In 2 brothers there were no abnormal findings in the MLPA analysis and subsequent Sanger sequencing of the STS gene revealed a hemizygous nonsynonymous missense mutation in exon 9 Supplemental Figure 1C encoding for p. RC, a cytosine to thymidine change at position g. This mutation has previously been reported in a patient with XLI Serum testosterone was at age-appropriate low levels in all prepubertal subjects Figure 3.
After puberty, serum testosterone concentrations were significantly lower in STSD patients than in sex- and age-matched controls. However, hour urinary excretion of the 2 major metabolites of active androgens, androsterone and etiocholanolone, did not differ between STSD and controls Figure 3.
We found no gross abnormalities regarding pubertal progression and development in children and adolescents with STSD. Their steroid metabolome was indicative of mild androgen deficiency, with significantly lower circulating concentrations of DHEA and testosterone. We have genetically characterized the entire cohort and found abnormalities of the STS gene in all patients. Importantly, deletions of the neighboring KAL1 gene resulting in Kallmann syndrome with anosmic hypogonadotropic hypogonadism were not present in this cohort.
Similarly, other forms of contiguous gene deletion syndromes frequently described in patients with XLI 21 , 22 , were not detected, hence the changes we found can only be associated with the loss of STS gene function. The importance of HDHD1 in normal physiology is not well understood; an Hdhd1 knockout mouse has not yet been reported. One can speculate that HDHD1 contributes to some phenotypic features observed in patients with XLI; however, detailed genotype-phenotype studies are lacking partially due to insufficient genetic characterization of XLI patients of earlier cohorts.
The one patient with an undescended testis in our cohort also had a HDHD1 deletion. However, at present there is no conclusive evidence for functional involvement of HDHD1 in testicular descent. One patient in our cohort had a partial deletion of exon 7 of the STS gene. Although partial STS deletions have been reported in XLI 26 , 27 , the deletion of exon 7 appears to be a novel finding. In addition, 2 brothers in our study carried the known p.
Pubertal development and progression was not abnormal in this cohort of STSD patients; Tanner stages, testicular volumes and height SDS did not differ from controls. The onset of pubertal changes reported by the STSD patients in our cohort was between 11 and However, our cohort included 5 boys with STSD who were clinically at the beginning of puberty according to their testicular volume and Tanner stages.
Of those, 3 had not developed any pubic hair by the age of 13, which is somewhat late. To investigate in more detail whether the onset of pubertal development in STSD boys is normal or delayed would require the prospective observation of a cohort of prepubertal individuals with STSD. None of our STSD patients had children at the time of study participation.
This, in line with previous studies in patients with XLI for review, see Ref. Previous studies on steroid production in STSD have mostly focused on cholesterol sulfate and DHEAS; the latter was not consistently reported as elevated, perhaps due to the different methodologies employed for steroid quantification Table 2. Previously, the most detailed information was available from an adult Danish cohort of 20 XLI patients Although no detailed information on physical and pubertal development was provided, the investigators found biochemical evidence of mild androgen deficiency with increased levels of DHEAS, suggesting an effect of STS on peripheral sex steroid activation.
In addition, LH was higher in STSD than in 40 matched controls, suggesting compensatory activation of the hypothalamic-pituitary-gonadal axis. Our study is the first to cover the complete age range from prepuberty to young adulthood with detailed information on pubertal phenotype and genotype. The latter enabled us to exclude any effect of contiguous gene deletions on the observed changes in steroid concentrations. Our results in children and adolescents with STSD are in keeping with those in the Danish adult cohort 12 , indicating the presence of mild androgen deficiency.
Urinary steroid metabolome analysis in our STSD cohort demonstrated normal overall androgen metabolite excretion despite lower concentrations of DHEA available for peripheral androgen inactivation. However, the results from this study do not suggest that patients with STSD require routine endocrine follow-up as they seem to progress through puberty without significant abnormalities. We also report, for the first time, a significantly increased ratio of serum DHEA over serum DHEAS in healthy prepubertal children that decreases steeply after puberty.
