X-linked Ichthyosis Research Articles

Deletions of VCX‐A and NLGN4: a variable phenotype including normal intellect

Patients with Xp22.3 interstitial and terminal deletions have been shown to be affected by intellectual disability (ID) or autism. Previously, VCX-A (variably charged protein X-A), located at Xp22.3, was introduced as a gene for ID and its presence was suggested to be sufficient to maintain normal mental development. Recent reports suggest that mutations in NLGN4 (neuroligin 4), located at that same region, are involved in autistic disorders and ID. In the current case study, we clinically and molecularly describe a pedigree of three generations affected by contiguous gene syndrome that includes features of X-linked ichthyosis and Kallmann syndrome. Molecular analysis revealed the presence of an interstitial deletion spanning approximately 4.5Mb at Xp22.3. The centromeric breakpoint was localized between markers DXS1467 and DXS8051, proximal to KAL-1. The telomeric breakpoint was localized between markers DXS89 and DXS1060, distal to NLGN4. The deletion of VCX-A and NLGN4 in this family prompted us to examine the cognitive functions of our two adult patients using comprehensive intellectual and neurocognitive assessment. Normal intellectual function was found in one patient and mild ID was revealed in the other. Neither patient met any Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria for a pervasive developmental disorder such as autism. These findings suggest that deletion of VCX-A and NLGN4 can result in variable phenotypic features and that normal mental development can be achieved despite this deletion, emphasizing the importance of environmental factors and possible modifier genes.

Deletion of distal promoter of VCXA in a patient with X-linked ichthyosis associated with borderline mental retardation

X-linked ichthyosis (XLI) is caused by deficiency of steroid sulfatase (STS) activity. About 90% XLI patients have large deletions involving the entire STS gene and flanking regions. Recently, VCXA, which is located approximately 0.7Mb telomeric to the STS gene, was reported as a candidate gene for mental retardation (MR) in patients with XLI. To delineate the X-chromosomal deletion of a XLI patient with borderline mental retardation. We carried out FISH analysis to show that the whole STS gene is deleted, and PCR analysis for fine-scale deletion mapping. The deleted segment is approximately 1.6Mb in size, and includes the entire STS and VCXB1 genes. VCXA itself is intact, but its promoter is deleted. A deletion that includes the VCXA promoter is associated with borderline mental retardation in a patient with XLI.

Barrier Dysfunction and Pathogenesis of Neutral Lipid Storage Disease with Ichthyosis (Chanarin–Dorfman Syndrome)

Neutral lipid storage disease with ichthyosis (NLSDI; Chanarin-Dorfman syndrome) is an ichthyosiform syndrome, often associated with mutations in a lipid hydrolase, CGI-58. The presence of oil red O-positive, neutral lipid droplets in tissue biopsies, and/or in leukocytes on blood smears, coupled with a constellation of multisystem abnormalities and a pruritic ichthyosiform erythroderma, are together diagnostic of NLSDI. We investigated the pathogenesis of the ichthyosiform erythroderma in patients from three unrelated kindreds with a clinical diagnosis of NLSDI. Basal permeability barrier function and stratum corneum (SC) integrity were abnormal, but barrier recovery rates were faster than normal, as in atopic dermatitis. The basal barrier abnormality was linked to the secretion of lipid micro-inclusions, first segregated within lamellar bodies (LB), which then form a non-lamellar phase within the SC interstices, shown by combined ruthenium tetroxide post-fixation and lipid-retaining resin-white embedding. With colloidal lanthanum nitrate perfusion, excess water/solute movement was restricted to the SC interstices, and further localized to non-lamellar domains. Phase separation of excess stored lipid provides a unifying pathogenic mechanism not only for NLSDI, but also in several other inherited ichthyosiform disorders of lipid metabolism, such as recessive X-linked ichthyosis and type 2 Gaucher's disease.

