Disorders of sexual development associated with sex chromosomes: an update
DOI:
https://doi.org/10.48193/revistamexicanadeurologa.v82i4.910Palabras clave:
Trastornos del desarrollo sexual (DSD),, Síndrome de Klinefelter (47,XXY), Sindrome de Turner, Genes diferencialmente expresadosResumen
Descripción: los trastornos del desarrollo sexual (DSD, disorders of sex development) son condiciones congénitas que se caracterizan por la discordancia entre la apariencia externa (masculinidad o feminidad) y la constitución cromosómica o sexo gonadal. Estas manifestaciones están relacionadas con alteraciones a nivel del desarrollo gonadal y del tracto urinario-genital e incluso del sistema reproductivo-endocrino. Dentro de las causas de estas se encuentran las genéticas, las cuales son provocadas por anomalías cromosómicas, en particular de los cromosomas sexuales, o por alteración de genes involucrados con el desarrollo embrionario de los órganos sexuales; como también, anomalías que generen la interrupción de la síntesis de hormonas específicas.
Relevancia: en el grupo de trastornos del desarrollo sexual ligado a alteraciones en el número de cromosomas se encuentran el síndrome de Klinefelter (47,XXY) (SK) y el síndrome de Turner (45,X) (ST). Reportes en la literatura mencionan que las aneuploidias de los cromosomas sexuales impactan directamente en los genes, factores transcripcionales y mecanismos epigenéticos que afectan la expresión génica.
Conclusiones: en la literatura, son escasos los estudios moleculares comparativos entre pacientes con síndrome de Turner (ST) o Klinefelter (SK), siendo estos fundamentales para comprender los procesos génicos que están relacionados con el desarrollo de las patologías de estos pacientes, y así contribuir al mejoramiento del diagnóstico, tratamiento y asesoría médica del paciente con ST ó SK, impactando directamente en la calidad de vida de estos. En este artículo se presenta una revisión bibliográfica actualizada de los trastornos del desarrollo sexual asociados a los cromosomas sexuales, específicamente del ST y SK.
Referencias
Núñez RG, Alarcón BMG. Fecundación Humana. Aspectos moleculares. Revisión Bibliográfica. MULTIMED. 2018;22(6):1260–79.
MacLaughlin DT, Donahoe PK. Sex Determination and Differentiation. N Engl J Med. 2004;350(4):367–78. doi: https://doi.org/10.1056/nejmra022784
Hutson JM, Warne GL, Grover SR. Disorders of Sex Development: An Integrated Approach to Management. Australia: Springer Science & Business Media; 2012. 311 p.
Lee PA, Houk CP, Ahmed SF, Hughes IA, International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics. 2006;118(2):e488-500. doi: https://doi.org/10.1542/peds.2006-0738
Bashamboo A, McElreavey K. Human sex-determination and disorders of sex-development (DSD). Semin Cell Dev Biol. 2015;45:77–83. doi: https://doi.org/10.1016/j.semcdb.2015.10.030
Mårild K, Størdal K, Hagman A, Ludvigsson JF. Turner Syndrome and Celiac Disease: A Case-Control Study. Pediatrics. 2016;137(2):e20152232. doi: https://doi.org/10.1542/peds.2015-2232
Albisu Y. Síndrome de Turner. XVIII Curso de formación continuada. Gipuzkoa; 2001; Sociedad Vasco-Navarra de Pediatría.
Pessia E, Makino T, Bailly-Bechet M, McLysaght A, Marais GAB. Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc Natl Acad Sci U S A. 2012;109(14):5346–51. doi: https://doi.org/10.1073/pnas.1116763109
Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031):400–4. doi: https://doi.org/10.1038/nature03479
Manotas MC, Calderón JC, López-Kleine L, Suárez-Obando F, Moreno OM, Rojas A. Identification of common differentially expressed genes in Turner (45,X) and Klinefelter (47,XXY) syndromes using bioinformatics analysis. Mol Genet Genomic Med. 2020;8(11):e1503. doi: https://doi.org/10.1002/mgg3.1503
Zhang X, Hong D, Ma S, Ward T, Ho M, Pattni R, et al. Integrated functional genomic analyses of Klinefelter and Turner syndromes reveal global network effects of altered X chromosome dosage. Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4864–73. doi: https://doi.org/10.1073/pnas.1910003117
Colorado Garzon FA, Matta Camacho NE, Sanchez A. Sex-Determination systems and their evolution: Mammals. Acta Biológica Colombiana. 2012;17(1):3–18.
