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Olaf Hiort - One of the best experts on this subject based on the ideXlab platform.
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Current models of care for disorders of sex development - results from an International survey of specialist centres.
Orphanet Journal of Rare Diseases, 2016Co-Authors: Andreas Kyriakou, Arianne B. Dessens, Jillian Bryce, Violeta Iotova, Anders Juul, Maciej R. Krawczynski, Agneta Nordenskjöld, Marta Rozas, Caroline Sanders, Olaf HiortAbstract:To explore the current models of practice in centres delivering specialist care for children with disorders of sex development (DSD), an international survey of 124 clinicians, identified through DSDnet and the I-DSD Registry, was performed in the last quarter of 2014. A total of 78 (63 %) clinicians, in 75 centres, from 38 countries responded to the survey. A formal national network for managing DSD was reported to exist in 12 (32 %) countries. The paediatric specialists routinely involved in the initial evaluation of a newborn included: endocrinologist (99 %), surgeon/urologist (95 %), radiologist (93 %), neonatologist (91 %), clinical geneticist (81 %) and clinical psychologist (69 %). A team consisting of paediatric specialists in endocrinology, surgery/urology, clinical psychology, and nursing was only possible in 31 (41 %) centres. Of the 75 centres, 26 (35 %) kept only a local DSD registry and 40 (53 %) shared their data in a multicentre DSD registry. Attendance in local, national and international DSD-related educational programs was reported by 69, 78 and 84 % clinicians, respectively. Participation in audits/quality improvement exercises in DSD care was reported by 14 (19 %) centres. In addition to complex biochemistry and molecular genetic investigations, 40 clinicians (51 %) also had access to next generation sequencing. A genetic test was reported to be more preferable than biochemical tests for diagnosing 5-alpha reductase Deficiency and 17-beta hydroxysteroid dehydrogenase 3 Deficiency by 50 and 55 % clinicians, respectively. DSD centres report a high level of interaction at an international level, have access to specialist staff and are increasingly relying on molecular genetics for routine diagnostics. The quality of care provided by these centres locally requires further exploration.
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a novel missense mutation of 5 alpha reductase type 2 gene srd5a2 leads to severe male pseudohermaphroditism in a turkish family
Urology, 2005Co-Authors: Mithat Bahceci, Olaf Hiort, Ahmet Resit Ersay, Alpaslan Tuzcu, Annette Richterunruh, Deniz GokalpAbstract:Abstract Objectives To analyze the steroid 5-alpha reductase type 2 gene ( SRD5A2 ) in 2 siblings with severe male pseudohermaphroditism suspected to have 5-alpha reductase Deficiency in a Turkish family. Methods Two female siblings of a family with 7 children were referred to the urology department because of bilateral inguinal masses. The patients had presented after birth with ambiguous genitalia, but no further diagnostic procedures had been performed, and they were raised as girls until the ages of 13 and 15 years. At this time, both had striking ambiguity of the genitalia, with a clitoris-like phallus, severely bifid scrotum, pseudovaginal perineoscrotal hypospadias, a rudimentary prostate, and inguinal testes. Karyotype was 46,XY. Basal and stimulated levels of serum testosterone (T), dihydrotestosterone (DHT), and T/DHT ratio indicated 5-alpha reductase Deficiency. Molecular genetic analysis was performed on deoxyribonucleic acid from peripheral blood leukocytes by single-stranded conformational polymorphism analysis and direct sequencing. Results Analysis of the SRD5A2 gene revealed a new homozygous missense mutation in exon 2. At codon 123, we identified a GGA to AGA change resulting in a missense amino acid change from glycine to arginine (G123R). Both parents and the 2 healthy sisters and 3 brothers were all heterozygous at codon 123 for the same mutation. Conclusions We report a novel homozygous missense mutation in exon 2 of the 5-alpha reductase type 2 gene that led to severe undervirilization in 2 siblings.
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Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase Deficiency.
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Olaf Hiort, Gernot H G Sinnecker, Holger Willenbring, A. Lehners, A. Zöllner, Dagmar StruveAbstract:5 alpha-Reductase Deficiency is a rare autosomal recessive disorder of defective virilization in karyotypic males due to reduced conversion of testosterone to dihydrotestosterone. The gene encoding the affected 5 alpha-reductase type 2 enzyme has recently been cloned, and mutations within the coding region have been discovered as the cause of this disease. We address the possibility of a rapid nonradioactive molecular genetic screening technique for initial diagnosis and report different point mutations in this gene in eight unrelated patients with clinical features of 5 alpha-reductase Deficiency. For molecular genetic analysis, DNA from peripheral blood leukocytes was studied. The coding region of the 5 alpha-reductase type 2 gene was characterized by exon-specific PCR amplification, nonradioactive single strand conformation analysis, and direct sequencing. In seven patients, homozygous point mutations were identified (Leu55-Gln, delta Met157, Gly196-Ser, Arg227-Gln, Ala228-Thr, and His231-Arg). One ind...
