Importantly, the PCNA binding site of p57 was found to participate in mediating growth inhibition (Watanabe et al., 1998) and gain-of-function mutations in this domain were later discovered to cause the development of growth-restriction syndromes such as IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) and Silver Russell (see below) (Arboleda et al., 2012; Brioude et al., 2013b). This evidence concerns the gene CDKN1C and Metaphyseal dysplasia.