Yu RN, Ito M, Saunders TL, Camper SA, Jameson JL. Role of Ahch in gonadal development and gametogenesis. Nat Genet. 1998;20(4):353–7. doi: https://doi.org/10.1038/3822
Chirinos ARC, Rodríguez CEAM. Determinación sexual primaria o sexo genético. Revisión. MedULA. 2007;16(2):55–63.
Makiyan Z. Studies of gonadal sex differentiation. Organogenesis. 2016;12(1):42–51. doi: https://doi.org/10.1080/15476278.2016.1145318
Stévant I, Nef S. Genetic Control of Gonadal Sex Determination and Development. Trends Genet. 2019;35(5):346–58. doi: https://doi.org/10.1016/j.tig.2019.02.004
Sajjad Y. Development of the genital ducts and external genitalia in the early human embryo. J Obstet Gynaecol Res. 2010;36(5):929–37. doi: https://doi.org/10.1111/j.1447-0756.2010.01272.x
Díaz-Hernández V, Merchant-Larios H. Consideraciones generales en el establecimiento del sexo en mamíferos. TIP Revista especializada en ciencias químico-biológicas. 2017;20(1):27–39.
Morel Y, Roucher F, Mallet D, Plotton I. Genetic of gonadal determination. Ann Endocrinol (Paris). 2014;75(2):32–9. doi: https://doi.org/10.1016/j.ando.2014.04.005
Binet A, Gorduza D, Kallas Chemaly A, Gay C-L, Margain L, Scalabre A, et al. Desarrollo genital normal y patológico. EMC - Urología. 2017;49(2):1–10. doi: https://doi.org/10.1016/S1761-3310(17)83675-6
Chassot AA, Gregoire EP, Magliano M, Lavery R, Chaboissier MC. Genetics of Ovarian Differentiation: Rspo1, a Major Player. SXD. 2008;2(4–5):219–27. doi: https://doi.org/10.1159/000152038
Lucas-Herald AK, Bashamboo A. Gonadal Development. Understanding Differences and Disorders of Sex Development (DSD). 2014; 27:1–16. doi: https://doi.org/10.1159/000363608
Sarkar A, Hochedlinger K. The Sox Family of Transcription Factors: Versatile Regulators of Stem and Progenitor Cell Fate. Cell Stem Cell. 2013;12(1):15–30. doi: https://doi.org/10.1016/j.stem.2012.12.007
Swain A, Zanaria E, Hacker A, Lovell-Badge R, Camerino G. Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nat Genet. 1996;12(4):404–9. doi: https://doi.org/10.1038/ng0496-404
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;89(5):315.e1-315.e19. doi: https://doi.org/10.1016/j.anpedi.2018.06.009
Eggers S, Ohnesorg T, Sinclair A. Genetic regulation of mammalian gonad development. Nat Rev Endocrinol. 2014;10(11):673–83. doi: https://doi.org/10.1038/nrendo.2014.163
Granada ML, Audí L. El laboratorio en el diagnóstico multidisciplinar del desarrollo sexual anómalo o diferente (DSD): I) Fisiología, clasificación, abordaje y metodología II) Marcadores bioquímicos y genéticos diagnósticos en los 46,XX. Advances in Laboratory Medicine / Avances en Medicina de Laboratorio. 2021;2(4):481–93. doi: https://doi.org/10.1515/almed-2020-0119
Hughes IA, Houk C, Ahmed SF, Lee PA. Consensus statement on management of intersex disorders. Archives of Disease in Childhood. 2006;91(7):554–63. doi: https://doi.org/10.1136/adc.2006.098319
Ostrer H. Disorders of sex development (DSDs): an update. J Clin Endocrinol Metab. 2014;99(5):1503–9. doi: https://doi.org/10.1210/jc.2013-3690
Fernández N, Moreno O, Rojas A, Céspedes C, Forero C, Mora L, et al. Manejo transdisciplinario de pacientes con desórdenes del desarrollo sexual en Colombia. Limitantes para un manejo oportuno e integral. Urología Colombiana. 2017;26(3):164–8. doi: https://doi.org/10.1016/j.uroco.2016.06.004
Zarante I, Franco L, López C, Fernández N. Frequencies of congenital malformations: assessment and prognosis of 52,744 births in three cities of Colombia. Biomédica. 2010;30(1):65–71. doi: https://doi.org/10.7705/biomedica.v30i1.154
Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology. 1938;23(5):566–74.
