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Biological assessment of abnormal genitalia

Published:November 19, 2012DOI:https://doi.org/10.1016/j.jpurol.2012.10.002

      Abstract

      Biological assessment of abnormal genitalia is based on an ordered sequence of endocrine and genetic investigations that are predicated on knowledge obtained from a suitable history and detailed examination of the external genital anatomy. Investigations are particularly relevant in 46,XY DSD where the diagnostic yield is less successful than in the 46,XX counterpart. Advantage should be taken of spontaneous activity of the pituitary-gonadal axis in early infancy rendering measurements of gonadotrophins and sex steroids by sensitive, validated assays key to assessing testicular function. Allied measurement of serum anti-Müllerian hormone completes a comprehensive testis profile of Leydig and Sertoli cell function.
      Genetic assessment is dominated by analysis of a plethora of genes that attempts to delineate a cause for gonadal dysgenesis. In essence, this is successful in up to 20% of cases from analysis of SRY and SF1 (NR5A1) genes. In contrast, gene mutation analysis is highly successful in 46,XY DSD due to defects in androgen synthesis or action. The era of next generation sequencing is increasingly being applied to investigate complex medical conditions of unknown cause, including DSD. The challenge for health professionals will lie in integrating vast amounts of genetic information with phenotypes and counselling families appropriately. How tissues respond to hormones is apposite to assessing the range of genital phenotypes that characterise DSD, particularly for syndromes associated with androgen resistance. In vitro methods are available to undertake quantitative and qualitative analysis of hormone action. The in vivo equivalent is some assessment of the degree of under-masculinisation in the male, such as an external masculinisation score, and measurement of the ano-genital distance. This anthropometric marker is effectively a postnatal readout of the effects of prenatal androgens acting during the masculinisation programming window. For investigation of the newborn with abnormal genitalia, a pragmatic approach can be taken to guide the clinician using appropriate algorithms.

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      References

        • Dean A.
        • Smith L.B.
        • Macpherson S.
        • Sharpe R.M.
        The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats.
        Int J Androl. 2012; 35: 330-339
        • Brain C.E.
        • Creighton S.M.
        • Mushtaq I.
        • Carmichael P.A.
        • Barnicoat A.
        • Honour J.W.
        • et al.
        Holistic management of DSD.
        Best Pract Res Clin Endocrinol Metab. 2010; 24: 335-354
        • Ahmed S.F.
        • Khwaja O.
        • Hughes I.A.
        The role of a clinical score in the assessment of ambiguous genitalia.
        BJU Int. 2000; 85: 120-124
        • Sinnecker G.H.
        • Hiort O.
        • Dibbelt L.
        • Albers N.
        • Dörr H.G.
        • Hauss H.
        • et al.
        Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.
        Am J Med Genet. 1996; 63: 223-230
        • Quigley C.A.
        • De Bellis A.
        • Marschke K.B.
        • el-Awady M.K.
        • Wilson E.M.
        • French F.S.
        Androgen receptor defects: historical, clinical, and molecular perspectives.
        Endocr Rev. 1995; 16: 271-321
        • Plotton I.
        • Gay C.L.
        • Bertrand A.M.
        • et al.
        AMH determination is essential for the management of 46, XY DSD patients.
        Horm Res. 2009; 72: 365
        • Faisal Ahmed S.
        • Achermann J.C.
        • Arlt W.
        • Balen A.
        • Conway G.
        • Edwards Z.
        • et al.
        UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development.
        Clin Endocrinol. 2011;
        • Forest M.G.
        • Sizonenko P.C.
        • Cathiard A.M.
        • Bertrand J.
        Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy.
        J Clin Invest. 1974; 53: 819-828
        • Kulle A.E.
        • Riepe F.G.
        • Melchior D.
        • Hiort O.
        • Holterhus P.M.
        A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone and dihydrotestosterone in paediatric blood samples: age-and sex-specific reference data.
        J Clin Endocrinol Metab. 2010; 95: 239-409
        • Krone N.
        • Hughes B.A.
        • Lavery G.G.
        • Stewart P.M.
        • Arlt W.
        • Shackleton C.H.
        Gas chromatography/mass spectrometry (GC/MS) remains a pre-eminent discovery toll in clinical steroid investigations even in the ear of fast liquid chromatography tandem mass spectrometry (LC/MS/MS).
        J Steroid Biochem Mol Biol. 2010; 121: 496-504
        • Hughes I.A.
        • Houk C.
        • Ahmed S.F.
        • Lee P.A.
        • LWPES Consensus Group, ESPE Consensus Group
        Consensus statement on management of intersex disorders.
        Arch Dis Child. 2006; 91: 554-563
      1. Bashamboo A, McElreavey K. Gene mutations associated with anomalies of human gonad formation. Sex Dev 2012 Oct 3 [Epub ahead of print].

        • Morel Y.
        • Plotton I.
        • Mallet D.
        • Nicolino M.
        • Bertrand A.M.
        • David M.
        • et al.
        Studies of a cohort of 46, XY with DSD including steroid biosynthesis deficiencies.
        Adv Exp Med Biol. 2011; 707: 15-17
        • Brinkmann A.O.
        Molecular mechanisms of androgen action – a historical perspective.
        Methods Mol Biol. 2011; 776: 3-24
        • Hughes I.A.
        • Davies J.D.
        • Bunch T.I.
        • Pasterski V.
        • Mastroyannopoulou K.
        • MacDougall J.
        Androgen insensitivity syndrome.
        Lancet. 2012; ([Epub ahead of print])
        • Thankamony A.
        • Ong K.K.
        • Dunger D.B.
        • Acerini C.L.
        • Hughes I.A.
        Anogenital distance from birth to 2 years: a population study.
        Environ Health Perspect. 2009; 117: 1786-1790
        • Eisenberg M.L.
        • Hsieh M.H.
        • Walters R.C.
        • Krasnow R.
        • Lipshultz L.I.
        The relationship between anogenital distance, fatherhood and fertility in adult men.
        PLoS One. 2011; 6: e18973
        • Hsieh M.H.
        • Eisenberg M.L.
        • Hittleman A.B.
        • Wilson J.M.
        • Tasian G.B.
        • Baskin L.S.
        Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance.
        Hum Reprod. 2012; 27: 1577-1580
        • Kamrath C.
        • Hochberg Z.
        • Hartmann M.F.
        • Remer T.
        • Wady S.A.
        Increased activation of the alternative ‘backdoor’ pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis.
        J Clin Endocrinol Metab. 2012; 97: 367-375
        • Bashamboo A.
        • Ledig S.
        • Wieacker P.
        • Achermann J.C.
        • McElreavey K.
        New technologies for the identification of novel genetic markers of disorders of sex development (DSD).
        Sex Dev. 2012; 4: 213-224
        • Ku C.S.
        • Cooper D.N.
        • Polychronakos C.
        • Naidoo N.
        • Wu M.
        • Soong R.
        Exome sequencing: dual role as a discovery and diagnostic tool.
        Ann Neurol. 2012; 71: 5-14
        • Solomon B.D.
        • Hadley D.W.
        • Pineda-Alvarez D.E.
        • NISC Comparative Sequencing Program
        • Kamat A.
        • Teer J.K.
        Incidental medical information in whole-exome sequencing.
        Pediatrics. 2012; 129: 1605-1611