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46,XX sex reversal 1(SRXX1)

MedGen UID:
411324
Concept ID:
C2748895
Congenital Abnormality; Disease or Syndrome
Synonyms: 46,XX SEX REVERSAL, SRY-POSITIVE; SRY-positive 46,XX testicular disorder of sex development
SNOMED CT: Ovotesticular disorder of sex development (1234907000)
 
Gene (location): SRY (Yp11.2)
 
Monarch Initiative: MONDO:0100250
OMIM®: 400045

Disease characteristics

Nonsyndromic 46,XX testicular disorders/differences of sex development (DSD) are characterized by: the presence of a 46,XX karyotype; external genitalia ranging from typical male to ambiguous; two testicles; azoospermia; absence of müllerian structures; and absence of other syndromic features, such as congenital anomalies outside of the genitourinary system, learning disorders / cognitive impairment, or behavioral issues. Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia. Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency. [from GeneReviews]
Authors:
Emmanuèle C Délot  |  Eric J Vilain   view full author information

Additional description

From OMIM
A disorder of sex development (DSD) is a 'congenital condition in which development of chromosomal, gonadal, or anatomic sex is atypical.' 46,XX DSD is a disorder of gonadal (ovarian) development, which may be complete or partial (Lee et al., 2006). Sex-reversed 46,XX individuals can present as phenotypically normal males, as men with genital ambiguities, or as true hermaphrodites (Ahmad et al., 2012). 46,XX male sex reversal is a condition in which a phenotypically normal male has a female genotype. A 'true hermaphrodite' must have both mature ovarian and mature testicular tissue with histologic evidence of follicles and tubules, respectively (van Niekerk and Retief, 1981). It is a genetically heterogeneous condition. Genetic Heterogeneity of 46,XX Sex Reversal Another form of 46,XX sex reversal (SRXX2; 278850) is caused by duplication or triplication in a regulatory region upstream of the SOX9 gene (608160) on chromosome 17q24. SRXX3 (300833) is caused by duplications or deletions in the SOX3 (313430) regulatory region on chromosome Xq26. SRXX4 (617480) is caused by mutation in the NR5A1 gene (184757) on chromosome 9q33. SRXX5 (618901) is caused by mutation in the NR2F2 gene (107773) on chromosome 15q26.  http://www.omim.org/entry/400045

Clinical features

From HPO
Azoospermia
MedGen UID:
2150
Concept ID:
C0004509
Disease or Syndrome
Absence of any measurable level of sperm,whereby spermatozoa cannot be observed even after centrifugation of the semen pellet.
Clitoral hypertrophy
MedGen UID:
57848
Concept ID:
C0156394
Finding
Hypertrophy of the clitoris.
True hermaphroditism
MedGen UID:
78595
Concept ID:
C0266361
Disease or Syndrome
The presence of both ovarian and testicular tissues either in the same or in opposite gonads. Affected persons have ambiguous genitalia and may have 46,XX or 46,XY karyotypes or 46,XX/XY mosaicism.
Bicornuate uterus
MedGen UID:
78599
Concept ID:
C0266387
Congenital Abnormality
The presence of a bicornuate uterus.
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.
Sex reversal
MedGen UID:
868596
Concept ID:
C4022995
Finding
Development of the reproductive system is inconsistent with the chromosomal sex.
Ovotestis
MedGen UID:
1634511
Concept ID:
C4551490
Congenital Abnormality
A gonad that contains both ovarian follicles and testicular tubular elements.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Elevated circulating follicle stimulating hormone level
MedGen UID:
867192
Concept ID:
C4021550
Finding
An elevated concentration of follicle-stimulating hormone in the blood.
Elevated circulating luteinizing hormone level
MedGen UID:
868698
Concept ID:
C4023101
Finding
An elevated concentration of luteinizing hormone in the blood.
Gynecomastia
MedGen UID:
6694
Concept ID:
C0018418
Disease or Syndrome
Abnormal development of large mammary glands in males resulting in breast enlargement.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for 46,XX sex reversal 1 in Orphanet.

Professional guidelines

PubMed

Syryn H, Van De Vijver K, Cools M
Horm Res Paediatr 2023;96(2):180-189. Epub 2021 Sep 1 doi: 10.1159/000519323. PMID: 34469891
Kremen J, Chan YM
Curr Opin Endocrinol Diabetes Obes 2019 Feb;26(1):54-59. doi: 10.1097/MED.0000000000000452. PMID: 30507699
Moshiri M, Chapman T, Fechner PY, Dubinsky TJ, Shnorhavorian M, Osman S, Bhargava P, Katz DS
Radiographics 2012 Oct;32(6):1599-618. doi: 10.1148/rg.326125507. PMID: 23065160

