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3-M Syndrome

, MD, PhD
Clinical Genetics Department
Hôpital Jeanne de Flandre
Centre Hospitalier Régional Universitaire de Lille
Lille, France

Initial Posting: ; Last Update: January 26, 2012.

Summary

Disease characteristics. 3-M syndrome is characterized by severe pre- and postnatal growth retardation (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of 3-M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with 3-M syndrome have hypogonadism and, occasionally, hypospadias.

Diagnosis/testing. The diagnosis of 3-M syndrome is suggested in children with all of the following:

  • Low birth weight
  • Severe growth retardation
  • Characteristic facies (relatively large head, triangular face, hypoplastic midface, full eyebrows, fleshy nose tip, long philtrum, prominent mouth and lips, pointed chin)
  • Characteristic radiologic findings (slender long bones with diaphyseal constriction and flared metaphyses, tall vertebral bodies that become foreshortened over time, anterior wedging of thoracic vertebral bodies, irregular upper and lower endplates, thoracic kyphoscoliosis, spina bifida occulta, small pelvic bones, small iliac wings, broad thorax with slender and horizontal ribs, and slightly delayed bone age)

Mutations in one of three genes are now known to cause 3-M syndrome: CUL7, OBSL1, and CCDC8.

Management. Treatment of manifestations: Surgical bone lengthening may be an option. Adaptive aids for people with short stature are appropriate. Significant joint laxity should prompt orthopedic evaluation and measures to control the development of arthritis. Males with 3-M syndrome should be referred for endocrinologic evaluation regarding gonadal function at puberty.

Surveillance: Monitoring of growth every 6-12 months on standard growth charts, with special attention to growth velocity.

Genetic counseling. 3-M syndrome is inherited in an autosomal recessive manner. Each sib of a proband with 3-M syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the disease-causing mutations have been identified in an affected family member. Prenatal ultrasound examination reveals slowing of growth of all long bones.

Diagnosis

Clinical Diagnosis

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

  • Typical facial features including relatively large head, triangular face, hypoplastic midface, full eyebrows, fleshy nose tip, long philtrum, prominent mouth and lips, and pointed chin. Facial appearance varies among affected individuals [van der Wal et al 2001, Marik et al 2002].
  • Additional features such as a short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, and short fifth fingers [van der Wal et al 2001]
  • Prominent heels and loose joints
  • Male hypogonadism and hypospadias

Radiographic findings. The diagnosis of 3-M syndrome can be established by the observation of the following nonspecific radiographic findings, which may not be present in the first two years of life.

  • Long bones are slender with diaphyseal constriction and flared metaphyses, which seem to be the main radiologic features of 3-M syndrome. Increased radiolucency is unusual [van der Wal et al 2001]. The metacarpal index, used to document slender long bones, is usually high.
  • Vertebral bodies are tall with 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 reveals that the vertebral index of L1 is a useful tool to document 3-M syndrome, although tall vertebrae are a nonspecific 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.
  • Pelvic bones are small, especially the pubis and the ischium. 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.
  • Other findings include dolichocephaly, 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.

Molecular Genetic Testing

Gene. CUL7, OBSL1, and CCDC8 are the only genes in which mutations are known to cause 3-M syndrome [Huber et al 2005, Hanson et al 2009, Huber et al 2009, Hanson et al 2011]. See Table 1 and Table A. Genes and Databases.

Evidence for further locus heterogeneity. Because mutations in the three genes identified to date do not account for 100% of 3-M syndrome, it is postulated that mutation of other genes (potentially members of the same pathway) may be involved [Huber et al 2011].

Table 1. Summary of Molecular Genetic Testing Used in 3-M Syndrome

Gene 1Proportion of 3-M Syndrome Attributed to Mutations in This GeneTest MethodMutations Detected 2
CUL777.5% 3Sequence analysis Sequence variants 4
Deletion / duplication analysis 5Exonic and whole-gene deletions 6
OBSL116% 3Sequence analysisSequence variants 4
Deletion / duplication analysis 5Exonic and whole-gene deletions 6
CCDC8 Unknown 7Sequence analysisSequence variants 4

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Huber et al [2011]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications of CUL7 or OBSL1 have been reported to cause 3-M syndrome. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

7. Probably <5%, but only one publication to date; see Hanson et al [2011].

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Holder-Espinasse et al 2011; see full text]. Note: CCDC8 had not been identified when the CUGC was published.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis is based on clinical and radiographic findings.