Little is known about normal physiological regulation of STS, with some evidence of cytokine-mediated changes in STS expression and activity 36 , In addition, it is possible that cofactors of STS could exhibit age- and sex steroid-dependent changes. Sulfatase modifying factor 1 is responsible for the posttranslational modification of a highly conserved cysteine residue to a unique formylglycine residue in the active site of the STS enzyme that is crucially required for catalytic activity; changes in sulfatase modifying factor 1 impact on STS activity with human inactivating mutations resulting in multiple sulfatase deficiency 38 , In summary, we have demonstrated by steroid metabolome analysis that the impact of STSD on androgen generation is small, resulting in only mild androgen deficiency that is apparently compensated for by up-regulation of peripheral androgen activation.
We suggest that this represents a mechanism to fine tune tissue-specific androgen action, priming the body for the subsequent changes in gonadal androgen production during puberty. We thank the patients and their parents for their willingness to participate in this study and the Ichthyosis Support Group United Kingdom for their help with patient recruitment.
Disclosure Summary: R. All other authors have nothing to disclose. N Engl J Med. Google Scholar. J Clin Endocrinol Metab. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev. The regulation of steroid action by sulfation and desulfation. Hum Genet. X-linked ichthyosis: an oculocutaneous genodermatosis. J Am Acad Dermatol. Prevalence of steroid sulfatase deficiency in California according to race and ethnicity. Prenat Diagn. Stratum corneum lipids in disorders of cornification.
Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis. J Clin Invest. High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency. J Lipid Res. X-linked ichthyosis: increased blood cholesterol sulfate and electrophoretic mobility of low-density lipoprotein.
Abnormal androgen and oestrogen metabolism in men with steroid sulphatase deficiency and recessive X-linked ichthyosis. Clin Endocrinol Oxf. J Inherit Metab Dis. X-linked ichthyosis: relation between cholesterol sulphate, dehydroepiandrosterone sulphate and patient's age.
Br J Dermatol. Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. Liquid chromatography-tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals.
Clin Chem. Development of a method for the measurement of dehydroepiandrosterone sulphate by liquid chromatography-tandem mass spectrometry. Ann Clin Biochem. Congenital adrenal hyperplasia caused by mutant P oxidoreductase and human androgen synthesis: analytical study.
Novel missense mutation ArgCys in a patient with steroid sulphatase-deficiency. Cloning of a cDNA for steroid sulfatase: frequent occurrence of gene deletions in patients with recessive X chromosome-linked ichthyosis. An atypical contiguous gene syndrome: molecular studies in a family with X-linked Kallmann's syndrome and X-linked ichthyosis. Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols.
X-linked ichthyosis: an update. Biochem J. Modified nucleosides: an accurate tumour marker for clinical diagnosis of cancer, early detection and therapy control. Br J Cancer. A study of the steroid sulfatase gene in families with X-linked ichthyosis using polymerase chain reaction. Acta Derm Venereol. Deletion of exons 1—5 of the STS gene causing X-linked ichthyosis. J Invest Dermatol. Practical Endocrinology and Diabetes in Children.
Google Preview. Variations in the pattern of pubertal changes in boys. Arch Dis Child. Hyperandrogenism in polycystic ovary syndrome. Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock.
Reed MJ , Purohit A. Breast cancer and the role of cytokines in regulating estrogen synthesis: an emerging hypothesis. Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate DHEAS to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency.
Arthritis Rheum. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. Regulation of serum testosterone in men with steroid sulfatase deficiency: response to human chorionic gonadotropin. J Steroid Biochem. Gas-chromatographic determination of cholesterol sulfate in plasma and erythrocytes, for the diagnosis of recessive X-linked ichthyosis.
Serum steroid sulphates in ichthyosis. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Skip Nav Destination Article Navigation. They are very fine, punctate opacities that are usually deposited in the posterior corneal stroma or Descemet membrane.
However, in addition, and unrelated to any preceding history of cryptorchidism, there is a small risk of testicular germ cell tumors. The latter is not related to a preceding history of cryptorchidism. Nor is the cryptorchidism related to co-deletion of contiguous genes, including the Kallmann syndrome gene locus.
In addition to the corneal opacities and gonadal variations noted above, deletions of contiguous genes along with STS produce a more complex phenotype. The resulting phenotype roughly corresponds to the specific genes that are deleted. Females with large deletions have occasionally been affected, in part dependent on their pattern of X-inactivation in relevant tissues. This boy has short stature, cognitive disability, brachydactyly, craniofacial variations and interestingly, only mild cutaneous scaling involving the ears, upper chest, and the front of his neck.