Recent clinical studies

Etiology

Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, White SM, Lachlan K, Ahimaz P, Sewda A, Bastarache L, Thomas-Wilson A, Stoler JM, Bramswig NC, Baptista J, Stals K, Demurger F, Cogne B, Isidor B, Bedeschi MF, Peron A, Amiel J, Zackai E, Schacht JP, Iglesias AD, Morton J, Schmetz A; Undiagnosed Diseases Network, Seidel V, Lucia S, Baskin SM, Thiffault I, Cogan JD, Gordon CT, Chung WK, Bowdin S, Bhoj E
Eur J Hum Genet 2023 Oct;31(10):1117-1124. Epub 2023 Jul 27 doi: 10.1038/s41431-023-01434-5. PMID: 37500725Free PMC Article
Costanzo M, Touzon MS, Marino R, Guercio G, Ramirez P, Mattone MC, Pérez Garrido N, Bailez MM, Vaiani E, Ciaccio M, Galluzzo Mutti ML, Belgorosky A, Berensztein E
Eur J Endocrinol 2022 Sep 1;187(3):451-462. Epub 2022 Jul 29 doi: 10.1530/EJE-22-0283. PMID: 35900314
Lambert S, Peycelon M, Samara-Boustani D, Hyon C, Dumeige L, Peuchmaur M, Fiot E, Léger J, Simon D, Paye-Jaouen A, Bouligand J, Siffroi JP, Carel JC, McElreavey K, El Ghoneimi A, Brachet C, Bouvattier C, Martinerie L
Clin Endocrinol (Oxf) 2021 Apr;94(4):667-676. Epub 2020 Dec 26 doi: 10.1111/cen.14389. PMID: 33296530
Kremen J, Chan YM, Swartz JM
Curr Opin Urol 2017 Jan;27(1):1-6. doi: 10.1097/MOU.0000000000000353. PMID: 27798415Free PMC Article
Van Batavia JP, Kolon TF
J Pediatr Urol 2016 Dec;12(6):418-425. Epub 2016 Nov 3 doi: 10.1016/j.jpurol.2016.09.015. PMID: 27856173

Diagnosis

Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, White SM, Lachlan K, Ahimaz P, Sewda A, Bastarache L, Thomas-Wilson A, Stoler JM, Bramswig NC, Baptista J, Stals K, Demurger F, Cogne B, Isidor B, Bedeschi MF, Peron A, Amiel J, Zackai E, Schacht JP, Iglesias AD, Morton J, Schmetz A; Undiagnosed Diseases Network, Seidel V, Lucia S, Baskin SM, Thiffault I, Cogan JD, Gordon CT, Chung WK, Bowdin S, Bhoj E
Eur J Hum Genet 2023 Oct;31(10):1117-1124. Epub 2023 Jul 27 doi: 10.1038/s41431-023-01434-5. PMID: 37500725Free PMC Article
Lambert S, Peycelon M, Samara-Boustani D, Hyon C, Dumeige L, Peuchmaur M, Fiot E, Léger J, Simon D, Paye-Jaouen A, Bouligand J, Siffroi JP, Carel JC, McElreavey K, El Ghoneimi A, Brachet C, Bouvattier C, Martinerie L
Clin Endocrinol (Oxf) 2021 Apr;94(4):667-676. Epub 2020 Dec 26 doi: 10.1111/cen.14389. PMID: 33296530
Josso N, Rey RA
Front Endocrinol (Lausanne) 2020;11:619. Epub 2020 Sep 8 doi: 10.3389/fendo.2020.00619. PMID: 33013698Free PMC Article
Baloch HM, Boyum R, Vietor NO, Shakir MKM, Hoang TD
Endocr Pract 2018 Feb;24(2):233. Epub 2017 Nov 16 doi: 10.4158/EP-2017-0088. PMID: 29144796
van Niekerk WA
Am J Obstet Gynecol 1978 Apr 15;130(8):862-75. doi: 10.1016/0002-9378(78)90263-6. PMID: 345819

Therapy

de Oliveira FM, Barros BA, Dos Santos AP, Campos NLV, Mazzola TN, Filho PL, Andrade LALA, Guaragna MS, de Mello MP, Guerra-Junior G, Vieira TAP, Maciel-Guerra AT
Am J Med Genet A 2023 Feb;191(2):592-598. Epub 2022 Nov 23 doi: 10.1002/ajmg.a.63051. PMID: 36416214
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Mol Med Rep 2020 Jan;21(1):97-106. Epub 2019 Nov 12 doi: 10.3892/mmr.2019.10819. PMID: 31746433Free PMC Article
Johnson EK, Finlayson C, Finney EL, Harris CJ, Tan SY, Laronda MM, Lockart BA, Chen D, Rowell EE, Cheng EY, Yerkes EB
Horm Res Paediatr 2019;92(2):84-91. Epub 2019 Sep 11 doi: 10.1159/000502644. PMID: 31509845
Acimi S, Bessahraoui M, Acimi MA, Abderrahmane N, Debbous L
Int Urol Nephrol 2019 Mar;51(3):395-399. Epub 2018 Dec 13 doi: 10.1007/s11255-018-2058-8. PMID: 30547360
Parada-Bustamante A, Ríos R, Ebensperger M, Lardone MC, Piottante A, Castro A
Fertil Steril 2010 Nov;94(6):2330.e13-6. Epub 2010 May 7 doi: 10.1016/j.fertnstert.2010.03.066. PMID: 20451191

