Hum Genet (1986) 72:237-240 © Springer-Verlag 1986 X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome A . Ballabio 1' *, G. Parenti 1 , P. Tippett 2 , C. MondeHo 3, S. Di Maio 1, A. Tenore 1 , and G. Andria 4 1 Departments of Paediatrics, II Faculty of Medicine, Via S. Pansini 5, 1-80131 Napoli, Italy 2MRC Blood Group Unit, London, UK 3Laboratory of Human Molecular Genetics, Imperial Cancer Research Fund, London, UK 4Department of Paediatrics, Faculty of Medicine, University of Reggio Calabria, Italy Summary. We report a large Italian pedigree in which five out of six males are affected by a syndrome, following an X-linked inheritance pattern, characterized by ichthyosis, hypo- gonadotropic hypogonadism, and anosmia. The concurrence of features of X-linked ichthyosis (XLI) with those of Kallmann syndrome, another disease often inherited as an X- linked trait, prompted us to perform biochemical, cytogenet- ic, and molecular studies in relation to the short arm of the X chromosome (Xp). Steroid sulphatase (STS) activity was found to be completely deficient in all affected members of the family. Prometaphase chromosome analyses of two obli- gate heterozygous women and one affected male showed nor- mal karyotypes. Xg blood group antigen analysis and molecu- lar studies employing cloned DNA sequences from the distal segment of the Xp (probes RC8,782, dic56, and M1A), did not provide evidence for deletions or rearrangements of the X chromosome. The linkage analysis showed no crossovers be- tween the disease,Xg, and DXS143,the locus defined by probe dic56, thus suggesting the possibility of a linkage be- tween these two markers of the distal segment of Xp and the X-linked ichthyosis, hypogonadism, and anosmia syndrome. Introduction In the last few years a deficiency of steroid sulphatase (STS), previously demonstrated to be the basic defect of X-linked ichthyosis (XLI) (Shapiro et al. 1978), has also been found in some patients affected by "ichthyosis and male hypogonad- ism" (McKusick 1983) and "Rud syndrome" (Bergsma 1979; Traupe and Happle 1983; Andria et al. 1983, 1984a). On ac- count of these observations, the spectrum of clinical manifes- tations of STS deficiency has been expanded, including also altered gonadal function and anosmia together with impaired placentaloestrogen production and ichthyosis (Traupe and Happle 1983; Andria et al. 1984b). * Present address: Paediatric Research Unit, Guy's Hospital, London Bridge, London SE1, UK. Offprint requests to: G. Andria, Departments of Paediatrics, II Fa- culty of Medicine, Via S. Pansini 5, 1-80131 Napoli, Italy Occasionally patients with STS deficiency have an abnor- mal karyotype, characterized by X/Y translocations or dele- tions of Xp. In these subjects hypogonadism, mental retarda- tion, short stature, bone dysplasia, and dysmorphic features, as additional findings to the classical skin pattern of XLI, have been observed (see Shapiro 1984 for review). A new family, in which five male members had ichthyosis, hypogonadism, and anosmia and showed STS deficiency in fibroblasts, prompted us to investigate the genetic basis of the syndrome. In particular we wanted to study a possible rela- tionship between this disease and the Kallmann syndrome, a disorder often inherited as an X-linked trait and also charac- terized by hypogonadotropic hypogonadism and anosmia (McKusick 1983). A working hypothesis was that the Kallmann syndrome locus might be localized on Xp, close to the XLI/STS locus, and deleted, together with it, by a chro- mosomal rearrangement in our family. High resolution (HR) karyotyping,Xg blood group analysis, and DNA studies, using cloned DNA sequences from the distal segment of Xp, were carried out to test this hypothesis. We also performed linkage studies in order to compare our family with that described by Perrin et al. (1976). These au- thors reported a large pedigree affected by an X-linked syn- drome of ichthyosis, hypogonadism, mental retardation, and anosmia. STS activity was not assayed in this family and a linkage between the disease and Xg blood group, whose locus is known to be linked to the XLI/STS locus (Keats et al. 1981), was clearly ruled out, the highest value of lod scores being -0.096 at theta = 0.40. Our linkage analyses included Xg blood group and restriction fragment length polymorphisms (RFLPs) localized on Xp. Case reports We studied five boys from 10 to 15 years old, born to two sis- ters. The family tree is shown in Fig. 1. Delivery was compli- cated by prolonged labour in two subjects (III-2, III-4) and caesareansection was needed in the other three patients (III-5, III-6, IIf-8). Low levels of urinary oestriol, during the last part of pregnancy, was documented in III-2, III-5, and in