| Ichthyosis is a hereditary disorder of cutaneous keratinization characterized by a dry skin and generalized scaling of the skin, caused by disorders or abnormal differentiation of epidermal cells dynamic stability mechanism. The ichthyotic dermatoses are classified into4categories based on the mode of inheritance and the characteristic clinical manifestations:ichthyosis vulgaris, X-linked ichthyosis (XLI), lamellar ichthyosis, bullous ichthyosiform erythroderma, collodion baby and heavy collodion baby. X-linked ichthyosis(XLI) is one of the most important type of ichthyosis, inherited in an X-linked recessive mode, the clinical manifestations occur early in life and involve generalized dryness and scaling of the skin with dark scales, not improvement with age,and gradually deteriorated. The extensor surfaces of limbs, lateral aspects of the trunk, neck, face and ears are often involved. The skin condition often improves during the summer season, but aggravates during winter and dry season. XLI may occur solely as a skin disorder or be associated with other findings, such as ocular changes (up to50%), cryptorchidism(20%), chondrodysplasia punctata, mental retardation, and epilepsy, such as Rud syndrome, Conradi syndrome, Kallmann syndrome. XLI affects almost exclusively males, and females are generally only for carriers. XLI affects roughly1:2000to1:6000males, there is no noticeable racial or geographic predilection. XLI histopathologic expression is hyperkeratosis, granular layer normal or slightly thickened, accidentally thin, no hair follicles, epdermics can be slightly thickened. The histopathology of XLI is nonspecific and affected skin may appear normal or resemble skin affected by ichthyosis vulgaris, so the histopathology is generally not useful in mading a diagnosis of XLI. The diagnosis of XLI depends on clinical characteristics usually, but the diagnosis of XLI may be confirmed through biochemical or genetic analysis. Direct biochemical techniques can be used to demonstrate deficiency of STS activity in skin fibroblasts, leukocytes, and keratinocytes; Southern blot, fluorescent in situ hybridization, and polymerase chain reaction are methods for confirming a causative mutation or deficience for XLI. Serum protein electrophoresis of XLI may be performed to show increased mobility of the beta-lipoprotein fraction as a result of elevated serum cholesterol sulfate levels, therefore, serum protein electrophoresis can offer help to the diagnosis of XLI. XLI cannot be cured, so far, methods of treatment is to relieve symptom, for example through hydration, lubrication and keratolysis of the three mechanisms to relieve dry skin and reduce skin scales, topical use emollient cream or oil of keratolytics and topical use or taking orally retinoic acid derivatives, such as10%cholesterol cream,40%to60%propylene glycol in water, urea, lactic acid, glycolic acid,0.5%to60%salicylic acid, isotretinoin and0.1%tretinoin cream. XLI rarely affects normal life functions of patients, but influences of the external image, bring the physical and mental pressure to patients and their family members, experience a significantly reduced quality of life. Due to XLI cannot be cured and inherited in an X-linked recessive mode, so judgment carriers, to some extent, prevent children born is very important.XLI is most commonly caused by a genetic defect leading to a deficiency or mutation of the enzyme steroid sulfatase (STS) encoded by STS gene. STS is one of microsomal enzyme widely distributed in mammalian tissues, the molecular weight is62kDa. The gene coding for STS has been mapped to the short arm of the X chromosome at Xp22.3, spans about164Kb and contains10exons. STS hydrolysis cholesterol sulfate (CSO4), the hydrolysis of CSO4normally generates some of the cholesterol required for the barrier. As the CSO4accumulated to a certain degree leads to corneodesmosome degradation and normal desquamation. A deficiency or mutation of STS results in the accumulation of cholesterol sulfate in the membranes of stratum corneum cells. Cholesterol sulfate is thought to play a role in membrane integrity and normal desquamation within the stratum corneum. Therefore, a pathological increase in quantity of cholesterol sulfate changes the physical properties between the corneous cell membrane, resulting in increased intracellular stability and cohesion. The end result is normal skin desquamation process delay and a phenotype of excess scaling. STS is located on Xp22.3and the area from the function of X chromosome inactivation. Based on LYON hypothesis, normal female one X chromosome inactivation can ensure that men and women genetic balance, and the STS gene avoids the inactivation, results in XLI female carriers STS activity reduce, so they only have manifestation of dry skin in winter, without any other identifiable phenotype. But there are7cases of female patients were reported, the genetic change needs to be further studied.According to statistics, about90%of XLI patients present large deletions of the STS gene and flanking sequences, a few case reports have described partial deficiency and point mutations in the gene, and a small number of cases may be because of genetic alterations of the X chromosome that do not affect STS, there may exist certain genetic heterogeneity. DXS1139to DXS22S1or DXS278breakpoint sites are the most frequent pattern of complete deletion