3-M Syndrome: A Local Case Report

Background

3-M syndrome is a rare hereditary disorder characterized by severe growth retardation, distinctive facial dysmorphic features, and skeletal abnormalities [1]. The name 3-M is derived from the initials of the 3 researchers who first identified it: Miller, McKusick, and Malvaux [1]. Mutations in any 1 of the following 3 genes – CUL7, OBSL1, and CCDC8 – are responsible for the occurrence of this disorder [1]. It is inherited through an autosomal recessive pattern [1] and is considered very rare, so far less than 100 cases worldwide have been identified.

Individuals with 3-M syndrome suffer from severe prenatal growth retardation due to growth delays during fetal development, resulting in a low birth weight. Growth delays continue after birth throughout childhood and adolescence, ultimately leading to a short stature. Many of the physical features associated with the disorder are congenital. Characteristic craniofacial abnormalities typically include a long, narrow head that is disproportionate to the body size, a broad and prominent forehead, and a triangular-shaped face with a hypoplastic midface, pointed chin, long philtrum, prominent mouth, depressed nasal bridge, fleshy-tipped upturned nose, large ears, and full lips [1–4].

Skeletal anomalies are not present at birth, but develop in the individual and include delayed bone maturation, long and slender tubular bones, and tall vertebral bodies [1,2]. Joint hyper-mobility and increased risk of hip dislocation has been reported in individuals [1,3]. Abnormal spinal curvature, either kyphoscoliosis or hyperlordosis, causing back pain can also occur in this disorder [1,3].

Additional physical abnormalities in some children include an abnormally short, broad neck and thorax, square shoulders, flared shoulder blades, unusual curving of the 5th finger, and prominent heels [1,3,4].

Mutations in the CUL7 gene cause 3-M syndrome, although genetic heterogeneity has been reported involving 2 other causative genes: OBSL1 and CCDC8 [1,3,4]. Since CUL7 is involved in chondrocyte growth and proliferation, in 3-M syndrome, reduced cell mitosis during the early gestation period could be the cause of retarded growth. In particular, these mutations disrupt the ability of the protein cullin-7 to bring together the components of the ubiquitine-proteasome system, which is involved in degradation of unwanted proteins. Therefore, impaired ubiquitination may have a role in the pathogenesis of IUGR in humans.

This is first case report from a local population and adds this new patient to the literature on 3M syndrome.

Case Report

INVESTIGATIONS:

His metabolic screen, including mucopolysaccharide screen, was normal. His hormone studies, including cortisol, Growth hormones, IGF-2, IGFBP, and testosterone, were normal. MRI brain showed moderate cerebellar atrophy with brain stem and supratentorial volume loss. A skeletal maturation study showed delayed bone age about 1 year less than chronological age. but did not reveal slender long bones or tall vertebral bodies.

GENETIC:

CGH array showed excessive homozygosity encompassing at least 12% of the genome. By whole-exome sequencing, a homozygous variant in the CUL7 gene, c.3115-1G>C; Chr6 (GRCh37): g.43013141C>G, was detected. This has been previously described as disease-causing 3-M syndrome. Therefore, a diagnosis of 3-M syndrome was confirmed.

Discussion

The clinical features and genetic testing in our patient confirmed the diagnosis of 3-M syndrome, but our patient did not show the radiological findings like slender long bones or tall vertebral bodies. Our patient also showed mild development delay, while patients with 3-M syndrome have normal cognitive development and intelligence. While looking for the cause of delayed development, an MRI brain showed cerebellar atrophy with brain stem and supratentorial volume loss.

3-M syndrome is characterized by a triangular-shaped face with frontal bossing, mild malar hypoplasia, depressed nasal bridge with a fleshy tip of nose, upturned nares, and full lips. Patients usually have large heads for their height, dolichocephaly, and normal intelligence. Other clinical findings are a short wide thorax, brachydactyly, clinodactyly, micromelia, and prominent heels. Both sexes are affected equally. No hormonal deficiencies are detected. Our patient had almost all of the typical clinical features, along with the above-mentioned bony abnormalities, but did not show radiological findings of slender long bones with thin diaphysis and tall vertebral bodies. These findings may appear later in some patients. The radiographic examination, although abnormal, is not diagnostic, as similar X-ray changes have been documented in other disorders.

Maksimova et al. reported on 43 patients with short stature, hydrocephaloid skull, and typical face in an isolated Yakut population. Although clinical findings were similar to 3-M syndrome but slender long bones and tall vertebral bodies have not been commonly observed in this short-stature syndrome in Yakuts (3), as in our patient [5].

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 [6]. Le Merrer et al. (1991) suggested that this was a distinct disorder with features of 3-M syndrome [6].

Physical findings of several entities such as Silver-Russell syndrome (SRS) are similar to 3-M syndrome. Silver-Russell syndrome has many similarities with 3-M syndrome: intrauterine growth retardation, short stature, triangular face, relatively large skull, asymmetry of body or limbs, and clinodactyly. Mild mental retardation also can be found in patients with SRS, but abnormalities of the skeletal system have not been reported. Our patient showed mild developmental delay, as in SRS, but had positive homozygous variant in the CUL7 gene, which confirms 3-M syndrome. The mode of inheritance is autosomal recessive in 3-M syndrome. CUL7 mutation in 6p21.1 has been found in several families [7].

Using direct sequencing, Huber et al. (2005) found 25 distinct mutations in the cullin-7 gene (CUL7; 609577) in 29 families with 3-M syndrome [7].

In all 43 affected individuals with Yakut short-stature syndrome, Maksimova et al. (2007) identified homozygosity for a founder mutation in the CUL7 gene [5]. Delayed bone age (3) has been reported in 3M syndrome patients; our patient’s was 1 year behind his chronological age.

Our patient had an incidental finding of cerebellum atrophy with volume loss of the brain stem and supratentorium, which has not been previously reported in the literature.

Conclusions

An early diagnosis is important for genetic counseling in 3-M syndrome, especially in countries like Saudi Arabia, where consanguineous marriages are common, and autosomal recessive genetic disorders leading to severe short stature should be kept in mind.

3-M syndrome should always be considered in the differential diagnosis of patients with growth retardation of prenatal onset.