Ford CE, Jones KW, Polani PE, De Almeida JC, Briggs JH. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome). Lancet. 1959;1(7075):711–3. doi: https://doi.org/10.1016/s0140-6736(59)91893-8
Collin J. An introduction to Turner syndrome. Paediatr Nurs. 2006;18(10):38–43; quiz 44. doi: https://doi.org/10.7748/paed.18.10.38.s23
Martin RH. Meiotic errors in human oogenesis and spermatogenesis. Reprod Biomed Online. 2008 Apr;16(4):523–31. doi: https://doi.org/10.1016/s1472-6483(10)60459-2
Chuchracki M, Szczepaniak A, Sedziak A, Ziółkowska K, Opala T. [Frequency of prevalence of Turner syndrome in fetuses of patients referred to genetic amniocentesis in 2007-2011]. Przegl Lek. 2012;69(10):1011–4.
Goecke C, García H. Actualización en el manejo del Síndrome de Turner en niñas y adolescentes. Revisión de la Literatura e Incorporación de Recomendaciones de las nuevas Guías Clínicas. Rev chil endocrinol diabetes. 2018;148–55.
Bispo AVS, Dos Santos LO, Burégio-Frota P, Galdino MB, Duarte AR, Leal GF, et al. Effect of chromosome constitution variations on the expression of Turner phenotype. Genet Mol Res. 2013;12(4):4243–50. doi: https://doi.org/10.4238/2013.march.13.13
Canto P, Kofman-Alfaro S, Jiménez AL, Söderlund D, Barrón C, Reyes E, et al. Gonadoblastoma in Turner syndrome patients with nonmosaic 45,X karyotype and Y chromosome sequences. Cancer Genet Cytogenet. 2004;150(1):70–2. doi:https://doi.org/10.1016/j.cancergencyto.2003.08.011
Cabrol S, Saab C, Gourmelen M, Raux-Demay M, Le Bouc Y. Syndrome de Turner: croissance staturopondérale et maturation osseuse spontanées. Archives de Pédiatrie. 1996 Apr 1;3(4):313–8. doi: https://doi.org/10.1016/0929693X(96)84683-5
Castelo-Branco C. Management of Turner syndrome in adult life and beyond. Maturitas. 2014;79(4):471–5. doi: https://doi.org/10.1016/j.maturitas.2014.08.011
Shi L, Wu J. Epigenetic regulation in mammalian preimplantation embryo development. Reproductive Biology and Endocrinology. 2009;7(1):59. doi: https://doi.org/10.1186/1477-7827-7-59
Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet. 2001;2(1):59–67. doi: https://doi.org/10.1038/35047580
Tsuchiya KD, Willard HF. Chromosomal domains and escape from X inactivation: comparative X inactivation analysis in mouse and human. Mamm Genome. 2000;11(10):849–54. doi: https://doi.org/10.1007/s003350010175
Helena Mangs A, Morris B. The Human Pseudoautosomal Region (PAR): Origin, Function and Future. CG. 2007;8(2):129–36. doi: https://doi.org/10.2174/13892020778036814
Bondy CA. Genomic imprinting in Turner syndrome. In: International Congress Series. Elsevier; 2006. p. 21–5.
