Three M syndrome

Three M syndrome is inherited in an autosomal recessive pattern. It is characterised by severe pre- and postnatal growth restriction, relative macrocephaly, dysmorphic facial features, skeletal anomalies and normal intelligence.

Growth

• Severe pre- and postnatal growth restriction.
• Proportionate short stature (typically five standard deviations (5SD) below the mean, though the body, arms and legs are in the usual proportions), with final adult height at 120 to 130 centimetres (5SD to 6SD below the mean).
• Relative macrocephaly.

Dysmorphic facial features

These are variable among affected individuals and change over time.

• Evident in infancy:
  • dolichocephaly (increased anterior-posterior diameter of the head);
  • midface retrusion (flat midface);
  • thick eyebrows;
  • fleshy nasal tip; and
  • full lips.
• Beyond infancy:
  • face becomes triangular, with a pointed chin and long philtrum.

Musculoskeletal anomalies

These are present by early childhood and may include:

• short, broad neck;
• square shoulders;
• winged scapulae;
• short thorax;
• lumbar hyperlordosis;
• spina bifida occulta;
• clinodactyly of the fifth fingers;
• joint hypermobility (generalised or isolated);
• developmental dysplasia of the hip (DDH);
• pes planus; and
• prominent heels.

Radiographic features

These are subtle and may include those listed below.

• At birth:
  • broad thorax, thin ribs.
• After two years of age (usually):
  • slender long bones, with diaphyseal constriction and flared metaphysis;
  • tall vertebral bodies, anterior wedging of thoracic vertebral bodies, irregular upper and lower endplates and thoracic kyphoscoliosis; and
  • small pelvic bones (especially the pubis and ischium), flared iliac wings, small obturator foramina and hip dislocation.
• Slightly delayed bone age.

Other associated features include flattened coronal suture, narrowed intraorbital distance, elbow dysplasia, shortened ulna, pseudoepiphysis of the second metacarpal bone and prominent talus.

Additional features

• Normal intelligence.
• Normal thyroid function.
• Normal growth hormone levels – though some children may have normal-high baseline insulin-like growth factor 1 (IGF-1) levels.
• In males, hypogonadism and hypospadias have been reported; females have normal ovarian function.

Differential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Floating-Harbour syndrome, Mulibrey nanism, fetal alcohol syndrome and Bloom syndrome.

Pathogenic variants in three genes are now known to cause Three M syndrome:

• CUL7 (75% of cases);
• OBSL1 (20% of cases); and
• CCDC8 (5% of cases).

These genes are involved in a pathway that affects cell proliferation and growth. CUL7 pathogenic variants are associated with more significant growth impairment.

Diagnosis is based on clinical and radiological features and confirmed by molecular genetic testing. For information about testing, see Presentation: Child with proportionate short stature and no learning difficulties.

Three M syndrome is an autosomal recessive condition.

If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
• 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
• 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

The parents of most individuals affected with Three M syndrome are carriers of the condition and therefore have a 25% (one in four) chance of having another affected child.

When a suspected case of Three M syndrome is identified, a referral to clinical genetics for clinical review and testing is recommended.

Management of children with Three M syndrome is complex and should be delivered via a multidisciplinary team that includes clinical genetics, paediatrics, endocrinology, orthopaedics, oral and maxillofacial surgery, and allied healthcare professionals where required.
For newborns, a hip ultrasound scan is advised to screen for developmental dysplasia of the hip. Growth and pubertal progress should be monitored closely, and treatment with recombinant human growth hormones can be considered. For males with Three M syndrome, referral for endocrine assessment of gonadal function at puberty is advised.

For clinicians

• GeneReviews: 3-M syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Three M syndrome
• NHS England: National Genomic Test Directory
• Orpanet: 3M syndrome
• U.S. National Library of Medicine: ClinicalTrials.gov (database)

References:

• Huber C, Munnich A and Cormier-Daire V. ‘The 3M syndrome‘. Best Practice & Research Clinical Endocrinology & Metabolism 2011: volume 25, issue 1, pages 143–151. DOI: 10.1016/j.beem.2010.08.015

For patients

• Genetic and Rare Diseases Information Center: 3-M syndrome