Information on the following diseases can be found in the Related Disorders section of this report:

• Russell-Silver syndrome
• Bloom syndrome
• Le Merrer syndrome
• Associated congenital disorders (general)

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 thought to be 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.

In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait 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. (Again, in the case of Three M syndrome, some carriers may exhibit some mild symptoms associated with the disorder.) The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but usually will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

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).

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. The name "Three M syndrome" 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.

Many of the symptoms and physical features associated with the disorder are apparent at birth (congenital). In some cases, individuals who carry a single copy of the disease gene (heterozygotes) may exhibit mild symptoms associated with Three M syndrome.

Symptoms of the following disorders may be similar to those of Three M syndrome. Comparisons may be useful for a differential diagnosis:

Russell-Silver syndrome is a rare genetic disorder characterized by growth delays before birth (prenatal or intrauterine growth retardation); overgrowth of one side of the body (hemihypertrophy or asymmetry); characteristic facial malformations; and/or other physical abnormalities. Affected newborns may be abnormally small and have low birth weight. Because growth delays and immature bone development (delayed bone age) continue after birth (postnatally), affected children may exhibit short stature and be unusually small and thin for their age. In most cases, asymmetry or overgrowth of one side of the body is also obvious at birth. Characteristic facial abnormalities may include a triangular-shaped face with a small, pointed chin; an abnormally prominent forehead (frontal bossing); bluish discoloration of the tough, outer membranes covering the eyeballs (blue sclera); an unusually small, wide mouth; down-turned corners of the mouth; and/or an abnormally small jaw (micrognathia). Additional abnormalities may include permanent fixation of the fifth fingers in a bent position (clinodactyly); webbing of the second and third toes (syndactyly); underdevelopment (hypoplasia) of certain bones of the fingers (phalanges); development of smooth, coffee-colored patches on the skin (cafe-au-lait spots); and/or abnormalities of the kidneys and urinary tract. The range and severity of symptoms associated with the disorder vary greatly from case to case. Most cases of Russell-Silver syndrome are the result of genetic changes (mutations) that occur randomly for no apparent reason (sporadic). (For more information on this disorder, choose "Russell Silver" as your search term in the Rare Disease Database.)

Bloom syndrome, a rare inherited disorder, is characterized by short stature (dwarfism) due to growth deficiency before and after birth (prenatal and postnatal growth retardation) and distinctive skin abnormalities of the facial area including the development of abnormally red, inflamed areas that resemble a mild sunburn (erythema), sensitivity of the skin to sunlight (photosensitivity), and abnormal widening (dilation) of groups of small blood vessels (telangiectasia) causing redness. Such skin abnormalities of the facial area are typically in a "butterfly" pattern across the cheeks and the nose. However, in some cases, skin abnormalities may also affect the forearms, hands, ears, and/or neck. Individuals with Bloom syndrome may also have characteristic abnormalities of the head and facial (craniofacial) area including underdeveloped cheekbones (malar hypoplasia), abnormal narrowness of the face, a prominent nose, and/or an unusually small lower jaw (mandible). In addition, affected individuals may be more prone to developing certain malignancies (e.g., leukemia, etc.) than the general population. Bloom syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Bloom" as your search term in the Rare Disease Database.)

There are other rare inherited disorders that may be characterized by low birth weight, short stature, and/or craniofacial, finger (digital), and/or skeletal abnormalities similar to those occurring in association with Three M syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Diagnosis
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.

Identification of the gene that causes Three M syndrome may eventually lead to molecular genetic testing 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: prpl@cc.nih.gov

TEXTBOOKS
Schmandt S, Pearl PL. 3-M Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:259.

Buyce ML. Editor-in-Chief. Birth Defects Encyclopedia. Blackwell Scientific Publications. Center for Birth Defects Information Services, Inc., Dover, MA; 1990:1545.

Gorlin RJ, Cohen MM Jr., Levin LS, Eds. Syndromes of the Head and Neck. 3rd ed. Oxford University Press, New York, NY;1990:319-20.

JOURNAL ARTICLES
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, V. A.; Malvaux, P.; Temtamy, S. A.; Salinas, C. F. The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects. 1975;11:39-47.

FROM THE INTERNET
Holder-Espinasse M, Winter RM. Updated:12/8/2005. 3-M Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:273750; Last Update:10/14/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=273750 Accessed on: April 28, 2006.