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

Berra, Marta; Williams, Emma; Muroni, Barbara; Creighton, Sarah M.; Honour, John W.; Rumsby, Gill; Conway, Gerard S.

doi:10.1530/eje-10-0930

Cited by 49 publications

(49 citation statements)

References 34 publications

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“…In these circumstances, genetic testing is required. In a previous study, we found that SRD5A2 mutations occurred in 43% of women in this clinical subgroup (14). We now extend this work by presenting the results of screening for HSD17B3 and AR mutations in partially virilised women with 46,XY DSD of unknown aetiology.…”

Section: Introductionsupporting

confidence: 59%

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Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development

Phelan

Williams

Cardamone

et al. 2015

European Journal of Endocrinology

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Context and objective: The precise diagnosis of partially virilised women with 46,XY disorders of sex development (DSD) is often obscure. In practice, this group often comes under the poorly defined, clinically based label of partial androgen insensitivity syndrome (PAIS). In a previous study, we found that 5a-reductase 2 (SRD5A2) mutations occurred in 43% of women in this subgroup. We expand this work to include biochemical and genetic screening for 17b-hydroxysteroid dehydrogenase (HSD17B3) and androgen receptor (AR) mutations. Methods: Analysis of serum androgens (androstenedione and testosterone) and genetic analyses for HSD17B3 and AR were performed in 42 women from 36 pedigrees with partially virilised 46,XY DSD in whom SRD5A2 deficiency had been excluded by urine steroid profiling. Results: Out of 36 unrelated women, 14 (38%) were found to have HSD17B3 mutations and one (2.7%) to have an AR defect. Six novel pathogenic HSD17B3 mutations were identified: three splice site mutations and three missense changes.Seven patients with HSD17B3 deficiency tested before gonadectomy had basal testosterone/androstenedione (T/A) ratio !0.8 (sensitivity 100% and specificity 91%). Conclusions: HSD17B3 deficiency is prevalent in the adolescent and adult 46,XY female DSD population and is often associated with lesser degrees of virilisation compared with those with 5a-reductase deficiency. This diagnosis should be considered for individuals labelled as PAIS, particularly, but not exclusively, those who present with virilisation at puberty or primary amenorrhoea. Before gondadectomy, T/A ratio is useful to aid diagnosis, but after gonadectomy sequencing of HSD17B3 must be performed to confirm the diagnosis.

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Section: Introductionsupporting

confidence: 59%

“…Prader staging at birth was estimated from available information and cannot be considered perfectly accurate, but is included to convey an idea of virilisation at birth. All subjects had urinary steroid profiles performed to exclude SRD5A2 deficiency as described previously (14).…”

Section: Subjectsmentioning

confidence: 99%

Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development

Phelan

Williams

Cardamone

et al. 2015

European Journal of Endocrinology

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“…Eleven articles mentioned the methodology of their DHT assays. USP was used for diagnosing 5ARD in 3 studies, with all the patients showing low 5␣-and 5␤-reduced steroid metabolite ratios (5,10,12 ). Regarding molecular diagnosis, 141 patients (94.6%) had 2 mutations detected in SRD5A2 to confirm the diagnosis.…”

Section: Resultsmentioning

confidence: 99%

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

Chan¹,

But²,

Lee³

et al. 2013

Clinical Chemistry

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BACKGROUND 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5β-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

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“…The diagnostic guidance for disorders in sexual development is based almost entirely on pediatric experience, whereas very few guidelines are available for adults [10]. These genetic disorders have a variety of causes, such as SRY gene mutations, resulting in cases of pure gonadal dysgenesis [11], steroidogenic factor mutations (NR5A1) and mutations of the genes encoding the androgen receptor, such as 17β-hydroxysteroid dehydrogenase-3 and 5α-reductase-2, which form a poorly defined clinical group known as partial androgen insensitivity syndrome (PAIS) [5,7,9,10].…”

Section: Discussionmentioning

confidence: 99%

“…These genetic disorders have a variety of causes, such as SRY gene mutations, resulting in cases of pure gonadal dysgenesis [11], steroidogenic factor mutations (NR5A1) and mutations of the genes encoding the androgen receptor, such as 17β-hydroxysteroid dehydrogenase-3 and 5α-reductase-2, which form a poorly defined clinical group known as partial androgen insensitivity syndrome (PAIS) [5,7,9,10]. Morris syndrome or testicular feminization is the most common form of PAIS [4], and is the form that we strongly believe our patient presented with.…”

Section: Discussionmentioning

confidence: 99%

Sertoli-Leydig tumor and male pseudohermaphroditism discovered during inguinal hernia surgery

et al. 2014

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AbstractThe diagnosis of inguinal hernia is usually clinical and it is performed with high sensitivity and specificity. Very occasionally, it may be confused with other diseases (lymphadenopathy, testicular pathology,etc). We report a rare case of a 80-year-old woman with a clinical diagnosis of hernia, which was underwent surgery and a tumor from the hernia orifice was found. After histological analysis we discovered that the misdiagnosed hernia was actually a tumor on a rudimentary testis. After radiological, gynecological and cytogenetic assessment we obtained an unexpected diagnosis: Male psheudohermaphroditism and Sertoli-Leydigtumor (SLCT) development on the testis. Diagnostic guidance for disorders of sexual development is based almost entirely on pediatric experience and very few guidelines are available for adults. Male pseudohermaphroditism is an intersex condition in which the carriers show a phenotype that includes external female genitalia, but a male genetic and gonadal sex. SLCT are sex-cord stromal tumors which develop in ovary and very rarely in the testis, representing 0.1–0.5% of ovarian tumors and less than 0.2% of testicular tumors. Thus far 24 case have been reported in the literature in which SLCT tumor has developed on testis.

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

Cited by 49 publications

References 34 publications

Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development

Screening for mutations in 17β-hydroxysteroid dehydrogenase and androgen receptor in women presenting with partially virilised 46,XY disorders of sex development

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

Sertoli-Leydig tumor and male pseudohermaphroditism discovered during inguinal hernia surgery

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