Editing 5α-Reductase 2 deficiency (section)

==Diagnosis==
Diagnosis is usually made between birth and puberty. Pseudovaginal perineoscrotal hypospadias presenting with female-appearing genitalia and pubertal virilization is the classical syndrome attributed to 5αR2D, but modern diagnostic methods can diagnose the deficiency shortly after birth and recognize the broad spectrum of presentation.<ref name="Mendonca2016"/>

The initial diagnosis of 46,XY DSD is indicated by overt genital abnormality. The objective clinical evaluation of dysmorphic features to diagnose 46,XY DSD for apparent female genitalia includes enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia:  nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family history and prenatal history are also taken into account in the evaluation. [[karyotype|Karyotyping]] and [[SRY]] gene analysis on samples from peripheral [[leukocyte]]s will exclude [[sex chromosome]] abnormalities. With the determination of an XY karyotype and normal SRY, the differential diagnosis of 46,XY DSD is made with endocrinological measurements of T/DHT ratios<ref>{{cite journal |last1=Hiort |first1=Olaf |last2=Willenbring |first2=Holger |last3=Albers |first3=Norbert |last4=Hecker |first4=Wolfgang |last5=Engert |first5=Jürgen |last6=Dibbelt |first6=Leif |last7=Sinnecker |first7=Gernot H. G. |title=Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency |journal=European Journal of Pediatrics |date=June 1996 |volume=155 |issue=6 |pages=445–451 |doi=10.1007/BF01955179|pmid=8789759 |s2cid=24236741 }}</ref> (which indicate 5αR2 activity) and precise anatomical imaging since 5αR2D can be difficult to distinguish from other causes of 46,XY DSD (e.g., partial androgen insensitivity syndrome and 17β- hydroxysteroid dehydrogenase type 3 enzyme deficiencies).<ref name="Cheon2011">{{cite journal |last1=Cheon |first1=Chong Kun |title=Practical approach to steroid 5alpha-reductase type 2 deficiency |journal=European Journal of Pediatrics |date=January 2011 |volume=170 |issue=1 |pages=1–8 |doi=10.1007/s00431-010-1189-4|pmid=20349245 |s2cid=25945759 }}</ref>

