3M syndrome (ORPHA:2616)
A rare primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, large head size, a spectrum of minor anomalies (including facial dysmorphism) and normal intelligence.
Epidemiology
Approximately 200 cases have been reported to date and the condition is rare. However, the phenotype is likely under-recognized.
Clinical description
Infants present with severe prenatal and postnatal growth retardation, birth weight usually at or below the 2nd centile. Growth impairment is greater in those with CUL7 variants. The head circumference is relatively large. Characteristic facial features include: triangular-shaped face, pointed chin, frontal bossing, hypoplastic midface, fleshy, upturned nose , prominent mouth and lips. These features often become less noticeable with age. Short broad neck and thorax, prominent trapezii, winged scapulae, square shoulders, hyperlordosis and clinodactyly of the fifth finger are seen in some children. Prominent fleshy heels in infancy are a common and distinctive feature. Joint hypermobility and an increased risk of congenital hip dislocation may be present. Hyperlordosis can cause back pain. Intelligence is unaffected and development is usually normal. Some cases of impaired fertility and hypospadias have been noted in males , though this is not universal, while females have normal ovarian function. Patients reach a final adult height of about 120-130 cm (5-6 standard deviations below the mean).
Etiology
Pathogenic variants in three different genes are known to cause 3M syndrome. Variants in in the CUL7 at 6p21.1 are found in around 75% patients. Other genes known to be involved are OBSL1 (2q35), in 20% of cases and CCDC8 (19q13.33) in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear although the poor response to growth hormone in many patients indicates a degree of resistance to the GH/IGF1 pathway.
Diagnostic methods
Diagnosis is based primarily on clinical features (e.g. low birth weight, severe growth retardation, prominent fleshy heels). In some, specific radiological findings will be found including slender/ 'gracile' long bones, relatively tall vertebral bodies, foreshortening of vertebral bodies with increasing age, small pelvic bones and a broad thorax with slender and horizontal ribs. The occurrence of these radiological findings, however, is highly variable. Children with 3M syndrome usually have normal GH levels. Molecular genetic testing can identify pathogenic variants in one of the causal genes, confirming diagnosis in the majority of cases. Some children with 3M syndrome demonstrate normal-high baseline insulin-like growth factor (IGF-I) concentrations.
Differential diagnosis
Differential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Mulibrey nanism, fetal alcohol syndrome, and microdeletion of chromosome 20p13p12.
Antenatal diagnosis
Prenatal and preimplantation diagnosis is possible in families with a known disease causing variant.
Genetic counseling
3M syndrome is inherited autosomal recessively and genetic counseling is recommended for affected families. In a family with an index patient, the sibling recurrence risk is 25%.
Management and treatment
Once diagnosed the child should be seen by a pediatric endocrinologist for monitoring of growth and pubertal progress and for consideration of recombinant human growth hormone (GH) therapy. Monitoring of growth every 6-12 months is recommended until achievement of final height. Adaptive aids for people with short stature and physiotherapy are possible treatment options. Newborns should have a hip ultrasound scan to screen for developmental dysplasia of the hip. Children can be treated with recombinant human growth hormone. In general, the response to treatment is relatively poor, however a trial of treatment over 1 year may show a reasonable response. Overall treatment with growth hormone is more successful if started early and continued long term. The issue of fertility should be discussed with male patients at the end of puberty and semen analysis offered.
Prognosis
3M syndrome is not a life-threatening condition and the prognosis is good.

                            Last update: 
                            September 2020


                            - Expert reviewer(s): 
                            Pr Jill CLAYTON-SMITH | ITHACA*


                                * European Reference Network