Molecular genetic testing is appropriate if the diagnosis is not clinically certain, if prenatal diagnosis is considered, and/or if relatives want to be tested. The recommended order of testing the three genes is by likelihood of identifying disease causing mutations:

1.

CUL7

2.

If no CUL7 disease-causing mutations are identified, OBSL1

3.

If no OBSL1 disease-causing mutations are identified, CCDC8

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The most striking feature of 3-M syndrome is the severe growth retardation, starting in utero. Birth length is 40-42 cm, whereas the head size is normal for gestational age, giving a disproportionate appearance. Catch-up growth does not occur; final height is 5-6 SD below the mean (i.e., 120-130 cm) [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 males with 3-M syndrome.

Two reports suggested that the association of joint hypermobility and intracerebral vascular aneurysms in 3-M syndrome could indicate a generalized disorder of connective tissue.

Temtamy et al [2006] report on new orodental findings including prominent premaxilla, hypoplastic maxilla, thick patulous lips, high-arched palate, median fissured tongue, delayed eruption of teeth, enamel hypocalcification, and malocclusion.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported to date.

Nomenclature

The name 3-M derives from the initials of the authors who first described the condition.

Dolichospondylic dysplasia, described by Elliott et al [2002], is probably the same as 3-M syndrome. Findings include normal facial appearance except for epicanthal folds and ocular hypertelorism, borderline intellectual disability, and radiographic findings similar to 3-M syndrome.

Prevalence

3-M syndrome is rare. The prevalence is not known; approximately 100 affected individuals have been reported in the literature since the first case in 1975 [Miller et al 1975].

Differential Diagnosis

Intrauterine growth retardation is a nonspecific finding that occurs in approximately 0.17% of all live-born children. 3-M syndrome must be distinguished from other forms of intrauterine growth retardation-malformation syndromes, including the following:

  • Gloomy face syndrome is likely the same condition as 3-M. In one report, the facial features and the mode of inheritance are identical; however, radiologic abnormalities were absent. No follow-up information is available; the characteristic radiologic findings could have appeared at a later time.
  • Russell-Silver syndrome (RSS) is characterized by intrauterine growth retardation accompanied by postnatal growth deficiency. The birth weight of affected individuals is typically two or more SD below the mean, and postnatal growth two or more SD below the mean for length or height. Affected individuals typically have proportionately short stature, normal head circumference, typical facial features, and limb length asymmetry that may result from hemihypotrophy with diminished growth of the affected side; however, considerable clinical variability is seen. About 10% of individuals with RSS will have maternal disomy for chromosome 7.

    Limb length asymmetry is seen in more than 50% of those with RSS, but not in individuals with 3-M syndrome. Characteristic radiologic findings of 3-M syndrome are not found in Russell-Silver syndrome. Russell-Silver syndrome usually occurs in a single individual in a family.
  • Dubowitz syndrome includes characteristic facial appearance (small face with sloping forehead, broad nasal bridge, shallow supraorbital ridge, broad nasal tip, short palpebral fissures, telecanthus, ptosis, displastic ears), microcephaly, mental deficiency, and infantile eczema as well as prenatal and postnatal growth deficiency. Microcephaly, eczema, a characteristic facial appearance, and intellectual disability are the main features differentiating Dubowitz syndrome from 3-M syndrome. Dubowitz syndrome is inherited in an autosomal recessive manner.
  • Mulibrey nanism includes prenatal and postnatal growth deficiency with relatively large hands, triangular facies with frontal bossing and depressed nasal bridge, small tongue, yellowish dots on the fundus, and pericardial constriction. Elongated sella turcica and cystic bone changes of the tibiae are also seen. At birth, individuals with Mulibrey nanism are usually not as small as those with 3-M syndrome. The facial features are different, with a high forehead and a pseudo-hydrocephalic skull configuration. Molecular genetic testing of TRIM37, the gene in which mutations cause this disorder, can be used in differentiating Mulibrey nanism from 3-M syndrome [Avela et al 2000]. Mulibrey nanism is inherited in an autosomal recessive manner.
  • Fetal alcohol syndrome. Microcephaly, decreased subcutaneous fat, hirsutism, nail hypoplasia, facial appearance, and intellectual disability are the primary features differentiating this disorder from 3-M syndrome. A history of maternal alcoholism is usually present.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 3-M syndrome, the following evaluations are recommended:

