3-M syndrome is an autosomal recessive disorder characterised by severe pre- and post-natal growth failure, a characteristic facial appearance (triangular shaped face, fleshy tipped nose) and radiological features (slender long bones and tall vertebrae). 3-M syndrome is known to be caused by mutations throughout the Cullin 7 gene, identified in a range of ethnic groups including Brazilian, European, Moroccan, Yakutskian and Indian.
We have now identified individuals with 3-M syndrome in two consanguineous families of Pakistani origin. In the first family there were two affected male siblings, aged 10 years and 9 months respectively, with heights of 100.6 and 53 cm (height SDS −6.1 and −7.9). The older boy had a markedly delayed bone age. The facial phenotype of both children was consistent with 3-M syndrome. The index case from the second family also had a clinical diagnosis of 3-M. Sequencing of cullin 7 identified two distinct nonsense mutations; in the first family a two base pair deletion in exon 18 (c.3379_3380delTG, p.W1127E) and in the second family a one base pair deletion in exon 22 (c.4191delC, p.H1397H), were found in the affected children. Both would result in a frame shift and a premature stop codon with nonsense mediated decay of the mRNA and no protein produced.
Cullin 7 has a role as a scaffold protein in assembling an E3 ubiquitin ligase enzyme with Skp1, Fbxw8 and ROC1. The CUL7 and Fbxw8 knockout mice have a similar phenotype with intrauterine growth retardation and death from respiratory distress at birth. We hypothesised that children with a clinical diagnosis of 3-M syndrome but without mutations in CUL7 may have pathogenic mutations in Fbxw8. Sequencing of three patients with non-CUL7 3-M syndrome has demonstrated no mutations in Fbxw8.
We report novel mutations in CUL7, the first in a Pakistani family and the first in exons 18 and 22. We have also excluded Fbxw8 mutations as a cause of non-CUL7 3-M syndrome.
05 - 07 Nov 2008
British Society for Paediatric Endocrinology and Diabetes