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3-M Syndrome
[3M Dwarfism] - Authors: Muriel Holder-Espinasse, MD                      Robin M Winter, FRCP, F Med Sci 

About the Authors 

Initial Posting:   25 March 2002  Last Revision:   8 May 2002  - =Summary=

Disease characteristics. 3-M syndrome is characterized by pre- and postnatal growth retardation, distinctive dsflkgjd facial features (relatively large head, frontal bossing, triangular face, pointed djhgls and prominent chin, fleshy and upturned nose, full lips, full eyebrows, and a hypoplastic midface), and radiological abnormalities. Intelligence is normal.

Diagnosis/testing. The diagnosis of 3-M syndrome is suggested in children with a low birth weight, severe growth retardation, a final height between 5 and 6 SD below the mean, and characteristic facies. Characteristic radiological findings are slender long bones, thin ribs, foreshortened vertebral bodies appearing tall, spina bifida occulta, small pelvis, small iliac wings, and retarded bone age. There are no diagnostic laboratory findings, and the molecular basis of the syndrome is still unknown.

Genetic counseling. 3-M syndrome is inherited in an autosomal recessive manner. Sibs of a proband with 3-M syndrome have a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. There is no molecular genetic testing. Prenatal diagnosis by ultrasound examination has been performed, showing shortening of long bones and thoracic hypoplasia.

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=Diagnosis=

Clinical Diagnosis
The diagnosis of 3-M syndrome is suggested in children with :


 * Severe pre- and post-natal growth retardation
 * Typical facial features including triangular or "hatchet-shaped" face, relatively large head, hypoplastic midface, full eyebrows, fleshy nose tip, long philtrum, prominent mouth and lips and pointed chin [Cantu et al 1981, Winter et al 1984]. Facial phenotypes vary among patients [van der Wal et 2001].
 * Additional features such as a short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, and short fifth fingers [Winter et al 1984, van der Wal et al 2001]
 * Prominent heels and loose joints
 * Normal intelligence
 * A family history consistent with autosomal recessive inheritance. A positive family history is helpful but not necessary.

Testing
Radiographic findings. The diagnosis can be established by the observation of the following non-specific radiographic findings, which may not be present in the first two years of life.


 * Slender long bones with diaphyseal constriction and flared metaphyses seem to be the main radiological features of 3-M syndrome. Increased radiolucency is unusual [Miller et al 1975, Winter et al 1984, Hennekam et al 1987, van Goethem & Malvaux 1987, van der Wal et al 2001]. The metacarpal index, used to document slender long bones, is usually high.
 * Vertebral bodies are tall and have a reduced anterior-posterior and transverse diameter, especially in the lumbar region. Foreshortening of the vertebral bodies becomes more apparent with increasing age. Calculation of the vertebral index at different ages reveal that the vertebral index of L1 is a useful tool to document 3-M syndrome, alkthough tall vertebrae are a non-specific finding that may be secondary to scoliosis or hypotonia. Anterior wedging of thoracic vertebral bodies, irregular upper and lower endplates, thoracic kyphoscoliosis, and spina bifida occulta are also features of 3-M syndrome.
 * The pelvic bones, especially the pubis and the ischium, are small [Miller et al 1975]. The iliac wings are flared and the obturator foramina are small, although the latter may be positional. The femoral necks can be short.
 * Thorax is broad with slender and horizontal ribs.
 * Bone age is slightly delayed.
 * Dolicocephaly, flattened coronal suture, narrowed intraorbital distance, elbow dysplasia, shortened ulna, pseudo-epiphyses of the second metacarpal bone, clinodactyly of the little fingers, dislocated hips, and prominent talus have also been reported in 3-M syndrome.

Molecular Genetic Testing
''GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. -ED.''

The molecular basis of 3-M syndrome is still unknown. Therefore, no molecular genetic testing is available.

=Clinical Description=
 * The most striking feature of 3-M syndrome is the severe growth retardation, starting in utero [Cantu et al 1981, Feldmann et al 1989]. Birth length is between 40 and 42 cm, whereas the head size is normal for gestational age, giving a disproportionate appearance [Feldmann et al 1989]. Catch-up growth does not occur; final height is between 5 and 6 SD below the mean (i.e., 120-130 cm) [Feldmann et al 1989, van der Wal et al 2001].
 * Whereas female gonadal function appears normal, males with 3-M syndrome may have gonadal dysfunction and subfertility or infertility as documented by high FSH levels, low testicular volume, and abnormal semen analysis [van der Wal et al 2001]. Hypospadias has been seen in a few patients [Winter et al 1984].
 * Two reports suggested that the association of joint hypermobility and intracerebral vascular aneurysms in 3-M syndrome could be linked to a generalized disorder of connective tissue [Mueller et al 1992, Hennekam et al 1994].

