Three M Syndrome
Synonyms: 3-M Syndrome, 3M Syndrome
Melita Irving, MBBS, MD(Res) and Muriel Holder-Espinasse, MD, PhD.
Author Information and AffiliationsInitial Posting: March 25, 2002; Last Update: February 7, 2019.
Estimated reading time: 17 minutes
Summary
Clinical characteristics.
Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three 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 three M syndrome have hypogonadism and occasionally hypospadias.
Diagnosis/testing.
The diagnosis of three M syndrome is established in a proband with characteristic clinical and radiographic features. Identification of biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 can establish the diagnosis if clinical and radiographic features are inconclusive.
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 three 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.
Three M syndrome is inherited in an autosomal recessive manner. Each sib of a proband with three 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 pathogenic variants have been identified in an affected family member. Prenatal ultrasound examination reveals slowing of growth of all long bones.
Diagnosis
Suggestive Findings
Three M syndrome should be suspected in a proband with a combination of the following clinical and radiographic features.
Clinical features
Facial features. Relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, full lips, and pointed chin. Facial appearance varies among affected individuals [
van der Wal et al 2001,
Marik et al 2002].
Musculoskeletal features. Short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or isolated joint hypermobility, prominent heels, and pes planus
Genitourinary anomalies in males. Hypogonadism and hypospadias
Intelligence. Usually unaffected
Radiographic features are subtle and may include the following (most often present after age 2 years):
Long bones are slender with diaphyseal constriction and flared metaphyses. The femoral necks can be short.
Vertebral bodies are tall with reduced anterior-posterior and transverse diameter (especially in the lumbar region), anterior wedging of the thoracic vertebral bodies, and irregular upper and lower endplates; thoracic kyphoscoliosis; spina bifida occulta.
Thorax is relatively broad with slender, horizontal ribs.
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.
Bone age is slightly delayed. There is a high metacarpal index.
Other
findings include dolichocephaly, flattened coronal suture, narrowed intraorbital distance, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, dislocated hips, and prominent talus.
Establishing the Diagnosis
The diagnosis of three M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features described in Suggestive Findings. Identification of biallelic pathogenic variants in one of the genes listed in Table 1 can confirm the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent or serial single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of three M syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of three M syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of three M syndrome, molecular genetic testing approaches can include concurrent or serial single-gene testing) or use of a multigene panel.
Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis of CUL7 first, followed by sequence analysis of OBSL1, then CCDC8. If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis of CCDC8, CUL7, and/or OBSL1 can be performed next to detect intragenic deletions or duplications.
A multigene panel that includes
CCDC8,
CUL7,
OBSL1 and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Option 2
When the diagnosis of three M syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Three M Syndrome
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| Gene 1, 2 | Proportion of Three M Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method |
|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 |
|---|
|
CCDC8
| <5% 6 | 100% 6 | None reported 6 |
|
CUL7
| 77.5% 7 | 100% 7 | None reported 7 |
|
OBSL1
| 16% 7, 8 | 100% 7 | None reported 7, 8 |
| Unknown 9 | >1.5% | |
- 1.
Genes are listed alphabetically.
- 2.
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
- 7.
- 8.
- 9.
Pathogenic variants in CCDC8, CUL7, and OBSL1 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].
Clinical Characteristics
Clinical Description
Growth deficiency. The most striking feature of three M syndrome is the severe intrauterine growth restriction. Birth length is 40-42 cm, whereas the head size is normal for gestational age. Catch-up growth does not occur; final height is 5-6 standard deviations below the mean (i.e., 120-130 cm) [van der Wal et al 2001], resulting in proportionate short stature.
Although most children with three M syndrome are evaluated for growth hormone (GH) deficiency, only one individual has been reported with an incomplete response to GH stimulation, suggesting partial deficiency of GH [Miller et al 1975]. 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 three M syndrome [van der Wal et al 2001]. No obvious demonstration of growth hormone efficacy has been published to date [Huber et al 2011, Meazza et al 2013].
Facial features. Infants with three M syndrome have a relatively large head, triangular face, midface retrusion, thick eyebrows, fleshy nose tip, long philtrum, thick lips, and pointed chin. Facial appearance varies among affected individuals [van der Wal et al 2001, Marik et al 2002] and changes over time, with the pointed chin, long philtrum, and triangular face becoming more pronounced.
