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3-M syndrome

MedGen UID:
336440
Concept ID:
C1848862
Disease or Syndrome
Synonyms: 3-MSBN; 3M SYNDROME; Three M syndrome; Three-M slender-boned nanism
SNOMED CT: 3-M syndrome (702342007); 3M syndrome (702342007); Le Merrer syndrome (702342007); Miller-McKusick-Malvaux syndrome (702342007); Dolichospondylic dysplasia (702342007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Related genes: CCDC8, OBSL1, CUL7
 
Monarch Initiative: MONDO:0007477
OMIM®: 273750
OMIM® Phenotypic series: PS273750
Orphanet: ORPHA2616

Disease characteristics

Excerpted from the GeneReview: 3-M Syndrome
3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias. [from GeneReviews]
Authors:
Rhoda Akilapa  |  Melita Irving  |  Muriel Holder-Espinasse   view full author information

Additional descriptions

From OMIM
3M syndrome is an autosomal recessive disorder characterized by distinctive facial features, severe prenatal and postnatal growth retardation, and normal mental development. The main skeletal anomalies are long, slender tubular bones, reduced anteroposterior diameter of the vertebral bodies, and delayed bone age. Other skeletal manifestations include joint hypermobility, joint dislocation, winged scapulae, and pes planus (summary by Badina et al., 2011). Genetic Heterogeneity of 3M Syndrome Also see 3M syndrome-2 (3M2; 612921), caused by mutation in the OBSL1 gene (610991) on chromosome 2q35, and 3M syndrome-3 (3M3; 614205), caused by mutation in the CCDC8 gene (614145) on chromosome 19q13.  http://www.omim.org/entry/273750
From MedlinePlus Genetics
3-M syndrome is a disorder that causes skeletal abnormalities including short stature (dwarfism) and unusual facial features. 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 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.

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.  https://medlineplus.gov/genetics/condition/3-m-syndrome

Professional guidelines

PubMed

Akalın A, Özalkak Ş, Yıldırım R, Karakaya AA, Kolbaşı B, Durmuşalioğlu EA, Kökali F, Ürel-Demir G, Öz V, Ünal E, Atik T, Şimşek-Kiper PÖ, Elcioglu NH
Eur J Pediatr 2024 Dec 7;184(1):68. doi: 10.1007/s00431-024-05855-2. PMID: 39643721
Karacan Küçükali G, Keskin M, Aycan Z, Savaş-Erdeve Ş, Çetinkaya S
Eur J Med Genet 2023 Oct;66(10):104828. Epub 2023 Sep 4 doi: 10.1016/j.ejmg.2023.104828. PMID: 37673300
Holder-Espinasse M, Irving M, Cormier-Daire V
Eur J Hum Genet 2014 Apr;22(4) Epub 2013 Jul 31 doi: 10.1038/ejhg.2013.156. PMID: 23900270Free PMC Article

Recent clinical studies

Etiology

Akalın A, Özalkak Ş, Yıldırım R, Karakaya AA, Kolbaşı B, Durmuşalioğlu EA, Kökali F, Ürel-Demir G, Öz V, Ünal E, Atik T, Şimşek-Kiper PÖ, Elcioglu NH
Eur J Pediatr 2024 Dec 7;184(1):68. doi: 10.1007/s00431-024-05855-2. PMID: 39643721
Meazza C, Lausch E, Pagani S, Bozzola E, Calcaterra V, Superti-Furga A, Silengo M, Bozzola M
Ital J Pediatr 2013 Mar 21;39:21. doi: 10.1186/1824-7288-39-21. PMID: 23517720Free PMC Article
Demir K, Altıncık A, Böber E
J Pediatr Endocrinol Metab 2013;26(1-2):147-50. doi: 10.1515/jpem-2012-0239. PMID: 23457316
Badina A, Pejin Z, Odent T, Buzescu A, Huber C, Cormier-Daire V, Glorion C, Pannier S
Clin Dysmorphol 2011 Apr;20(2):114-116. doi: 10.1097/MCD.0b013e328343f958. PMID: 21383554
Mueller RF, Buckler J, Arthur R, Bonsor G, Dear P, Walters K, Towns GM
J Med Genet 1992 Jun;29(6):425-7. doi: 10.1136/jmg.29.6.425. PMID: 1619640Free PMC Article

Diagnosis

Karacan Küçükali G, Keskin M, Aycan Z, Savaş-Erdeve Ş, Çetinkaya S
Eur J Med Genet 2023 Oct;66(10):104828. Epub 2023 Sep 4 doi: 10.1016/j.ejmg.2023.104828. PMID: 37673300
HabibUllah H, Al-Baradie R, Bashir S
Am J Case Rep 2019 Jan 9;20:36-38. doi: 10.12659/AJCR.912736. PMID: 30622233Free PMC Article
Holder-Espinasse M, Irving M, Cormier-Daire V
Eur J Hum Genet 2014 Apr;22(4) Epub 2013 Jul 31 doi: 10.1038/ejhg.2013.156. PMID: 23900270Free PMC Article
Clayton PE, Hanson D, Magee L, Murray PG, Saunders E, Abu-Amero SN, Moore GE, Black GC
Clin Endocrinol (Oxf) 2012 Sep;77(3):335-42. doi: 10.1111/j.1365-2265.2012.04428.x. PMID: 22624670
Badina A, Pejin Z, Odent T, Buzescu A, Huber C, Cormier-Daire V, Glorion C, Pannier S
Clin Dysmorphol 2011 Apr;20(2):114-116. doi: 10.1097/MCD.0b013e328343f958. PMID: 21383554