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phenotypic classification of male pseudohermaphroditism due to steroid 5α reductase 2 Deficiency
American Journal of Medical Genetics, 1996Co-Authors: Gernot H G Sinnecker, Leif Dibbelt, Norbert Albers, Helmuth G Dorr, Michael Hemminghaus, W Hoepffner, U Heinrich, H. Haus, Olaf Hiort, Martin HolderAbstract:Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5{alpha}-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5{alpha}-reductase 2 Deficiency (SRD). T/DHT-ratios were highly increased in the classical syndrome, but variable in the less severe affected patients. Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5{alpha}-reductase Deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms ofmore » undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5{alpha}-reductase 2 Deficiency. 22 refs., 2 figs., 2 tabs.« less
Deniz Gokalp - One of the best experts on this subject based on the ideXlab platform.
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a novel missense mutation of 5 alpha reductase type 2 gene srd5a2 leads to severe male pseudohermaphroditism in a turkish family
Urology, 2005Co-Authors: Mithat Bahceci, Olaf Hiort, Ahmet Resit Ersay, Alpaslan Tuzcu, Annette Richterunruh, Deniz GokalpAbstract:Abstract Objectives To analyze the steroid 5-alpha reductase type 2 gene ( SRD5A2 ) in 2 siblings with severe male pseudohermaphroditism suspected to have 5-alpha reductase Deficiency in a Turkish family. Methods Two female siblings of a family with 7 children were referred to the urology department because of bilateral inguinal masses. The patients had presented after birth with ambiguous genitalia, but no further diagnostic procedures had been performed, and they were raised as girls until the ages of 13 and 15 years. At this time, both had striking ambiguity of the genitalia, with a clitoris-like phallus, severely bifid scrotum, pseudovaginal perineoscrotal hypospadias, a rudimentary prostate, and inguinal testes. Karyotype was 46,XY. Basal and stimulated levels of serum testosterone (T), dihydrotestosterone (DHT), and T/DHT ratio indicated 5-alpha reductase Deficiency. Molecular genetic analysis was performed on deoxyribonucleic acid from peripheral blood leukocytes by single-stranded conformational polymorphism analysis and direct sequencing. Results Analysis of the SRD5A2 gene revealed a new homozygous missense mutation in exon 2. At codon 123, we identified a GGA to AGA change resulting in a missense amino acid change from glycine to arginine (G123R). Both parents and the 2 healthy sisters and 3 brothers were all heterozygous at codon 123 for the same mutation. Conclusions We report a novel homozygous missense mutation in exon 2 of the 5-alpha reductase type 2 gene that led to severe undervirilization in 2 siblings.
Julianne Imperato-mcginley - One of the best experts on this subject based on the ideXlab platform.
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Mutations of the 5α-reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α-reductase-2 Deficiency
Clinical Endocrinology, 1997Co-Authors: Patricia Canto, Julianne Imperato-mcginley, Felipe Vilchis, Bertha Chávez, Osvaldo Mutchinick, Gregorio Pérez-palacios, Alfredo Ulloa-aguirre, Juan Pablo MéndezAbstract:BACKGROUND AND OBJECTIVE: Male pseudohermaphroditism due to 5 alpha-reductase Deficiency was originally described in 1974. Recently, 5 alpha-reductase Type 2 gene defects have been found generally to be due to point mutations within the 5 exons of the 5 alpha-reductase-2 gene. In this report, we describe the molecular study of patients with 5 alpha-reductase Deficiency. DESIGN: Previously diagnosed patients with 5 alpha-reductase Deficiency were sampled in order to perform molecular studies. PATIENTS: Eight 5 alpha-reductase deficient individuals from 6 unrelated families. MEASUREMENTS: Single-strand conformational polymorphism and DNA sequencing were performed after polymerase chain reaction amplification of each of the 5 exons of the gene. RESULTS: Five different missense mutations were found. In 4 patients a cytosine to guanine substitution was observed at codon 212 in exon 4. Two siblings presented a cytosine to adenine substitution at codon 207 in exon 4. Another patient exhibited a guanine to adenine substitution at codon 34 in exon 1, whilst one individual presented 2 mutations: a guanine to adenine substitution at codon 115 in exon 2 and a guanine to adenine substitution at codon 203 in exon 4 (previously undescribed mutation). CONCLUSIONS: The presence of the same mutation in 4 patients from 3 families indicates the increased prevalence of this mutation in a particular ethnic group, suggesting a common ancestry for the gene defect in these patients. The existence of hot spots is supported by the mutations in codons 34 and 207 which have also been found in other ethnic groups. Interestingly, the patient who presented 2 different mutations, one of them previously undescribed, was reared as a male and exhibited a more masculine phenotype. Further studies in patients with this and other mutations will be needed to verify genotype-phenotype correlation.
