Alternative titles; symbols
ORPHA: 2616; DO: 0060241;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19q13.32 | 3-M syndrome 3 | 614205 | Autosomal recessive | 3 | CCDC8 | 614145 |
A number sign (#) is used with this entry because of evidence that 3M syndrome-3 (3M3) is caused by homozygous mutation in the CCDC8 gene (614145) on chromosome 19q13.
3M syndrome is characterized by poor postnatal growth and distinctive facial features, including triangular facies, frontal bossing, fleshy tipped nose, and fleshy lips. Other features may include skeletal anomalies and prominent heels (summary by Hanson et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity of 3M syndrome, see 3M1 (273750).
Hanson et al. (2011) described 5 unrelated probands, all born of consanguineous Asian parents, with 3M syndrome. All had poor growth, fleshy tipped nose, short thorax, and prominent heels. More variable, but common features included anteverted nares, triangular face, dolichocephaly, frontal bossing, midface hypoplasia, long philtrum, pointed chin, prominent ears, short neck, and square shoulders. Less common features included tall vertebral bodies, slender long bones, clinodactyly, hyperlordosis, transverse chest groove, and hip dysplasia.
Al-Dosari et al. (2012) reported 3 Saudi sibs (family F), born to first-cousin parents, with 3M syndrome. The proband was a 4-year-old girl who had intrauterine growth retardation and a birth weight of 1.7 kg; she had 2 weeks of neonatal intensive care unit care because of a transitory respiratory difficulty. Development was mildly delayed. Examination revealed proportionate short stature, high forehead, small midface, significant malar hypoplasia, full lips, and a hyperlordotic posture. Skeletal survey showed elongated vertebral bodies, small pelvis, and slender tubular bones. Her older sister and younger brother were similarly affected.
Liao et al. (2017) studied 2 Pakistani sisters with mild 3M syndrome and mutation in the CCDC8 gene. Both had intrauterine growth retardation, and showed dysmorphic features including frontal bossing, triangular face, midface hypoplasia, depression of nasal bridge, upturned nares, fleshy nose and lips, exaggerated lumbar lordosis, and prominent heels. Skeletal survey in the older sister revealed gracile long bones and ribs, pectus excavatum, and spina bifida occulta with a vertebral ossification defect at L4-L5, but normal vertebral height. The authors stated that these features were mild in presentation and were appreciated in retrospect when the molecular diagnoses was known. Heights at last follow-up, at 11.9 and 10.2 years of age, respectively, were -2.2 SDS and -2.7 SDS. The authors noted that the consanguineous Pakistani parents were rather tall, so the actual degree of growth failure was more significant than it might appear.
The transmission pattern of 3M3 in the families reported by Hanson et al. (2011) was consistent with autosomal recessive inheritance.
By autozygosity mapping followed by exome sequencing of 3 Asian patients with 3M syndrome-3, Hanson et al. (2011) identified 2 different homozygous 1-bp duplications in the CCDC8 gene (614145.0001 and 614145.0002). Both mutations were predicted to result in truncation, consistent with a loss of function. The findings supported the hypothesis that the 3M syndrome results from defects in a pathway controlling human growth.
In 3 Saudi sibs (family F) with 3M syndrome, Al-Dosari et al. (2012) identified homozygosity for an insertion/deletion in the CCDC8 gene (614145.0003).
In 2 Pakistani sisters with mild 3M syndrome, Liao et al. (2017) identified homozygosity for a previously reported frameshift mutation in the CCDC8 gene (614145.0001). The authors noted that the sisters had relatively mild short stature, thus expanding the anthropometric phenotype of 3M syndrome.
Al-Dosari, M. S., Al-Shammari, M., Shaheen, R., Faqeih, E., AlGhofely, M. A., Boukai, A., Alkuraya, F. S. 3M syndrome: an easily recognizable yet underdiagnosed cause of proportionate short stature. J. Pediat. 161: 139-145, 2012. [PubMed: 22325252] [Full Text: https://doi.org/10.1016/j.jpeds.2011.12.051]
Hanson, D., Murray, P. G., O'Sullivan, J., Urquhart, J., Daly, S., Bhaskar, S. S., Biesecker, L. G., Skae, M., Smith, C., Cole, T., Kirk, J., Chandler, K., Kingston, H., Donnai, D., Clayton, P. E., Black, G. C. M. Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth. Am. J. Hum. Genet. 89: 148-153, 2011. [PubMed: 21737058] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.028]
Liao, L., Gan, H.-W., Hwa, V., Dattani, M., Dauber, A. Two siblings with a mutation in CCDC8 presenting with mild short stature: a case of 3-M syndrome. Horm. Res. Paediat. 88: 364-370, 2017. [PubMed: 28675896] [Full Text: https://doi.org/10.1159/000477907]