Clinical characteristics, cytogenetic and molecular findings in patients with disorders of sex development

Abstract

The clinical characteristics of patients with disorders of sex development (DSD), and the diagnostic values of classic cytogenetic and molecular genetic assays for DSD were investigated. In the enrolled 56 cases, there were 9 cases of 46,XY DSD, 6 cases of Turner syndrome (TS), one case of Super female syndrome, 25 cases of Klinefelter syndrome, 14 cases of 46,XX DSD, and one case of autosomal balanced rearrangements with hypospadias. The diagnosis of sex was made through physical examination, cytogenetic assay, ultrasonography, gonadal biopsy and hormonal analysis. PCR was used to detect SRY, ZFX, ZFY, DYZ3 and DYZ1 loci on Y and X chromosomes respectively. The DSD patients with the same category had similar clinical characteristics. The karyotypes in peripheral blood lymphocytes of all patients were identified. PCR-based analysis showed presence or absence of the X/Y-linked loci in several cases. Of the 9 cases of 46,XY DSD, 6 were positive for SRY, 9 for ZFX/ZFY, 9 for DYZ3 and 8 for DYZ1 loci. Of the 6 cases of TS, only 1 case with the karyotype of 45,X,/46,XX/46,XY was positive for all 5 loci. Of the 25 cases of Klinefelter syndrome, all were positive for all 5 loci. In one case of rare Klinefelter syndrome variants azoospermia factor (AZF) gene detection revealed the loss of the AZFa+AZFb region. In 14 cases of 46,XX DSD, 7 cases were positive for SRY, 14 for ZFX, 7 for ZFY, 7 for ZYZ3, and 5 for DYZ1. PCR can complement and also confirm cytogenetic studies in the diagnosis of sex in cases of DSD.

Keywords

disorders of sex development / Turner syndrome / Klinefelter syndrome / SRY / azoospermia factor

References

[1] JacobsPA, RossA. Structural abnormalities of the Y chromosome in man. Nature, 1966, 210(5034): 352-354

[2] DavisRM. Localization of male-determining factors in man: A thorough review of structural anomalies of the Y chromosome. J Med Genet, 1981, 18(3): 161-195

[3] SinclairAH, BertaP, PalmerMS, et al.. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature, 1990, 346(6281): 240-244

[4] TianL, ZhangJW, ShenCX, et al.. Cytogenetics and Y chromosome AZF microdeletions in infertile patients with mosaic karyotype Klinefelter syndrome. Zhonghua Nan Ke Xue (Chinese), 2012, 18(6): 545-550

[5] BartholdJS. Disorders of sex differentiation: a pediatric urologist’s perspective of new terminology and recommendations. J Urol, 2011, 185(2): 393-400

[6] AaronsonIA. Terminology for disorders of sex development: clarity or confusion. J Urol, 2011, 185(2): 388-389

[7] NishiMY, CostaEM, OliveiraSB, et al.. The role of SRY mutations in the etiology of gonadal dysgenesis in patients with 45,X/46,XY disorder of sex development and variants. Horm Res Paediatr, 2011, 75(1): 26-31

[8] WijchersPJ, YandimC, PanousopoulouE, et al.. Sexual dimorphism in mammalian autosomal gene regulation is determined not only by SRY but by sex chromosome complement as well. Dev Cell, 2010, 19(3): 477-484

[9] SiklarZ, BerberogluM, AdiyamanP, et al.. Disorders of gonadal development: a broad clinical, cytogenetic and histopathologic spectrum. Pediatr Endocrinol Rev, 2007, 4(3): 210-217

[10] OliveiraRM, VerreschiIT, LipayMV, et al.. Y chromosome in Turner syndrome: review of the literature. Sao Paulo Med J, 2009, 127(6): 373-378

[11] KhandelwalA, AgarwalA, JilohaRC. A 47,XXY female with gender identity disorder. Arch Sex Behav, 2010, 39(5): 1021-1023

[12] TilfordCA, Kuroda-KawaguchiT, SkaletskyH, et al.. A physical map of the human Y chromosome. Nature, 2001, 409(6822): 943-945

[13] CoolsM, PleskacovaJ, StoopH, et al.. Gonadal pathology and tumor risk in relation to clinical characteristics in patients with 45,X/46, XY mosaicism. J Clin Endocrinol Metab, 2011, 96(7): E1171-1180

[14] LauYF, LiY, KidoT. Gonadoblastoma locus and the TSPY gene on the human Y chromosome. Birth Defects Res C Embryo Today, 2009, 87(1): 114-122

[15] HersmusR, de LeeuwBH, WolffenbuttelKP, et al.. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD). Mol Cell Endocrinol, 2008, 291(1–2): 1-10

[16] BashambooA, RahmanMM, PrasadA, et al.. Fate of SRY, PABY, DYS1, DYZ3 and DYZ1 loci in Indian patients harbouring sex chromosomal anomalies. Mol Hum Reprod, 2004, 11(2): 117-127

[17] YorifugiT, MuroiJ, KawaiM, et al.. PCR-based detection of mosaicism in Turner syndrome patients. Hum Genet, 1997, 99(1): 62-65

[18] ShahidM, DhillonVS, KhalilHS, et al.. A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient. BMC Med Genet, 2010, 11(19): 131

[19] CoolsM, BoterM, van GurpR, et al.. Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads. Clin Endocrinol (Oxf), 2007, 67(2): 184-192

[20] BojesenA, JuulS, GravholtCH. Prenatal and postnatal prevalence of Klinefelter syndrome: a National Registry Study. J Clin Endocrinol Metab, 2003, 88(2): 622-626

[21] LanfrancoF, KamischkeA, ZitzmannM, et al.. Klinefelter’s syndrome. Lancet, 2004, 364(9430): 273-283

[22] NieschlagE, BehreHM, WieackerP, et al.. NieschlagE, BehreHM, NieschlagS, et al.. Störungen im Bereich der Testes. Andrologie: Grundlagen und Klinik der reproduktiven Gesundheit des Mannes, 20093rd editionHeidelberg, Springer, 199-244

[23] TüttelmannF, GromollJ. Novel genetic aspects of Klinefelter’s syndrome. Mol Hum Reprod, 2010, 16(6): 386-395

[24] MaiburgM, ReppingS, GiltayJ. The genetic origin of Klinefelter syndrome and its effect on spermatogenesis. Fertil Steril, 2012, 98(2): 253-260

[25] DamianD, PauloS. Disorder of sexual development: Still a big challenge. J Pediatr Endocrinol Metab, 2007, 20(7): 749-750