New Case of 3M Syndrome Associated with a Mutation in the CUL7 Gene

Abstract

Introduction: 3M Syndrome (3MS) is an autosomal recessive disorder with a worldwide prevalence of 200 cases. The related genes are CUL7, OBSL1, and CCDC8. Clinical manifestations include growth delay and various facial, skeletal, and radiological abnormalities.

Objective: To characterize a case of 3MS.

Methods: A 5-year-old male, the firstborn of non-consanguineous parents, with a family history of developmental delay in a fourth-degree relative. He was born by cesarean section at 41.5 weeks, negative STORCH screen, birth weight of 3360 g, and length of 52 cm, with no gestational or perinatal complications. Developmental milestones included sitting at 7 months, walking at 10 months, and bisyllables at 11 months. Brain MRI showed thinning of the corpus callosum, supratentorial T2 FLAIR hyperintensity, and frontal white matter presence. Carpogram showed skeletal delay. Physical examination revealed a height of 104.6 cm (-0.89 SD), weight of 16.4 kg (-0.67 SD), and head circumference of 54 cm (+2.18 SD). Dysmorphic features included a prominent forehead, triangular face, low nasal bridge, small and concave nose, malar hypoplasia, backward-tilted ears, pectus excavatum, rhizomelic shortening in limbs, and small hands and feet with a bilateral simian crease.

Results and Discussion: The karyotype was normal 46 XY (25), genomic hybridization was negative, and molecular exome sequencing revealed two variants in the CUL7 gene. The first variant was c.1834C>T (p.Pro612Ser), a heterozygous variant of uncertain clinical significance, and the second was c.1388G>A (p.Arg463His), also heterozygous and of uncertain significance. This case presents typical dysmorphic features, growth delay, and limb abnormalities, with the additional findings of pectus excavatum and mild delay, which differ from other cases.

Conclusion: More case reports are needed to enhance the characterization of patients with 3M Syndrome.