3M syndrome is a rare autosomal recessive disorder that combines intrauterine growth retardation (IUGR) and postnatal growth retardation. Additionally, this syndrome is characterized by dysmorphic facial features (large head, dolichocephaly, frontal bossing, a triangular face, long philtrum and hypoplastic midface) and certain radiological abnormalities. The latter includes slender long bones and ribs, foreshortened vertebral bodies, and small pelvis. The name of this disorder comes from the initials of the three researchers (Miller, McKusik and Malvaux) who first identified it.
The characteristic radiologic findings of 3M syndrome are used to rule out similar disorders such as Silver-Russel syndrome (SRS), particularly the lack of limb length asymmetry that is present in over half of those with autosomal recessive SRS. The severity of symptoms and physical features varies considerably from case to case. Prenatal diagnosis is possible by ultrasonography. Supplying growth hormone to patients can help to increase body height.
Akawi et al. (2011) presented the case of a Jordanian family with three affected children from first-cousin parents. The eldest of these children is an 11-year-old girl, who had, along with her two siblings, a symmetrical short stature. The girl also suffered delayed bone age, partial syndactyly of second and third toes, hyperextensible joints, mild hepatosplenomegaly, and mild bifrontal brain atrophy. The younger brother had, in addition to the above, micrognathia and bluish sclera. Furthermore, a paternal aunt of these children had a son who was affected by similar symptoms, and whose parents are also consanguineous. The underlying genetic cause behind these symptoms is likely to be an indel in the first exon of the OBSL1 gene (c.681_682delinsTT), which corresponds to the protein changes; p.[H227H; Q228X]. The Q228X leads to a truncated protein that is probably eliminated by the nonsense-mediated decay (NMD) surveillance. Mutations in OBSL1 are linked with 3M syndrome, therefore, these patients were arguably suffering the latter syndrome as opposed to Silver-Russell syndrome.
[See: United Arab Emirates > Akawi et al., 2011].
Al-Dosari et al. (2012) characterized a cohort of 14 patients 3M syndrome born to six consanguineous Saudi families (A-F). Genomic DNA analysis revealed that patients of families D and E shared a novel homozygous identical mutation of 1bp deletion in exon 3 of OBSL1 (c.1306del, p.Arg436Glyfs*14). The affected group included a 5.5-year-old girl and a 9-month-old boy from family D, who both received a diagnosis of severe intrauterine growth retardation, which persisted in the form of severe proportionate short stature postnatally. In family E, the index case was a 9.5-year-old girl of normal intelligence with severe proportionate short stature. Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. Al-Dosari et al. (2012) emphasized that increased awareness about this syndrome among pediatricians and endocrinologists is needed to avoid a costly and unnecessary diagnostic odyssey.
Akawi et al. (2011) studied an Emirati family with Omani origin. The consanguineous parents had six affected children out of a total of 12. Three of the affected children had IUGR and postnatal short stature with feeding problems. Several dysmorphic features were observed including prominent forehead, triangular face, large eyes, depressed nasal bridge, short neck, short thorax, bilateral clinodactyly, and pectus excavatum. The underlying genetic cause behind these symptoms is likely to be a missense mutation in exon 2 of OBSL1 (c.1119G>C), which corresponds to the protein change; p.W373C. p.W373C has a destructive effect on OBSL1 protein as it affects a highly conserved amino acid residue. Mutations in OBSL1 are linked with 3M syndrome; therefore, these patients are arguably suffering the latter syndrome as opposed to Silver-Russell syndrome.