Steroid Sulphatase Deficiency Research Articles

Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis).

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

Dysmorphology of inborn errors of metabolism.

As we discover the molecular mechanism of disorders, eventually all dysmorphic syndromes will ultimately be considered biochemical defects. An overview on the recognition and classification of dysmorphic features will be provided. Categories of inborn errors of metabolism associated with dysmorphic manifestations will be discussed. For e.g. abnormal eye findings are an important clue to the diagnosisin galactosemia, cystinosis, Lowe syndrome, and homocystinuria. Unusual kinky hair is seen in Menkes disease. Skin findings typically lead to the diagnosis in Fabry, Hunter and steroid sulphatase deficiency. Infants who have peroxisomal disorders (Zellweger) pyruvate dehydrogenase deficiency, cholesterol biosynthetic disorders (Smith-Lemli-Opitz), multipleacyl-CoA dehydrogenase deficiency (glutaric aciduria type II), infants of mothers with phenylketonuria have striking facial dysmorphism and structural anomalies at birth. In other disorders dysmorphic features may not be present at birth but may develop with age at varying rates such as in lysosomal storage disorders (mucopolysaccharidoses, oligosaccharidoses), congenital disorders of glycosylation and mitochondrial disorders. Salient clinical features, biochemical defects, molecular basis, and diagnostic strategies will be discussed to permit early treatment of these disorders.

Ictiosis ligada al cromosoma X asociada a epilepsia, hiperactividad, autismo y retraso mental, por microdeleción Xp22.31

X-chromosome-linked ichthyosis is caused by mutation or deletion of the STS gene associated with a deficiency of the enzyme steroid sulphatase, located in the distal part of the short arm of the X chromosome (Xp22.3-pter), close to the pseudo-autosomal region. Depending on its size, it can present as an isolated entity or combined with a syndrome caused by neighbouring genes, thus associating itself with other monogenic diseases as well as other mental disorders. The most relevant findings from the literature review are the importance of the Xp22.3-pter region and the higher incidence of neurological disorders among males (attention deficit hyperactivity disorder, autism and X-linked mental retardation). The role and implication of these genes in the disease are discussed and the authors suggest a possible contribution of the gene PNPLA4, which was originally described as GS2 and codes for calcium-independent phospholipase A2 beta, involved in lipoprotein metabolism, as one of the causes of autism. Improvements have been observed following treatment with citicoline, thanks to the role this nootropic plays in the biosynthesis of structural phospholipids involved in the formation and repair of the neuronal membrane.

An unusual case of neonatal erythroderma

AimsTo describe a rare form of erythroderma in a neonate, the investigations undertaken and the progress to date of a rare and life threatening skin condition.MethodsCase report and review of...

Segregation analysis in X-linked ichthyosis: paternal transmission of the affected X-chromosome

Steroid sulphatase (STS) deficiency has been described in a diversity of ethnic populations. The phenotype of STS deficiency, X-linked ichthyosis (XLI), is a genodermatosis characterized by dark scaly skin. About 90% of patients with XLI have complete deletion of the entire STS gene and flanking sequences. The variable number tandem repeats, on either side of the STS gene, appear to play an important role in these interstitial deletions due to nonallelic homologous recombination (NAHR). It is difficult to establish if this NAHR occurs between two chromosomes, between sister chromatids or between the same chromatid. To identify the parental origin of the affected X-chromosome in seven unrelated sporadic cases of XLI. Amplification of the regions from DXS89 to DXS1134 (telomeric-centromeric) including the 5' and 3' ends of the STS gene was performed through polymerase chain reaction. GeneScan analysis was performed using the DXS987, DXS8051 and DXS1060 markers located on the short arm of the X-chromosome. Fluorescence in situ hybridization analysis was performed with a digoxigenin-labelled cDNA STS probe. STS gene deletion in patients with XLI involved the sequences DXS1139 and DXF22S1. In five families segregation analysis showed paternal transmission of the affected X-chromosome in the XLI carrier. It was not possible to determine the parental origin of the affected X-chromosome in two families. These data strongly suggest that STS gene deletion occurred in the male meiosis probably due to an intrachromosomal event, recombination between S232 sequences on the same DNA molecule, or during the process of DNA replication.