Therapy

Karacan Küçükali G, Keskin M, Aycan Z, Savaş-Erdeve Ş, Çetinkaya S
Eur J Med Genet 2023 Oct;66(10):104828. Epub 2023 Sep 4 doi: 10.1016/j.ejmg.2023.104828. PMID: 37673300
Lee IK, Lim HH, Kim YM
Yonsei Med J 2020 Nov;61(11):981-985. doi: 10.3349/ymj.2020.61.11.981. PMID: 33107243Free PMC Article
Guo MH, Shen Y, Walvoord EC, Miller TC, Moon JE, Hirschhorn JN, Dauber A
Horm Res Paediatr 2014;82(1):44-52. Epub 2014 Jun 20 doi: 10.1159/000360857. PMID: 24970356Free PMC Article
Meazza C, Lausch E, Pagani S, Bozzola E, Calcaterra V, Superti-Furga A, Silengo M, Bozzola M
Ital J Pediatr 2013 Mar 21;39:21. doi: 10.1186/1824-7288-39-21. PMID: 23517720Free PMC Article
Clayton PE, Hanson D, Magee L, Murray PG, Saunders E, Abu-Amero SN, Moore GE, Black GC
Clin Endocrinol (Oxf) 2012 Sep;77(3):335-42. doi: 10.1111/j.1365-2265.2012.04428.x. PMID: 22624670

Prognosis

Lee IK, Lim HH, Kim YM
Yonsei Med J 2020 Nov;61(11):981-985. doi: 10.3349/ymj.2020.61.11.981. PMID: 33107243Free PMC Article
Hu L, Wang X, Jin T, Han Y, Liu J, Jiang M, Yan S, Fu X, An B, Huang S
J Clin Lab Anal 2020 Jul;34(7):e23265. Epub 2020 Mar 6 doi: 10.1002/jcla.23265. PMID: 32141654Free PMC Article
Pulavarti SV, Huang YJ, Pederson K, Acton TB, Xiao R, Everett JK, Prestegard JH, Montelione GT, Szyperski T
J Struct Funct Genomics 2014 Dec;15(4):209-14. Epub 2014 Jul 3 doi: 10.1007/s10969-014-9185-y. PMID: 24989974Free PMC Article
Meazza C, Lausch E, Pagani S, Bozzola E, Calcaterra V, Superti-Furga A, Silengo M, Bozzola M
Ital J Pediatr 2013 Mar 21;39:21. doi: 10.1186/1824-7288-39-21. PMID: 23517720Free PMC Article
Demir K, Altıncık A, Böber E
J Pediatr Endocrinol Metab 2013;26(1-2):147-50. doi: 10.1515/jpem-2012-0239. PMID: 23457316

Clinical prediction guides

Akalın A, Özalkak Ş, Yıldırım R, Karakaya AA, Kolbaşı B, Durmuşalioğlu EA, Kökali F, Ürel-Demir G, Öz V, Ünal E, Atik T, Şimşek-Kiper PÖ, Elcioglu NH
Eur J Pediatr 2024 Dec 7;184(1):68. doi: 10.1007/s00431-024-05855-2. PMID: 39643721
Karacan Küçükali G, Keskin M, Aycan Z, Savaş-Erdeve Ş, Çetinkaya S
Eur J Med Genet 2023 Oct;66(10):104828. Epub 2023 Sep 4 doi: 10.1016/j.ejmg.2023.104828. PMID: 37673300
Hu L, Wang X, Jin T, Han Y, Liu J, Jiang M, Yan S, Fu X, An B, Huang S
J Clin Lab Anal 2020 Jul;34(7):e23265. Epub 2020 Mar 6 doi: 10.1002/jcla.23265. PMID: 32141654Free PMC Article
Pulavarti SV, Huang YJ, Pederson K, Acton TB, Xiao R, Everett JK, Prestegard JH, Montelione GT, Szyperski T
J Struct Funct Genomics 2014 Dec;15(4):209-14. Epub 2014 Jul 3 doi: 10.1007/s10969-014-9185-y. PMID: 24989974Free PMC Article
Meazza C, Lausch E, Pagani S, Bozzola E, Calcaterra V, Superti-Furga A, Silengo M, Bozzola M
Ital J Pediatr 2013 Mar 21;39:21. doi: 10.1186/1824-7288-39-21. PMID: 23517720Free PMC Article

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