  • Assessment of joint mobility by physical examination
  • Assessment of gonadal function in pubertal males by physical examination and serum concentrations of FSH, LH, and testosterone
  • Medical genetics consultation

Treatment of Manifestations

The predominant management issues are ultimate adult stature and growth:

  • Surgical bone lengthening may be an option for some.
  • Adaptive aids for people with short stature are appropriate. Significant joint laxity should prompt orthopedic evaluation and measures to control the development of arthritis. Males with 3-M syndrome should be referred for endocrinologic evaluation regarding gonadal function at puberty.
  • Treatment with growth hormone is indicated in the presence of documented growth hormone deficiency, but treatment of children with normal serum concentration of growth hormone is experimental. GH treatment should be carried out in a center with experience in managing growth disorders.

    Note: (1) Although 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, suggesting partial deficiency of GH [Miller et al 1975]. (2) Several individuals with short stature have been treated with exogenous GH without positive result [Miller et al 1975]. One report suggested that high-dosage GH treatment may be effective in 3-M syndrome [van der Wal et al 2001]. No obvious demonstration of growth hormone efficiency has been published to date [Huber et al 2011].
  • Hip dislocation has been reported, probably secondary to joint laxity [Badina et al 2011, Huber et al 2011].

Surveillance

Monitoring of growth every six to 12 months on standard growth charts with special attention to growth velocity is recommended.

Evaluation of Relatives at Risk

Early diagnosis of at-risk sibs allows for early orthopedic evaluation and measures to control the development of arthritis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Management of pregnancy for affected women is identical to that for women with other forms of dwarfism or small stature, which is mainly to reduce the risk of premature birth.

When a fetus is diagnosed prenatally (usually as the result of molecular genetic testing of an at-risk sib), no special surveillance during the pregnancy is warranted and no special issues regarding delivery have been identified.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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, cultural, or ethical 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 parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are usually asymptomatic, although some reports have suggested that characteristic facies, a prominent talus, and slender long bones could be observed in carriers.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

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 individual gave birth to a son with no clinical or radiologic manifestations of 3-M syndrome.
  • Males with 3-M syndrome may be infertile.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. The diagnosis of 3-M syndrome is rarely suspected during pregnancy, since intrauterine growth restriction (IUGR) is not specific, and the skeletal findings only appear after birth.

In one report of a child diagnosed with 3-M syndrome, measurement at 18 weeks’ gestation showed femur and tibia lengths on the fifth centile and radius, ulna, and humerus lengths below the fifth centile. At 22 weeks' gestation, slowing of growth of all long bones was observed [Meo et al 2000].

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member in a research laboratory.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. 3-M Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for 3-M Syndrome (View All in OMIM)

273750THREE M SYNDROME 1; 3M1
609577CULLIN 7; CUL7
610991OBSCURIN-LIKE 1; OBSL1
612921THREE M SYNDROME 2; 3M2
614145COILED-COIL DOMAIN-CONTAINING PROTEIN 8; CCDC8
614205THREE M SYNDROME 3; 3M3

CUL7

Normal allelic variants. CUL7 comprises 26 exons.

Pathogenic allelic variants. Forty-five distinct mutations have been identified in 21 families [Huber et al 2005, Huber et al 2009]. A novel homozygous c.4581dupT mutation in CUL7 was found; it resulted in a frameshift and predicted a premature stop codon in members of the Yakut population affected with 3-M syndrome [Maksimova et al 2007]. See Table 2. One individual with 3-M syndrome had uniparental isodisomy for chromosome 6 [Huber et al 2009].

