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46,XY sex reversal 9(SRXY9)

MedGen UID:
863566
•Concept ID:
C4015129
•
Disease or Syndrome
Synonyms: 46,XY SEX REVERSAL, ZFPM2-RELATED; SRXY9
 
Gene (location): ZFPM2 (8q23.1)
 
Monarch Initiative: MONDO:0014480
OMIM®: 616067

Clinical features

From HPO
Gonadal dysgenesis
MedGen UID:
9075
•Concept ID:
C0018051
•
Congenital Abnormality
A congenital disorder characterized by the presence of extremely hypoplastic gonads preventing the development of secondary sex characteristics.
See: Feature record | Search on this feature
Ambiguous genitalia
MedGen UID:
78596
•Concept ID:
C0266362
•
Congenital Abnormality
A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale
See: Feature record | Search on this feature
Fused labia minora
MedGen UID:
332475
•Concept ID:
C1837532
•
Finding
Fusion of the labia minora as a result of labial adhesions resulting in vaginal obstruction.
See: Feature record | Search on this feature
Sex reversal
MedGen UID:
868596
•Concept ID:
C4022995
•
Finding
Development of the reproductive system is inconsistent with the chromosomal sex.
See: Feature record | Search on this feature
Autistic behavior
MedGen UID:
163547
•Concept ID:
C0856975
•
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients.
Gui B, Song Y, Su Z, Luo FH, Chen L, Wang X, Chen R, Yang Y, Wang J, Zhao X, Fan L, Liu X, Wang Y, Chen S, Gong C
J Med Genet 2019 Oct;56(10):685-692. Epub 2019 Jun 11 doi: 10.1136/jmedgenet-2018-105915. PMID: 31186340

Recent clinical studies

Etiology

Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.
Kim GJ, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, German J, Cole T, Mann J, Seguin JH, Zipf W, Costigan C, Schmiady H, Rostásy M, Kramer M, Kaltenbach S, Rösler B, Georg I, Troppmann E, Teichmann AC, Salfelder A, Widholz SA, Wieacker P, Hiort O, Camerino G, Radi O, Wegner M, Arnold HH, Scherer G
J Med Genet 2015 Apr;52(4):240-7. Epub 2015 Jan 20 doi: 10.1136/jmedgenet-2014-102864. PMID: 25604083
Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold.
Chen YS, Racca JD, Phillips NB, Weiss MA
Proc Natl Acad Sci U S A 2013 Sep 17;110(38):E3567-76. Epub 2013 Sep 3 doi: 10.1073/pnas.1300828110. PMID: 24003159Free PMC Article
Frasier syndrome: four new cases with unusual presentations.
Guaragna MS, Lutaif AC, Bittencourt VB, Piveta CS, Soardi FC, Castro LC, Belangero VM, Maciel-Guerra AT, Guerra-Junior G, Mello MP
Arq Bras Endocrinol Metabol 2012 Nov;56(8):525-32. doi: 10.1590/s0004-27302012000800011. PMID: 23295293
Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA.
Barbaro M, Balsamo A, Anderlid BM, Myhre AG, Gennari M, Nicoletti A, Pittalis MC, Oscarson M, Wedell A
Eur J Hum Genet 2009 Nov;17(11):1439-47. Epub 2009 May 6 doi: 10.1038/ejhg.2009.70. PMID: 19417767Free PMC Article
Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation.
Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM
J Mol Biol 2001 Sep 21;312(3):481-99. doi: 10.1006/jmbi.2001.4977. PMID: 11563911