Prevalence
Three-M syndrome is a rare condition. The prevalence is not known, but less than 40 patients have been reported in the literature since the first case in 1975 [Miller et al 1975].

=Differential Diagnosis=

Intrauterine growth retardation is a non-specific finding that occurs in approximately 0.17% of all live-born children [Spranger et al 1976]. Three-M syndrome must be distinguished from other forms of intrauterine growth retardation-malformation syndromes, including:


 * Russell-Silver syndrome.  Differentiation from Russell-Silver syndrome is difficult because of the clinical heterogeneity of this syndrome [Feldmann et al 1989]. The small triangular face is similar. Final height is smaller in 3-M syndrome. Head circumference is below the 3rd centile in Russell-Silver syndrome, but normal in 3-M syndrome. Characteristic radiological findings of 3-M syndrome are not found in Russell-Silver syndrome. Russell-Silver syndrome usually occurs sporadically [Spranger et al 1976].
 * Bloom syndrome. Patients with this condition have microcephaly, a telangiectatic erythema after exposure to sunlight, multiple chromosome breaks, and a very different facial appearance [Spranger et al 1976].
 * Dubowitz syndrome.  Microcephaly, eczema, a characteristic facial appearance and mental retardation are the main differences with 3-M syndrome.
 * Mulibrey nanism.  At birth, patients with mulibrey nanism are usually not as small as patients with 3-M syndrome. The facial features are different with a high forehead and a pseudo-hydrocephalic skull configuration. A high-pitched voice, abnormal retinal pigmentation, cardiomyopathy, limited physical capacity, elongated sella turcica, and cystic bone changes of the tibiae are the main features of this condition [Spranger et al 1976] The gene for this disorder has been identified (chromosomal locus 17q22-q23), and molecular genetic testing can be used in differentiating mulibrey nanism from 3-M syndrome [Avela et al 2000].
 * Fetal alcohol syndrome.  Microcephaly, hirsutism, nail hypoplasia, facial appearance and mental retardation are the main differences with 3-M syndrome.
 * Gloomy face dwarfism.  The significant features of this syndrome include facial dysmorphism with gloomy face and very short stature, but no radiologic abnormality or hormone deficiency. Mental development is normal. The mode of inheritance seems to be autosomal recessive [Le Merrer et al 1991]. This condition may in fact represent 3-M syndrome in the first year or so of life.

=Management=


 * The predominant management issues are ultimate adult stature and growth. Careful monitoring of growth with special attention to growth velocity is essential. Most children with 3-M syndrome are evaluated for growth hormone deficiency. Only one individual has been reported with an incomplete response to growth hormone (GH) stimulation; this suggests partial deficiency of GH [Miller et al 1975] in 3-M syndrome. Because of their short stature, several patients have been treated with exogenous GH without positive result [Miller et al 1975]. However, a recent report suggested that high dose GH treatment may be effective in 3-M syndrome [van der Wal et al 2001].
 * Treatment with growth hormone is necessary in the presence of documented growth hormone deficiency, but treatment of children with normal serum concentration of growth hormone is experimental. This treatment needs to be carried out in a center with experience in managing growth disorders. Surgical bone lengthening may sometimes be offered as an option.
 * Significant joint laxity should prompt an orthopedic evaluation.
 * Males with 3-M syndrome should be referred for endocrinological evaluation regarding gonadal function at puberty.

=Genetic Counseling=

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal or cultural issues that individuals may face or to substitute for consultation with a genetics professional. -ED.

Mode of Inheritance
3-M syndrome is inherited in an autosomal recessive manner.

Risk to Family Members
Parents of a proband. The unaffected parents are obligate carriers (heterozygotes) and are usually asymptomatic, although some reports suggested that characteristic facies, a prominent talus, and slender long bones could be observed in carriers [Garcia-Cruz & Cantu 1979, Hennekam et al 1987].

Sibs of a proband. At conception, sibs have a 25% chance of being affected, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected and not a carrier. The unaffected sibs of a proband have a 2/3 chance of being a carrier.

Offspring of a proband. The offspring of an individual with 3-M syndrome are obligate heterozygotes (carriers). Females with 3-M syndrome are fertile. One patient who gave birth to a son with no clinical or radiological manifestations of 3-M syndrome has been reported [Hennekam 1989].

Males with 3-M syndrome may be infertile.

The risk that the child of an individual with 3-M syndrome would be affected depends upon her/his partner's carrier status. As this condition is very rare, this risk is probably very low, unless an affected individual marries a relative.

Other family members. Sibs of the proband's parents are at 50% risk of also being carriers.

Related Genetic Counseling Issues
Carrier testing. It is not possible to detect carrier status on a molecular basis, as the gene responsible for 3-M syndrome is unknown.

