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3-M syndrome is a autosomal recessive disorder characterized by severe growth retardation, distinctive physical features, and skeletal abnormalities. This disorder is caused by mutations in one of the following three genes: CUL7, OBSL1, and CCDC8. 3M syndrome is very rare, less than 100 cases worldwide have been reported to date.

Symptoms

Individuals with 3-M syndrome suffer from severe prenatal growth retardation due to growth delays during fetal development resulting in a low birth weight. Growth delays continue after birth throughout childhood and adolescence, ultimately leading to a short stature.

Many of the physical features associated with the disorder are congenial. Characteristic craniofacial abnormalities typically include a long, narrow head that is disproportionate to the body size (dolichocephalic), a broad and prominent forehead, and a triangular-shaped face with a hypoplastic midface, pointed chin, prominent mouth, fleshy anteverted nares, large ears, and full lips. In some cases, the teeth may be abnormally crowded together.

Skeletal anomalies aren't present at birth but develop in the individual and include delayed bone age, slender long tubular bones, and tall vertebral bodies. Joint hypermobility and increased risk of hip dislocation has also been presented in individuals. Abnormal spinal curvature, either kyhoscholiosis or hyperloordosis, can cause back pain. Additional abnormalities include an abnormally short broad neck and thorax, square shoulders, flared shoulder blades, clinodactyly of the 5th finger, and prominent heels are seen in some children.

Mental development is unaffected in this disorder.

Diagnosis

Diagnosis is based on the presence of the clinical features associated with the disorder and can be determined shortly after birth. Radio-graphic findings can show the skeletal malformations characteristic of this disorder.

Furthermore, molecular genetic testing can be done on the individual to confirm the diagnosis and specify which of the causal genes was involved. The recommended order of testing the three genes is by the likelihood of that mutation occurring: 77.5% for CUL7, 16% for OBSL1, and the percentage is unknown for CCDC8 because it is so rare.

Causes & Prevention

3-M syndrome is an inheritable autosomal recessive disorder. The individual must receive two copies of the mutated gene from each parent. An individual can be a carrier for the disorder if they inherit only one mutant copy of the gene, but will not present any of the symptoms associated with the disorder.

3-M syndrome is caused by a mutation most often in the gene CUL7, but can also be seen with mutations in the OBS1 and CCDC8 genes at a lower frequency.

Since 3-M syndrome is a genetic condition there is no specific methods to prevent the disorder. However, prenatal testing, which is molecular testing of the fetus during pregnancy, may be available for families with a history of this disorder.

Mechanism

The majority of 3-M syndrome patients have been identified with CUL7 mutations. 3-M syndrome linked to mutations in the Cullin 7 gene, contains instructions for protein expression of Cullin-7. Cullin-7 acts as scaffold protein in the E3 ubiquitin ligase complex. Mutations in the CUL7 gene blocks the ability of the cullin-7 protein to bring together the components of this E3 ubiquitin ligase complex. The complexes role is to tag damaged and excess proteins in the cell with ubiquitin. Ubiquitin serves as a signal molecule for proteasomes, which then bind to the tagged proteins and degrade them. This ubiquitin-proteasome system acts as the cell's quality control system by breaking down unwanted proteins. Additionally, the system regulates the level of proteins involved in critical cell activities such as the timing of cell division and growth. Impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.

The skeletal abnormalities that are present in individuals with this disorder suggests that the CUL7 gene may play a specific role in the endochondral ossification process. Initial research suggests that CUL7 is involved in chondrocyte growth and proliferation.

Treatment & Prognosis

The treatment of 3-M syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), dental specialists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment. In some cases, orthopedic techniques, surgery, and/or other supportive techniques may be used to help treat certain skeletal abnormalities associated with 3-M syndrome. Surgery and/or supportive measures may also be used to help treat or correct certain craniofacial, digital, and/or other abnormalities associated with the disorder. In addition, in affected individuals with dental abnormalities, braces, oral surgery, and/or other corrective techniques may be used to help treat or correct such malformations. Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with 3-M syndrome or heterozygosity for the disorder. Other treatment for 3-M syndrome is symptomatic and supportive.

Recent Research

1. Article focuses on genetic heterogeneity in 3M syndrome, in contrast to the clinical homogeneity. (https://www.nature.com/ejhg/journal/v17/n3/pdf/ejhg2008200a.pdf)
2. Focus on the mutations in the CCDC8 gene that cause 3M syndrome in very rare cases.
3. Research exploring possibilities for treatment and prevention of inherited and acquired genetic disorders.