Trastornos del desarrollo sexual en individuos 46,XX: una actualización

Autores/as

DOI:

https://doi.org/10.48193/revistamexicanadeurologa.v81i4.800

Palabras clave:

46,XX, trastorno del desarrollo sexual-TDS, trastornos del desarrollo gonadal (ovárico), FISH, SRY, SOX9

Resumen

Resumen

La interrupción de los procesos de determinación o diferenciación sexual por cualquier factor genético o ambiental puede resultar en un trastorno del desarrollo sexual (TDS) con discordancia entre el sexo cromosómico, gonadal y anatómico. Dicha discordancia tendrá diferentes expresiones en el fenotipo, incluidas anomalías en los genitales internos y/o genitales externos.

Material y métodos: Con la finalidad de actualizar conceptos relacionados con TDS con cariotipo 46,XX sin alteraciones numéricas o estructurales, se realizó una búsqueda de información de los últimos 10 años en los que se describen tres subcategorías: trastornos del desarrollo gonadal (ovárico), trastornos relacionados con el exceso androgénico y otras anomalías (atresia vaginal, extrofia cloacal, anomalías uterinas y adherencias labiales).

Conclusión: La gran variabilidad de las manifestaciones fenotípicas en este tipo de TDS puede crear confusión en los enfoques diagnósticos guiados por los hallazgos clínicos. Esta variabilidad de presentación, junto con la falta de conocimiento de la fisiopatología, puede contribuir a diagnósticos tardíos o no concluyentes. Por estas razones, profundizar en el conocimiento de las causas y manifestaciones clínicas redundará en el bienestar del paciente y su familia.

Referencias

Acién P, Acién M. Disorders of Sex Development: Classification, Review, and Impact on Fertility. J Clin Med. 2020 Nov 4;9(11):3555. doi: https://dx.doi.org/10.3390%2Fjcm9113555

Kousta E, Papathanasiou A, Skordis N. Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals. Hormones (Athens). 2010 Sep;9(3):218–131. doi: https://doi.org/10.14310/horm.2002.1272

Kremen J, Chan Y-M, Swartz JM. Recent findings on the genetics of disorders of sex development. Curr Opin Urol. 2017 Jan;27(1):1–6. doi: https://doi.org/10.1097/mou.0000000000000353

García-Acero M, Moreno O, Suárez F, Rojas A. Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach. Curr Urol. 2019;13(4):169–78. doi: https://doi.org/10.1159/000499274

Migeon CJ, Wisniewski AB. Human sex differentiation and its abnormalities. Best Pract Res Clin Obstet Gynaecol. 2003 Feb;17(1):1–18. doi: https://doi.org/10.1053/ybeog.2003.0354

Guerrero-Fernández J, Azcona San Julián C, Barreiro Conde J, Bermúdez de la Vega JA, Carcavilla Urquí A, Castaño González LA, et al. [Management guidelines for disorders / different sex development (DSD)]. An Pediatr (Engl Ed). 2018 Nov;89(5):315.e1-315.e19. doi: https://doi.org/10.1016/j.anpedi.2018.06.009

Barseghyan H, Délot E, Vilain E. New genomic technologies: an aid for diagnosis of disorders of sex development. Horm Metab Res. 2015 May;47(5):312–20. doi: https://doi.org/10.1055/s-0035-1548831

MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med. 2004 Jan 22;350(4):367–78. doi: https://doi.org/10.1056/nejmra022784

Sarafoglou K, Ostrer H. Clinical review 111: familial sex reversal: a review. J Clin Endocrinol Metab. 2000 Feb;85(2):483–93. doi: https://doi.org/10.1210/jcem.85.2.6418

García-Acero M, Molina M, Moreno O, Ramirez A, Forero C, Céspedes C, et al. Gene dosage of DAX-1, determining in sexual differentiation: duplication of DAX-1 in two sisters with gonadal dysgenesis. Mol Biol Rep. 2019 Jun;46(3):2971–8. doi: https://doi.org/10.1007/s11033-019-04758-y

Sekido R, Lovell-Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature. 2008 Jun 12;453(7197):930–4. doi: https://doi.org/10.1038/nature06944

Vetro A, Dehghani MR, Kraoua L, Giorda R, Beri S, Cardarelli L, et al. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3. Eur J Hum Genet. 2015 Aug;23(8):1025–32. doi: https://doi.org/10.1038/ejhg.2014.237