Prognosis

Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, White SM, Lachlan K, Ahimaz P, Sewda A, Bastarache L, Thomas-Wilson A, Stoler JM, Bramswig NC, Baptista J, Stals K, Demurger F, Cogne B, Isidor B, Bedeschi MF, Peron A, Amiel J, Zackai E, Schacht JP, Iglesias AD, Morton J, Schmetz A; Undiagnosed Diseases Network, Seidel V, Lucia S, Baskin SM, Thiffault I, Cogan JD, Gordon CT, Chung WK, Bowdin S, Bhoj E
Eur J Hum Genet 2023 Oct;31(10):1117-1124. Epub 2023 Jul 27 doi: 10.1038/s41431-023-01434-5. PMID: 37500725Free PMC Article
Li Z, Liu J, Peng Y, Chen R, Ge P, Wang J
Medicine (Baltimore) 2020 Oct 2;99(40):e22530. doi: 10.1097/MD.0000000000022530. PMID: 33019456Free PMC Article
Chen CQ, Liu Z, Lu YS, Pan M, Huang H
Medicine (Baltimore) 2020 May 29;99(22):e20472. doi: 10.1097/MD.0000000000020472. PMID: 32481455
Ganie Y, Aldous C, Balakrishna Y, Wiersma R
J Pediatr Endocrinol Metab 2017 Jan 1;30(1):11-18. doi: 10.1515/jpem-2016-0152. PMID: 27754965
Hyon C, Chantot-Bastaraud S, Harbuz R, Bhouri R, Perrot N, Peycelon M, Sibony M, Rojo S, Piguel X, Bilan F, Gilbert-Dussardier B, Kitzis A, McElreavey K, Siffroi JP, Bashamboo A
Am J Med Genet A 2015 Aug;167A(8):1851-8. Epub 2015 Apr 21 doi: 10.1002/ajmg.a.37101. PMID: 25900885

Clinical prediction guides

Ganapathi M, Matsuoka LS, March M, Li D, Brokamp E, Benito-Sanz S, White SM, Lachlan K, Ahimaz P, Sewda A, Bastarache L, Thomas-Wilson A, Stoler JM, Bramswig NC, Baptista J, Stals K, Demurger F, Cogne B, Isidor B, Bedeschi MF, Peron A, Amiel J, Zackai E, Schacht JP, Iglesias AD, Morton J, Schmetz A; Undiagnosed Diseases Network, Seidel V, Lucia S, Baskin SM, Thiffault I, Cogan JD, Gordon CT, Chung WK, Bowdin S, Bhoj E
Eur J Hum Genet 2023 Oct;31(10):1117-1124. Epub 2023 Jul 27 doi: 10.1038/s41431-023-01434-5. PMID: 37500725Free PMC Article
Wei J, Liu C, Zhang M, Liu S, Fu J, Lin P
BMC Med Genomics 2022 Sep 5;15(1):188. doi: 10.1186/s12920-022-01347-0. PMID: 36064700Free PMC Article
Lambert S, Peycelon M, Samara-Boustani D, Hyon C, Dumeige L, Peuchmaur M, Fiot E, Léger J, Simon D, Paye-Jaouen A, Bouligand J, Siffroi JP, Carel JC, McElreavey K, El Ghoneimi A, Brachet C, Bouvattier C, Martinerie L
Clin Endocrinol (Oxf) 2021 Apr;94(4):667-676. Epub 2020 Dec 26 doi: 10.1111/cen.14389. PMID: 33296530
Melardi JW, Cunha DFS, Steinmetz L, Damiani D
Pediatr Endocrinol Rev 2020 Jun;17(3):243-249. doi: 10.17458/per.vol17.2020.msc.pubertyovotesticulardsd. PMID: 32741155
López-Hernández B, Méndez JP, Coral-Vázquez RM, Benítez-Granados J, Zenteno JC, Villegas-Ruiz V, Calzada-León R, Soderlund D, Canto P
Reprod Biomed Online 2018 Jul;37(1):107-112. Epub 2018 Apr 4 doi: 10.1016/j.rbmo.2018.03.017. PMID: 29673731

Recent systematic reviews

Barros BA, Guaragna MS, Fabbri-Scallet H, Palandi de Mello M, Guerra-Júnior G, Maciel-Guerra AT
Sex Dev 2022;16(4):242-251. Epub 2023 Jan 19 doi: 10.1159/000526036. PMID: 36657429
Van Batavia JP, Kolon TF
J Pediatr Urol 2016 Dec;12(6):418-425. Epub 2016 Nov 3 doi: 10.1016/j.jpurol.2016.09.015. PMID: 27856173

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