Diagnosis

FGF9 variant in 46,XY DSD patient suggests a role for dimerization in sex determination.
Croft B, Bird AD, Ono M, Eggers S, Bagheri-Fam S, Ryan JM, Reyes AP, van den Bergen J, Baxendale A, Thompson EM, Kueh AJ, Stanton P, Thomas T, Sinclair AH, Harley VR
Clin Genet 2023 Mar;103(3):277-287. Epub 2022 Nov 28 doi: 10.1111/cge.14261. PMID: 36349847Free PMC Article
A Novel Intronic Splice-Site Mutation of the CYP11A1 Gene Linked to Adrenal Insufficiency with 46,XY Disorder of Sex Development.
Matusik P, Gach A, Zajdel-Cwynar O, Pinkier I, Kudela G, Gawlik A
Int J Environ Res Public Health 2021 Jul 5;18(13) doi: 10.3390/ijerph18137186. PMID: 34281122Free PMC Article
Inv dup del(9p): prenatal diagnosis and molecular cytogenetic characterization by fluorescence in situ hybridization and array comparative genomic hybridization.
Chen CP, Su YN, Chern SR, Hsu CY, Tsai FJ, Wu PC, Lee CC, Chen YT, Lee MS, Wang W
Taiwan J Obstet Gynecol 2011 Mar;50(1):67-73. doi: 10.1016/j.tjog.2011.01.038. PMID: 21482378
WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review.
Dai YL, Fu JF, Hong F, Xu S, Shen Z
Acta Paediatr 2011 Jul;100(7):e39-42. Epub 2011 Feb 14 doi: 10.1111/j.1651-2227.2011.02167.x. PMID: 21314844
Ovotestes and XY sex reversal in a female with an interstitial 9q33.3-q34.1 deletion encompassing NR5A1 and LMX1B causing features of Genitopatellar syndrome.
Schlaubitz S, Yatsenko SA, Smith LD, Keller KL, Vissers LE, Scott DA, Cai WW, Reardon W, Abdul-Rahman OA, Lammer EJ, Lifchez CA, Magenis E, Veltman JA, Stankiewicz P, Zabel BU, Lee B
Am J Med Genet A 2007 May 15;143A(10):1071-81. doi: 10.1002/ajmg.a.31685. PMID: 17431898

Therapy

Possible fetal determinants of male infertility.
Juul A, Almstrup K, Andersson AM, Jensen TK, Jørgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebæk NE
Nat Rev Endocrinol 2014 Sep;10(9):553-62. Epub 2014 Jun 17 doi: 10.1038/nrendo.2014.97. PMID: 24935122
Experiment of nurture: ablatio penis at 2 months, sex reassignment at 7 months, and a psychosexual follow-up in young adulthood.
Bradley SJ, Oliver GD, Chernick AB, Zucker KJ
Pediatrics 1998 Jul;102(1):e9. doi: 10.1542/peds.102.1.e9. PMID: 9651461

Prognosis

The human doublesex-related gene, DMRT2, is homologous to a gene involved in somitogenesis and encodes a potential bicistronic transcript.
Ottolenghi C, Veitia R, Barbieri M, Fellous M, McElreavey K
Genomics 2000 Mar 1;64(2):179-86. doi: 10.1006/geno.2000.6120. PMID: 10729224
Experiment of nurture: ablatio penis at 2 months, sex reassignment at 7 months, and a psychosexual follow-up in young adulthood.
Bradley SJ, Oliver GD, Chernick AB, Zucker KJ
Pediatrics 1998 Jul;102(1):e9. doi: 10.1542/peds.102.1.e9. PMID: 9651461

Clinical prediction guides

Inherited Missense Mutation Occurring in Arginine76 of the SRY Gene Does Not Account for Familial 46, XY Sex Reversal.
Wang N, Zhu W, Han B, Wang H, Zhu H, Chen Y, Chen Y, Liu J, Liu Y, Zhao S, Song H, Qiao J
J Clin Endocrinol Metab 2020 May 1;105(5) doi: 10.1210/clinem/dgaa109. PMID: 32140723
Possible fetal determinants of male infertility.
Juul A, Almstrup K, Andersson AM, Jensen TK, Jørgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebæk NE
Nat Rev Endocrinol 2014 Sep;10(9):553-62. Epub 2014 Jun 17 doi: 10.1038/nrendo.2014.97. PMID: 24935122
Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold.
Chen YS, Racca JD, Phillips NB, Weiss MA
Proc Natl Acad Sci U S A 2013 Sep 17;110(38):E3567-76. Epub 2013 Sep 3 doi: 10.1073/pnas.1300828110. PMID: 24003159Free PMC Article
Chromosome 9p deletion syndrome and sex reversal: novel findings and redefinition of the critically deleted regions.
Onesimo R, Orteschi D, Scalzone M, Rossodivita A, Nanni L, Zannoni GF, Marrocco G, Battaglia D, Fundarò C, Neri G
Am J Med Genet A 2012 Sep;158A(9):2266-71. Epub 2012 Jul 20 doi: 10.1002/ajmg.a.35489. PMID: 22821627
XY sex reversal and gonadal dysgenesis due to 9p24 monosomy.
McDonald MT, Flejter W, Sheldon S, Putzi MJ, Gorski JL
Am J Med Genet 1997 Dec 19;73(3):321-6. PMID: 9415692

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