Clinical characteristics.

3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias.

Diagnosis/testing.

The diagnosis of 3-M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features and/or biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Referral to pediatric endocrinologist for consideration of growth hormone in prepubertal children. Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment. Surgical limb lengthening may also be an option. Orthopedic evaluation in individuals with hip dislocation, scoliosis, and significant joint laxity is essential. Management of hypogonadism per endocrinologist. Urology referral may be needed for hypospadias. In neonates with severe respiratory distress, neonatal/pediatric intensive care team input and follow up with a pediatric respiratory physician.

Surveillance: Monitor growth every six to 12 months on standard growth charts, with special attention to growth velocity. Assess for joint hypermobility and kyphoscoliosis annually. Assess for hip dislocation at each visit in infancy especially in those with delayed walking. Consider echocardiogram in adolescence to evaluate aortic root diameter.

Evaluation of relatives at risk: It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs.

Pregnancy management: Follow pregnancy management guidelines as for women with other forms of dwarfism or small stature to reduce the risk of premature birth.

Genetic counseling.

3-M syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CCDC8, CUL7, or OBSL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

3-M syndrome should be suspected in a proband with a combination of the following clinical, radiographic, and family history features.

Clinical features

• Short stature of prenatal onset [Lugli et al 2016]. Typical height is five standard deviations below the mean for age and sex [Shapiro et al 2017].
• Facial features. Relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin. In infancy, facial nevus simplex and infraorbital fullness [Hu et al 2017, Tüysüz et al 2021]. Facial appearance varies among affected individuals [van der Wal et al 2001, Marik et al 2002] and changes with age [Akalın et al 2024].
• Musculoskeletal features. Short broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus
• Genitourinary anomalies in males. Hypogonadism and hypospadias
• Intelligence. Typically normal

Radiographic features are subtle and may include the following (most often present after age two 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 end plates; thoracic kyphoscoliosis; spina bifida occulta.
• Thorax is relatively broad with slender, horizontal ribs. Pectus carinatum/excavatum is common [Hu et al 2017, Tüysüz et al 2021].
• 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 can be slightly delayed or normal. The metacarpal index and vertebral index are increased.
• Other findings include dolichocephaly, flattened coronal suture, elbow dysplasia, shortened ulna, pseudoepiphyses of the second metacarpal bone, and prominent talus.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of 3-M syndrome can be established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features described in Suggestive Findings, and/or i biallelic pathogenic (or likely pathogenic) variants in one of the genes listed in Table 1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Neonatal period. Some children with 3-M syndrome present in the neonatal period with feeding difficulties requiring early feeding support [Hu et al 2017]. A small proportion of infants suffer from significant respiratory distress and/or recurrent respiratory tract infections in early life that can be life threatening [Deeb et al 2015]. This is more common in the Yakut population, in which 41% of affected infants had asphyxia and respiratory distress at birth and 25.6% required mechanical ventilation [Maksimova et al 2007].

Growth deficiency. The most striking feature of 3-M syndrome is 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 five to six standard deviations below the mean for age and sex [van der Wal et al 2001, Tüysüz et al 2021, Akalın et al 2024], resulting in proportionate short stature.

Most children with 3-M syndrome are evaluated for growth hormone (GH) deficiency. A small proportion are found to have partial or significant GH deficiency [van der Wal et al 2001, Clayton et al 2012, Deeb et al 2015, Karacan Küçükali et al 2023, Akalın et al 2024]. A growing number of children have also been found to have GH insensitivity demonstrated by failure of insulin-like growth factor 1 (IGF-1) generation [Akalın et al 2024]. Treatment with GH has shown variable results, with a good response in some individuals and poor response in others. Recombinant human IGF-1 therapy has been tried in one individual with CUL7-related 3-M syndrome with a poor response and significant side effects [Yang & Patni 2020]. Given the varying response to treatment, a trial of GH therapy with close monitoring of growth velocity and measurement of serum IGF-1 levels should be considered [Clayton et al 2012, Deeb et al 2015, Karacan Küçükali et al 2023, Akalın et al 2024].

Facial features. Infants with 3-M syndrome have a relatively large head, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, pointed chin, nevus simplex, and infraorbital fullness [Hu et al 2017, Tüysüz et al 2021]. Facial appearance varies among affected individuals [van der Wal et al 2001, Marik et al 2002] and changes over time, with the triangular face, long philtrum, and pointed chin becoming more pronounced, and loss of the nevus simplex and infraorbital fullness.

Musculoskeletal features present by early childhood and variably include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, and hyperlordosis. Spina bifida occulta, clinodactyly of the fifth fingers, transverse palmar crease, generalized or distal joint hypermobility, prominent heels, and pes planus are reported. Developmental dysplasia of the hips has been reported with delayed diagnosis [Badina et al 2011]. Bilateral congenital hip dislocation has been reported in other individuals [Khachnaoui-Zaafrane et al 2022]. Transverse grooves in the lower rib cage have been reported [Hu et al 2017, Tüysüz et al 2021].

Radiographic features

• The long bones are slender with diaphyseal constriction and flared metaphyses; these appear 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.
• The vertebral bodies are tall with reduced anterior-posterior and transverse diameter, especially in the lumbar region. Reduced anterior-posterior diameter 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 end plates, thoracic kyphoscoliosis, and spina bifida occulta are also features of 3-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 can be slightly delayed but has been reported to be normal in some individuals [Hu et al 2017].
• Other findings include dolichocephaly, flattened coronal suture, 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 follicle-stimulating hormone (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. Note: Female gonadal function appears normal.