Table 2. CUL7 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.4333C>Tp.Arg1445TerNM_014780​.3
NP_055595​.2
c.4391A>Cp.His1464Pro
c.4581dupT
(4582_4583insT)
p.Arg1528SerfsTer26
(Arg1528LeufsTer26)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. CUL7 encodes cullin-7, which comprises 1698 amino acids. Cullin-7 belongs to the cullin family, which is composed of structurally related proteins that share an evolutionarily conserved cullin domain. Cullin-7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8), and ROC1 and promotes ubiquitination. Cullin-7 uses its central region to interact with the Skp1-Fbx29 heterodimer [Huber et al 2005].

Abnormal gene product. CUL7 nonsense mutation p.Arg1445Ter and missense mutation p.His1464Pro render cullin-7 deficient in recruiting ROC1, suggesting that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans [Huber et al 2005].

OBSL1

Normal allelic variants. OBSL1 comprises 22 exons. Alternative splicing results in three splice forms that encode different protein isoforms.

Pathogenic allelic variants. To date, all identified pathogenic allelic variants have occurred in exons 1-6 and are either nonsense or frameshift.

Normal gene product. OBSL1 encodes obscuring-like1, which comprises three splice forms designated A, B, and C, containing 1896, 1401, and 1025 amino acids respectively. Obscurin-like1 is a putative cytoskeletal adaptor protein that acts with cullin-7 in a common cellular pathway. Obscurin is a muscle protein localized to sarcomeres implicated in cell signaling [Hanson et al 2009].

Abnormal gene product. All identified OBSL1 mutations occurred in the first six exons and induced the nonsense-mediated decay (NMD) pathway. Therefore, all mutant alleles would fail to produce OBSL1 protein. Furthermore, mutations near the N terminus lead to loss of all OBSL1 isoforms, explaining the clustering of mutations in this region of the gene [Hanson et al 2009].

CCDC8

Normal allelic variants. CCDC8 comprises a single exon.

Pathogenic allelic variants. CCDC8 variants lead to the generation of a premature-termination codon [Hanson et al 2011].

Normal gene product. CCDC8 is a single-exon gene encoding coiled-coil domain-containing protein 8, a protein of 538 amino acids, with a coiled-coil domain located between residues 349-369 and 513-535 and an alanine rich domain located between residues 299 and 471.

Abnormal gene product. Mutations would generate truncated CCD8 with subsequent loss of function. Neither variant would be expected to lead nonsense-mediated decay [Hanson et al 2011].

