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A primordial growth disorder characterized by low birth weight, reduced birth length, severe postnatal growth restriction, a spectrum of minor anomalies (including facial dysmorphism) and normal intelligence.
ORPHA:2616Classification level: Disorder
- 3-M syndrome
- Dolichospondylic dysplasia
- Gloomy face syndrome
- Le Merrer syndrome
- Yakut short stature syndrome
- Prevalence: Unknown
- Inheritance: Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: Q87.1
- OMIM: 273750 612921 614205
- UMLS: C1848862 C1851996 C2678312
- MeSH: -
- GARD: 5667
- MedDRA: -
Approximately 200 cases have been reported to date but as the condition is likely under-recognized, the true figure is probably higher.
Infants present with severe postnatal (and prenatal) growth retardation, usually associated with a low birth weight (<2nd centile). Characteristic facial features include: triangular-shaped face, frontal bossing, hypoplastic midface, fleshy tipped nose, prominent mouth and lips and pointed chin. These features often become less noticeable with age. Short broad neck and thorax, prominent trapezii, winged scapulae, square shoulders, hyperlordosis and clinodactyly of the 5th finger are seen in some children. Prominent fleshy heels in infancy are a universal feature. Joint hypermobility and an increased risk of congenital hip dislocation may also be reported. Hyperlordosis can cause back pain. Intelligence is unaffected and age-related developmental milestones are met. Some cases of impaired fertility and hypospadias have been noted in males while females have normal ovarian function. Patients reach a final adult height of about 120-130 cm (5-6 standard deviations below the mean).
Mutations in the CUL7 gene (6p21.1) are most often responsible for 3M syndrome (67% of cases). Other causal mutations include those in the OBSL1 gene (2q35), in 28% of cases, or the CCDC8 gene (19q13.33), in 5% of cases. The precise mechanisms leading to growth failure in 3M syndrome remain unclear.
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, 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 mutations in one of the causal genes, confirming diagnosis. Some children with 3M syndrome demonstrate normal-high baseline insulin-like growth factor (IGF-I) concentrations.
Differential diagnoses include Silver-Russell syndrome, Dubowitz syndrome, Mulibrey nanism, and fetal alcohol syndrome (see these terms).
Prenatal diagnosis is possible in families with a known disease causing mutation.
3M syndrome is inherited autosomal recessively and genetic counseling is possible.
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 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 GH (r-hGH). In general, the response to treatment is modest, however a trial of treatment over 1 year (GH doses of 35-45 microgram/kg/day with monitoring of serum IGF-I levels) may show a reasonable response. In this case, r-hGH should be continued long-term. Higher r-hGH doses (up to 70 microgram/kg/day) have been used in individual cases. The issue of fertility should be discussed with male patients at the end of puberty and semen analysis offered.
3M syndrome is not a life-threatening condition and the prognosis is good.