ESPE Abstracts

Background: Silver-Russell syndrome (SRS) is a congenital developmental disorder characterised by pre- and post-natal growth failure, relative macrocephaly, hemihypotrophy, and fifth-finger clinodactyly. Recent studies have shown that gain-of-function mutations of CDKN1C result in IMAGe syndrome (IMAGeS) characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and male genital abnormalities, whereas less severe gain-of-function mutations of CDKN1C have been identified in a large family with maternally inherited SRS. Thus, it has been suggested that relatively severe and mild CDKN1C gain-of-function effects lead to IMAGeS and SRS, respectively. Notably, IMAGeS patients satisfy the diagnostic criteria for SRS proposed by Nechine et al., and IMAGeS and SRS patients with CDKN1C mutations invariably lack hemihypotrophy characteristic of SRS.

Results: We report duplications of maternally derived chromosome 11p15 involving CDKN1C in three Japanese patients (cases 1 and 2 from family A, and case 3 from family B) with SRS phenotype lacking hemihypotrophy. Chromosome analysis showed 46, XX, der (16) t (11; 16) (p15.3; q24.3) mat in case 1, 46, XY, der (16) t (11; 16) (p15.3; q24.3) mat in case 2, and a de novo 46, XX, der (17) t (11; 17) (p15.4; q25.3) in case 3. Genomewide oligonucleotide-based array comparative genomic hybridization, microsatellite analysis, pyrosequencing-based methylation analysis, and direct sequence analysis revealed the presence of maternally derived extra copies of the distal chromosome 11p involving the wild-type CDKN1C (a ~7.98 Mb region in cases 1 and 2, and a ~4.43 Mb region in case 3).

Conclusion: The results, in conjunction with the previous findings in patients with similar duplications encompassing CDKN1C and in those with intragenic mutations of CDKN1C, imply that duplications of CDKN1C as well as relatively mild gain-of-function mutations of CDKN1C lead to SRS subtype that usually lack hemihypotrophy.

Funding: This work was supported by Grants-in-Aid for Scientific Research (A) (25253023) and Research (B) (23390083) from the Japan Society for the Promotion of Science, Grants for Research on Intractable Diseases (H22-161) from the Ministry of Health, Labor and Welfare, and Grant for National Center for Child Health and Development (25–10).