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5 alpha-reductase-2 gene mutations in the Dominican Republic.
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: M. D. Katz, C. Herrera, J. Baez, M. Defillo-ricart, C. H. L. Shackleton, Julianne Imperato-mcginleyAbstract:Male pseudohermaphroditism due to 5 alpha-reductase Deficiency was clinically and biochemically described in a large Dominican kindred of 23 families with 38 affected subjects in 1974. Recently, the 5 alpha-reductase-2 gene defect in the large Dominican kindred was found to be due to a single base substitution of thymidine (TGG) for cytosine (CGG) on exon 5 of the 5 alpha-reductase-2 gene, causing a tryptophan replacement of arginine at amino acid 246 (R246W) of the enzyme. In the present report, affected subjects from four additional Dominican families were studied to determine whether they carried the same 5 alpha-reductase-2 gene defect as the large kindred, suggesting a common ancestry for the gene defect within this small country. Using single strand conformational polymorphism and DNA sequencing, two other mutations of the 5 alpha-reductase-2 gene were found in affected subjects from two of the four families. A point mutation on exon 2 of the 5 alpha-reductase-2 gene, in which substitution of adenin...
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Luteinizing hormone pulsatility in subjects with 5-Alpha-Reductase Deficiency and decreased dihydrotestosterone production.
The Journal of Clinical Endocrinology and Metabolism, 1994Co-Authors: William J. Canovatchel, Teofilo Gautier, David Volquez, Sophie Huang, Elizabeth Wood, Martin Lesser, Julianne Imperato-mcginleyAbstract:The pattern of LH pulsatility in male pseudohermaphrodites with inherited 5 alpha-reductase-2 Deficiency (5 alpha RD) and decreased levels of plasma dihydrotestosterone was compared to that in normal males. Analysis of 10-min plasma LH sampling during either a 10- or 24-h period demonstrated that the subjects with 5 alpha RD had 1) a mean plasma LH level, mean LH pulse amplitude, and mean plasma LH nadir that were approximately twice normal; and 2) a mean LH pulse frequency similar to that in normal males, whether described as pulses per h or pulses per study period. An increased plasma LH response to GnRH administration was also noted. The findings suggest that a Deficiency of DHT results in decreased negative feedback at the level of the hypothalamus and/or pituitary, resulting in an increase in mean plasma LH, LH pulse amplitude, and LH responsiveness to GnRH. In response to increased LH, mean plasma testosterone (T), free T, and plasma estradiol (E2) are increased. The pulse amplitude is increased des...
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The androgen control of sebum production. Studies of subjects with dihydrotestosterone Deficiency and complete androgen insensitivity.
The Journal of Clinical Endocrinology and Metabolism, 1993Co-Authors: Julianne Imperato-mcginley, Teofilo Gautier, J. Epstein, P. PochiAbstract:To evaluate the androgen control of sebum, subjects with complete androgen insensitivity and male pseudohermaphrodites with inherited 5 alpha-reductase Deficiency and decreased dihydrotestosterone (DHT) production had sebum production studied. A hydrophobic polymeric film applied to the forehead was used to measure sebum production through the use of air filled micropores. Sebum scores of normal preadrenarchal children (ages 2-6), and normal age-matched adult males and females, were studied as well as males treated with the 5 alpha-reductase inhibitor, finasteride, for benign prostatic hyperplasia who were studied at baseline and after drug therapy. Androgen insensitive subjects had no sebum production by this methodology, and the results were identical to preadrenarchal children. In contrast, adult male pseudohermaphrodites with 5 alpha-reductase Deficiency and a selective decrease in DHT production had sebum production scores identical to normal age-matched males. Males with benign prostatic hyperplasia...
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Prostate visualization studies in males homozygous and heterozygous for 5 alpha-reductase Deficiency.
