IMAGe syndrome: clinical and genetic implications based on investigations in three Japanese patients

Summary 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.