Three M Syndrome 1

A number sign (#) is used with this entry because of evidence that the 3M syndrome-1 (3M1) is caused by homozygous or compound heterozygous mutation in the CUL7 gene (609577) on chromosome 6p21.

Description

3M syndrome is an autosomal recessive disorder characterized by distinctive facial features, severe prenatal and postnatal growth retardation, and normal mental development. The main skeletal anomalies are long, slender tubular bones, reduced anteroposterior diameter of the vertebral bodies, and delayed bone age. Other skeletal manifestations include joint hypermobility, joint dislocation, winged scapulae, and pes planus (summary by Badina et al., 2011).

Genetic Heterogeneity of 3M Syndrome

Also see 3M syndrome-2 (3M2; 612921), caused by mutation in the OBSL1 gene (610991) on chromosome 2q35, and 3M syndrome-3 (3M3; 614205), caused by mutation in the CCDC8 gene (614145) on chromosome 19q13.

Clinical Features

Miller et al. (1975) observed a brother and sister, offspring of first-cousin parents, with low birth weight dwarfism, narrow facies, grooved lower anterior thorax, and clinodactyly. Intelligence was normal. Spranger et al. (1976) described 2 pairs of sibs who appeared to have the same disorder. Winter et al. (1984) reported 5 patients from 4 families, including 2 male sibs.

Hennekam et al. (1987) found a total of 19 patients in the literature and reported the findings in 3 affected sibs. They suggested that this syndrome was probably first described by Fuhrmann et al. (1972). Flannery (1989) suggested that the 3M syndrome be called 'dolichospondylic dysplasia' because of the tall or apparently tall vertebral bodies. This feature was first commented on by Fuhrmann et al. (1972). Hennekam (1989) found relatively high vertebral bodies in 3 Dutch patients, according to the normal values of Brandner (1970, 1972). Spranger (1989) pointed out that tall vertebral bodies are a nonspecific manifestation of muscular hypotonia and therefore the term 'dolichospondylic dysplasia' would lead to diagnostic confusion. Furthermore, the skeletal changes of primordial dwarfism are those of a hypoplasia and not of a dysplasia.

Garcia-Cruz and Cantu (1979) noted mild features of 3M syndrome in presumed heterozygotes.

Feldmann et al. (1989) described 2 additional sibs with the 3M syndrome and discussed the differential diagnosis, with particular emphasis on the Russell-Silver syndrome (268650).

Le Merrer et al. (1991) reported the cases of 9 children with primordial dwarfism and facial dysmorphism characterized as 'gloomy face.' Despite very short stature, there were no radiologic abnormalities of the skeleton and no hormone deficiency was found. Mental development was normal. Four boys and 5 girls in 4 sibships were affected; the parents were consanguineous in at least 3 of the 4 sibships. Le Merrer et al. (1991) suggested that this was a distinct disorder with features of 3M syndrome.

Mueller et al. (1992) described a child with features consistent with the 3M syndrome who presented with acute hydrocephalus consequent to hemorrhage from one of two intracranial aneurysms, one on the intracavernous carotid artery and one on the left posterior inferior cerebellar artery.

Van der Wal et al. (2001) reported 3 boys and 3 girls with 3M syndrome from 4 families, 2 of which had known parental consanguinity. The authors compared the features of these patients with those of 28 cases from the literature. Van der Wal et al. (2001) noted that 3M syndrome can be differentiated from other types of dwarfism by clinical criteria and by the demonstration of characteristically slender long bones and foreshortened vertebral bodies.

Elliott et al. (2002) described 2 unrelated female patients with normocephaly, short stature, mild malar hypoplasia, narrowed nasal body with a fleshy tip, full lips, and normal intelligence. Both had tall vertebral bodies, overtubulation of long bones, and short tubular bones of the hands and feet. Because the patients lacked many of the typical features of 3M syndrome, or dolichospondylic dysplasia, the authors suggested that they may have had a distinct disorder.