Analysis of the VCX3A, VCX2 and VCX3B genes shows that VCX3A gene deletion is not sufficient to result in mental retardation in X-linked ichthyosis

X-linked ichthyosis (XLI), an inborn error of metabolism, is due to steroid sulphatase (STS) deficiency. Most patients with XLI harbour complete deletion of the STS gene and flanking sequences. The presence of low copy number repeats on either side of the STS gene seems to have a major role in the high frequency of these deletions. Some patients with XLI with terminal deletions of Xp22.3 involving marker DXS1139 and the STS gene show mental retardation (MR); VCX3A is the only gene located on this critical region. To analyse the VCX3A, VCX, VCX2 and VCX3B genes in 80 unrelated Mexican patients with XLI with normal intelligence. STS activity was measured in the leucocytes using 7-[3H]-dehydroepiandrosterone sulphate as a substrate. Amplification of the regions from telomeric DXS89 to centromeric DXS1134 including both extremes of the STS and the VCX3A, VCX, VCX2 and VCX3B genes was performed using polymerase chain reaction. No STS activity was detected in the patients with XLI (0.00 pmol mg(-1) protein h(-1)). We observed two different deletion patterns: the first group included 62 patients with deletion of VCX3A and VCX genes. The second group included 18 patients with breakpoints at several regions on either side of the STS gene not including the VCX3A gene. These data indicate that more complex mechanisms, apart from possible VCX3A gene participation, are occurring in the genesis of MR in XLI, at least in the sample of Mexican patients analysed.

X‐chromosome inactivation: role in skin disease expression

AbstractThe occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X‐linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male‐lethal X‐linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi–Hünermann–Happle syndrome, oral–facial–digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X‐linked non‐lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ–Siemens–Touraine, IFAP (ichthyosis follicularis–alopecia–photophobia) syndrome and X‐linked dyskeratosis congenita. Analogous X‐inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X‐linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X‐linked trait can be explained by skewing of X inactivation. Some X‐linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female ‘carriers’ of these disorders do not show mosaicism. A well‐known example is X‐linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding α‐galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern. Conclusion: In the various X‐linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X‐linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.

X-chromosome inactivation: role in skin disease expression

The occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X-linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male-lethal X-linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi-Hünermann-Happle syndrome, oral-facial-digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X-linked non-lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ-Siemens-Touraine, IFAP (ichthyosis follicularis-alopecia-photophobia) syndrome and X-linked dyskeratosis congenita. Analogous X-inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X-linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X-linked trait can be explained by skewing of X inactivation. Some X-linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female 'carriers' of these disorders do not show mosaicism. A well-known example is X-linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding alpha-galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern. In the various X-linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X-linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.

X-linked ichthyosis in southern Italy ★

Few surveys on the frequency of X-linked ichthyosis (XLI) in large communities are available, and no study has been conducted in Italy. We report the frequency of X-linked ichthyosis in young men who enlisted as conscripts in the Italian navy. Prior to enlistment, all potential conscripts aged 18 years and living in the coastal regions of southern Italy are examined at the Draft Council's Medical Unit of the Italian Navy in Taranto. Subjects who show any pathologic condition are referred to our Navy Hospital. All the subjects referred to our department with an ichthyosiform condition underwent a thorough dermatologic examination and completed a questionnaire regarding their personal and familial history. From January 1998 through December 2000, 60,761 young men were examined at the Draft Council's Medical Unit. Twelve cases of X-linked ichthyosis were diagnosed, with a frequency of 1:5,063 or 1.9 per 10,000 (95% confidence interval based on the Poisson distribution 1.0-2.8). All the patients had a family history confirming the X-linked inheritance. Three of 12 cases (25%) involved corneal opacities. No other significant associated pathologic change was observed. In conclusion, the frequency of X-linked ichthyosis in southern Italy is roughly in agreement with estimates from other surveys, which range from 1:4,000 to 1:6,500.1Wells R.S. Kerr C.B. Clinical features of autosomal dominant and sex-linked ichthyosis in an English population.Br Med J. 1966; 1: 947-950Crossref PubMed Scopus (161) Google Scholar, 2Ziprkowski L. Feinstein A. A survey of ichthyosis vulgaris in Israel.Br J Derm. 1972; 86: 1-8Crossref PubMed Scopus (29) Google Scholar, 3de Unamuno P. Martin-Pascual A. Garcia-Perez A. X-linked ichthyosis.Br J Dermatol. 1977; 97: 53-58Crossref PubMed Scopus (19) Google Scholar Corneal opacities have been regarded as a relevant clinical marker in the diagnosis of X-linked ichthyosis.4Costagliola C. Fabbrocini G. Illiano G.M. Scibelli C. Delfino M. Ocular findings in X-linked ichthyosis a survey on 38 cases.Ophthalmologica. 1991; 3: 152-155Crossref Scopus (37) Google Scholar We confirmed this finding, which was observed in about a quarter of our cases. X-linked ichthyosis has been associated with cryptorchidism;5Unamuno P. Martin C. Fernandez E. X-linked ichthyosis and cryptorchidism.Dermatologica. 1986; 172: 326-329Crossref PubMed Scopus (13) Google Scholar, 6Cuevas-Covarrubias S.A. Kofman-Alfaro S.H. Beirana Palencia A. Diaz-Zagoya J.C. Accuracy of the clinical diagnosis of recessive X-linked ichthyosis vs ichthyosis vulgaris.J Dermatol. 1996; 23: 594-597PubMed Google Scholar however, none of our patients showed this pathologic change. Although we did not measure the steroid sulfatase (steryl-sulfatase) activity in our patients,6Cuevas-Covarrubias S.A. Kofman-Alfaro S.H. Beirana Palencia A. Diaz-Zagoya J.C. Accuracy of the clinical diagnosis of recessive X-linked ichthyosis vs ichthyosis vulgaris.J Dermatol. 1996; 23: 594-597PubMed Google Scholar, 7Yoshiike T. Matsui T. Ogawa H. Steroid sulphatase deficiency in patients initially diagnosed as ichthyosis vulgaris or recessive X-linked ichthyosis.Br J Dermatol. 1985; 112: 431-433Crossref PubMed Scopus (18) Google Scholar we believe the accuracy of physical examination, which involved a large male sample, homogeneous with reference to age, race, and country of origin, was such to yield sufficiently reliable data.