Musculoskeletal features present by early childhood variably include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, and hyperlordosis. Short fifth fingers, prominent heels, and loose joints are reported. Developmental dysplasia of the hips has been reported with delayed diagnosis [Badina et al 2011].
Radiographic features
The
long bones are slender with diaphyseal constriction and flared metaphyses; these appear to be the main radiologic features of three M syndrome. Increased radiolucency is unusual [
van der Wal et al 2001]. The metacarpal index, used to document slender long bones, is usually high.
The 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 three 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 three M syndrome.
Thorax is broad with slender and horizontal ribs.
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.
Bone age is slightly delayed.
Other
findings include dolichocephaly, flattened coronal suture, narrowed intraorbital distance, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, clinodactyly of the fifth fingers, dislocated hips, and prominent talus.
Genitourinary anomalies in males may include 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 three M syndrome. Note: Female gonadal function appears normal.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been reported to date.
Nomenclature
The name "three M" derives from the initials of the authors who first described the condition. Three M syndrome may also be referred to as Le Merrer syndrome or Yakut short stature syndrome.
Dolichospondylic dysplasia, described by Elliott et al [2002], is probably the same as three M syndrome. Findings include normal facial appearance except for epicanthal folds and ocular hypertelorism, borderline intellectual disability, and radiographic findings similar to three M syndrome.
Gloomy face syndrome is likely the same condition as three 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 later [Le Merrer et al 1991].
Prevalence
Three M syndrome is rare. The prevalence is not known; approximately 100 affected individuals have been reported in the literature since the first published report 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. Three M syndrome must be distinguished from other forms of intrauterine growth retardation-malformation syndromes, including the following (see Table 2).
Table 2.
Disorders to Consider in the Differential Diagnosis of Three M Syndrome
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| Disorder | Gene(s) | MOI | Clinical Features of This Disorder |
|---|
| Overlapping w/3-M syndrome | Distinguishing from 3-M syndrome |
|---|
Silver-Russell syndrome
(SRS) | See
footnote
1 | Simplex | IUGR, postnatal growth deficiency |
|
Dubowitz
syndrome
(OMIM 223370) | Unknown | AR | IUGR | Microcephaly Eczema Characteristic facial features (small face w/sloping forehead, broad nasal bridge, shallow supraorbital ridge, broad nasal tip, short palpebral fissures, telecanthus, ptosis, dysplastic ears) Intellectual disability
|
Mulibrey
nanism
(OMIM 253250) |
TRIM37
| AR | IUGR | IUGR often less severe than in infants w/3-M Characteristic facial features (high forehead, pseudo-hydrocephalic skull configuration)
|
Fetal alcohol
syndrome | NA | NA | IUGR |
|
AR = autosomal recessive; IUGR = intrauterine growth restriction; MOI = mode of inheritance
- 1.
Hypomethylation of the paternal imprinting center 1 (IC1) of chromosome 11p15.5 is identified in 35%-50% of individuals with SRS. About 10% of individuals with SRS have maternal uniparental disomy for chromosome 7 (UPD7).
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with three M syndrome, the following evaluations are recommended if they have not already been completed:
Physical examination to assess for hip dislocation, joint mobility, and kyphoscoliosis
Referral to a pediatric endocrinologist for:
Evaluation for growth hormone deficiency (uncommon) at the time of diagnosis
Assessment of gonadal function in pubertal males by physical examination and serum concentrations of FSH, LH, and testosterone
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
The predominant management issues are ultimate adult stature and growth:
Significant joint laxity should prompt orthopedic evaluation and measures to control the development of arthritis.
Surgical bone lengthening may be an option for some.
Adaptive aids for people with short stature are appropriate.
Males with three M syndrome should be referred for endocrinologic evaluation for assessment of gonadal function at puberty.
Treatment with growth hormone is indicated in the presence of documented growth hormone (GH) 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: 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 three M syndrome [
van der Wal et al 2001]. No obvious demonstration of growth hormone efficiency has been published to date [
Huber et al 2011].
Surveillance
Monitor growth every six to 12 months on standard growth charts with special attention to growth velocity.
Monitor for hip dislocation in infancy, especially if walking is delayed.
Examine back annually for kyphoscoliosis.
Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic younger sibs of a proband and at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.
Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.
