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5-Alpha-Reductase Deficiency

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Olaf Hiort – 1st expert on this subject based on the ideXlab platform

  • Current models of care for disorders of sex development – results from an International survey of specialist centres.
    Orphanet Journal of Rare Diseases, 2016
    Co-Authors: Andreas Kyriakou, Arianne B. Dessens, Jillian Bryce, Violeta Iotova, Anders Juul, Maciej R. Krawczynski, Agneta Nordenskjöld, Marta Rozas, Caroline Sanders, Olaf Hiort

    Abstract:

    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.

  • a novel missense mutation of 5 alpha reductase type 2 gene srd5a2 leads to severe male pseudohermaphroditism in a turkish family
    Urology, 2005
    Co-Authors: Mithat Bahceci, Olaf Hiort, Ahmet Resit Ersay, Alpaslan Tuzcu, Annette Richterunruh, Deniz Gokalp

    Abstract:

    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.

  • 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, 1996
    Co-Authors: Olaf Hiort, Gernot H G Sinnecker, Holger Willenbring, A. Lehners, A. Zöllner, Dagmar Struve

    Abstract:

    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…

Deniz Gokalp – 2nd expert on this subject based on the ideXlab platform

  • a novel missense mutation of 5 alpha reductase type 2 gene srd5a2 leads to severe male pseudohermaphroditism in a turkish family
    Urology, 2005
    Co-Authors: Mithat Bahceci, Olaf Hiort, Ahmet Resit Ersay, Alpaslan Tuzcu, Annette Richterunruh, Deniz Gokalp

    Abstract:

    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 – 3rd expert on this subject based on the ideXlab platform

  • Mutations of the 5α-reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α-reductase-2 Deficiency
    Clinical Endocrinology, 1997
    Co-Authors: Patricia Canto, Julianne Imperato-mcginley, Felipe Vilchis, Bertha Chávez, Osvaldo Mutchinick, Gregorio Pérez-palacios, Alfredo Ulloa-aguirre, Juan Pablo Méndez

    Abstract:

    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.

  • 5 alpha-reductase-2 gene mutations in the Dominican Republic.
    The Journal of Clinical Endocrinology and Metabolism, 1996
    Co-Authors: M. D. Katz, C. Herrera, J. Baez, M. Defillo-ricart, C. H. L. Shackleton, Julianne Imperato-mcginley

    Abstract:

    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…

  • Luteinizing hormone pulsatility in subjects with 5-Alpha-Reductase Deficiency and decreased dihydrotestosterone production.
    The Journal of Clinical Endocrinology and Metabolism, 1994
    Co-Authors: William J. Canovatchel, Teofilo Gautier, David Volquez, Sophie Huang, Elizabeth Wood, Martin Lesser, Julianne Imperato-mcginley

    Abstract:

    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…