Family planning. The optimal time for determination of genetic risk is before pregnancy.

DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodologies and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA particularly when molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing
Prenatal testing using molecular genetic techniques is not offered because it is not clinically available. In the one report about prenatal ultrasonographic findings of 3-M syndrome, femur and tibia lengths were reported to be on the fifth centile and the radius, ulna, and humerus lengths were below the fifth centile at 18 weeks' gestation. At 22 weeks' gestation, slowing of growth of all long bones was observed [Meo et al 2000].

=Molecular Genetics=

Table 1. Molecular Genetics of 3-M Syndrome

Gene Locus Product Genomic Databases

Unknown Unknown Unknown

=Resources=

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

The Little People of America (LPA) PO Box 65030 Lubbock, TX 79464-5030 Phone: 888-LPA-2001 Fax: 806-797-8830 Email: LPADatabase@juno.com www.lpaonline.org

MAGIC Foundation for Children's Growth 6645 W North Ave Oak Park, IL 60301 Phone:  708-383-0808 Fax: 708-383-0899 Email:  mary@magicfoundation.org www.magicfoundation.org

Human Growth Foundation 997 Glen Cove Road Glen Head, NY 11545 Phone: 800-451-6434 Fax: 516-671-4055 Email: hgf1@hgfound.org www.hgfound.org =References=

Articles on 3-M Syndrome

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Literature Cited

 * Avela K, Lipsanen-Nyman M, Idanheimo N, Seemanova E, Rosengren S, Makela TP, Perheentupa J, Chapelle AD, Lehesjoki AE (2000) Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Nat Genet 25:298-301 [Medline]
 * Cantu JM, Garcia-Cruz D, Sanchez-Corona J, Fragoso R, Hernandez A, Nazara-Cazorla Z (1981) 3-M slender-boned nanism. An intrauterine growth retardation syndrome. Am J Dis Child 135:905-8 [Medline]
 * Feldmann M, Gilgenkrantz S, Parisot S, Zarini G, Marchal C (1989) 3M dwarfism: a study of two further sibs. J Med Genet 26:583-5 [Medline]
 * Flannery DB (1989) 3-M syndrome. Am J Med Genet 32:252-4 [Medline]
 * Garcia-Cruz D, Cantu JM (1979) Heterozygous expression in 3-M slender-boned nanism. Hum Genet 52:221-6 [Medline]
 * Hennekam RC, Bijlsma JB, Spranger J (1987) Further delineation of the 3-M syndrome with review of the literature. Am J Med Genet 28:195-209 [Medline]
 * Hennekam RCM (1989) Comment by Raoul C.M. Hennekam on the letter to the editor by Flannery. Am J Med Genet 32:253
 * Hennekam RC, Limburg M, Pals G (1994) 3-M syndrome and intracerebral aneurysms. J Med Genet 31:898 [Medline]
 * Le Merrer M, Brauner R, Maroteaux P (1991) Dwarfism with gloomy face: a new syndrome with features of 3-M syndrome. J Med Genet 28:186-91 [Medline]
 * Meo F, Pinto V, D Addario V (2000) 3-M syndrome: a prenatal ultrasonographic diagnosis. Prenat Diagn 20:921-23 [Medline]
 * Miller JD, McKusick VA, Malvaux P, Temtamy S, Salinas C (1975) The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects Orig Artic Ser 11:39-47 [Medline]
 * Mueller RF, Buckler J, Arthur R, Bonsor G, Dear P, Walters K, Towns GM (1992) The 3-M syndrome: risk of intracerebral aneurysm? J Med Genet 29:425-7 [Medline]
 * Spranger J (1989) Reply to Dr. Flannery. Am J Med Genet 32:254
 * Spranger J, Opitz JM, Nourmand A (1976) A new familial intrauterine growth retardation syndrome the "3-M syndrome." Eur J Pediatr 123:115-24 [Medline]
 * van der Wal G, Otten BJ, Brunner HG, van der Burgt I (2001) 3-M syndrome: description of six new patients with review of the literature. Clin Dysmorphol 10:241-52 [Medline]
 * Van Goethem H, Malvaux P (1987) The 3-M syndrome. A heritable low birthweight dwarfism. Helv Paediatr Acta 42:159-65 [Medline]
 * Winter RM, Baraitser M, Grant DB, Preece MA, Hall CM (1984) The 3-M syndrome. J Med Genet 21:124-8 [Medline]

=Author Information=

Muriel Holder-Espinasse, MD  Clinical Genetics Department Email: m.holder@ich.ucl.ac.uk Robin M Winter, FRCP, F Med Sci Clinical Genetics Department Email: r.winter@ich.ucl.ac.uk Institute of Child Health London

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