CCDC8 – 3-M syndrome

CCDC8 is one of three genes implicated in autosomal recessive 3-M syndrome (MONDO:0007477), a primordial growth disorder marked by prenatal and postnatal growth retardation with subtle skeletal anomalies. Biallelic loss-of-function mutations in CCDC8 have been identified in two sisters with mild short stature carrying a homozygous frameshift c.1057del (p.Ala353fs)[PMID:28675896] and in one independent family with a similar homozygous truncating variant[PMID:23018678]. Segregation evidence is limited to affected siblings without extended pedigree analysis, but recurrence of truncating alleles in unrelated patients supports a pathogenic role under an autosomal recessive model.

Functional characterization in patient-derived CCDC8(-/-) fibroblasts demonstrates impaired growth hormone signalling, with reduced STAT5b and ERK/MAPK activation after GH stimulation, while IGF1-mediated AKT activation remains intact[PMID:23018678]. These findings are consistent with a loss-of-function mechanism disrupting the GH-IGF axis. Although the genetic evidence is sparse, the concordant functional data provide moderate experimental support. Key Take-home: CCDC8 loss-of-function variants cause a clinically recognizable form of 3-M syndrome and should be included in diagnostic genetic testing for children with unexplained short stature and normal cognition.

References

• Hormone research in paediatrics • 2017 • Two Siblings with a Mutation in CCDC8 Presenting with Mild Short Stature: A Case of 3-M Syndrome. PMID:28675896
• Journal of molecular endocrinology • 2012 • Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling. PMID:23018678

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