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3M syndrome

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Alternate names

Three M syndrome; Gloomy face syndrome; 3M1; Dolichospondylic dysplasia; Le Merrer syndrome; 3-MSBN; Three-M slender-boned nanism; Yakut short stature syndrome; 3-M syndrome

Definition

3M syndrome is a growth disorder that causes short stature, characteristic facial features, and skeletal abnormalities. Intelligence is normal.

Summary

  • The name of this condition comes from the initials of three researchers who first identified it: Miller, McKusick, and Malvaux.
  • 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.

Epidemiology

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

Cause

  • 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.

Gene mutations

  • 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

  • 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.
  • 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).
  • Other common features include 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.
  • Other skeletal abnormalities that often occur in this disorder include a short, broad neck and chest; prominent shoulder blades; and shoulders that slope less than usual (square shoulders). Affected individuals 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 can also have unusual curving of the fingers (clinodactyly), short fifth (pinky) fingers, prominent heels, 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

  • Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
  • Anteverted nares(Nasal tip, upturned)
  • Broad forehead(Increased width of the forehead)
  • Bulbous nose
  • Delayed skeletal maturation(Delayed bone maturation)
  • Everted lower lip vermilion(Drooping lower lip)
  • Frontal bossing
  • Hypoplastic ischia
  • Hypoplastic pelvis
  • Hypoplastic pubic bone
  • Increased vertebral height
  • Intrauterine growth retardation(Prenatal growth deficiency)
  • Midface retrusion(Decreased size of midface)
  • Rocker bottom foot(Rocker bottom feet)
  • Scapular winging(Winged shoulder blade)
  • Short neck(Decreased length of neck)
  • Short stature(Decreased body height)
  • Slender long bone(Long bones slender)
  • Thick eyebrow(Bushy eyebrows)
  • Triangular face(Face with broad temples and narrow chin)

30%-79% of people have these symptoms

  • Abnormality of dental enamel(Abnormal tooth enamel)
  • Abnormality of the elbow(Abnormality of the elbows)
  • Delayed eruption of teeth(Delayed eruption)
  • Dolichocephaly(Long, narrow head)
  • Enlarged thorax(Wide rib cage)
  • Horizontal ribs
  • Hyperlordosis(Prominent swayback)
  • Hypoplasia of the ulna(Underdeveloped inner large forearm bone)
  • Joint hyperflexibility(Joints move beyond expected range of motion)
  • Long philtrum
  • Micromelia(Smaller or shorter than typical limbs)
  • Pointed chin(Pointy chin)
  • Protruding ear(Prominent ear)
  • Short thorax(Shorter than typical length between neck and abdomen)
  • Thin ribs(Slender ribs)

Diagnosis

The diagnosis of three M syndrome is established in a proband with characteristic clinical and radiographic features. Identification of biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 can establish the diagnosis if clinical and radiographic features are inconclusive.[1][1]. Clinical features

  • Short stature of prenatal onset . Typical height is -5.0 SDS (standard deviation score) .
  • Facial features. Relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, full lips, and pointed chin. Facial appearance varies among affected individuals .
  • Musculoskeletal features. Short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or isolated joint hypermobility, prominent heels, and pes planus
  • Genitourinary anomalies in males. Hypogonadism and hypospadias
  • Intelligence. Usually unaffected

Radiographic features are subtle and may include the following (most often present after age 2 years):

  • Long bones are slender with diaphyseal constriction and flared metaphyses. The femoral necks can be short.
  • Vertebral bodies are tall with reduced anterior-posterior and transverse diameter (especially in the lumbar region), anterior wedging of the thoracic vertebral bodies, and irregular upper and lower endplates; thoracic kyphoscoliosis; spina bifida occulta.
  • Thorax is relatively broad with slender, horizontal ribs.
  • Pelvic bones are small, especially the pubis and the ischium. The iliac wings are flared and the obturator foramina are small, although the latter may be positional.
  • Bone age is slightly delayed. There is a high metacarpal index.
  • Other findings include dolichocephaly, flattened coronal suture, narrowed intraorbital distance, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, dislocated hips, and prominent talus.

Treatment

  • Surgical bone lengthening may be an option.
  • Adaptive aids for people with short stature are appropriate.
  • Significant joint laxity should prompt orthopedic evaluation and measures to control the development of arthritis.
  • Males with three M syndrome should be referred for endocrinologic evaluation regarding gonadal function at puberty.[2][2].


References

  1. Irving M, Holder-Espinasse M. Three M Syndrome. 2002 Mar 25 [Updated 2019 Feb 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1481/
  2. Irving M, Holder-Espinasse M. Three M Syndrome. 2002 Mar 25 [Updated 2019 Feb 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1481/


NIH genetic and rare disease info

3M syndrome is a rare disease.


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