The Journal of Clinical Endocrinology and Metabolism, 1992Co-Authors: Julianne Imperato-mcginley, Teofilo Gautier, K Zirinsky, O Palomo, Evan A. Stein, E D Vaughan, John A. Markisz, E. Ramirez De Arellano, Elias KazamAbstract:Male pseudohermaphrodites with 5 alpha-reductase Deficiency have ambiguous genitalia and nonpalpable prostates on rectal examination, suggesting the dihydrotestosterone dependency of these structures. To clearly delineate the status of the prostate, male pseudohermaphrodites with 5 alpha-reductase Deficiency had transrectal sonography of the prostate performed, and the results were compared to that of age-matched male controls. In six male pseudohermaphrodites, magnetic resonance imaging studies of the prostate were also performed. Heterozygote fathers also had transrectal sonography of the prostate performed and the results compared to age-matched controls. The prostates of the male pseudohermaphrodites appeared as platelike soft tissue structures posterior to the urethra on both prostatic ultrasound and magnetic resonance imaging. Prostatic volume, as determined on prostatic ultrasound by two different methods, was significantly smaller (approximately one-tenth) than the volume of age-matched controls. ...
Mithat Bahceci - One of the best experts on this subject based on the ideXlab platform.
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a novel missense mutation of 5 alpha reductase type 2 gene srd5a2 leads to severe male pseudohermaphroditism in a turkish family
Urology, 2005Co-Authors: Mithat Bahceci, Olaf Hiort, Ahmet Resit Ersay, Alpaslan Tuzcu, Annette Richterunruh, Deniz GokalpAbstract:Abstract Objectives To analyze the steroid 5-alpha reductase type 2 gene ( SRD5A2 ) in 2 siblings with severe male pseudohermaphroditism suspected to have 5-alpha reductase Deficiency in a Turkish family. Methods Two female siblings of a family with 7 children were referred to the urology department because of bilateral inguinal masses. The patients had presented after birth with ambiguous genitalia, but no further diagnostic procedures had been performed, and they were raised as girls until the ages of 13 and 15 years. At this time, both had striking ambiguity of the genitalia, with a clitoris-like phallus, severely bifid scrotum, pseudovaginal perineoscrotal hypospadias, a rudimentary prostate, and inguinal testes. Karyotype was 46,XY. Basal and stimulated levels of serum testosterone (T), dihydrotestosterone (DHT), and T/DHT ratio indicated 5-alpha reductase Deficiency. Molecular genetic analysis was performed on deoxyribonucleic acid from peripheral blood leukocytes by single-stranded conformational polymorphism analysis and direct sequencing. Results Analysis of the SRD5A2 gene revealed a new homozygous missense mutation in exon 2. At codon 123, we identified a GGA to AGA change resulting in a missense amino acid change from glycine to arginine (G123R). Both parents and the 2 healthy sisters and 3 brothers were all heterozygous at codon 123 for the same mutation. Conclusions We report a novel homozygous missense mutation in exon 2 of the 5-alpha reductase type 2 gene that led to severe undervirilization in 2 siblings.
Gernot H G Sinnecker - One of the best experts on this subject based on the ideXlab platform.
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Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase Deficiency.
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Olaf Hiort, Gernot H G Sinnecker, Holger Willenbring, A. Lehners, A. Zöllner, Dagmar StruveAbstract:5 alpha-Reductase Deficiency is a rare autosomal recessive disorder of defective virilization in karyotypic males due to reduced conversion of testosterone to dihydrotestosterone. The gene encoding the affected 5 alpha-reductase type 2 enzyme has recently been cloned, and mutations within the coding region have been discovered as the cause of this disease. We address the possibility of a rapid nonradioactive molecular genetic screening technique for initial diagnosis and report different point mutations in this gene in eight unrelated patients with clinical features of 5 alpha-reductase Deficiency. For molecular genetic analysis, DNA from peripheral blood leukocytes was studied. The coding region of the 5 alpha-reductase type 2 gene was characterized by exon-specific PCR amplification, nonradioactive single strand conformation analysis, and direct sequencing. In seven patients, homozygous point mutations were identified (Leu55-Gln, delta Met157, Gly196-Ser, Arg227-Gln, Ala228-Thr, and His231-Arg). One ind...
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phenotypic classification of male pseudohermaphroditism due to steroid 5α reductase 2 Deficiency
American Journal of Medical Genetics, 1996Co-Authors: Gernot H G Sinnecker, Leif Dibbelt, Norbert Albers, Helmuth G Dorr, Michael Hemminghaus, W Hoepffner, U Heinrich, H. Haus, Olaf Hiort, Martin HolderAbstract:Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5{alpha}-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5{alpha}-reductase 2 Deficiency (SRD). T/DHT-ratios were highly increased in the classical syndrome, but variable in the less severe affected patients. Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5{alpha}-reductase Deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms ofmore » undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5{alpha}-reductase 2 Deficiency. 22 refs., 2 figs., 2 tabs.« less
