3-M syndrome

3-M syndrome
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3-M syndrome is a rare hereditary disorder characterized by severe growth retardation, facial dysmorphia, and skeletal abnormalities.[1] The name 3-M is derived from the initials of the three researchers who first identified it: Miller, McKusick, and Malvaux.[2] Mutations in any one of the following three genes: CUL7, OBSL1, and CCDC8 are responsible for the occurrence of this disorder.[2] It is inherited through an autosomal recessive pattern[2] and considered very rare, so far less than 100 cases worldwide have been identified.[3]

Symptoms

Growth retardation

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.[4]

Facial dysmorphia

Many of the physical features associated with the disorder are congenital. Characteristic craniofacial abnormalities typically include a long, narrow head that is disproportionate to the body size, a broad and prominent forehead, and a triangular-shaped face with a hypoplastic midface, pointed chin, prominent mouth, fleshy tipped upturned nose, large ears, and full lips.[4][5][6] The teeth may be abnormally crowded together in some affected individuals.[6]

Skeletal abnormalities

Skeletal anomalies aren't present at birth but develop in the individual and include delayed bone maturation, slender long tubular bones, and tall vertebral bodies.[7] Joint hyper-mobility and increased risk of hip dislocation has been presented in individuals.[5] Abnormal spinal curvature, either kyhoscholiosis or hyperlordosis, causing back pain can also be experienced from this disorder.[4][5]

Other abnormalities

Additional physical abnormalities include an abnormally short broad neck and thorax, square shoulders, flared shoulder blades, unusual curving of the 5th finger, and prominent heels can be seen in some children.[4][5][6]

In some cases, males have been reported to have impaired fertility due to the reduced production of sex hormones and hypospadias which is when the opening of the urethra is on the underside of the penis instead of the tip. In contrast, females are reported to have normal ovarian function with this disorder.[5][8]

Causes

3-M syndrome is most often caused by a mutation in the gene CUL7, but can also be seen with mutations in the genes OBS1 and CCDC8 at lower frequencies. This is an inheritable disorder and can be passed down from parent to offspring in an autosomal recessive pattern. An individual must receive two copies of the mutated gene,[7] one from each parent, in order to be have 3-M syndrome.[4] 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.[4]

Mechanism

CUL7 mutations

The majority of 3-M syndrome patients have been identified with CUL7 mutations. The Cullin 7 gene contains instructions for making the protein Cullin-7.[2] Cullin-7 acts as scaffold protein in the E3 ubiquitin ligase complex.[7] The role of this complex is to tag damaged and excess proteins in the cell with ubiquitin.[2] Intracellular and extracellular signals within the cell highly regulate when and which proteins are tagged with ubiquitin.[9] Once attached to the protein, ubiquitin serves as a signaling molecule to the proteasomes, which then bind to the ubiquinated proteins and degrades them.[2] This ubiquitin-proteasome system acts as the cell's quality control system by breaking down unwanted proteins.[2] Additionally, the system regulates the level of proteins involved in critical cell activities such as the timing of cell division and growth.[2] Mutations in the CUL7 gene blocks the ability of the cullin-7 protein to bring together the components of this E3 ubiquitin ligase complex.[2] This leads to impaired ubiquination and hence the aggregation of damaged, misfolded, and excess proteins.[2][7] Disruption of the protein degradation process plays a role in the pathogensis of prenatal growth retardation in humans, a key feature of 3-M syndrome.[7] The skeletal abnormalities that are present in individuals with this disorder suggests that this gene may play a role in the endochondral ossification process.[7] Preliminary data suggests that CUL7 is in fact involved in chondrocyte growth and proliferation.[7]

OBS1 and CCDC8 mutations

Not much is known about the mutations in the genes OBS1and CCD8 and their function in growth and development so far.[10] However, the implications of 3M syndrome suggest that both these genes encode for proteins that play a role in the CUL7 ubiquination pathway.[1]

Diagnosis

Due to the fact that many of the abnormalities associated with this disorder are congenital, the presence of these clinical features at birth is usually sufficient to make the diagnosis.[6] Diagnosis is suggested in children with the following: low birth weight, severe growth retardation, typical facial features, and characteristic radiological findings.[11]

  • Radio-graphic findings can show the skeletal malformations characteristic with this disorder, however these can only be seen in the individual after the first two years of life.[11] These usually reveal long bones that are slender, tall vertebral bodies that shorten over time, small pelvic bones, a broad thorax with slender ribs, and delayed bone age in affected individuals.[11]

Molecular genetic testing can be done on the individual to confirm the diagnosis and specify which of the genes were involved.[6] The recommended order of testing the three genes is by the likelihood of a mutation occurring in that gene: 77.5% for CUL7, 16% for OBSL1, and the percentage is unknown for CCDC8 because it is so rare.[11] Three common molecular methods used to test for mutations in a specific gene are a deletion/duplication analysis, targeted variant analysis, or a sequence analysis of the entire coding region.[8]