A New Type of Bacterial Sulfatase Reveals a Novel Maturation Pathway in Prokaryotes

Sulfatases are a highly conserved family of enzymes found in all three domains of life. To be active, sulfatases undergo a unique post-translational modification leading to the conversion of either a critical cysteine ("Cys-type" sulfatases) or a serine ("Ser-type" sulfatases) into a Calpha-formylglycine (FGly). This conversion depends on a strictly conserved sequence called "sulfatase signature" (C/S)XPXR. In a search for new enzymes from the human microbiota, we identified the first sulfatase from Firmicutes. Matrix-assisted laser desorption ionization time-of-flight analysis revealed that this enzyme undergoes conversion of its critical cysteine residue into FGly, even though it has a modified (C/S)XAXR sulfatase signature. Examination of the bacterial and archaeal genomes sequenced to date has identified many genes bearing this new motif, suggesting that the definition of the sulfatase signature should be expanded. Furthermore, we have also identified a new Cys-type sulfatase-maturating enzyme that catalyzes the conversion of cysteine into FGly, in anaerobic conditions, whereas the only enzyme reported so far to be able to catalyze this reaction is oxygen-dependent. The new enzyme belongs to the radical S-adenosyl-l-methionine enzyme superfamily and is related to the Ser-type sulfatase-maturating enzymes. This finding leads to the definition of a new enzyme family of sulfatase-maturating enzymes that we have named anSME (anaerobic sulfatase-maturating enzyme). This family includes enzymes able to maturate Cys-type as well as Ser-type sulfatases in anaerobic conditions. In conclusion, our results lead to a new scheme for the biochemistry of sulfatases maturation and suggest that the number of genes and bacterial species encoding sulfatase enzymes is currently underestimated.

Commercial assay for steroid sulphatase activity in X-linked ichthyosis

Commercial assay for steroid sulphatase activity in X-linked ichthyosis

Point mutation in the STS gene in a severely affected patient with X-linked recessive ichthyosis

This article does not have an abstract.

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.

Steroid Sulfatase Deficiency With Bilateral Periventricular Nodular Heterotopia

This report presents a case of steroid sulfatase deficiency with bilateral periventricular nodular heterotopia. A 13-year-old male was diagnosed as having steroid sulfatase deficiency because steroid sulfatase activity was not detected in his leukocytes. In deoxyribonucleic acid studies, steroid sulfatase locus and adjacent loci were found to be deleted in his deoxyribonucleic acid. Cranial magnetic resonance imaging revealed periventricular nodular heterotopia, disclosing an irregular contour of the lateral walls of the lateral ventricles due to small nodular masses that were isointense as to the gray matter. In steroid sulfatase deficiency patients, bilateral periventricular nodular heterotopia must be considered.

Both N-terminal and C-terminal regions of steroid sulfatase are important for enzyme activity

Steroid sulfatase (STS) is localized in the endoplasmic reticulum and catalyzes desulfation of 3beta-hydroxysteroid sulfates. X-linked ichthyosis (XLI) is an inherited skin disorder caused by deficiency of STS enzyme activity. We previously reported a case in which XLI with a one-base change in the STS gene and variation in amino acid Q560P developed. In this study, we performed molecular analysis to determine the importance of terminal regions of STS and the effect of mutant STS on STS enzyme activity. To examine the effect of terminal truncated STS on the enzyme activity, N- and C-terminal truncated STS expression vectors were transfected into COS-1 cells. The activity of truncated STS lacking the N-terminal regions declined, and the activity of C-terminal-truncated STS declined with extension of the truncated C-terminal region. Although the results of pulse-chase experiments showed that a one-base mutant STS (Q560P) and C-terminal-truncated STS (deltaC2 (1-559)) had no effects on protein synthesis and degradation, the mutant STS and C-terminal-truncated STS have dominant negative effect on STS enzyme activity when the STS mutant or truncated STS protein and a wild-type STS protein coexist in cells. Results of coprecipitation of the truncated STS with an STS-FLAG fusion protein showed that STS formed a dimer conformation in cells. In this study, we have shown that both the N-terminal region and C-terminal region are important for STS enzyme activity. The C-terminal mutant has a dominant negative effect on wild-type STS.

Low Estriol Levels in the Maternal Triple-Marker Screen as a Predictor of Isolated Adrenocorticotropic Hormone Deficiency Caused by a New Mutation in the TPIT Gene