Submicroscopic Xpter deletion in a boy with growth and mental retardation caused by a familial t(X;14)

In a 3-year-old boy with short stature, developmental delay, and dry skin, steroid sulphatase deficiency and a submicroscopic terminal deletion of Xp were found. Except for the short stature, no major clinical signs of X-linked recessive chondrodysplasia punctata could be observed. His mother had lowered steroid sulphatase activity compatible with carriership for X-linked ichthyosis and a submicroscopic translocation (X;14)(p22.31;p11.1). This finding combined with a normal amplification of exons 1, 5, and 10 of the STS gene from propositus' DNA suggested a breakpoint upstream of the STS gene. The submicroscopic maternal translocation had important implications for genetic counseling. This case report illustrates that contiguous gene syndrome related to the Xpter region may have an atypical clinical presentation and the usefulness of combined clinical, biochemical, molecular, and fluorescence in situ hybridization analysis. Am. J. Med. Genet. 87:189–194, 1999. © 1999 Wiley-Liss, Inc.

Steroid sulphatase deficiency is the major cause of extremely low oestriol production at mid-pregnancy: a urinary steroid assay for the discrimination of steroid sulphatase deficiency from other causes

A method for determining whether a pregnant woman with an extremely low serum oestriol (ELSE) measurement of mid-trimester is carrying a fetus with steroid sulphatase deficiency or another more serious disorder is described. We undertook GC/MS analysis of steroids in random maternal urine samples and quantified oestriol, oestriol precursors (dehydroepiandrosterone (DHEA), 5-androstene-3 beta, 17 beta-diol, 16 alpha-hydroxy-dehydroepiandrosterone and 5-androstene-3 beta, 16 alpha, 17 beta-triol), pregnanediol, and five other steroids largely unaffected by pregnancy (androsterone, etiocholanolone, tetrahydrocortisol, 5 alpha-tetrahydrocortisol and tetrahydrocortisone). Thirty-two samples collected from seven normal pregnant women between the 7th and 27th week of pregnancy and 22 from individuals with ELSE were analysed. Diagnostic ratios of excreted products were developed. These included ratios of oestriol and oestriol precursors to the cumulative value for the five non-pregnancy-related steroids and ratios of oestriol and oestriol precursors to pregnanediol and to each other. Our data demonstrated high 3 beta-hydroxy-5-ene steroid excretion in all ELSE patients together with low urinary oestriol excretion, a situation only consistent with deficiency of steroid sulphatase. The normal individuals had high oestriol and low excretion of oestriol precursors. No patient in our series showed the low oestriol levels and low oestriol precursor values that would indicate a fetal adrenal abnormality as the underlying defect.