Kubota T, Wakui K, Nakamura T, Ohashi H, Watanabe Y, Yoshino M, et al. The proportion of cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females. CGR. 2002;99(1–4):276–84. doi: https://doi.org/10.1159/000071604
De La Fuente R, Hahnel A, Basrur PK, King WA. X inactive-specific transcript (Xist) expression and X chromosome inactivation in the preattachment bovine embryo. Biol Reprod. 1999 Mar;60(3):769–75. doi:https://doi.org/10.1095/biolreprod60.3.769
Bejarano Ramírez N, Redondo Calvo FJ, Galán Gómez E. Complications related to Turner syndrome. Med Clin (Barc). 2017;149(1):39–40. doi:
https://doi.org/10.1016/j.medcli.2017.02.016
Ríos Orbañanos I, Vela Desojo A, Martinez-Indart L, Grau Bolado G, Rodriguez Estevez A, Rica Echevarria I. Turner syndrome: From birth to adulthood. Endocrinol Nutr. 2015 Dec 1;62(10):499–506. doi: https://doi.org/10.1016/j.endoen.2015.11.011
Klinefelter Hf Jr, Reifenstein Ec Jr, Albright F Jr. Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion of Follicle-Stimulating Hormone1. The Journal of Clinical Endocrinology & Metabolism. 1942;2(11):615–27. doi: https://doi.org/10.1210/jcem-2-11-615
Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88(2):622–6. doi: https://doi.org/10.1210/jc.2002-021491
Thomas NS, Hassold TJ. Aberrant recombination and the origin of Klinefelter syndrome. Human Reproduction Update. 2003;9(4):309–17. doi: https://doi.org/10.1093/humupd/dmg028
Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet. 2004;364(9430):273–83. doi: https://doi.org/10.1016/s0140-6736(04)16678-6
Ottesen AM, Aksglaede L, Garn I, Tartaglia N, Tassone F, Gravholt CH, et al. Increased Number of Sex Chromosomes Affects Height in a Nonlinear Fashion: A Study of 305 Patients With Sex Chromosome Aneuploidy. Am J Med Genet A. 2010;152A(5):1206–12. doi: https://doi.org/10.1002/ajmg.a.33334
Navarro-Cobos MJ, Balaton BP, Brown CJ. Genes that escape from X-chromosome inactivation: Potential contributors to Klinefelter syndrome. Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):226–38. doi: https://doi.org/10.1002/ajmg.c.31800
Rappold GA, Durand C, Decker E, Marchini A, Schneider KU. New roles of SHOX as regulator of target genes. Pediatr Endocrinol Rev. 2012;9 Suppl 2:733–8.
Aszpis S, Gottlieb S, Knoblovits P, Pacenza N, Pasqualini T, Rey R, et al. Síndrome de Klinefelter: Viejos y nuevos conceptos. Rev Argent Endocrinol Metab. 2006;43(1):22–39.
Radicioni AF, Ferlin A, Balercia G, Pasquali D, Vignozzi L, Maggi M, et al. Consensus statement on diagnosis and clinical management of Klinefelter syndrome. Journal of endocrinological investigation. 2010;33(11):839–50. doi: https://doi.org/10.1007/bf03350351
Giltay JC, Maiburg MC. Klinefelter syndrome: clinical and molecular aspects. Expert Rev Mol Diagn. 2010;10(6):765–76. doi: https://doi.org/10.1586/erm.10.63
Sawalha AH, Harley JB, Scofield RH. Autoimmunity and Klinefelter’s syndrome: When men have two X chromosomes. Journal of Autoimmunity. 2009;33(1):31–4. doi: https://doi.org/10.1016/j.jaut.2009.03.006
Nielsen J. Diabetes mellitus in patients with aneuploid chromosome aberrations and in their parents. Humangenetik. 1972;16(1):165–70. doi:
https://doi.org/10.1007/bf00394004
Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA, UK Clinical Cytogenetics Group. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005 Aug 17;97(16):1204–10. doi:
https://doi.org/10.1093/jnci/dji240
Hasle H, Mellemgaard A, Nielsen J, Hansen J. Cancer incidence in men with Klinefelter syndrome. Br J Cancer. 1995;71(2):416–20. doi:
https://doi.org/10.1038/bjc.1995.85
Arai N, Homma M, Abe M, Baba Y, Murai S, Watanuki M, et al. Impact of CD123 expression, analyzed by immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia. Int J Hematol. 2019;109(5):539–44. doi:
https://doi.org/10.1007/s12185-019-02616-y
Potter N, Jones L, Blair H, Strehl S, Harrison CJ, Greaves M, et al. Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia. Leukemia. 2019 Apr;33(4):893–904. doi: https://doi.org/10.1038/s41375-018-0297-4