García-Acero M, Moreno-Niño O, Suárez-Obando F, Molina M, Manotas MC, Prieto JC, et al. Disorders of sex development: Genetic characterization of a patient cohort. Mol Med Rep. 2020 Jan;21(1):97–106. doi: https://dx.doi.org/10.3892%2Fmmr.2019.10819

Verkauskas G, Jaubert F, Lortat-Jacob S, Malan V, Thibaud E, Nihoul-Fékété C. The long-term followup of 33 cases of true hermaphroditism: a 40-year experience with conservative gonadal surgery. J Urol. 2007 Feb;177(2):726–31; discussion 731. doi: https://doi.org/10.1016/j.juro.2006.10.003

Khadilkar KS, Budyal SR, Kasaliwal R, Sathe PA, Kandalkar B, Sanghvi BV, et al. Ovotesticular Disorder of sex development: A Single-Center Experience. Endocr Pract. 2015 Jul;21(7):770–6. doi: https://doi.org/10.4158/ep15606.or

Ahmad A, Ayub F, Saleem I, Ahmad N. Initial assessment of a child with suspected disorder of sex development. J Pak Med Assoc. 2019 May;69(5):711–7.

Terribile M, Stizzo M, Manfredi C, Quattrone C, Bottone F, Giordano DR, et al. 46,XX Testicular Disorder of Sex Development (DSD): A Case Report and Systematic Review. Medicina (Kaunas). 2019 Jul 12;55(7):E371. doi: https://doi.org/10.3390/medicina55070371

Alves C, Braid Z, Coeli FB, Mello MP de. 46,XX male - testicular disorder of sexual differentiation (DSD): hormonal, molecular and cytogenetic studies. Arq Bras Endocrinol Metabol. 2010 Nov;54(8):685–9. doi: https://doi.org/10.1590/s0004-27302010000800004

Li T-F, Wu Q-Y, Zhang C, Li W-W, Zhou Q, Jiang W-J, et al. 46,XX testicular disorder of sexual development with SRY-negative caused by some unidentified mechanisms: a case report and review of the literature. BMC Urol. 2014 Dec 22;14:104. doi: https://dx.doi.org/10.1186%2F1471-2490-14-104

Grinspon RP, Rey RA. Disorders of Sex Development with Testicular Differentiation in SRY-Negative 46,XX Individuals: Clinical and Genetic Aspects. Sex Dev. 2016;10(1):1–11. doi: https://doi.org/10.1159/000445088

Lee GM, Ko JM, Shin CH, Yang SW. A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication. Ann Pediatr Endocrinol Metab. 2014 Jun;19(2):108–12. doi: https://doi.org/10.6065/apem.2014.19.2.108

Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, et al. Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature. J Pediatr Endocrinol Metab. 2005 Aug;18(8):739–48. doi: https://doi.org/10.1515/jpem.2005.18.8.739

Croft B, Ohnesorg T, Hewitt J, Bowles J, Quinn A, Tan J, et al. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nat Commun. 2018 Dec 14;9(1):5319. doi: https://doi.org/10.1038/s41467-018-07784-9

Hyon C, Chantot-Bastaraud S, Harbuz R, Bhouri R, Perrot N, Peycelon M, et al. Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD). Am J Med Genet A. 2015 Aug;167A(8):1851–8. doi: https://doi.org/10.1002/ajmg.a.37101

Kim G-J, Sock E, Buchberger A, Just W, Denzer F, Hoepffner W, et al. Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development. J Med Genet. 2015 Apr;52(4):240–7. doi: https://doi.org/10.1136/jmedgenet-2014-102864

Benko S, Gordon CT, Mallet D, Sreenivasan R, Thauvin-Robinet C, Brendehaug A, et al. Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development. J Med Genet. 2011 Dec;48(12):825–30. doi: https://doi.org/10.1136/jmedgenet-2011-100255

Xiao B, Ji X, Xing Y, Chen Y-W, Tao J. A rare case of 46, XX SRY-negative male with approximately 74-kb duplication in a region upstream of SOX9. Eur J Med Genet. 2013 Dec;56(12):695–8. doi: https://doi.org/10.1016/j.ejmg.2013.10.001

Gonen N, Futtner CR, Wood S, Garcia-Moreno SA, Salamone IM, Samson SC, et al. Sex reversal following deletion of a single distal enhancer of Sox9. Science. 2018 Jun 29;360(6396):1469–73. doi: https://doi.org/10.1126/science.aas9408

Bashamboo A, McElreavey K. Human sex-determination and disorders of sex-development (DSD). Semin Cell Dev Biol. 2015 Sep;45:77–83. doi: https://doi.org/10.1016/j.semcdb.2015.10.030

Gore AC. Neuroendocrine targets of endocrine disruptors. Hormones (Athens). 2010;9(1):16–27.