Badina et al. (2011) reported 2 unrelated patients, diagnosed with 3M syndrome at birth, who presented at age 10 and 20 months, respectively, with bilateral hip dislocation. The authors noted that for children with 3M syndrome, the short length and low birth weight make hip examination more difficult, and they suggested that ligamentous laxity may predispose to hip dislocation, as well as impair treatment. Badina et al. (2011) recommended that patients with 3M syndrome be referred to a pediatric orthopedic surgeon soon after birth.

Yakut Short Stature Syndrome

Maksimova et al. (2007) identified 43 patients from 37 Yakut families with a short stature syndrome similar to 3M syndrome. Clinical features included pre- and postnatal growth retardation, triangular facies with hypoplastic midface, frontal bossing, depressed nasal root, short wide thorax, brachydactyly, and micromelia. All had normal intelligence. Many infants (41.9%) had severe asphyxia and respiratory distress at birth. In 5 families (11.6%), affected newborns died shortly after birth of unknown causes. A few patients showed slender tubular bones or tall vertebral bodies similar to the 3M syndrome. Lungs of an affected fetus showed insufficient development of the cartilaginous lamina of the bronchi. Examination of the placenta of 1 case showed a marked increase in the number of chorionic villi with syncytial knots and abnormal vascularization. The Yakuts are an East Asian population isolated in the northeastern part of Siberia who emigrated from southern to northern Siberia in the 13th or 14th century. The population showed a bottleneck effect at some point, suggesting that they are a genetic isolate.

Mapping

Using homozygosity mapping in 7 consanguineous families with 3M syndrome, Huber et al. (2005) detected linkage of the underlying gene to a 3.84-Mb interval on chromosome 6p21.1.

Heterogeneity

Huber et al. (2009) reported 10 unrelated 3M patients without mutations in the CUL7 gene. In addition, linkage to the CUL7 locus on chromosome 6p21.1 was excluded in 6 consanguineous families with the disorder, indicating genetic heterogeneity. The authors did not perform linkage analysis of the OBSL1 region on chromosome 2q35. The phenotype was similar to those with CUL7 mutations.

Hanson et al. (2009) identified consanguineous families with 3M syndrome who did not show linkage to 3M1 on chromosome 6p21.1 or 3M2 on chromosome 2q35, indicating further genetic heterogeneity for this phenotype.

Molecular Genetics

Huber et al. (2005) found 25 distinct mutations in the cullin-7 gene (CUL7; 609577) in 29 families with 3M syndrome by direct sequencing. CUL7 assembles an E3 ubiquitin ligase complex containing SKP1 (601434), FBX29 (609073), and ROC1 (603814) and promotes ubiquitination. Using deletion analysis, Huber et al. (2005) found that CUL7 uses its central region to interact with the SKP1-FBX29 heterodimer. Functional studies indicated that the 3M-associated CUL7 nonsense and missense mutations R1445X (609577.0001) and H1464P (609577.0002), respectively, render CUL7 deficient in recruiting ROC1. On the whole, the results suggested that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans, this being a cardinal feature of the 3M syndrome.

In all 43 affected individuals with Yakut short stature syndrome, Maksimova et al. (2007) identified homozygosity for a founder mutation in the CUL7 gene (609577.0004).

Huber et al. (2009) identified CUL7 mutations (see, e.g., 609577.0005- 609577.0007) in 23 of 33 patients with the 3M syndrome. Nineteen novel mutations throughout the CUL7 gene were identified, including 1 case of paternal isodisomy of chromosome 6 encompassing a CUL7 mutation.

History

Le Merrer et al. (1991) discussed overlap of the 'gloomy face syndrome' with the 3M syndrome. Identity of the 3M syndrome and the 'gloomy face syndrome' was supported by clinical and radiographic long-term follow-up and was established by the demonstration by Huber et al. (2005) of mutations in the CUL7 gene in patients with either diagnosis.