Prevention

Since 3-M syndrome is a genetic condition there are no known methods to preventing this disorder.[4] However, genetic testing on expecting parents and prenatal testing, which is a molecular test that screens for any problems in the heath of a fetus during pregnancy, may be available for families with a history of this disorder to determine the fetus' risk in inheriting this genetic disorder.[4]

Treatment and prognosis

Treatment of 3-M syndrome is aimed at the specific symptoms presented in each individual.[4] With the various symptoms of this disorder being properly managed and affected individuals having normal mental development, 3-M syndrome is not a life - threatening condition and individuals are able to lead a near normal life with normal life expectancy.[4]

Treatment may involve the coordinated efforts of many healthcare professionals, such as pediatricians, orthopedists, dentists and/or other specialists depending on the symptoms.[4][6]

  • Possible management options for short stature are surgical bone lengthening or growth hormone therapy. [4]
  • Orthopedic techniques and surgery may be used to treat certain skeletal abnormalities.[6]
  • Plastic surgery may also be performed on individuals to help correct certain cranio-facial anomalies.[4]
  • Individuals with dental abnormalities may undergo corrective procedures such as braces or oral surgeries.[6]

Research directions

Recent research has been focused on studying large series of cases of 3-M syndrome to allow scientists to obtain more information behind the genes involved in the development of this disorder. Knowing more about the underlying mechanism can reveal new possibilities for treatment and prevention of genetic disorders like 3-M syndrome.

  • One study looks at 33 cases of 3M syndrome, 23 of these cases were identified as CUL7 mutations: 12 being homozygotes and 11 being heterozygotes.[7] This new research shows genetic heterogeneity in 3M syndrome, in contrast to the clinical homogeneity.[7] Additional studies are still ongoing and will lead to the understanding of this new information.[7]
  • This study provides more insight on the three genes involved in 3M syndrome and how they interact with each other in normal development.[12] It led to the discovery that the CUL7, OBS1, and CCDC8 form a complex that functions to maintain microtubule and genomic integrity.[12]

References

  1. 1 2 Erickson, Robert P; Wynshaw-Boris, Anthony Joseph (2016). Epstein's Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis: 3M Syndrome. Oxford Medicine Online. 3e.d. doi:10.1093/med/9780199934522.001.0001. ISBN 9780199934522.
  2. 1 2 3 4 5 6 7 8 9 10 "3-M syndrome". Genetics Home Reference (GHR). December 12, 2017.
  3. ↑ Holder-Espinasse, Muriel; Irving, Melita; Cormier-Daire, Valérie (March 2, 2011). "Clinical utility gene card for: 3M syndrome". European Journal of Human Genetics. 19 (9). doi:10.1038/ejhg.2011.32. PMC 3179355. PMID 21364696.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Three M Syndrome". DoveMed. November 8, 2016. Retrieved 2017-12-13.
  5. 1 2 3 4 5 Clayton P, Murray P. (February 2014). "3M syndrome". Orphanet.
  6. 1 2 3 4 5 6 7 8 "Three M Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2017-12-13.
  7. 1 2 3 4 5 6 7 8 9 10 Huber, C; Delezoide, A. L; Guimiot, F; Baumann, C; Malan, V; Le Merrer, M; Da Silva, D. B; Bonneau, D; Chatelain, P; Chu, C; Clark, R; Cox, H; Edery, P; Edouard, T; Fano, V; Gibson, K; Gillessen-Kaesbach, G; Giovannucci-Uzielli, M. L; Graul-Neumann, L. M; Van Hagen, J. M; Van Hest, L; Horovitz, D; Melki, J; Partsch, C. J; Plauchu, H; Rajab, A; Rossi, M; Sillence, D; Steichen-Gersdorf, E; et al. (2009). "A large-scale mutation search reveals genetic heterogeneity in 3M syndrome" (PDF). European Journal of Human Genetics. 17 (3): 395–400. doi:10.1038/ejhg.2008.200. PMC 2986175. PMID 19225462.
  8. 1 2 "Three M syndrome 1 - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-07.
  9. ↑ "Ubiquitin - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2017-12-13.
  10. ↑ Hanson, D.; Murray, P. G.; Coulson, T.; Sud, A.; Omokanye, A.; Stratta, E.; Sakhinia, F.; Bonshek, C.; Wilson, L. C. (December 1, 2012). "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling". Journal of Molecular Endocrinology. 49 (3): 267–275. doi:10.1530/jme-12-0034. ISSN 0952-5041. PMID 23018678.
  11. 1 2 3 4 Holder-Espinasse, Muriel (January 26, 2012). "3-M Syndrome". GeneReviews.
  12. 1 2 Yan, Jun; Yan, Feng; Li, Zhijun; Sinnott, Becky; Cappell, Kathryn M; Yu, Yanbao; Mo, Jinyao; Duncan, Joseph A; Chen, Xian; Cormier-Daire, Valerie; Whitehurst, Angelique W; Xiong, Yue (2014-06-05). "The 3M Complex Maintains Microtubule and Genome Integrity". Molecular Cell. 54 (5): 791–804. doi:10.1016/j.molcel.2014.03.047. ISSN 1097-2765. PMC 4165194. PMID 24793695.
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