previously described of STS gene and flanking sequences. Previous studies indicate that most XLI patients have entire STS and flanking sequences deletions caused by recombination between the locus DXS1139and the loci DXSF22S1or DXS278. G1.3and CRI-S232are interspersed on the X chromosome short arm flanking the steroid sulfatase locus. The presence of these low copy number repeats on either side of the STS gene, promoting unequal crossing over, seems to play a role in the high frequency of these interstitial deletions. CRI-S232is present in the X chromosome with a high degree of polymorphism while its presence in the Y chromosome is non-polymorphic, therefore, the disease appears as X-linked.Current research about the pathogenesis of XLI mainly aimed at the STS gene, just a few articles were reported abroad involves the flanking sequence of research, there was not yet about the STS gene and flanking sequence detection analysis report in China. It is necessary to study whether Chinese XLI patients STS gene and flanking sequences deficiency locus is consistent with the foreign literature reports. Due to XLI cannot be cured, so it is the only way to prenatal diagnosis and genetic therapy through detecting pathogenic gene. The aim of this research is to detect STS gene and flanking sequences deficiency locus of the pedigrees, and to determine the genetic mutations in patients with family.This research collected2pedigrees,3patients of8members in family1and1patient of7members in family2. Diagnostic criteria is according to the characteristic clinical manifestations of patients with full-term birth, dry skin, a generalized distribution of large, polygonal, dark brown scales, prominent itch. Whereas the facial, nails, palms and soles are usually spared. The skin condition often improves during the summer season, but aggravates during winter season. Combing with the genetic information of the family, finally diagnosed with XLI. Peripheral blood samples were collected from the families (including the patients and unaffected members) and fifty healthy controls after informed consent. Primers covering the entire coding and the exon-intron boundaries of the STS gene and flanking sequences DXS89-DXS1134were designed, and polymerase chain reaction (PCR) was performed. PCR amplification products were examined by agarose gel electrophoresis and then were observed under uv light. PCR products were gel-purified and direct-sequenced using the ABI-PRISM3730automatic sequencer (Applied Biosystems, America). All sequences were compared with GenBank DNA sequence of STS gene and flanking sequences DXS89-DXS1134to identify heterozygous mutation by using the chromas software.This study found that the three patients in family1showed a deletion pattern that including the STS gene and flanking sequence DXS1139to DXS22S1, but the unaffected members in the family1and the50normal healthy controls of STS gene and flanking sequences DXS89-DXS1134were amplified the corresponding size of DNA fragments. Sequencing results found no partial deficiency or point mutation by identifying heterozygous; the patient, unaffected members in the family2and the50normal healthy controls of STS gene and flanking sequences DXS89-DXS1134were all amplified the corresponding size of DNA fragments. Sequencing results found no partial deficiency or point mutation by identifying heterozygous.PCR analysis of the genomic regions flanking the STS gene revealed a microdeletion of the same genomic interval defined by DXS1139and DXF22S1in affected males of familiesl, which represents the most common deletion pattern seen in XLI previously described, were approximately25.7Mbp in size. Fortunately, the Kallman gene locates outside that range. Therefore, the pedigree ruled out contiguous gene syndromes and extracutaneous findings. But clinical phenotype severity is different among patients in affected males of familiesl, of which the most severe phenotype in proband. Ramesh R reported that FLG and STS concurrent mutations can adversely modify the phenotype in X-linked ichthyosis. Functionally, STS deficiency impacts on the biogenesis of stratum corneum lipids, whereas filaggrin mutation impacts on the protein components of the stratum corneum. One would therefore predict a filaggrin mutation and an STS mutation would be additive and lead to a more severe phenotype due to deficiencies in both the protein and lipid components of the skin barrier. But there may be other unknown factors, such as modifying genes and environmental factors, so whether FLG mutations increase the patient phenotype severity remains to be further studied. The patient in family2found no deficiency or point mutation by identifying heterozygous, there may be some genetic heterogeneity, specific mutation types need to be further studied.The research on XLI have been little carried out in China. Our research would provide scientific theoretical basis for pathogenesis, STS gene and flanking sequences function, prenatal diagnosis and genetic therapy. It is necessary to increase family samples to study whether Chinese XLI patients STS gene and flanking sequences deficiency locus is consistent with the foreign literature reports. Specific gene deletion fracture site has not been reported at home and abroad, it is our major work to find specific fracture site by narrowing the scope. |
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