3-M syndrome

3-M syndrome is a rare genetic disorder characterized by profound short stature, distinctive facial features, and skeletal abnormalities, caused by mutations in the CUL7 and OBSL1 genes.

Overview

3-M syndrome is a disorder that causes skeletal abnormalities including short stature (dwarfism) and unusual facial features. The name of this condition comes from the initials of three researchers who first identified it: Miller, McKusick, and Malvaux.

Individuals with 3-M syndrome grow extremely slowly before birth, and this slow growth continues throughout childhood and adolescence. They have low birth weight and length and remain much smaller than others in their family, growing to an adult height of approximately 4 feet to 4 feet 6 inches (120 centimeters to 130 centimeters). In some affected individuals, the head is normal-sized but looks disproportionately large in comparison with the body. In other people with this disorder, the head has an unusually long and narrow shape (dolichocephaly). Intelligence is unaffected by 3-M syndrome, and life expectancy is generally normal.

Physical Features and Skeletal Abnormalities

In addition to short stature, people with 3-M syndrome have a triangle-shaped face with a broad, prominent forehead and a ; the middle of the face is less prominent. Other common features include large ears, full eyebrows, an upturned nose with a fleshy tip, a long area between the nose and mouth, a prominent mouth, and full lips.

Other skeletal abnormalities that often occur in this disorder include a short, and chest; prominent shoulder blades; and shoulders that slope less than usual (square shoulders). Affected individuals may have such as a rounded upper back that also curves to the side (kyphoscoliosis) or exaggerated curvature of the lower back (hyperlordosis). People with 3-M syndrome can also have unusual curving of the fingers, short fifth (pinky) fingers, , and loose joints. Additional skeletal abnormalities, such as unusually slender long bones in the arms and legs; tall, narrow spinal bones (vertebrae); or slightly delayed bone age may be apparent in x-ray images.

Variant: Yakut Short Stature Syndrome

A variant of 3-M syndrome called Yakut short stature syndrome has been identified in the isolated Yakut population in the Russian province of Siberia. In addition to having most of the physical features characteristic of 3-M syndrome, people with this form of the disorder are often born with breathing problems that can be life-threatening in infancy.

Frequency

The prevalence of 3-M syndrome is unknown. About 100 individuals worldwide with this disorder have been described in the medical literature.

Causes

Mutations in the CUL7 gene cause 3-M syndrome in more than three-quarters of affected individuals, including those in the Yakut population. Mutations in the OBSL1 gene cause about 16 percent of cases of this disorder. Mutations in other genes, some of which have not been identified, account for the remaining cases.

The CUL7 gene provides instructions for making a protein called cullin-7. The cullin-7 protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system. Specifically, cullin-7 helps assemble a complex called an E3 ubiquitin ligase, which tags the unneeded proteins for degradation. The protein produced from the OBSL1 gene is thought to help maintain normal levels of cullin-7.

The ubiquitin-proteasome system helps regulate the level of proteins involved in several critical cell activities such as the timing of cell division and growth. In particular, the proteins produced from the genes associated with 3-M syndrome are thought to help regulate proteins involved in the body's response to growth hormones, although their specific role in this process is unknown.

Mutations in the CUL7 or OBSL1 gene prevent the cullin-7 protein from bringing together the components of the E3 ubiquitin ligase complex, interfering with the process of tagging unneeded proteins for degradation. The body's response to growth hormones may be impaired as a result. However, the specific relationship between CUL7 and OBSL1 gene mutations and the signs and symptoms of 3-M syndrome are unknown.