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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

The clinical diversity and molecular etiology in 46, XY disorders of sex development patients without uterus.
Ding L, Luo M, Deng S, Zhang D, Tian Q
Orphanet J Rare Dis 2025 Apr 17;20(1):187. doi: 10.1186/s13023-025-03719-y. PMID: 40247401Free PMC Article
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
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
Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency.
Geckinli BB, Toksoy G, Sayar C, Soylemez MA, Yesil G, Aydın H, Karaman A, Devranoglu B
Eur J Obstet Gynecol Reprod Biol 2014 Nov;182:211-5. Epub 2014 Sep 28 doi: 10.1016/j.ejogrb.2014.09.033. PMID: 25445102
Mutation analysis of subjects with 46, XX sex reversal and 46, XY gonadal dysgenesis does not support the involvement of SOX3 in testis determination.
Lim HN, Berkovitz GD, Hughes IA, Hawkins JR
Hum Genet 2000 Dec;107(6):650-2. Epub 2000 Nov 14 doi: 10.1007/s004390000428. PMID: 11153920

Diagnosis

The clinical diversity and molecular etiology in 46, XY disorders of sex development patients without uterus.
Ding L, Luo M, Deng S, Zhang D, Tian Q
Orphanet J Rare Dis 2025 Apr 17;20(1):187. doi: 10.1186/s13023-025-03719-y. PMID: 40247401Free PMC Article
Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development.
Jiang W, Yu J, Mao Y, Tang Y, Cao L, Du Q, Li J, Yang J
Mol Genet Genomic Med 2024 May;12(5):e2453. doi: 10.1002/mgg3.2453. PMID: 38769888Free PMC Article
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
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
Sex reversal following deletion of a single distal enhancer of Sox9.
Gonen N, Futtner CR, Wood S, Garcia-Moreno SA, Salamone IM, Samson SC, Sekido R, Poulat F, Maatouk DM, Lovell-Badge R
Science 2018 Jun 29;360(6396):1469-1473. Epub 2018 Jun 14 doi: 10.1126/science.aas9408. PMID: 29903884Free PMC Article

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
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
A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.
Cameron FJ, Hageman RM, Cooke-Yarborough C, Kwok C, Goodwin LL, Sillence DO, Sinclair AH
Hum Mol Genet 1996 Oct;5(10):1625-30. doi: 10.1093/hmg/5.10.1625. PMID: 8894698
Development of male gender identity/role and a sexual orientation towards women in a 46,XY subject with an incomplete form of the androgen insensitivity syndrome.
Gooren L, Cohen-Kettenis PT
Arch Sex Behav 1991 Oct;20(5):459-70. doi: 10.1007/BF01542408. PMID: 1747041

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