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46,XY sex reversal 6(SRXY6)

MedGen UID:
462414
•Concept ID:
C3151064
•
Disease or Syndrome
Synonyms: 46,XY GONADAL DYSGENESIS, PARTIAL OR COMPLETE, MAP3K1-RELATED; 46,XY SEX REVERSAL, PARTIAL OR COMPLETE, MAP3K1-RELATED
 
Gene (location): MAP3K1 (5q11.2)
 
Monarch Initiative: MONDO:0013410
OMIM®: 613762

Authors:
Lauren Mohnach  |  Patricia Y Fechner  |  Catherine E Keegan   view full author information

Clinical features

From HPO
Dysgerminoma
MedGen UID:
41680
•Concept ID:
C0013377
•
Neoplastic Process
The presence of a dysgerminoma, i.e., an undifferentiated germ cell tumor of the ovary.
See: Feature record | Search on this feature
Gonadoblastoma
MedGen UID:
104912
•Concept ID:
C0206661
•
Neoplastic Process
The presence of a gonadoblastoma, a neoplasm of a gonad that consists of aggregates of germ cells and sex cord elements.
See: Feature record | Search on this feature
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
Clitoral hypertrophy
MedGen UID:
57848
•Concept ID:
C0156394
•
Finding
Hypertrophy of the clitoris.
See: Feature record | Search on this feature
Chordee
MedGen UID:
66363
•Concept ID:
C0221182
•
Congenital Abnormality
Ventral, lateral, or ventrolateral bowing of the shaft and glans penis of more than 30 degrees.
See: Feature record | Search on this feature
Hypospadias
MedGen UID:
163083
•Concept ID:
C0848558
•
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
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
Hirsutism
MedGen UID:
42461
•Concept ID:
C0019572
•
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
See: Feature record | Search on this feature
Sparse axillary hair
MedGen UID:
348975
•Concept ID:
C1858574
•
Finding
Reduced number or density of axillary hair.
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
Idiopathic male pseudohermaphroditism: variations in presentation and management.
Meau-Petit V, Marcou V, Trivin C, Lortat-Jacob S, McElreavey K, Brauner R
J Pediatr Endocrinol Metab 2005 Jun;18(6):569-75. doi: 10.1515/jpem.2005.18.6.569. PMID: 16042324

Recent clinical studies

Etiology

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
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
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
Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype.
Paliwal P, Sharma A, Birla S, Kriplani A, Khadgawat R, Sharma A
Mol Hum Reprod 2011 Jun;17(6):372-8. Epub 2011 Jan 17 doi: 10.1093/molehr/gar002. PMID: 21242195

Diagnosis

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
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
Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype.
Paliwal P, Sharma A, Birla S, Kriplani A, Khadgawat R, Sharma A
Mol Hum Reprod 2011 Jun;17(6):372-8. Epub 2011 Jan 17 doi: 10.1093/molehr/gar002. PMID: 21242195
Campomelic dysplasia: echographic suspicion in the first trimester of pregnancy and final diagnosis of two cases.
Massardier J, Roth P, Michel-Calemard L, Rudigoz RC, Bouvier R, Dijoud F, Arnould P, Combourieu D, Gaucherand P
Fetal Diagn Ther 2008;24(4):452-7. Epub 2008 Nov 26 doi: 10.1159/000176299. PMID: 19033726
46,XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation.
Tajima T, Sasaki S, Tanaka Y, Kusunoki H, Nagashima T, Nonomura K, Fujieda K
Horm Res 2003;60(6):302-5. doi: 10.1159/000074249. PMID: 14646409

Therapy

'Idiopathic' partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?
Gaspari L, Paris F, Philibert P, Audran F, Orsini M, Servant N, Maïmoun L, Kalfa N, Sultan C
Eur J Endocrinol 2011 Oct;165(4):579-87. Epub 2011 Jul 25 doi: 10.1530/EJE-11-0580. PMID: 21788424
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
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
Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods.
Das DK, Sanghavi D, Gawde H, Idicula-Thomas S, Vasudevan L
Eur J Med Genet 2011 Nov-Dec;54(6):e529-34. Epub 2011 Jul 23 doi: 10.1016/j.ejmg.2011.04.010. PMID: 21816240

Clinical prediction guides

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
Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods.
Das DK, Sanghavi D, Gawde H, Idicula-Thomas S, Vasudevan L
Eur J Med Genet 2011 Nov-Dec;54(6):e529-34. Epub 2011 Jul 23 doi: 10.1016/j.ejmg.2011.04.010. PMID: 21816240
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
A novel mutation in the putative DNA helicase XH2 is responsible for male-to-female sex reversal associated with an atypical form of the ATR-X syndrome.
Ion A, Telvi L, Chaussain JL, Galacteros F, Valayer J, Fellous M, McElreavey K
Am J Hum Genet 1996 Jun;58(6):1185-91. PMID: 8651295Free PMC Article

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