<i>SRD5A2</i> gene analysis in an Italian population of under‐masculinized 46,XY subjects

Nicoletti, Annalisa; Baldazzi, Lilia; Balsamo, Antonio; Barp, Lorella; Pirazzoli, Piero; Gennari, Monia; Radetti, Giorgio; Cacciari, E; Cicognani, Alessandro

doi:10.1111/j.1365-2265.2005.02348.x

Cited by 52 publications

(57 citation statements)

References 20 publications

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“…As in the present girl the lack of appropriate endocrine investigation before gonadectomy did not provide indications for genes to be investigated, unsuccessful analysis of the AR gene was performed before screening of SRD5A2 , which permitted the identification of compound heterozygosity. The Q126R mutation we found in exon 2 has been previously reported in several patients from different countries [Wilson et al, 1993;Hackel et al, 2005], but it has not yet been described in Italian patients [Nicoletti et al, 2005;Bertelloni et al, 2007;Baldinotti et al, 2008]. This mutation is located in a highly conserved region of type 2 enzyme [Hackel et al, 2005] and its pathogenic role was confirmed by site-directed mutagenesis and in vitro assays [Wigley et al, 1994].…”

Section: Discussionsupporting

confidence: 49%

“…To explain the presence of the Q126R mutation in different populations, the existence of a common ancestor spreading the mutation across Europe and then in South America has been suggested, although the possibility of a hotspot cannot be excluded [Hackel et al, 2005]. The mutation H230P in exon 4 was not previously reported in Italian patients with 5 ␣ -reductase-2 deficiency [Nicoletti et al, 2005;Bertelloni et al, 2007;Baldinotti et al, 2008]. However, it has been first identified in an Italian-American boy from New York, who was a compound heterozygote for N193S and H230P [Saenger et al, 1978;Wigley et al, 1994].…”

Section: Discussionmentioning

confidence: 99%

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A Girl with Tomboy Behavior: Lesson from Misdiagnosis in a Baby with Ambiguous Genitalia

Dati

Baldinotti²,

Conidi³

et al. 2009

Sex Dev

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5α-Reductase-2 deficiency is a rare 46,XY disorder of sex differentiation caused by mutations in the 5α-reductase type 2 gene. It presents at birth with variable degree of undervirilization. Here, a baby with 5α-reductase-2 deficiency and misdiagnosis of complete androgen insensitivity syndrome, female sex assignment and early gonadectomy is described. During primary school, the girl developed tomboy behavior. Molecular analysis demonstrated compound heterozygosity for 5α-reductase type 2 gene mutations (exon 2: Q126R; exon 4: H230P). This child underlines the need for adequate endocrine and genetic testing for a definite diagnosis before gender is assigned in children with ambiguous genitalia and surgical interventions are carried out. Inadequate work-up may result in inappropriate gender assignment in infancy with possible inferences on outcome.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

A Girl with Tomboy Behavior: Lesson from Misdiagnosis in a Baby with Ambiguous Genitalia

Dati

Baldinotti²,

Conidi³

et al. 2009

Sex Dev

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“…In this study, we have shown that a significant proportion (41%) of 46XY DSD females have SRD5A2 deficiency and that this diagnosis should be considered for individuals labelled as PAIS, particularly, but not exclusively, those that virilise post-puberty. A similar prevalence of SRD5A2 mutations has been reported in a paediatric population of 46XY under-masculinised children (19), making this condition a more prominent component of the DSD population than previously considered.…”

Section: Discussionmentioning

confidence: 52%

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Berra¹,

Williams

Muroni

et al. 2011

European Journal of Endocrinology

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Context: The late presentation of steroid 5a-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5a/5b-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5a/5b ratios are not clearly defined in genetically confirmed cases. Objective: The aim of this study was to establish the frequency of SRD5A2 deficiency in an adult clinic for disorders of sexual development (DSD) focussing on 46XY partially virilised adult female subjects. We investigated the relationship between USP results and SRD5A2 genetic sequence and determined the cut-off for USP 5a/5b-reduced steroid ratios compared with gene sequencing for the identification of SRD5A2 deficiency. Methods: USP and SRD5A2 genetic analyses were performed in 23 adult females, aged 19-57 years, with 46XY DSD and in four males with confirmed SRD5A2 deficiency. 5a-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5a-tetrahydrocortisol (5a-THF)/tetrahydrocortisol (THF) and 5a-tetrahydrocorticosterone to tetrahydrocorticosterone (5a-THB/THB). Results: The SRD5A2 gene mutations were found in 10/23 (43%) females and in all four males. Totally, four novel mutations were identified. All mutation-positive subjects had A/Ae and 5a-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5a-THF/THF ratio was 90%. Conclusion: SRD5A2 deficiency is more prevalent than expected in the adult female 46XY DSD population. The clinical spectrum of this disorder may extend to a more female phenotype than previously considered to include individuals with little or no virilisation.

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“…A previous study revealed that the p.R246Q mutation decreases binding affinity for the nicotinamide adenine dinucleotide phosphate (NADPH) cofactor by disrupting the 5α-reductase type 2 enzyme and changing the optimal reaction pH [20]. The p.R246Q mutation is one of the most common mutations and has been identified in patients of various ethnic backgrounds including African-American, Pakistani, Italian, Austrian, Dominican, Brazilian, Egyptian, and Indian groups [8,21,22,23,24,25]. …”

Section: Discussionmentioning

confidence: 99%

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

Ko¹,

Cheon²,

Kim

et al. 2010

Horm Res Paediatr

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Aims: The aim of this study was to perform a 5α-reductase type 2 gene (SRD5A2) analysis in 6 Korean patients with external genitalia ranging from predominantly female to male in whom 5α-reductase type 2 deficiency was suspected. Patients: Six patients from five unrelated families participated, and all of their parents were non-consanguineous. Three patients presented with ambiguous genitalia at birth, and 2 were referred owing to delayed puberty. The other patient was presented incidentally during an operation for inguinal hernia. Basal and post-human chorionic gonadotropin-stimulated serum testosterone and dihydrotestosterone levels were determined, but neither the levels nor ratio yielded enough information for differential diagnosis. Confirmative diagnosis was achieved by SRD5A2 gene analysis. Results: Four different pathologic mutations were identified. All have already been reported, and are located in exon 1 (p.Q6X), exon 4 (p.G203S and c.655delT), and exon 5 (p.R246Q). p.R246Q was the most frequently identified mutation in our study, and c.655delT has been detected only in Korean patients to date. Conclusion: The molecular analysis is the most reliable method for a correct diagnosis of 5α-reductase type 2 deficiency. Identification of mutations also enables genetic counseling for families at risk.

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SRD5A2 gene analysis in an Italian population of under‐masculinized 46,XY subjects

Cited by 52 publications

References 20 publications

A Girl with Tomboy Behavior: Lesson from Misdiagnosis in a Baby with Ambiguous Genitalia

A Girl with Tomboy Behavior: Lesson from Misdiagnosis in a Baby with Ambiguous Genitalia

Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

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