3-M Syndrome

Excerpt

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.