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

Summary Objective Arboleda et al . have recently shown that IMAG e (intra‐uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome is caused by gain‐of‐function mutations of maternally expressed gene CDKN 1C on chromosome 11p15.5. However, there is no other report describing clinical findings in patients with molecularly studied IMAG e 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 IMAG e 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 CDKN 1C , pyrosequencing‐based methylation analysis of Kv DMR 1 and high‐density oligonucleotide array comparative genome hybridization analysis for chromosome 11p15.5 were performed, showing an identical de novo and maternally inherited CDKN 1C 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 CDKN 1C mutation would argue the following: [1] relative macrocephaly is consistent with maternal expression of CDKN 1C in most tissues and biparental expression of CDKN 1C in the foetal brain; [2] FGD ‐like phenotype can result from CDKN 1C mutation; and [3] genital abnormalities may primarily be ascribed to placental dysfunction. Furthermore, lack of CDKN 1C mutation in case 3 implies genetic heterogeneity in IMAG e syndrome.