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenocortical insufficiency, especially in children, and may be an underestimated cause of neonatal death. Early postnatal diagnosis may prevent hypoglycemic seizures, Addisonian crises, and death. There are also occasional reports of prenatal diagnosis of IAD by findings on the maternal triple-marker screen (TMST), a combined serum analyte test that measures levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the detection of Down syndrome and open neural-tube defects. An isolated low estriol level is usually correlated with compromised uteroplacental perfusion and frequently associated with fetal death. A low estriol level in the context of normal fetal sonography and growth, after exclusion of placental sulfatase deficiency and Smith-Lemli-Opitz syndrome, should raise the suspicion of deficient fetal steroidogenesis, which leads to decreased production of adrenal dehydroepiandrosterone sulfate. We describe 2 brothers with adrenal insufficiency resulting from IAD. The parents are first cousins whose first son is healthy. During the pregnancy of the second son, who died at the age of 7 weeks as a result of presumed cardiomyopathy, a low estriol level on the TMST was ignored because of a normal fetal ultrasound. In the third pregnancy, a low level was found again, and the mother was referred to our tertiary center. Ultrasonography revealed no abnormalities, and karyotype was normal. Normal levels of steroid sulfatase activity and 7-dehydrocholesterol ruled out X-linked ichthyosis and Smith-Lemli-Opitz syndrome, respectively. Postnatally, basal and stimulated cortisol and ACTH levels were low. Other pituitary functions were normal, suggesting the diagnosis of IAD. The patient was treated with a stress dose of hydrocortisone on day 2 of life, which was tapered to a maintenance dose. At the time of this writing, he was 7 months old, with normal growth and development. Recently, loss-of-function mutations in the human TPIT gene were detected in autosomal recessive IAD. TPIT is a cell-restricted T-box transcription factor that is important for the terminal differentiation of pituitary corticotrophs. Therefore, we performed molecular analysis of the TPIT gene, which revealed a new mutation (IVS4+1G>A) that affects the first nucleotide of the splice site at the 5' end of the fourth intron. This stop codon probably leads to loss of TPIT function by nonsense-mediated mRNA decay, as it does for other TPIT nonsense mutations. We recommend that pregnant women with an isolated low estriol level of unexplained etiology be referred for additional evaluation by a multidisciplinary team that includes a geneticist and pediatric endocrinologist. Prompt ACTH testing in the first postnatal days will allow for early diagnosis. The immediate institution of glucocorticoid therapy, with proper instructions for stress management, can prevent unnecessary neonatal death secondary to an easily treatable disease.

Clinico‐epidemiological features of primary hereditary ichthyoses in the Eastern province of Saudi Arabia

A total of 10 455 new dermatology patients were seen in the dermatology clinics of King Fahad Hospital of the University (KFHU), Al-Khobar, Saudi Arabia, between January 1990 and December 1995. We identified 71 patients with a histopathologically confirmed diagnosis of specific forms of primary hereditary ichthyoses (PHI). We have reviewed the epidemiological and clinical features of these patients. To document the epidemiological and clinical features of patients with PHI in the Eastern Province of Saudi Arabia. We used the dermatology out-patient department (OPD) logbooks to identify cases of PHI from new patients presenting with different dermatological problems over a 6-year period. We used specifically designed protocol forms to extract epidemiological and clinical data from the study patients' medical records. These were entered into a computer database and analyzed using standard statistical software. A total of 71 patients, 44 males and 27 females (male : female sex ratio of 1.63 : 1), were identified from a total of 10 455 new patients seen in our dermatology clinics between January 1990 and December 1995. The occurrence rate of PHI, in our clinics, was 0.67% or 7 per 1000 new dermatology cases. The clinical pattern of PHI showed that Icthyosis Vulgaris was the most common form seen, followed by Nonbullous Ichthyosiform Erythroderma. Thirty-one patients (44.7%) with Ichthyosis Vulgaris (IV) were seen: 12 patients (16.9%) with X-linked Recessive Ichthyosis (XLRI), four patients (5.6%) with Lamellar Ichthyosis (LI), three patients (4.2%) with Bullous Ichthyosiform Erythroderma (BIE) and 21 patients (29.6%) with Nonbullous Ichthyosiform Erythroderma (NBIE). There was a significantly high consanguinity rate in our patients (85%), and the family history was positive in 53 cases out of the 71 (75%). This preliminary study is the first report of its kind from Saudi Arabia and documents the clinico-epidemiological features of PHI patients in the Eastern Province. The high rate of parental consanguinity among our Saudi patients may account for the high proportion of patients with a positive family history. Consanguinity also probably explains why the most severe forms of PHI were seen in a significant number of new patients' siblings. These severe forms of PHI (Nonbullous Ichthyosiform Erythroderma, Bullous Ichthyosiform Erythroderma and Lamellar Ichthyosis) together constituted nearly 40% of all cases.

