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46,XY sex reversal 5(SRXY5)

MedGen UID:
414349
•Concept ID:
C2751317
•
Disease or Syndrome
Synonyms: 46,XY GONADAL DYSGENESIS, COMPLETE, CBX2-RELATED; 46,XY SEX REVERSAL, CBX2-RELATED; DISORDER OF SEX DEVELOPMENT, 46,XY, CBX2-RELATED; SEX REVERSAL, XY, CBX2-RELATED
 
Gene (location): CBX2 (17q25.3)
 
Monarch Initiative: MONDO:0013120
OMIM®: 613080

Clinical features

From HPO
Abnormal female external genitalia morphology
MedGen UID:
867445
•Concept ID:
C4021822
•
Anatomical Abnormality
Any structural abnormality of the female external genitalia.
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
Abnormal circulating luteinizing hormone concentration
MedGen UID:
663319
•Concept ID:
C0580438
•
Finding
An anomaly of the circulating level of luteinizing hormone (LH).
See: Feature record | Search on this feature
Elevated circulating follicle stimulating hormone level
MedGen UID:
867192
•Concept ID:
C4021550
•
Finding
An elevated concentration of follicle-stimulating hormone in the blood.
See: Feature record | Search on this feature
Abnormality of circulating cortisol level
MedGen UID:
868804
•Concept ID:
C4023214
•
Finding
An abnormality of the concentration of cortisol in the blood.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Primary amenorrhoea - cytogenetic study in 40 Indian women.
Banerjee B, Dutta A, Roy S, Halder A
J Obstet Gynaecol 2024 Dec;44(1):2348085. Epub 2024 May 6 doi: 10.1080/01443615.2024.2348085. PMID: 38708796
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
Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients.
Fukami M, Nishimura G, Homma K, Nagai T, Hanaki K, Uematsu A, Ishii T, Numakura C, Sawada H, Nakacho M, Kowase T, Motomura K, Haruna H, Nakamura M, Ohishi A, Adachi M, Tajima T, Hasegawa Y, Hasegawa T, Horikawa R, Fujieda K, Ogata T
J Clin Endocrinol Metab 2009 May;94(5):1723-31. Epub 2009 Mar 3 doi: 10.1210/jc.2008-2816. PMID: 19258400

Recent clinical studies

Etiology

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome.
Arts P, Garland J, Byrne AB, Hardy TSE, Babic M, Feng J, Wang P, Ha T, King-Smith SL, Schreiber AW, Crawford A, Manton N, Moore L, Barnett CP, Scott HS
Am J Med Genet A 2020 May;182(5):1273-1277. Epub 2020 Mar 6 doi: 10.1002/ajmg.a.61541. PMID: 32141698Free PMC Article
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
Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population.
Chan AO, But WM, Lee CY, Lam YY, Ng KL, Loung PY, Lam A, Cheng CW, Shek CC, Wong WS, Wong KF, Wong MY, Tse WY
Hong Kong Med J 2015 Dec;21(6):499-510. Epub 2015 Oct 16 doi: 10.12809/hkmj144402. PMID: 26492835
A study of gender outcome of Egyptian patients with 46,XY disorder of sex development.
Ismail SI, Mazen IA
Sex Dev 2010 Sep;4(4-5):285-91. Epub 2010 Jul 24 doi: 10.1159/000317120. PMID: 20664246
Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester.
Michel-Calemard L, Lesca G, Morel Y, Boggio D, Plauchu H, Attia-Sobol J
Prenat Diagn 2004 Jul;24(7):519-23. doi: 10.1002/pd.935. PMID: 15300742

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
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
Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients.
Saranya B, Bhavani G, Arumugam B, Jayashankar M, Santhiya ST
J Genet 2016 Dec;95(4):911-921. doi: 10.1007/s12041-016-0716-0. PMID: 27994190
Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic.
Berra M, Williams EL, Muroni B, Creighton SM, Honour JW, Rumsby G, Conway GS
Eur J Endocrinol 2011 Jun;164(6):1019-25. Epub 2011 Mar 14 doi: 10.1530/EJE-10-0930. PMID: 21402750
Sex-reversed phenotype in association with two novel mutations c.2494delA and c.T3004C in the ligand-binding domain of the androgen receptor gene.
Galani A, Sofocleous C, Karahaliou F, Papathanasiou A, Kitsiou-Tzeli S, Kalpini-Mavrou A
Fertil Steril 2008 Nov;90(5):2008.e1-4. Epub 2008 Mar 14 doi: 10.1016/j.fertnstert.2008.01.030. PMID: 18342859

Therapy

Gender identity reversal in an adolescent with mixed gonadal dysgenesis.
Birnbacher R, Marberger M, Weissenbacher G, Schober E, Frisch H
J Pediatr Endocrinol Metab 1999 Sep-Oct;12(5):687-90. doi: 10.1515/jpem.1999.12.5.687. PMID: 10703543
A genetic male infant with female phenotype in camptomelic syndrome: a possible relationship to exposure to oral contraceptives during pregnancy.
Kim MR, Qazi QH, Anderson VM, Valencia GB
Am J Obstet Gynecol 1995 Mar;172(3):1042-3. doi: 10.1016/0002-9378(95)90042-x. PMID: 7892846

Prognosis

Identification of a novel homozygous NR5A1 variant in a patient with a 46,XY disorders of sex development.
Kırkgöz T, Gürsoy S, Acar S, Köprülü Ö, Özkaya B, Arslan G, Nalbantoğlu Ö, Hazan F, Özkan B
J Pediatr Endocrinol Metab 2024 Jun 25;37(6):575-579. Epub 2024 Apr 23 doi: 10.1515/jpem-2023-0551. PMID: 38650427
A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female.
Ambulkar PS, Waghmare JE, Verma Shivkumar P, Narang P, Pal AK
Andrologia 2021 Jun;53(5):e14011. Epub 2021 Feb 11 doi: 10.1111/and.14011. PMID: 33570214
Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene.
Känsäkoski J, Jääskeläinen J, Jääskeläinen T, Tommiska J, Saarinen L, Lehtonen R, Hautaniemi S, Frilander MJ, Palvimo JJ, Toppari J, Raivio T
Sci Rep 2016 Sep 9;6:32819. doi: 10.1038/srep32819. PMID: 27609317Free PMC Article

Clinical prediction guides

A missense mutation (c.226C>A) in HMG box SRY gene affects nNLS function in 46,XY sex reversal female.
Ambulkar PS, Waghmare JE, Verma Shivkumar P, Narang P, Pal AK
Andrologia 2021 Jun;53(5):e14011. Epub 2021 Feb 11 doi: 10.1111/and.14011. PMID: 33570214
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
Three novel and two known androgen receptor gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients.
Saranya B, Bhavani G, Arumugam B, Jayashankar M, Santhiya ST
J Genet 2016 Dec;95(4):911-921. doi: 10.1007/s12041-016-0716-0. PMID: 27994190
Phenotypic variability in congenital lipoid adrenal hyperplasia.
Joshi R, Das D, Tamhankar P, Shaikh S
Indian Pediatr 2014 May;51(5):399-400. PMID: 24953586
A novel human sex-determining gene linked to Xp11.21-11.23.
Rajender S, Thangaraj K, Gupta NJ, Leelavathy N, Rani DS, Nambiar RG, Kalavathy V, Santhiya ST, Rajangam S, Gopinath PM, Chakravarty B, Singh L
J Clin Endocrinol Metab 2006 Oct;91(10):4028-36. Epub 2006 Jul 25 doi: 10.1210/jc.2006-0950. PMID: 16868052

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