DiagnosisClinical DiagnosisThe 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 TestingGene. 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 SyndromeView in own windowGene Symbol Proportion of 3-M Syndrome Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityCUL777.5% ^{4Sequence analysis Sequence variants 1ClinicalDeletion / duplication analysis 2Exonic and whole-gene deletions 3OBSL116% 4Sequence analysisSequence variants 1Clinical Deletion / duplication analysis 2Exonic and whole-gene deletions 3 CCDC8 Unknown 5Sequence analysisSequence variants 1Clinical 1. 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.2. 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.3. 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.)4. Huber et al [2011] 5. 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. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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, CCDC8Carrier 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.Genetically Related (Allelic) Disorders3-M syndrome is the only disorder known to be associated with mutations in CUL7, OBSL1, or CCDC8.}

Natural HistoryThe 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 CorrelationsNo genotype-phenotype correlations have been reported to date.

Differential DiagnosisIntrauterine 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with 3-M syndrome, the following evaluations are recommended:Assessment of joint mobility by physical examinationAssessment of gonadal function in pubertal males by physical examination and serum concentrations of FSH, LH, and testosteroneMedical genetics consultationTreatment of ManifestationsThe 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].SurveillanceMonitoring 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 ManagementManagement 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 InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCUL76p21​.1Cullin-7CUL7 homepage - Mendelian genesCUL7OBSL12q35Obscurin-like protein 1OBSL1 homepage - Mendelian genesOBSL1CCDC819q13​.32Coiled-coil domain-containing protein 8 CCDC8Data 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) View in own window 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; 3M3CUL7Normal allelic variants. CUL7 comprises 26 exons. Pathologic 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 Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid Change
(Alias ¹)Reference Sequencesc.4333C>Tp.Arg1445*NM_014780​.3
NP_055595​.2c.4391A>Cp.His1464Proc.4581dupT
(4582_4583insT)p.Arg1528Serfs*26
(Arg1528Leufs*26)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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.Arg1445* 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]. OBSL1Normal allelic variants. OBSL1 comprises 22 exons. Alternative splicing results in three splice forms that encode different protein isoforms. Pathologic allelic variants. To date, all identified pathologic 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]. CCDC8Normal allelic variants. CCDC8 comprises a single exon.Pathologic 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].