OBJECTIVE: Arboleda et al. have recently shown that IMAGe (intra-uterine growth 
restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital 
abnormalities) syndrome is caused by gain-of-function mutations of maternally 
expressed gene CDKN1C on chromosome 11p15.5. However, there is no other report 
describing clinical findings in patients with molecularly studied IMAGe 
syndrome. Here, we report clinical and molecular findings in Japanese patients.
PATIENTS: We studied a 46,XX patient aged 8·5 years (case 1) and two 46,XY 
patients aged 16·5 and 15·0 years (cases 2 and 3).
RESULTS: Clinical studies revealed not only IMAGe syndrome-compatible phenotypes 
in cases 1-3, but also hitherto undescribed findings including relative 
macrocephaly and apparently normal pituitary-gonadal endocrine function in cases 
1-3, familial glucocorticoid deficiency (FGD)-like adrenal phenotype and the 
history of oligohydramnios in case 2, and arachnodactyly in case 3. Sequence 
analysis of CDKN1C, pyrosequencing-based methylation analysis of KvDMR1 and 
high-density oligonucleotide array comparative genome hybridization analysis for 
chromosome 11p15.5 were performed, showing an identical de novo and maternally 
inherited CDKN1C gain-of-function mutation (p.Asp274Asn) in cases 1 and 2, 
respectively, and no demonstrable abnormality in case 3.
CONCLUSIONS: The results of cases 1 and 2 with CDKN1C mutation would argue the 
following: [1] relative macrocephaly is consistent with maternal expression of 
CDKN1C in most tissues and biparental expression of CDKN1C in the foetal brain; 
[2] FGD-like phenotype can result from CDKN1C mutation; and [3] genital 
abnormalities may primarily be ascribed to placental dysfunction. Furthermore, 
lack of CDKN1C mutation in case 3 implies genetic heterogeneity in IMAGe 
syndrome.