result, the PITX1 gene is abnormally active during arm and hand development. Because the PITX1 protein normally directs lower limb structure, bones, muscles, and tendons in the arms and hands develop more like those in the legs and feet, leading to the features of Liebenberg syndrome. Development of the lower limbs is normal in people with this condition.

Other disorders

PITX1 gene mutations have been found to cause lower limb abnormalities, including an inward- and upward-turning foot (clubfoot) and absence or severe shortening of a bone in the lower leg called the tibia (tibial hemimelia). These gene mutations have also been found in people with extra toes (polydactyly), specifically a severe form of the abnormality called mirror-image polydactyly. These mutations delete a large part of the PITX1 gene or the whole gene, or change a single protein building block (amino acid) in the PITX1 protein. Unlike the mutations that cause Liebenberg syndrome (described above), these genetic changes reduce the amount of functional PITX1 protein, which disrupts normal development of the lower limbs. The upper limbs are normal in individuals with these PITX1 gene mutations.

Other Names for This Gene

• BFT
• hindlimb expressed homeobox protein backfoot
• hindlimb-expressed homeobox protein backfoot
• homeobox protein PITX1
• paired-like homeodomain 1
• paired-like homeodomain transcription factor 1
• pituitary homeo box 1
• pituitary homeobox 1
• pituitary otx-related factor
• POTX
• Ptlx
• PTX1

Genomic Location

Liebenberg syndrome is inherited in an autosomal dominant pattern, which means having a genetic change that affects the PITX1 gene on one copy of the chromosome in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Liebenberg syndrome is a rare condition. Fewer than 10 affected families have been described in the medical literature.