Última actualización:
June 11, 2012
Años publicados: 1997, 1998, 1999, 2006, 2009, 2012
NORD gratefully acknowledges Dr. Muriel Holder-Espinasse, Service de Genetique Clinique, Hopital Jeanne de Flandre, France, for assistance in the preparation of this report.
Summary
Three M syndrome is an extremely rare genetic disorder characterized by low birth weight, short stature (dwarfism), characteristic abnormalities of the head and facial (craniofacial) area, distinctive skeletal malformations, and/or other physical abnormalities. Characteristic craniofacial malformations typically include a long, narrow head (dolichocephaly), an unusually prominent forehead (frontal bossing), and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. In addition, in some affected children, the teeth may be abnormally crowded together; as a result, the upper and lower teeth may not meet properly (malocclusion). Skeletal abnormalities associated with the disorder include unusually thin bones, particularly the shafts of the long bones of the arms and legs (diaphyses); abnormally long, thin bones of the spinal column (vertebrae); and/or distinctive malformations of the ribs and shoulder blades (scapulae). Affected individuals may also have additional abnormalities including permanent fixation of certain fingers in a bent position (clinodactyly), unusually short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints. The range and severity of symptoms and physicial features may vary from case to case. Intelligence appears to be normal. Three M syndrome is inherited as an autosomal recessive genetic trait.
Introduction
The name «three M» refers to the last initials of three researchers (J.D. Miller, V.A. McKusick, P. Malvaux) who were among the first to identify the disorder and report their findings in the medical literature in 1972.
Three M syndrome is an extremely rare inherited disorder characterized by low birth weight, delayed bone age, and short stature; characteristic malformations of the head and facial (craniofacial) area; and/or finger (digital) and/or skeletal malformations.
In most cases, infants with Three M syndrome are unusually small and have a low birth weight despite being carried to term. This is due to growth delays during fetal development (intrauterine growth retardation). Growth delays and immature bone development (growth retardation and delayed bone maturation) typically continue after birth (postnatally), leading to short stature (dwarfism) with proportional development of the arms and legs (as opposed to short stature with abnormally small arms and legs [short-limbed dwarfism]).
Many affected infants also have distinctive abnormalities of the head and facial (craniofacial) area. In most cases, premature closure of fibrous joints (sagittal sutures) between certain bones (parietal bones) of the skull may restrict lateral growth of the head, causing it to appear abnormally long and narrow (dolichocephaly). In addition, the forehead may be abnormally prominent (frontal bossing), and the face may be triangular shaped with a prominent, pointed chin. Infants with the disorder may also have abnormally flat cheeks and cheekbones (malar area), large ears, a prominent mouth with widely spread (patulous) lips, and/or underdeveloped upper jaw bones (maxillary hypoplasia). In addition, in some cases, the teeth may be abnormally crowded together, particularly toward the front of the mouth (anterior crowding); as a result, the upper and lower teeth may not meet properly (malocclusion).
In many infants with Three M syndrome, the neck may be abnormally short and wide, the muscles that cover the upper, back portion of the neck and shoulders (trapezius muscles) may be unusually large and prominent, and the shoulders may appear square and high with wide, flared shoulder blades (winged scapulae). In many cases, affected individuals may also have additional skeletal malformations. For example, the shafts of the long bones (diaphyses) of the arms and legs may be abnormally slender, a condition that tends to become more pronounced with age. The ribs may be narrow, with abnormal, thin depressions (grooves) above their edges (costal margins). Due to abnormalities of the elongated bone forming the middle portion of the chest (sternum), the chest may be abnormally short and/or may appear sunken (pectus excavatum) or unusually prominent (pectus carinatum). Affected infants may also have malformations of bones of the spinal column (vertebrae) including abnormally long, thin vertebrae. In some cases, additional skeletal malformations may include abnormal smallness of bones of the hips (ischium) and the pubic area. In a few cases, affected infants may have a malformation of the spinal column in which incomplete closure of certain vertebrae leaves a portion of the spinal cord exposed (spina bifida). (For more information on this condition, please choose «Spina Bifida» as your search term in the Rare Disease Database.)
In some cases, individuals with Three M syndrome may have additional abnormalities. Affected individuals may have permanent fixation of certain fingers in a bent position (clinodactyly), abnormally short fifth fingers, and/or increased flexibility (hyperextensibility) of the joints.
In some cases, individuals who carry a single copy of the disease gene for Three M syndrome (heterozygotes) may exhibit some of the physical findings associated with the disorder. Such findings are typically milder than those associated with full expression of the disorder. Such individuals (heterozygotes) may exhibit subtle craniofacial abnormalities, abnormally thin bones, and/or unusually prominent ankle bones (talus).
Three M syndrome is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Individuals who carry a single copy of the defective gene for Three M syndrome (heterozygotes) may exhibit some mild physical findings associated with the disorder (e.g., subtle craniofacial abnormalities and/or unusually slender bones). Mutations in one of three genes are now known to cause 3-M syndrome: CUL7, OBSL1, and CCDC8. Because mutations in the three genes identified to date do not account for 100% of patients affected with 3-M syndrome, it is postulated that mutations of other genes (potentially members of the same pathway) may be involved.