Rahier J, Guiot Y, Sempoux C. Morphologic analysis of focal and diffuse forms of congenital hyperinsulinism. Semin Pediatr Surg. 2011 Feb;20(1):3–12. doi: https://doi.org/10.1053/j.sempedsurg.2010.10.010

Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M. Perspectives in Pediatric Pathology, Chapter 5. Gonadal Dysgenesis. Pediatr Dev Pathol. 2015 Aug;18(4):259–78. doi: https://doi.org/10.2350/14-04-1471-pb.1

Baronio F, Ortolano R, Menabò S, Cassio A, Baldazzi L, Di Natale V, et al. 46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features. Int J Mol Sci. 2019 Sep 17;20(18):E4605. doi: https://doi.org/10.3390/ijms20184605

Auchus RJ, Chang AY. 46,XX DSD: the masculinised female. Best Pract Res Clin Endocrinol Metab. 2010 Apr;24(2):219–42. doi: https://doi.org/10.1016/j.beem.2009.11.001

Podgórski R, Aebisher D, Stompor M, Podgórska D, Mazur A. Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods. Acta Biochim Pol. 2018;65(1):25–33. doi: https://doi.org/10.18388/abp.2017_2343

Han TS, Walker BR, Arlt W, Ross RJ. Treatment and health outcomes in adults with congenital adrenal hyperplasia. Nat Rev Endocrinol. 2014 Feb;10(2):115–24. doi: https://doi.org/10.1038/nrendo.2013.239

Bulsari K, Falhammar H. Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Endocrine. 2017 Jan;55(1):19–36. doi: https://doi.org/10.1007/s12020-016-1189-x

Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005 Jun 18;365(9477):2125–36. doi: https://doi.org/10.1016/s0140-6736(05)66736-0

Bessiène L, Lombès M, Bouvattier C. [Differences of Sex Development (DSD): Controversies and Challenges]. Ann Endocrinol (Paris). 2018 Sep;79 Suppl 1:S22–30. doi: https://doi.org/10.1016/s0003-4266(18)31235-6

Hiort O. Long-term management of patients with disorders of sex development (DSD). Ann Endocrinol (Paris). 2014 May;75(2):64–6. doi: https://doi.org/10.1016/j.ando.2014.03.008

Bai Y, Li J, Wang X. Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review. J Ovarian Res. 2017 Mar 14;10:16. doi: https://dx.doi.org/10.1186%2Fs13048-017-0312-9

Unal E, Demiral M, Yıldırım R, Taş FF, Ceylaner S, Özbek MN. Cytochrome P450 oxidoreductase deficiency caused by a novel mutation in the POR gene in two siblings: case report and literature review. Hormones (Athens). 2021 Jun;20(2):293–8. doi: https://doi.org/10.1007/s42000-020-00249-z

Shackleton C, Marcos J, Arlt W, Hauffa BP. Prenatal diagnosis of P450 oxidoreductase deficiency (ORD): a disorder causing low pregnancy estriol, maternal and fetal virilization, and the Antley-Bixler syndrome phenotype. Am J Med Genet A. 2004 Aug 30;129A(2):105–12. doi: https://doi.org/10.1002/ajmg.a.30171

Vitellius G, Lombes M. GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome. Eur J Endocrinol. 2020 Feb 1;182(2):R15–27. doi: https://doi.org/10.1530/eje-19-0811

Huizenga NA, de Lange P, Koper JW, de Herder WW, Abs R, Kasteren JH, et al. Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene. J Clin Endocrinol Metab. 2000 May;85(5):2076–81. doi: https://doi.org/10.1210/jcem.85.5.6542

Lin L, Ercan O, Raza J, Burren CP, Creighton SM, Auchus RJ, et al. Variable phenotypes associated with aromatase (CYP19) insufficiency in humans. J Clin Endocrinol Metab. 2007 Mar;92(3):982–90. doi: https://doi.org/10.1210/jc.2006-1181

Morcel K, Camborieux L, Programme de Recherches sur les Aplasies Müllériennes, Guerrier D. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Orphanet J Rare Dis. 2007 Mar 14;2:13. doi: https://doi.org/10.1186/1750-1172-2-13

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2021-09-29

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