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Three M Syndrome

Last updated Sept. 3, 2019

Approved by: Maulik P. Purohit MD, MPH


Image of a young boy with Three M Syndrome at 15 (a) and 17.5 (b) years old showing facial dismorphism, short stature, broad thorax, sternum carinatum.

What are the other Names for this Condition? (Also known as/Synonyms)

  • 3M Syndrome
  • Three-M Slender Boned Nanism
  • Yakut Short Stature Syndrome 

What is Three M Syndrome? (Definition/Background Information)

  • Three M Syndrome is a rare, genetic, hereditary disorder characterized by low birth weight, dwarfism (short stature), abnormal facial features, and skeletal abnormalities
  • Distinctive physical features and severe growth retardation are the main characteristics of Three M Syndrome. However, the affected individual’s Intelligence level is not affected and they are able to lead their lives having a normal life expectancy
  • Three M Syndrome is a very rare disorder and only 50 affected individuals have been identified so far all over the world. The condition is caused by mutation in the  CUL7 gene
  • A diagnosis of Three M Syndrome may be established by genetic testing and a thorough physical examination of infant at the time of birth
  • The treatment of the condition is aimed at separately managing each symptom of the condition. There is no effective prevention of Three M Syndrome, since it is an inherited disorder

Who gets Three M Syndrome? (Age and Sex Distribution)

  • Three M Syndrome is in an inherited disorder and symptoms of the disorder are manifested at the time of birth
  • It is a very rare condition; only 50 cases have been diagnosed worldwide so far 

What are the Risk Factors for Three M Syndrome? (Predisposing Factors)

  • The only risk factor associated with Three M Syndrome is the family history of the disorder 

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider. 

What are the Causes of Three M Syndrome? (Etiology)

  • Three M Syndrome is caused by alterations and changes that occur in the CUL7 gene, which is involved in providing instructions to produce a protein called Cullin-7
  • This protein plays an important role in the ubiquitin-protessome system that helps in breaking down unwanted proteins
  • A defect in the CUL7 gene affects the ability of the Cullin-7 protein in attaching other proteins to ubiquitin and subsequently, in the breaking down of unwanted proteins
  • Three M Syndrome is inherited in an autosomal recessive pattern in which both copies of the gene in each cell are affected
  • The parents of the affected individual carry one copy of the damaged gene, but themselves do not exhibit any signs and symptoms of the condition (because both gene copies have to be abnormal in order for the disorder to be manifested) 

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected). 

What are the Signs and Symptoms of Three M Syndrome?

The common signs and symptoms associated with Three M Syndrome include:

  • Low birth weight
  • Very slow growth before birth which continues in the childhood and adolescence
  • Short stature
  • Disproportionate head to the body size; head is narrow and long in shape- dolichocephalic
  • Triangle-shaped face, pointed chin
  • Broad and prominent forehead
  • Large ears
  • Full eyebrows
  • Upturned nose with a fleshy tip
  • Philtrum - a greater distance between the nose and mouth
  • Prominent mouth, full lips
  • Abnormal formation of the teeth
  • Short, broad neck and chest; prominent shoulders
  • Abnormal spinal curvature such as:
    • Kyphoscoliosis -  the back is curved to the sides
    • Hyperlordosis - unusual curving or bending of the lower back
  • Clinodactyly (unusual curving of the fingers), short fifth finger
  • Prominent heels
  • Loose joints, slender long bones in the arms and legs
  • Tall and narrow vertebrae
  • Delayed bone age 

How is Three M Syndrome Diagnosed?

Three M Syndrome is usually diagnosed shortly after birth or within a few days of birth.

  • A clinical evaluation of the signs and symptoms are usually sufficient to make the diagnosis
  • Specialized x-ray studies can help discover the various abnormalities associated with the disorder
  • Genetic testing can help confirm the disorder
  • Some children with Three M Syndrome have higher levels of insulin-like growth factor-1 (IGF-1), but the growth hormone levels are normal 

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis. 

What are the possible Complications of Three M Syndrome?

Complications associated with Three M Syndrome include:

  • Hypogonadism: Reduced production of sex hormones
  • Hypospadias: Urethral opening is present on the underside of the penis
  • Aneurysms: Clots may develop in the blood vessel walls of the brain
  • Scoliosis: A musculoskeletal disorder characterized by sideways curving of the spine
  • Intrauterine growth retardation: Slow growth rate of the fetus in the womb during pregnancy
  • Dwarfism
  • Kyphosis: A condition marked by outward curvature of the spine causing hunching or Dowager’s hump
  • Skull bossing: Bones of the skull are bigger than normal
  • Clinodactyly: Fifth finger curves towards the fourth finger

How is Three M Syndrome Treated?

The treatment of Three M Syndrome is aimed at treating each symptom separately. The treatment measures may involve:

  • The coordinated efforts of many specialists are involved in the treatment of Three M Syndrome. These include:
    • Pediatricians
    • Orthopedists (physicians specializing in skeletal disorder)
    • Dental specialist     
    • Other healthcare professionals
  • The following treatment methods are used to treat certain specific skeletal abnormalities:
    • Orthopedic techniques
    • Surgery, which is advised in the treatment of certain craniofacial, digital, and other abnormalities
    • Other supportive techniques and therapy
  • For dental abnormalities
    • Braces
    • Oral surgery   
    • Other corrective techniques
  • Regular follow-up efforts should be done to assess the improvements in the symptoms associated with Three M Syndrome
  • Surgical bone lengthening may be one of the treatment methods.
  • Individuals with short stature can be benefitted through the use of adaptive aids and physiotherapy. Children with short stature can also be treated with recombinant growth hormone
  • Use of joint laxity should help in controlling the development of arthritis
  • Males with this disease should undergo endocrinological evaluation for associated hypogonadism and fertility issues
  • Genetic counseling will be very useful for the affected individuals and their families 

How can Three M Syndrome be Prevented?

  • Currently, there are no specific methods or guidelines to prevent Three M Syndrome, since it is a genetic condition
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders 

What is the Prognosis of Three M Syndrome? (Outcomes/Resolutions)

  • Three M Syndrome is a very rare disorder and the various symptoms associated with it may be appropriately managed
  • The intelligence level of the child is not affected, and hence, individuals are able to lead a near normal life with normal life expectancy

Additional and Relevant Useful Information for Three M Syndrome:

  • The name of this disorder is derived from the first letters of 3 researchers who were instrumental in discovering this disorder namely, Miller, McKusick, and Malvaux
  • Another disorder that is almost similar to Three M Syndrome with minor differences in the symptoms is Yakut short stature syndrome in which the affected individual is born with respiratory problems that can be fatal
  • The European Society for Pediatric Endocrinology (ESPE) is undergoing research on the complex mix of proteins associated with CUL7 and OBSL1 genes, which contribute to the growth of humans

What are some Useful Resources for Additional Information?

References and Information Sources used for the Article:

Helpful Peer-Reviewed Medical Articles:

Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: Aug. 25, 2015
Last updated: Sept. 3, 2019