Three M syndrome is an extremely rare inherited disorder that appears to affect males and females in equal numbers. Approximately 25 cases have been reported in the medical literature since the disorder was first described in 1972.
In some cases, growth retardation and/or other characteristic findings suggestive of Three M syndrome may be detected before birth (prenatally) by ultrasound. In fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus.
In most cases, Three M syndrome is diagnosed shortly after birth, based upon a thorough clinical evaluation, identification of characteristic physical findings (e.g., low birth weight, short stature, characteristic craniofacial and skeletal malformations, etc.), and/or a variety of specialized tests, such as advanced imaging techniques. Specialized x-ray studies may detect, confirm, and/or characterize certain craniofacial malformations (e.g., dolicocephaly, maxillary hypoplasia) as well as other skeletal abnormalities often associated with the disorder such as distinctive malformations of the vertebrae, the long bones, the ribs, and/or the shoulder blades. It is possible that the diagnosis is made later during infancy, since the clinical and radiological anomalies can appear secondarily.
Molecular genetic testing for mutations in th. CUL7 (77.5 %), OBSL1 (16%) or CCDC8 (rare) genes is available to confirm a suspected diagnosis.
Treatment
The treatment of Three M syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), dental specialists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
In some cases, orthopedic techniques, surgery, and/or other supportive techniques may be used to help treat certain skeletal abnormalities associated with Three M syndrome. Surgery and/or supportive measures may also be used to help treat or correct certain craniofacial, digital, and/or other abnormalities associated with the disorder. In addition, in affected individuals with dental abnormalities, braces, oral surgery, and/or other corrective techniques may be used to help treat or correct such malformations.
Genetic counseling will be of benefit for affected individuals and their families. Family members of affected individuals should also receive regular clinical evaluations to detect any symptoms and physical characteristics that may be potentially associated with Three M syndrome or heterozygosity for the disorder. Other treatment for Three M syndrome is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
Contact for additional information about three M syndrome:
Dr. Muriel Holder-Espinasse
Service de Génétique Clinique
Hôpital Jeanne de Flandre
CHRU
Lille, France
Clinical Genetics Department
Guy’s Hospital
London SE1 9RT
UK
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., craniofacial malformations, short stature, skeletal abnormalities, etc.].)
TEXTBOOKS
Schmandt S, Pearl PL. 3-M Syndrome. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:259.
Buyse ML. Editor-in-Chief. Birth Defects Encyclopedia.Cambridge, MA: Blackwell Scientific Publications; 1990:1545.
Gorlin RJ, Cohen MM Jr., Levin LS, Eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press;1990:319-20.
JOURNAL ARTICLES
Holder-Espinasse M, Irving M, Cormier-Daire V. Clinical utility gene card for: 3M syndrome. Eur J Hum Genet. 2011;19(9).
Hanson D, Murray PG, O’Sullivan J, et al. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am J Hum Genet. 2011;89:148-53.
Huber C, Delezoide A-L, Guimiot F, et al. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet. 2009;17:395-400.
Temtamy SA, Aglan MS, Ashour AM, et al. 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol. 2006;15:55-64.
Huber C, Dias-Santagata D, Glaser A. Identification of mutations in CUL7 in 3-M syndrome. Nat Genet. 2005;37:1119-24.
Le Merrer M, Brauner, R.; Maroteaux, P. Dwarfism with gloomy face: a new syndrome with features of 3-M syndrome. J Med Genet. 1991;28:186-91.
Feldmann M, Gilgenkrantz S, Parisot S, Zarini G, Marchal C. 3M dwarfism: a study of two further sibs. J Med Genet. 1989;26:583-5.
Hennekam RCM, Bijlsma J B, Spranger J. Further delineation of the 3-M syndrome with review of the literature. Am J Med Genet. 1987;28:195-209.
Winter RM, Baraitser M, Grant D B, Preece M A, Hall C M. The 3-M syndrome. J Med Genet. 1984;21:124-8.
Garcia-Cruz D, Cantu JM. Heterozygous expression in 3-M slender-boned nanism. Hum Genet. 1979;52:221-6.
Spranger JW, Opitz J M, Nourmand A. A new familial intrauterine growth retardation syndrome: the «3M syndrome.» Europ J. Pediat. 1976;123:115-24.
Miller JD, McKusick VA, Malvaux P, Temtamy S A, Salinas CF. The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects. 1975;11:39-47.
INTERNET
Holder-Espinasse M. (Updated January 26, 2012). 3-M Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at https://www.genetests.org. Accessed June 7, 2012.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Three M Syndrome 1; 3M1. Entry No: _273750. Last Edited March 29, 2012. Available at: https://www.ncbi.nlm.nih.gov/omim/. Accessed June 7, 2012.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
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