His mother, who carries the deletion, has Madelung deformity and short stature. He has mild scaling on the anterior neck due to the STS deletion. Individuals found to have larger contiguous gene deletions will clearly need a more multidisciplinary approach to management. Therefore it is important to assess the child for other abnormalities such as short stature, developmental delay or behavioral issues, hypogonadism, renal anomalies, and visual problems.
In a recent series of pregnancies that were ascertained because of low serum unconjugated estriol levels in the mothers, a revised estimate of the population incidence of XLI was 1 in Other causes of low estriol levels include trisomy 21, trisomy 18, and Smith-Lemli-Opitz syndrome, a recessive disorder of cholesterol biosynthesis due to deficiency of 7-dehydrocholesterol reductase.
Additional confirmatory studies are in progress. Standard approaches to the management of XLI involve facilitating the shedding of scale and inhibiting excessive keratinization. Oral therapy, eg, with retinoids, is rarely necessary in XLI. Combinations of moisturizing agents and keratolytics are typically employed and humidification of the ambient air may be helpful. Long soaking baths with mechanical debridement using a rough sponge can also be helpful.
Bath oils that lubricate, followed by topical emollients, may also be helpful. In older children and adults, useful topical keratolytics are lactic acid, glycolic acid, salicylic acid 0. In infants, however, these agents may be associated with high levels of cutaneous absorption and subsequent toxicity.
Therefore, moisturizing agents are the favored treatment modality in this age group. Topical retinoic acid derivatives eg, isotretinoin and tazarotene have also been utilized in the treatment of XLI. Affected males and their physicians should also be told of the small risk of testicular tumors and encouraged to perform periodic testicular examination.
Males with contiguous gene deletions eg, Figure 4 and Figure 5 have other clinical features that may need directed treatment. Clinical genetics evaluation and counseling should be offered in simplex cases and is imperative in cases with contiguous gene deletions and a complex phenotype.
This would be the mainstay of treatment for infants and young children. From a cutaneous standpoint, the patient is usually easily managed with conservative treatment, preferably using only emollients with occasional keratolytics for maintenance. Ongoing ophthalmologic follow-up should not be necessary. Periodic testicular examination is also suggested, with any detected variation in shape or size of the testes meriting more directed evaluation by imaging studies, tumor markers, and surgical consultation.
Systemic manifestations of contiguous gene deletions may require management by multiple medical and surgical specialists, for example, in genetics, endocrinology, orthopedics, ophthalmology, and other fields. Prenatal testing is certainly possible and is easily justified if there is a contiguous gene deletion syndrome with more serious consequences. It can also be useful for reassurance if maternal serum screening detects low estriol levels.
Also, there may be modest differences in the way labor and delivery are handled. A pregnancy of a male fetus with XLI can be associated with very low maternal serum estriol levels. This typically provokes a high level of anxiety because of the possibility of more serious chromosomal and genetic conditions eg, Down syndrome, Smith-Lemli-Opitz syndrome, multiple sulfatase deficiency.
Such a situation merits immediate evaluation and diagnostic testing for confirmation of the diagnosis. The patient with a contiguous gene deletion will require a multidisciplinary approach to management as discussed above. J Am Acad Dermatol. A thorough, up-to-date review of XLI and its management. Oji, V, Traupe, H. Am J Cin Dermatol. This is a comprehensive review of all syndromic and non-syndromic forms of ichthyosis, with detailed approaches to management.
Acta Derm Venereol. The authors reported that both daily application of topical tazarotene and weekly application of glycolic acid resulted in marked improvement of the scaling in XLI, but that the topical tazarotene effects lasted longer. Prenat Diagn. This large study aimed to ascertain all prenatally diagnosed cases of STS deficiency over a 5-year period, revised the population incidence of the disorder based on this data, and determined the incidence of larger contiguous STS gene deletions in the study population.
J Eur Acad Dermatol Venerol. Among 40 subjects with XLI, the authors detected complete gene deletions in 30 and partial deletions in 10, a higher rate of partial deletions than in previous reports. There was no genotype-phenotype correlation. J Invest Dermatol.