Tob is a potential marker gene for the basal layer of the epidermis and is stably expressed in human primary keratinocytes

Epidermis consists of multiple layers, from the proliferating basal layer to terminal differentiated cornified layers, and these layers are defined by differentiation status. Tob gene product is known to be a member of the BTG antiproliferative protein family. We investigated the expression pattern of Tob gene product to understand the possible role in differentiation of keratinocytes and epidermis. In this study, we examined the expression of Tob gene product in the primary cultured human keratinocytes and in the in vivo epidermis. The expression of Tob gene product was assessed by Western blotting analysis. Cellular localization of Tob was detected using the green fluorescent protein-tagged Tob cDNA expression construct. In vivo expression of Tob gene product in the epidermis was determined by immunohistochemistry with paraffin sections. Tob family members are degraded by the ubiquitine-proteasome system triggered by the growth signal. Tob is stably and abundantly expressed in primary cultured human keratinocytes. Furthermore, the expression of Tob in the keratinocytes persists during the differentiation induced by calcium; however, it was not detected in primary cultured fibroblasts. Also, the subcellular localization of Tob is mainly in the cellular membrane in the primary human keratinocytes. We evaluated Tob expression in normal skin, oral mucosa and different diseases, such as psoriasis, X-linked ichthyosis and squamous cell carcinoma (SCC). Using immunohistochemical analysis, we observed that Tob was selectively expressed in the basal layer of X-linked ichythyosis and the hyperproliferative basal layer of psoriasis and oral mucosa as well as in normal epidermis. In SCC, the expression of Tob gene product was relatively decreased. Tob is stably expressed in primary human keratinocytes and it is specifically expressed in the basal layer of in vivo epidermis.

STS gene in a pedigree with X-linked ichthyosis

To investigate the gene mutation in a pedigree with X-linked ichthyosis (XLI) and to explore the relationship between the mutation and its clinical manifestations, genomic DNA of affected members, the normal member of the pedigree and 50 unrelated normal members was extracted with a whole blood genomic DNA extraction kit and the DNA was used as a template for the polymerase chain reaction (PCR)-mediated amplification of exon 1 and exon 10 of the STS gene. hHb6 (human hair basic keratin) gene was used as the internal control. Our results showed that the STS gene was deleted in affected members in the pedigree with X-linked ichthyosis. The normal member of the pedigree and 50 unrelated normal members had no such deletion. The proband and his mother had products in the internal control after PCR amplification. The blank control had no product. It is concluded that deletion of the STS gene existed in this pedigree with X-linked ichthyosis, and it is responsible for the unique skin lesions of X-linked ichthyosis.

The expression of the 27-kd heat shock protein in keratinization disorders: an immunohistological study

In human skin, the 27-kd heat shock protein (hsp27), a member of the small hsp family, is expressed mainly in the upper epidermal layers. Hsp27 functions as a molecular chaperone and is involved in the regulation of cell growth and differentiation. According to experimental evidence, epidermal hsp27, through its chaperone function, might play a role in the assembly of keratin filaments and the cornified cell envelope. This study was conducted to assess the expression pattern of hsp27 in a panel of different ichthyoses. Twelve hereditary and acquired skin diseases associated with an ichthyotic phenotype and 2 corresponding mouse models were investigated by immunohistochemistry on formalin-fixed paraffin-embedded tissue, using a monoclonal antibody specific for hsp27. In ichthyosis vulgaris, lamellar ichthyosis, Sjögren-Larsson syndrome, Netherton syndrome, and acquired ichthyosiform skin condition, the pattern of hsp27 expression resembles healthy human skin. Hsp27 expression was reduced in bullous ichthyosiform erythroderma and annular epidermolytic ichthyosis, and absent in X-linked recessive ichthyosis (1/3 patients) and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome (1/1). In X-linked dominant chondrodysplasia, 3 small samples are completely negative and 2 larger samples show a pattern resembling random X inactivation. In the mouse models, tattered and bare patches, representing the murine analogues to X-linked dominant chondrodysplasia and congenital hemidysplasia with ichthyosiform nevus and limb defects syndrome, expression of hsp25 (the murine homologue of hsp27) also showed lyonization, demonstrating a clear-cut link between hsp27 expression and underlying molecular pathology. Our results show that loss of hsp27 is a rare event in human epidermis that is associated with specific genetic defects. Among the cases described here, these defects are either in suprabasal keratins or in enzymes involved in cholesterol biosynthesis. The expression and chaperone function of hsp27 might be modified by low/absent epidermal cholesterol and aberrant substrates (ie, keratins) resulting in protein misfolding, dyskeratosis, and thus contribute to the ichthyotic phenotype.