The measurement of the serum DHT concentration is challenging since the concentrations are low and DHT has a high level of cross-reactivity. A high level of assay specificity is required to measure concentrations of DHT since serum T levels are generally 10-fold higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret since the normal ratio level varies according to age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels demonstrate elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with [[human chorionic gonadotropin|human chorionic gonadotropin (hCG)]] (alternatively, [[testosterone enanthate]]) is required in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge<ref>{{cite journal |last1=Clarkson |first1=Jenny |last2=Herbison |first2=Allan E. |title=Hypothalamic control of the male neonatal testosterone surge |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |date=19 February 2016 |volume=371 |issue=1688 |pages=20150115 |doi=10.1098/rstb.2015.0115|pmid=26833836 |pmc=4785901 }}</ref> and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns.<ref>{{cite journal |last1=Achermann |first1=John C. |last2=Domenice |first2=Sorahia |last3=Bachega |first3=Tania A. S. S. |last4=Nishi |first4=Mirian Y. |last5=Mendonca |first5=Berenice B. |title=Disorders of sex development: effect of molecular diagnostics |journal=Nature Reviews Endocrinology |date=August 2015 |volume=11 |issue=8 |pages=478–488 |doi=10.1038/nrendo.2015.69|pmid=25942653 |s2cid=19704336 |url=https://discovery.ucl.ac.uk/id/eprint/1492403/ }}</ref><ref>{{cite journal |last1=Maimoun |first1=Laurent |last2=Philibert |first2=Pascal |last3=Cammas |first3=Benoit |last4=Audran |first4=Françoise |last5=Bouchard |first5=Philippe |last6=Fenichel |first6=Patrick |last7=Cartigny |first7=Maryse |last8=Pienkowski |first8=Catherine |last9=Polak |first9=Michel |last10=Skordis |first10=Nicos |last11=Mazen |first11=Inas |last12=Ocal |first12=Gonul |last13=Berberoglu |first13=Merih |last14=Reynaud |first14=Rachel |last15=Baumann |first15=Clarisse |last16=Cabrol |first16=Sylvie |last17=Simon |first17=Dominique |last18=Kayemba-Kay's |first18=Kabangu |last19=De Kerdanet |first19=Marc |last20=Kurtz |first20=François |last21=Leheup |first21=Bruno |last22=Heinrichs |first22=Claudine |last23=Tenoutasse |first23=Sylvie |last24=Van Vliet |first24=Guy |last25=Grüters |first25=Annette |last26=Eunice |first26=Marumudi |last27=Ammini |first27=Ariachery C. |last28=Hafez |first28=Mona |last29=Hochberg |first29=Ze'ev |last30=Einaudi |first30=Sylvia |last31=Al Mawlawi |first31=Horia |last32=del Valle Nuñez |first32=Cristóbal J. |last33=Servant |first33=Nadège |last34=Lumbroso |first34=Serge |last35=Paris |first35=Françoise |last36=Sultan |first36=Charles |title=Phenotypical, Biological, and Molecular Heterogeneity of 5α-Reductase Deficiency: An Extensive International Experience of 55 Patients |journal=The Journal of Clinical Endocrinology & Metabolism |date=February 2011 |volume=96 |issue=2 |pages=296–307 |doi=10.1210/jc.2010-1024|pmid=21147889 |doi-access= }}</ref> Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals.<ref name="Mendonca2016"/> 5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via [[gas chromatography–mass spectrometry]].<ref>{{cite journal |last1=Chan |first1=Angel On Kei |last2=But |first2=Betty Wai Man |last3=Lee |first3=Ching Yin |last4=Lam |first4=Yuen Yu |last5=Ng |first5=Kwok Leung |last6=Tung |first6=Joanna Yuet Ling |last7=Kwan |first7=Elaine Yin Wah |last8=Chan |first8=Yuk Kit |last9=Tsui |first9=Teresa Kam Chi |last10=Lam |first10=Almen Lai Na |last11=Tse |first11=Wing Yee |last12=Cheung |first12=Pik To |last13=Shek |first13=Chi Chung |title=Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential? |journal=Clinical Chemistry |date=1 May 2013 |volume=59 |issue=5 |pages=798–806 |doi=10.1373/clinchem.2012.196501|pmid=23513070 |doi-access=free }}</ref>

[[Ultrasonography]] is the primary means for assessing internal reproductive organs for diagnosis while [[genitography]] and [[voiding cystourethrography]] are used to resolve structures such as urethral and vaginal tracts.<ref name="Chavhan2008">{{cite journal |last1=Chavhan |first1=Govind B. |last2=Parra |first2=Dimitri A. |last3=Oudjhane |first3=Kamaldine |last4=Miller |first4=Stephen F. |last5=Babyn |first5=Paul S. |last6=Pippi Salle |first6=Foao L. |title=Imaging of Ambiguous Genitalia: Classification and Diagnostic Approach |journal=RadioGraphics |date=November 2008 |volume=28 |issue=7 |pages=1891–1904 |doi=10.1148/rg.287085034|pmid=19001646 }}</ref><ref>{{cite journal |last1=Parisi |first1=Melissa A |last2=Ramsdell |first2=Linda A |last3=Burns |first3=Mark W |last4=Carr |first4=Michael C |last5=Grady |first5=Richard E |last6=Gunther |first6=Daniel F |last7=Kletter |first7=Gadi B |last8=McCauley |first8=Elizabeth |last9=Mitchell |first9=Michael E |last10=Opheim |first10=Kent E |last11=Pihoker |first11=Catherine |last12=Richards |first12=Gail E |last13=Soules |first13=Michael R |last14=Pagon |first14=Roberta A |title=A Gender Assessment Team: experience with 250 patients over a period of 25 years |journal=Genetics in Medicine |date=June 2007 |volume=9 |issue=6 |pages=348–357 |doi=10.1097/GIM.0b013e3180653c47|pmid=17575501 |s2cid=21141446 |doi-access=free }}</ref> The use of pelvic [[MRI]] for diagnostic imaging for 5αR2D remains controversial.<ref name="Chavhan2008"/>