Other. Aortic root dilatation has been reported in two sibs with 3-M syndrome [Akalın et al 2024].

Phenotype Correlations by Gene

Individuals with CUL7-related 3-M syndrome have been shown to have shorter stature than those with OBSL1-related 3-M syndrome [Tüysüz et al 2021, Akalın et al 2024]. Otherwise, the clinical and radiographic features seen in CUL7 and OBSL1 are indistinguishable.

The number of reported individuals with CCDC8-related 3-M syndrome is too small to draw any gene-specific phenotype correlations. One study suggests a better GH response in individuals with CCDC8-related 3-M syndrome. Further data is needed to support this theory.

Genotype-Phenotype Correlations

The CUL7 founder pathogenic variant reported in the Yakut population, c.4581dupT, may be associated with an increased risk of respiratory distress in the neonatal period. Maksimova et al [2007] reported 41.9% of children homozygous for this variant presented with asphyxia and respiratory distress at birth, and 25.6% of these children required mechanical ventilation.

Nomenclature

3-M syndrome may also be referred to as Le Merrer syndrome or Yakut short stature syndrome. Individuals previously reported to have dolichospondylic dysplasia [Elliott et al 2002] and Gloomy face syndrome are now understood to have 3-M syndrome [Unger et al 2023].

Prevalence

3-M syndrome is rare. The prevalence is not known; approximately 250 affected individuals have been reported in the literature since the first published report in 1975 [Miller et al 1975]. 3-M syndrome is more common in offspring of consanguineous parents, particularly in regions where founder pathogenic variants have been identified.

A CUL7 founder pathogenic variant, c.4451_4452delTG, has been identified in the Maghreb population in Tunisia [Khachnaoui-Zaafrane et al 2022] and the Yakut population (c.4581dupT) [Maksimova et al 2007].

A recurrent pathogenic variant in OBSL1 (c.1273dupA) appears to be an emerging founder variant in the Turkish population [Huber et al 2011, Keskin et al 2017, Simsek-Kiper et al 2019, Tüysüz et al 2021, Akalın et al 2024].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 3-M syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4). The predominant management issues are ultimate adult stature and growth.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs. 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.

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 presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a CCDC8, CUL7, or OBSL1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are typically asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a CCDC8, CUL7, or OBSL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are typically asymptomatic.

Offspring of a proband. The offspring of an individual with 3-M syndrome are obligate heterozygotes (carriers) for a 3-M syndrome-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of 3-M syndrome-related pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the 3-M syndrome-related pathogenic variants in the family.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk 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.
• Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a CCDC8, CUL7, or OBSL1 pathogenic variant, particularly if consanguinity is likely. Founder variants have been identified in several populations (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. Short long bones have been reported prenatally in 3-M syndrome, with a diagnosis being made at 24 weeks' gestation in one report [Hu et al 2017]. Frontal bossing and bilateral temporal narrowing were also detected. These findings are not specific for 3-M syndrome but would suggest a skeletal dysplasia and would be highly suggestive of 3-M syndrome if the parents are known to be carriers.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CUL7 encodes cullin-7. This large protein acts as a scaffold for the assembly of E3 ubiquitin ligase by binding to ROC1, a small RING finger protein. Cullin-7 is expressed in the cytoplasm and localizes to the centrosome. It is essential for successful anaphase and telophase during mitosis by regulating microtubule dynamics.

OBSL1 encodes obscurin-like protein 1 (OBSL1), which acts as a cytoskeletal adaptor.

CCDC8 encodes coiled-coil domain-containing protein 8 (CCDC8).

A study by Yan et al [2014] identified that cullin-7, OBSL1, and CCDC8 function within the same pathway and physically interact to form a joint complex known as the 3-M E3 complex. This complex is believed to be critical in microtubule regulation.

Further research by Wang et al [2019] demonstrated that CCDC8 localizes to the plasma membrane, where it anchors the 3-M E3 complex. Loss of function in any of the 3-M syndrome-causing genes disrupts the ubiquitylation of membrane-associated LL5β, impairing the regulation of cell migration.

Mechanism of disease causation. Loss of function

Author Notes

Rhoda Akilapa, BMBS, BMedSci
Skeletal Dysplasia Service, Evelina Children's Hospital, London
Clinical Genetics Service, Guy's & St Thomas' Hospital, London
Email: ku.shn.ttsg@apalika.adohr

Dr Akilapa is happy to communicate with persons who have any questions regarding diagnosis of 3-M syndrome or other considerations.

Melita Irving, MBBS, MD
Skeletal Dysplasia Service, Evelina Children's Hospital, London
Clinical Genetics Service, Guy's & St Thomas' Hospital, London
Email: ku.shn.ttsg@gnivri.atilem

Dr Irving is also interested in hearing from clinicians treating families affected by 3-M syndrome and other skeletal dysplasias in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Muriel Holder-Espinasse, MD, PhD
Clinical Genetics Service, Guy's & St Thomas' Hospital, London
Email: ku.shn.ttsg@redloh.leirum

Author History

Rhoda Akilapa, BMBS, BMedSci (2025-present)
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

• 27 February 2025 (sw) Comprehensive update posted live
• 7 February 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Comprehensive update posted live
• 25 March 2002 (me) Review posted live
• 31 January 2002 (mhe) Original submission

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