Steroid sulphatase deficiency is the major cause of extremely low oestriol production at mid‐pregnancy: a urinary steroid assay for the discrimination of steroid sulphatase deficiency from other causes

Steroid sulphatase deficiency is the major cause of extremely low oestriol production at mid‐pregnancy: a urinary steroid assay for the discrimination of steroid sulphatase deficiency from other causes

X-linked ichthyosis: relation between cholesterol sulphate, dehydroepiandrosterone sulphate and patient's age.

Steroid sulphatase deficiency is a feature of recessive X-linked ichthyosis (RXLI) that causes the accumulation of sulphated steroids (SS) in various organs and cells. In a previous study, we detected elevated cholesterol sulphate (CS) and dehydroepiandrosterone sulphate (DHEAS) serum levels in a group of 15 RXLI patients selected in a narrow age range. In the present study both CS and DHEAS serum levels were qualitatively and quantitatively determined using gas-chromatographic analysis in a group of 33 RXLI patients ranging in age from 3 to 70 years. The levels of CS and DHEAS were significantly increased in all patients. Variations in SS were related both to patients' ages and clinical course of the disease; Serum SS levels start to increase in early infancy, peak at puberty, remain elevated in adults and decrease slightly in the elderly.

Allergic disease as an association of steroid sulphatase deficiency.

Ten of 31 patients with steroid sulphatase (STS) deficiency were found to have an allergic disease (bronchial asthma, allergic rhinitis, or atopic dermatitis). STS deficiency may predispose patients to allergic disease.

X-linked ichthyosis with hypogonadism: not always Kallmann's syndrome

We describe two males with congenital ichthyosis secondary to steroid sulphatase deficiency who also manifested delayed puberty with biochemical features of hypogonadotrophic hypogonadism. In the first patient a history of cryptorchidism and the clinical findings of anosmia, micropenis and bimanual synkinesis suggested a contiguous gene syndrome, comprising X-linked Kallmann's syndrome and X-linked ichthyosis. An X-Y chromosomal translocation involving the Xp22.3 locus was identified; deletions of the STS locus and of exons 10-14 of the KAL locus were subsequently demonstrated. The second patient was euosmic and, although the STS locus was deleted in association with a pericentric inversion involving Xp22.3, no deletions were detected at the KAL locus. Clinically, he was felt to have constitutionally delayed puberty rather than hypogonadotropic hypogonadism and this diagnosis was substantiated by his subsequent development.

Steroid sulphatase deficiency: identification of heterozygotes using hydrolysis of dehydroepiandrosterone sulphate by peripheral leucocytes.

Diagnosis of X-linked recessive ichthyosis, which is expressed only in males, can readily be made by measurement of leucocyte steroid sulphatase activity. However, because the gene for steroid sulphatase activity partly escapes from the process of X-chromosome inactivation associated with gene dosage compensation, identification of heterozygotes (females) is more difficult. We have measured the steroid sulphatase (by hydrolysis of dehydroepiandrosterone sulphate) and beta-glucuronidase (by hydrolysis of methylumbelliferyl glucuronide) activities in leucocytes from 18 heterozygotes, 100 normal females, 100 normal males and 11 affected subjects. When the ratio of the activities of steroid sulphatase and beta-glucuronidase in mixed leucocytes was plotted as a function of the steroid sulphatase activity, 85% heterozygotes were distinguished from normal females. Measurement of steroid sulphatase activity alone with these cells enabled identification of 78% heterozygotes. Measurements on mononuclear leucocytes were much less effective. Thrombocytes showed 1% of the steroid sulphatase activity of leucocytes. In females, leucocyte steroid sulphatase activity was independent of the stage of the ovarian cycle at which the cells were collected.

Hypogonadotrophic hypogonadism with hyposmia, X‐linked ichthyosis, and renal malformation syndrome

