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Genetics Home Reference: your guide to understanding genetic conditions
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3-M syndrome

Reviewed June 2008

What is 3-M syndrome?

3-M syndrome is a disorder that causes short stature (dwarfism), unusual facial features, and skeletal abnormalities. 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 120 centimeters to 130 centimeters (4 feet to 4 feet 6 inches). Affected individuals have a normally sized head that looks disproportionately large in comparison with their body. The head may be unusually long and narrow in shape (dolichocephalic).

In addition to short stature, people with 3-M syndrome have a triangle-shaped face with a broad, prominent forehead (frontal bossing) and a pointed chin; the middle of the face is less prominent (hypoplastic midface). They may have large ears, full eyebrows, an upturned nose with a fleshy tip, a long area between the nose and mouth (philtrum), a prominent mouth, and full lips.

Affected individuals may have a short, broad neck and chest with prominent shoulder blades and square shoulders. They may have abnormal spinal curvature 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 may also have unusual curving of the fingers (clinodactyly), short fifth (pinky) fingers, prominent heels, and loose joints. Other 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.

3-M syndrome can also affect other body systems. Males with 3-M syndrome may produce reduced amounts of sex hormones (hypogonadism) and occasionally have the urethra opening on the underside of the penis (hypospadias). People with this condition may be at increased risk of developing bulges in blood vessel walls (aneurysms) in the brain. Intelligence is unaffected by 3-M syndrome, and life expectancy is generally normal.

A variant of 3-M syndrome called Yakut short stature syndrome has been identified in an isolated population in 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 respiratory problems that can be life-threatening in infancy.

How common is 3-M syndrome?

3-M syndrome is a rare disorder. About 50 individuals with this disorder have been identified worldwide.

What genes are related to 3-M syndrome?

Mutations in the CUL7 gene cause 3-M syndrome. The CUL7 gene provides instructions for making a protein called cullin-7. This protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system.

Cullin-7 helps to assemble a complex known as an E3 ubiquitin ligase. This complex tags damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth.

Mutations in the CUL7 gene that cause 3-M syndrome disrupt the ability of the cullin-7 protein to bring together the components of the E3 ubiquitin ligase complex, interfering with the process of tagging other proteins with ubiquitin (ubiquitination). It is not known how impaired ubiquitination results in the specific signs and symptoms of 3-M syndrome.

Related Gene(s)

Changes in this gene are associated with 3-M syndrome.

  • CUL7

How do people inherit 3-M syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of 3-M syndrome?

These resources address the diagnosis or management of 3-M syndrome and may include treatment providers.

  • Gene Review: 3-M Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1481/)
  • Genetic Testing Registry: Three M syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1848862)

You might also find information on the diagnosis or management of 3-M syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/3-m-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/3-m-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about 3-M syndrome?

You may find the following resources about 3-M syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for 3-M syndrome?

  • dolichospondylic dysplasia
  • Le Merrer syndrome
  • 3-MSBN
  • three-M slender-boned nanism
  • three M syndrome
  • Yakut short stature syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about 3-M syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding 3-M syndrome?

autosomal ; autosomal recessive ; cell ; cell division ; clinodactyly ; degrade ; dwarfism ; dysplasia ; gene ; hypogonadism ; hypospadias ; inherited ; kyphoscoliosis ; ligase ; philtrum ; population ; proteasome ; protein ; recessive ; respiratory ; short stature ; stature ; syndrome ; ubiquitin

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Huber C, Dias-Santagata D, Glaser A, O'Sullivan J, Brauner R, Wu K, Xu X, Pearce K, Wang R, Uzielli ML, Dagoneau N, Chemaitilly W, Superti-Furga A, Dos Santos H, Mégarbané A, Morin G, Gillessen-Kaesbach G, Hennekam R, Van der Burgt I, Black GC, Clayton PE, Read A, Le Merrer M, Scambler PJ, Munnich A, Pan ZQ, Winter R, Cormier-Daire V. Identification of mutations in CUL7 in 3-M syndrome. Nat Genet. 2005 Oct;37(10):1119-24. Epub 2005 Sep 4. (http://www.ncbi.nlm.nih.gov/pubmed/16142236?dopt=Abstract)
  • Maksimova N, Hara K, Miyashia A, Nikolaeva I, Shiga A, Nogovicina A, Sukhomyasova A, Argunov V, Shvedova A, Ikeuchi T, Nishizawa M, Kuwano R, Onodera O. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. J Med Genet. 2007 Dec;44(12):772-8. Epub 2007 Aug 3. (http://www.ncbi.nlm.nih.gov/pubmed/17675530?dopt=Abstract)
  • Marik I, Marikova O, Kuklik M, Zemkova D, Kozlowski K. 3-M syndrome in two sisters. J Paediatr Child Health. 2002 Aug;38(4):419-22. (http://www.ncbi.nlm.nih.gov/pubmed/12174011?dopt=Abstract)
  • Temtamy SA, Aglan MS, Ashour AM, Ramzy MI, Hosny LA, Mostafa MI. 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol. 2006 Apr;15(2):55-64. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16531729?dopt=Abstract)
  • van der Wal G, Otten BJ, Brunner HG, van der Burgt I. 3-M syndrome: description of six new patients with review of the literature. Clin Dysmorphol. 2001 Oct;10(4):241-52. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11665997?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2008
Published: July 21, 2014