Two brothers with an STS point mutation and differing degrees of severity were reported. The more severely affected brother also had a nonsense, presumably pathologic, mutation in filaggrin. Thus, the authors proposed that filaggrin mutations may be modifiers of the cutaneous phenotype in XLI. J Dermatol Sci. Two brothers with differing clinical severity of ichthyosis due to STS deficiency are presented. J Intellectual Disability Res.
Two affected adult males were discordant with respect to their intelligence one normal, one impaired , suggesting that there may be other genetic and environmental modifiers of this aspect of the phenotype. Genes Brain Behav. They correlated this particular SNP with decreased STS gene expression in normal frontal cortex post-mortem brain, noted that the brain and adipose tissue STS transcripts are unique compared with STS transcripts in other tissues.
The neonatal type is the most severe form, with signs and symptoms appearing soon after birth. Affected individuals have deterioration of tissue in the nervous system leukodystrophy , which can contribute to movement problems, seizures, developmental delay, and slow growth. They also have dry, scaly skin ichthyosis and excess hair growth hypertrichosis. Skeletal abnormalities can include abnormal side-to-side curvature of the spine scoliosis , joint stiffness, and dysostosis multiplex, which refers to a specific pattern of skeletal abnormalities seen on x-ray.
Individuals with the neonatal type typically have facial features that can be described as " coarse. Many of the signs and symptoms of neonatal multiple sulfatase deficiency worsen over time. The late-infantile type is the most common form of multiple sulfatase deficiency. It is characterized by normal cognitive development in early childhood followed by a progressive loss of mental abilities and movement psychomotor regression due to leukodystrophy or other brain abnormalities. Individuals with this form of the condition do not have as many features as those with the neonatal type, but they often have ichthyosis, skeletal abnormalities, and coarse facial features.
The juvenile type is the rarest form of multiple sulfatase deficiency. Signs and symptoms of the juvenile type appear in mid- to late childhood. Affected individuals have normal early cognitive development but then experience psychomotor regression; however, the regression in the juvenile type usually occurs at a slower rate than in the late-infantile type.
Ichthyosis is also common in the juvenile type of multiple sulfatase deficiency. Life expectancy is shortened in individuals with all types of multiple sulfatase deficiency. Typically, affected individuals survive only a few years after the signs and symptoms of the condition appear, but life expectancy varies depending on the severity of the condition and how quickly the neurological problems worsen.
Multiple sulfatase deficiency is estimated to occur in 1 per million individuals worldwide. More than cases have been reported in the scientific literature. Multiple sulfatase deficiency is caused by mutations in the SUMF1 gene. This gene provides instructions for making an enzyme called formylglycine-generating enzyme FGE. This enzyme is found in a cell structure called the endoplasmic reticulum , which is involved in protein processing and transport.
The FGE enzyme modifies other enzymes called sulfatases, which aid in breaking down substances that contain chemical groups known as sulfates. These substances include a variety of sugars, fats, and hormones. Most SUMF1 gene mutations severely reduce the function of the FGE enzyme or lead to the production of an unstable enzyme that is quickly broken down. The activity of multiple sulfatases is impaired because the FGE enzyme modifies all known sulfatase enzymes.
Sulfate-containing molecules that are not broken down build up in cells, often resulting in cell death. The death of cells in particular tissues, specifically the brain, skeleton, and skin, cause many of the signs and symptoms of multiple sulfatase deficiency.
Research indicates that mutations that lead to reduced FGE enzyme function are associated with the less severe cases of the condition, whereas mutations that lead to the production of an unstable FGE enzyme tend to be associated with the more severe cases of multiple sulfatase deficiency. This condition is inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations.
The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Genetics Home Reference has merged with MedlinePlus. Without activation, sulfatases are not able to do their jobs in the cell Multiple sulfatase deficiency is a condition that mainly affects the brain, skin, and skeleton. Because the signs and symptoms of multiple sulfatase deficiency vary widely, researchers have split the condition into three types: neonatal, late-infantile, and juvenile Informational site on steroid sulfatase deficiency X-linked icthyosis.