The aim of this study was the endocrinological, enzymatic, and genetic evaluation of a family with a complex syndrome associating hypogonadotrophic hypogonadism with hyposmia, X-linked ichthyosis and renal malformation. Hypothalamic-pituitary-testicular function, olfaction, steroid sulphatase activity, and morphological renal studies were assessed. DNA molecular analyses were carried out in all the patients. Two brothers and their maternal uncle showed the clinical picture of congenital ichthyosis, hypogonadism, hyposmia and unilateral renal maldevelopment. LH and FSH were determined by RIA basally and after GnRH stimulation, and the test repeated after a period of GnRH priming. Testosterone response to hCG was measured. Arylsulphatase C assay was performed as a measure of steroid sulphatase activity. DNA amplification analysis and Southern blot analysis of four Xp22.3 loci were performed. Low levels of gonadotophins, basally and after acute GnRH, increased clearly after GnRH priming. Low testosterone levels increased promptly after hCG. Subnormal levels of arylsulphatase C were detected. Hyposmia and renal hypoplasia or aplasia were demonstrated. A large Xp 22.3 deletion including the genes responsible for X-linked ichthyosis (steroid sulphatase deficiency) and Kallmann syndrome was demonstrated. The absence of the gene encoding steroid sulphatase accounts for the X-linked ichthyosis in these patients, whereas the absence of the Kallmann syndrome gene accounts for hypogonadism, anosmia and for the single kidney found in two of the three patients.

Second-trimester maternal serum screening using alpha-fetoprotein, human chorionic gonadotrophin, and unconjugated oestriol: experience of a regional programme.

Over a 2-year period from January 1991 to December 1992, second-trimester maternal serum screening for Down's syndrome using alpha-fetoprotein (alpha FP), human chorionic gonadotrophin (hCG), and unconjugated oestriol (uE3) was made available to five health districts in East Anglia, with a total population of 1.2 million. Amniocentesis was offered when the risk of Down's syndrome at term was 1:200 or greater. 25,359 singleton pregnancies were screened, representing an uptake of 77 per cent. The recall rate for the 24 per cent of women who had not had a dating scan prior to the test was 9.4 per cent compared with 3.9 per cent for those who had been scanned (P < 0.0005). Seventy-five per cent (36/48) of Down's syndrome pregnancies were detected for a false-positive rate of 4.0 per cent. Twenty-five out of 36 of detected Down's syndrome pregnancies were dated by scan prior to sampling, and in the 11 remaining cases, the dates were confirmed by scan after a high-risk result was obtained. The exclusion of uE3 from the screening protocol would have reduced the detection rate to 52 per cent (25/48) for the same false-positive rate. Eighty-five per cent of women identified at high risk accepted the offer of an amniocentesis. Other fetal abnormalities detected were trisomy 18 (3), trisomy 13 (2), 45,X (6), 69,XXX (5), other chromosome abnormalities (9), open neural tube defects (26), hydrocephalus (7), abdominal wall defects (4), and steroid sulphatase deficiency (6).

Prenatal detection of X-linked ichthyosis by maternal serum screening for Down syndrome.

Maternal serum unconjugated oestriol (uE3) was measured in 15,375 pregnancies during 2 years of second-trimester risk assessment for Down syndrome using biochemical markers. Very low levels of uE3 (< 0.1 MOM) were detected in 22 serum samples (0.14 per cent). Very low uE3 was associated with an adverse outcome in 13 pregnancies including fetal death and miscarriage (N = 11) anencephaly (N = 1), and Meckel-Gruber syndrome (N = 1). Dry scales on the skin appeared in the first year of life in four boys. From dermatological diagnosis, prenatal uE3 levels, and pedigree analysis, it is concluded that at least 5 in approximately 7500 male births in the study population are affected by steroid sulphatase deficiency, which is the biochemical defect in X-linked ichthyosis. Very low uE3 levels in the second trimester are indicative of this disease in pregnancies with normal ultrasound findings.

Deletion analysis maps ocular albinism proximal to the steroid sulphatase locus

We describe a pedigree in which four male members are affected by a contiguous gene abnormality involving the short arm of the X chromosome (Xp22.32). Bivariate flow cytometry of lymphoblastoid cell lines from two of these individuals and a normal male showed a 6-7 megabase deletion in affected males, and high resolution chromosomal G-banding of an obligate heterozygote showed the deletion to reside in the Xp22.32 region. Affected members had X-linked ichthyosis due to steroid sulphatase deficiency, Kallmann's syndrome, but no ocular albinism. In two out of four affected individuals studied, there was unilateral renal agenesis. Deletion analysis using the Xp22.32 markers MIC2, DXS31, DXS 89, GMGX9, DXS278, DXS143, and DXS9 showed that the deletion extended from DXS31 to DXS143 (inclusive). The absence of ocular albinism in this pedigree shows conclusively that the X-linked ocular albinism gene resides proximal to the DXS143 locus. Further, the inconstant association of unilateral renal agenesis with X-linked Kallmann's syndrome, even when the latter is caused by a complete deletion of the gene, suggests that the absence of the X-linked Kallmann gene can be compensated in renal development.