References

Literature Cited

  1. Avela K, Lipsanen-Nyman M, Idanheimo N, Seemanova E, Rosengren S, Makela TP, Perheentupa J, Chapelle AD, Lehesjoki AE. Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism. Nat Genet. 2000;25:298–301. [PubMed: 10888877]
  2. Badina A, Pejin Z, Odent T, Buzescu A, Huber C, Cormier-Daire V, Glorion C, Pannier S. Hip dislocation in 3-M syndrome: risk of misdiagnosis. Clin Dysmorphol. 2011;20:114–6. [PubMed: 21383554]
  3. Elliott AM, Graham JM, Curry CJ, Pal T, Rimoin DL, Lachman RS. Spectrum of dolichospondylic dysplasia: two new patients with distinctive findings. Am J Med Genet. 2002;113:351–61. [PubMed: 12457407]
  4. Hanson D, Murray PG, O'Sullivan J, Urquhart J, Daly S, Bhaskar SS, Biesecker LG, Skae M, Smith C, Cole T, Kirk J, Chandler K, Kingston H, Donnai D, Clayton PE, Black GC. 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. [PMC free article: PMC3135816] [PubMed: 21737058]
  5. Hanson D, Murray PG, Sud A, Temtamy SA, Aglan M, Superti-Furga A, Holder SE, Urquhart J, Hilton E, Manson FDC, Scambler P, Black GCM, Clayton PE. The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1. Am J Hum Genet. 2009;84:801–6. [PMC free article: PMC2694976] [PubMed: 19481195]
  6. Holder-Espinasse M, Irving M, Cormier-Daire V. Clinical utility gene card for: 3M syndrome. Eur J Hum Genet. 2011;19 [PMC free article: PMC3179355] [PubMed: 21364696]
  7. Huber C, Delezoide A-L, Guimiot F, Baumann C, Malan V, Le Merrer M, Bezerra Da Silva D, 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 LM, 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, Stewart H, Unger S, Zenker M, Munnich A, Cormier-Daire V. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Eur J Hum Genet. 2009;17:395–400. [PMC free article: PMC2986175] [PubMed: 19225462]
  8. Huber C, Dias-Santagata D, Glaser A, O'Sullivan J, Brauner R, Wu K, Xu X, Pearce K, Wang R, Uzielli ML, Dagoneau N, Chemaitilly W, Superti-Furga A, Dos Santos H, Megarbane A, Morin G, Gillessen-Kaesbach G, Hennekam R, Van der Burgt I, Black GC, Clayton PE, Read A, Le Merrer M, Scambler PJ, Munnich A, Pan ZQ, Winter R, Cormier-Daire V. Identification of mutations in CUL7 in 3-M syndrome. Nat Genet. 2005;37:1119–24. [PubMed: 16142236]
  9. Huber C, Munnich A, Cormier-Daire V. The 3M syndrome. Best Pract Res Clin Endocrinol Metab. 2011;25:143–51. [PubMed: 21396581]
  10. Maksimova N, Hara K, Miyashia A, Nikolaeva I, Shiga A, Nogovicina A, Sukhomyasova A, Argunov V, Shvedova A, Ikeuchi T, Nishizawa M, Kuwano R, Onodera O. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. J Med Genet. 2007;44:772–8. [PMC free article: PMC2652813] [PubMed: 17675530]
  11. Marik I, Marikova O, Kuklik M, Zemkova D, Kozlowski K. 3-M syndrome in two sisters. J Paediatr Child Health. 2002;38:419–22. [PubMed: 12174011]
  12. Meo F, Pinto V, D'Addario V. 3-M syndrome: a prenatal ultrasonographic diagnosis. Prenat Diagn. 2000;20:921–3. [PubMed: 11113897]
  13. Miller JD, McKusick VA, Malvaux P, Temtamy S, Salinas C. The 3-M syndrome: a heritable low birthweight dwarfism. Birth Defects Orig Artic Ser. 1975;11:39–4. [PubMed: 1218233]
  14. Temtamy SA, Aglan MS, Ashour AM, Ramzy MI, Hosny LA, Mostafa MI. 3-M syndrome: a report of three Egyptian cases with review of the literature. Clin Dysmorphol. 2006;15:55–64. [PubMed: 16531729]
  15. van der Wal G, Otten BJ, Brunner HG, van der Burgt I. 3-M syndrome: description of six new patients with review of the literature. Clin Dysmorphol. 2001;10:241–52. [PubMed: 11665997]

Chapter Notes

Author History

Muriel Holder-Espinasse, MD, PhD (2002-present)
Robin M Winter, FRCP, F Med Sci; Institute of Child Health, London (2002-2004 *)

* Robin Winter was Professor of Clinical Genetics and Dysmorphology at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust. He contributed nearly 300 papers to medical journals on a wide breadth of topics and was an editor of the journal Clinical Dysmorphology and co-author of the London Dysmorphology and Neurogenetics Databases. Professor Winter died January 10, 2004 after a brief illness.

Revision History

  • 26 January 2012 (me) Comprehensive update posted live
  • 30 September 2010 (cd) Revision: sequence analysis and prenatal testing available clinically for CUL7 mutations. Mutations in OBSL1 also cause 3-M syndrome.
  • 30 March 2010 (me) Comprehensive update posted live
  • 23 June 2006 (ca) Comprehensive update posted to live Web site
  • 8 December 2005 (mhe) Revision: CUL7 mutations associated with 3-M syndrome
  • 11 May 2004 (me) Comprehensive update posted to live Web site
  • 25 March 2002 (me) Review posted to live Web site
  • 31 January 2002 (mhe) Original submission
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