Two Siblings with a Mutation in <b><i>CCDC8</i></b> Presenting with Mild Short Stature: A Case of 3-M Syndrome

Abstract

Background: Short stature can be caused by mutations in a multitude of different genes. 3-M syndrome is a rare growth disorder marked by severe pre- and postnatal growth retardation along with subtle dysmorphic features. There have only been 2 prior reports of mutations in CCDC8 causing 3-M syndrome. Methods: Two patients presenting with mild short stature underwent whole exome sequencing. The mutation was confirmed via Sanger sequencing. We compare the clinical characteristics of our 2 patients to patients previously reported with mutations in the same gene. Results: Exome sequencing identified a homozygous frameshift mutation in CCDC8 in both patients. They presented with a much milder phenotype than previously described patients with the same mutation. Conclusion: In this study, we report a case of 2 sisters with relatively mild short stature who were found via exome sequencing to carry a previously reported homozygous mutation in CCDC8. These patients expand the anthropometric phenotype of 3-M syndrome and demonstrate the power of exome sequencing in the diagnosis of children with short stature. 3-M syndrome should be considered in children with mild skeletal abnormalities, normal/high growth hormone-IGF axis parameters, and normal intelligence.

International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood

“…It is associated with reduced IGF2 expression and increased H19 expression, as also found in Silver-Russell syndrome (SRS). Characteristically, birth size is severely affected although individuals with milder intrauterine growth restriction have been reported ( 124 ).…”

New developments in the genetic diagnosis of short stature

“…Another example is 3-M syndrome which is a rare syndromic growth disorder due to mutations in CUL7, OBSL1, or CCDC8 that usually presents with extreme short stature, skeletal dysplasia, and facial abnormalities. Interestingly, Liao L et al report 2 siblings with a previously reported pathogenic CCDC8 variant but only mild short stature (height −2.2 to −2.7 SDS) and subtle facial abnormalities [35].…”