This condition causes extremely dry skin, which may be very itchy and have a dark appearance. The diagnosis can be made during pregnancy or after the baby is born.. X-linked ichthyosis is a genetic skin disorder that affects males. It is an inborn error of metabolism characterized by a deficiency of the enzyme steroid sulfatase. Under normal conditions, this enzyme breaks down metabolizes cholesterol sulfate, a member of the chemical family of steroids.
It is considered axiomatic in human genetics that the study of relatively rare disorders may yield far more in dividends than might be anticipated based on the incidence of the condition in question. This has clearly been demonstrated in studies of human steroid sulfatase deficiency and the steroid sulfatase system during the past few years The excessive skin scaling or hyperkeratosis is caused by a lack of breakdown and thus accumulation of cholesterol sulfate, a steroid that stabilizes cell membranes and adds cohesion, in the outer layers of the skin A pregnancy is described in a woman with X-linked steroid sulfatase deficiency and an unaffected but growth-retarded male fetus.
Her previous affected pregnancy that resulted in intrauterine fetal death was reported. Urinary estriol estimation in pregnancy is discussed Description. Recessive X-linked ichthyosis is a disorder caused by a mutation of the enzyme steroid sulfatase STS.
STS is involved in the metabolism of cholesterol sulphate in the skin. STS deficiency leads to accumulation of cholesterol sulphate in the outer layer of the skin leading to a dysfunctional skin barrier and retention of the outer skin cells.
Due to location of the STS gene within a small region of the X chromosome that escapes X-inactivation lyonization. Individuals affected with X-linked Ichthyosis have a variable presentation characterized by dry, scaly skin, sparse hair and conical teeth in affected males.
Low estriol on a maternal serum screen during pregnancy. A number sign is used with this entry because X-linked ichthyosis XLI , which results from steroid sulfatase deficiency, is caused by mutation or deletion of the STS gene on chromosome Xp Some patients have larger deletions at Xp Many different metaphors such as alligator, collodion, crocodile, fish, and porcupine skin have been used to describe the various types and stages of ichthyosis.
Most ichthyoses. Fluorescence in situ hybridization is a molecular cytogenetic technique in which fluorescently labeled DNA probes are hybridized to metaphase spreads or interphase nuclei. Applications include identification of structurally abnormal chromosomes, including identification of marker chromosomes. The defect involves the expression of a neutral pH optimal, microsomal sulfatase, which is chemically and genetically distinct from the lysosomal enzymes arylsulfatase A, arylsulfatase B, iduronate sulfatase, and heparan N-sulfatase If so, steroid sulfatase deficiency in the immediate postpartum period may be particularly disruptive to neural processes that normally occur within the maternal brain at this time.
Given the relationship between advanced maternal age and increased risk of developing PP, the current hypothesis would be strengthened by finding that steroid. X-linked recessive ichthyosis is caused by a deletion of the steroid sulfatase gene located on the X chromosome at the p The abnormality is seen more in males and affects approximately 1 in 6, NCBI steroid sulfatase deficiency, ichthyosis, x-linked.
SLOS and STSD both have low maternal serum unconjugated estriol uE3 levels Steroid-resistant nephrotic syndrome associated with steroid sulfatase deficiency—x-linked recessive ichthyosis: a case report and review of literature. Vineeta Batra. Renu Saxena. Related Papers. Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion.
English Alternative forms. Refevence 1. Andria, MD, A. Ballabio, MD, and G. Bhadravathi et al. Can you take injectable steroids orally, price order legal steroid bodybuilding drugs. Most of the legal anabolic steroids have verification codes on the package. These codes check the authenticity of a bought steroidon pharmacies website Multiple sulfatase deficiency is an inherited disorder characterized by a deficiency of several sulfatases and the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids.
The clinical manifestations represent the summation of two diseases: late infantile metachromatic leukodystrophy and mucopolysaccharidosis Specimen Requirements: Peripheral Blood: Peripheral blood must be collected aseptically in sodium heparin tubes usually green-top tubes and immediately rotated thoroughly to prevent clotting.
For infants, obtain approximately 2 cc. Obtain 5 - 7 cc for children and adults. The presence of low copy number repeats G1. Steroid sulfatase activity was undetectable in the X-linked ichthyosis patient, very low in the mother, and normal in the grandmother and sister.