Deletion of VCX-A due to NAHR plays a major role in the occurrence of mental retardation in patients with X-linked ichthyosis

X-linked ichthyosis (XLI) is often associated with a recurrent microdeletion at Xp22.31 due to non-allelic homologous recombination between the CRI-S232 low-copy repeat regions flanking the STS gene. The clinical features of these patients may include mental retardation (MR) and the VCX-A gene has been proposed as the candidate MR gene. Analysis of DNA from four XLI patients with MR by array-comparative genomic hybridization (array-CGH) on a 150 kb resolution X chromosome-specific array revealed a 1.5 Mb interstitial microdeletion with breakpoints in the CRI-S232 repeat sequences, each of which harbors a VCX gene. We demonstrate that the recombination sites in all four cases are situated in the 1 kb repeat unit 2 region present at the 3' ends of the VCX-A and VCX-B genes thereby deleting VCX-A and VCX-B1 but not VCX-B and VCX-C. Array-CGH with DNA of an XLI patient with MR and an inherited t(X;Y)(p22.31;q11.2) showed an Xpter deletion of 8.0 Mb resulting in the deletion of all four VCX genes and duplication of both VCY homologs. These data confirm the role of VCX-A in the occurrence of MR in XLI patients. Moreover, we propose a VCX/Y teamwork-dependent mechanism for the incidence of mental impairment in XLI patients.

X-linked recessive ichthyosis

A 13-year-old boy presented with a lifelong history of tightly-adherent, brown, polygonal scales that covered the extensor surfaces of the extremities, lateral aspects of the trunk, and neck. The clinical presentation and the history of a similar skin condition in the patient's male maternal relatives helped establish the diagnosis of X-linked recessive ichthyosis (XLI). Systemic manifestations of the steroid sulfatase (STS) deficiency underlying XLI include cryptorchidism, asymptomatic corneal opacities, and maternal failure to progress during labor. Most cases of XLI are caused by deletions of the STS gene, and contiguous gene syndromes may occur when the deletions extend to neighboring genes on the distal short arm of the X chromosome.

X-linked recessive ichthyosis in a girl: strategy for identifying the causal mechanism

X-linked recessive ichthyosis in a girl: strategy for identifying the causal mechanism

Topical Tazarotene 0.05% versus Glycolic Acid 70% Treatment in X-linked Ichthyosis due to Extensive Deletion of the STS Gene

Topical Tazarotene 0.05% versus Glycolic Acid 70% Treatment in X-linked Ichthyosis due to Extensive Deletion of the STS Gene

Steroid Sulfatase: Molecular Biology, Regulation, and Inhibition

Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and therefore has a pivotal role in regulating the formation of biologically active steroids. The enzyme is widely distributed throughout the body, and its action is implicated in physiological processes and pathological conditions. The crystal structure of the enzyme has been resolved, but relatively little is known about what regulates its expression or activity. Research into the control and inhibition of this enzyme has been stimulated by its important role in supporting the growth of hormone-dependent tumors of the breast and prostate. STS is responsible for the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, both of which can be converted to steroids with estrogenic properties (i.e., estradiol and androstenediol) that can stimulate tumor growth. STS expression is increased in breast tumors and has prognostic significance. The role of STS in supporting tumor growth prompted the development of potent STS inhibitors. Several steroidal and nonsteroidal STS inhibitors are now available, with the irreversible type of inhibitor having a phenol sulfamate ester as its active pharmacophore. One such inhibitor, 667 COUMATE, has now entered a phase I trial in postmenopausal women with breast cancer. The skin is also an important site of STS activity, and deficiency of this enzyme is associated with X-linked ichthyosis. STS may also be involved in regulating part of the immune response and some aspects of cognitive function. The development of potent STS inhibitors will allow investigation of the role of this enzyme in physiological and pathological processes.

Mutations in X-linked ichthyosis disrupt the active site structure of estrone/DHEA sulfatase

X-linked ichthyosis is an inherited genetic disorder of the skin that results from steroid sulfatase (STS) deficiency. Seven critical point mutations have been previously reported for the STS gene, six leading to amino acid substitutions and one to a premature termination of the polypeptide chain. The three-dimensional structure of the full-length human enzyme has been recently determined. Amino acid substitutions due to point mutations in X-linked ichthyosis are mapped onto the three-dimensional structure of human STS. In each case, the substitution appears to cause disruption of the active site architecture or to interfere with the enzyme's putative membrane-associating motifs crucial to the integrity of the catalytic cleft, thereby providing an explanation for the loss of STS activity.