Messina MF, Sgrò DL, Aversa T, Pecoraro M, Valenzise M, De Luca F. A characteristic cognitive and behavioral pattern as a clue to suspect Klinefelter syndrome in prepubertal age. J Am Board Fam Med. 2012;25(5):745–9. doi: https://doi.org/10.3122/jabfm.2012.05.110232
Ross JL, Roeltgen DP, Kushner H, Zinn AR, Reiss A, Bardsley MZ, et al. Behavioral and social phenotypes in boys with 47, XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics. 2012;129(4):769–78. doi: https://doi.org/10.1542/peds.2011-0719
Vawter MP, Harvey PD, DeLisi LE. Dysregulation of X-linked gene expression in Klinefelter’s syndrome and association with verbal cognition. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2007;144B(6):728–34. doi: https://doi.org/10.1002/ajmg.b.30454
Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. The Lancet Neurology. 2014;13(3):306–18. doi: https://doi.org/10.1016/s1474-4422(13)70302-8
Viana J, Pidsley R, Troakes C, Spiers H, Wong CC, Al-Sarraj S, et al. Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain. Epigenetics. 2014 Apr;9(4):587–99. doi: https://doi.org/10.4161/epi.27806
Pohl E, Muschal S, Kliesch S, Zitzmann M, Rohayem J, Gromoll J, et al. Molecular Aging Markers in Patients with Klinefelter Syndrome. Aging Dis. 2019;11(3):470–6. doi: https://doi.org/10.14336/ad.2019.0801
Mondal S, Bhattacharjee R, Chowdhury S, Mukhopadhyay S. Heterogeneity of Karyotypes in Turner Syndrome. Indian J Pediatr. 2021;88(2):175–175. doi:
https://doi.org/10.1007/s12098-020-03410-z
El-Mansoury M, Barrenäs M-L, Bryman I, Hanson C, Larsson C, Wilhelmsen L, et al. Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in Turner syndrome. Clin Endocrinol (Oxf). 2007;66(5):744–51. doi:
https://doi.org/10.1111/j.1365-2265.2007.02807.x
Álvarez-Nava F, Lanes R. Epigenetics in Turner syndrome. Clinical Epigenetics. 2018;10(1):45. doi: https://doi.org/10.1186/s13148-018-0477-0
Snijders Blok L, Madsen E, Juusola J, Gilissen C, Baralle D, Reijnders MRF, et al. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. The American Journal of Human Genetics. 2015;97(2):343–52. doi: https://doi.org/10.1016/j.ajhg.2015.07.004
Sharma D, Jankowsky E. The Ded1/DDX3 subfamily of DEAD-box RNA helicases. Critical Reviews in Biochemistry and Molecular Biology. 2014;49(4):343–60. doi: https://doi.org/10.3109/10409238.2014.931339
Dunford A, Weinstock DM, Savova V, Schumacher SE, Cleary JP, Yoda A, et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet. 2017;49(1):10–6. doi: https://doi.org/10.1038/ng.3726
Gibbons R. Alpha thalassaemia-mental retardation, X linked. Orphanet Journal of Rare Diseases. 2006 May 4;1(1):15. doi: https://doi.org/10.1186/1750-1172-1-15
Zitzmann M, Bongers R, Werler S, Bogdanova N, Wistuba J, Kliesch S, et al. Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome. J Clin Endocrinol Metab. 2015;100(3):E518-523. doi: https://doi.org/10.1210/jc.2014-2780
Viuff M, Skakkebaek A, Nielsen MM, Chang S, Gravholt CH. Epigenetics and genomics in Turner syndrome. Am J Med Genet C Semin Med Genet. 2019;181(1):68–75. doi: https://doi.org/10.1002/ajmg.c.31683
Chen D, Camponeschi A, Wu Q, Gerasimcik N, Li H, Shen X, et al. CD99 expression is strongly associated with clinical outcome in children with B-cell precursor acute lymphoblastic leukaemia. British Journal of Haematology. 2019;184(3):418–23. doi: https://doi.org/10.1111/bjh.15683
Perrault I, Hamdan FF, Rio M, Capo-Chichi J-M, Boddaert N, Décarie J-C, et al. Mutations in DOCK7 in Individuals with Epileptic Encephalopathy and Cortical Blindness. The American Journal of Human Genetics. 2014;94(6):891–7. doi: https://doi.org/10.1016/j.ajhg.2014.04.012
Panula S, Kurek M, Kumar P, Albalushi H, Padrell Sánchez S, Damdimopoulou P, et al. Human induced pluripotent stem cells from two azoospermic patients with Klinefelter syndrome show similar X chromosome inactivation behavior to female pluripotent stem cells. Human Reproduction. 2019;34(11):2297–310. doi: https://doi.org/10.1093/humrep/dez134
