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

Context

The late presentation of steroid 5α-reductase-2 (SRD5A2) deficiency in females is poorly characterised. The ratios of 5α/5β-reduced metabolites of adrenal steroids in a urine steroid profile (USP) can give an indication of SRD5A2 deficiency, although the diagnostic cut-off for 5α/5β 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 5α/5β-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. 5α-Reductase activity was assessed using the USP ratio of androsterone to aetiocholanolone (A/Ae), 5α-tetrahydrocortisol (5α-THF)/tetrahydrocortisol (THF) and 5α-tetrahydrocorticosterone to tetrahydrocorticosterone (5α-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 5α-THB/THB ratios below the lower limit of normal (100% sensitivity) while the sensitivity of 5α-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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Christa Flück, Anna Nordenström, S Faisal Ahmed, Salma R Ali, Marta Berra, Joanne Hall, Birgit Köhler, Vickie Pasterski, Ralitsa Robeva, Katinka Schweizer, Alexander Springer, Puck Westerveld, Olaf Hiort, Martine Cools and the COST Action BM1303 Working Group

The treatment and care of individuals who have a difference of sex development (DSD) have been revised over the past two decades and new guidelines have been published. In order to study the impact of treatments and new forms of management in these rare and heterogeneous conditions, standardised assessment procedures across centres are needed. Diagnostic work-up and detailed genital phenotyping are crucial at first assessment. DSDs may affect general health, have associated features or lead to comorbidities which may only be observed through lifelong follow-up. The impact of medical treatments and surgical (non-) interventions warrants special attention in the context of critical review of current and future care. It is equally important to explore gender development early and refer to specialised services if needed. DSDs and the medical, psychological, cultural and familial ways of dealing with it may affect self-perception, self-esteem, and psychosexual function. Therefore, psychosocial support has become one of the cornerstones in the multidisciplinary management of DSD, but its impact remains to be assessed. Careful clinical evaluation and pooled data reporting in a global DSD registry will allow linking genetic, metabolomic, phenotypic and psychological data. For this purpose, our group of clinical experts and patient and parent representatives designed a template for structured longitudinal follow-up. In this paper, we explain the rationale behind the selection of the dataset. This tool provides guidance to professionals caring for individuals with a DSD and their families. At the same time, it collects the data needed for answering unsolved questions of patients, clinicians, and researchers. Ultimately, outcomes for defined subgroups of rare DSD conditions should be studied through large collaborative endeavours using a common protocol.