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 the same as that for women with other forms of dwarfism or small stature, which is mainly to reduce the risk of premature birth.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Three 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 (i.e., carriers of one CCDC8, CUL7, or OBSL1 pathogenic variant).
Heterozygotes (carriers) are typically asymptomatic, although some reports have suggested that characteristic facies, a prominent talus, and slender long bones may 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 a carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are typically asymptomatic, although some reports have suggested that characteristic facies, a prominent talus, and slender long bones may be observed in carriers.
Offspring of a proband
The offspring of an individual with three M syndrome are obligate heterozygotes (carriers) for a CCDC8, CUL7, or OBSL1 pathogenic variant.
Females with three M syndrome are fertile.
Males with three M syndrome may be infertile.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CCDC8, CUL7, or OBSL1 pathogenic variant.
Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the CCDC8, CUL7, or OBSL1 pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Diagnosis
Molecular genetic testing. Once the three M syndrome-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Ultrasound examination. The diagnosis of three M syndrome is rarely suspected during pregnancy, since intrauterine growth restriction is not specific, and the skeletal findings only appear after birth.
In one report of a child diagnosed with three 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].
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
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
Little People of America
Phone: 888-LPA-2001; 714-368-3689
Fax: 707-721-1896
Email: info@lpaonline.org
MAGIC Foundation
Phone: 630-836-8200
Email: contactus@magicfoundation.org
UCLA International Skeletal Dysplasia Registry (ISDR)
Phone: 310-825-8998
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.
Three M Syndrome: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
CCDC8
Gene structure.
CCDC8 comprises a single exon (NM_032040.4). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. The three reported CCDC8 frameshift variants are predicted to lead to the generation of a premature-termination codon [Hanson et al 2011, Al-Dosari et al 2012].
Normal gene product.
CCDC8 is a single-exon gene encoding coiled-coil domain-containing protein 8, a protein of 538 amino acids (NP_114429.2), 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. Pathogenic variants are predicted to generate truncated CCD8 with subsequent loss of function. Neither would be expected to lead to nonsense-mediated decay [Hanson et al 2011].
CUL7
Gene structure.
CUL7 comprises 26 exons (NM_014780.3). For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants.More than 60 distinct pathogenic variants have been identified [Huber et al 2005, Huber et al 2009] (see Table A, for variant databases). A novel homozygous c.4581dupT pathogenic variant in CUL7 was found; it resulted in a frameshift and predicted a premature stop codon in members of the Yakut population with three M syndrome [Maksimova et al 2007]. One individual with three M syndrome had uniparental isodisomy for chromosome 6 [Huber et al 2009].
Table 3.
CUL7 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change
(Alias 1) | Predicted Protein Change
(Alias 1) | Reference Sequences |
|---|
| c.4333C>T | p.Arg1445Ter |
NM_014780.3
NP_055595.2
|
| c.4391A>C | p.His1464Pro |
c.4581dupT
(4582_4583insT) | p.Arg1528SerfsTer26
(Arg1528LeufsTer26) |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.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 variant p.Arg1445Ter and missense variant 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
Gene structure.
OBSL1 comprises 22 exons. Alternative splicing results in three splice forms that encode different protein isoforms. For a detailed summary of gene, alternative spliced transcripts, and protein information, see Table A, Gene.
Pathogenic variants. To date, all identified pathogenic variants have occurred in exons 1-6 and are either nonsense or frameshift.
Normal gene product.
OBSL1 encodes obscurin-like protein 1, which comprises three splice forms designated A, B, and C, containing 1896, 1401, and 1025 amino acids, respectively. Obscurin-like protein 1 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 pathogenic variants occurred in the first six exons; the majority are predicted to induce the nonsense-mediated decay pathway resulting in failure to produce obscurin-like protein 1. Furthermore, pathogenic variants near the N terminus lead to loss of all protein isoforms, explaining the clustering of pathogenic variants in this region of the gene [Hanson et al 2009].
References
Literature Cited
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Chapter Notes
Author History
Muriel Holder-Espinasse, MD, PhD (2002-present)
Melita Irving, MBBS, MD (2019-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
7 February 2019 (sw) Comprehensive update posted live
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 live
8 December 2005 (mhe) Revision: CUL7 mutations associated with 3-M syndrome
11 May 2004 (me) Comprehensive update posted live
25 March 2002 (me) Review posted live
31 January 2002 (mhe) Original submission
