In 1991, Ades et al. reported a family with Smith-Fineman-Myers syndrome [Ades et al., 1991]. Two brothers were affected with a condition consisting of severe mental retardation, microcephaly, growth failure, facial anomalies and bilateral cryptorchidism. To these authors, these clinical signs were evocative of the Smith-Fineman-Myers syndrome (SFM)(MIM 309580), first reported by Smith et al.[1980]. Another affected case with a similar condition was reported by Stephenson and Johnson [1985]. More recently, Guion-Almeida et al.[1998] described 2 boys thought to be monozygotic twins with a phenotype suggestive of SFM syndrome.

A new syndrome was characterised in 1991 of severe mental retardation, microcephaly, growth retardation, facial anomalies together with an unusual form of alpha-thalassemia linked to the X chromosome: the X-linked alpha-thalassemia with mental retardation syndrome (ATR-X)[Gibbons et al., 1991]. The XNP gene [Gecz et al., 1993] was shown to be responsible for ATR-X syndrome [Gibbons et al., 1995a]. There is a strong clinical overlap between the ATR-X phenotype and the phenotype reported by Ades et al.[1991], a fact that prompted Hall [1992] to suggest that the family of Ades et al. was de facto an ATR-X family. However, a careful examination of the erythrocytes of both the 2 affected patients and their phenotypically normal sister and mother failed to reveal any haemoglobin H inclusions [Ades, 1992], which was an essential phenotypic trait for a diagnosis of ATR-X syndrome in 1991. Since the initial description of mutations in the XNP/ATR-X gene, several patients have been described with mutations in the gene but without alpha-thalassemia [Villard et al., 1996a, b]. It became evident that an abnormal haematological status was not always associated with mutations in the XNP/ATR-X gene. These new data prompted us to search for mutations in the Ades et al. family.