Background: In disorders of sexual differentiation, sexual development may not conform to the chromosomal structure, thus
forming different types of abnormalities. Among these abnormalities is
syndrome 46, XX DSD where most patients are female phenotype with clitoral
hypertrophy that can go to complete masculinization especially in the presence
of the SRY gene. Objective: The goal of this work is to demonstrate a
relationship between the genotype and the phenotype in five patients karyotype
46, XX with the presence of the SRY gene.Methodology: The study involves five patients referred to the laboratory under suspicion of sexual development
anomalies.The diagnosis took place
through hormonal and echography examinations, a classic cytogenetic study (Barr
chromatin and karyotype) and an amplification of the SRY gene located on the Y
chromosome. The resulting PCR products were sent for sequencing.Results: Based
on the results of clinical and paraclinical tests carried out it was found
clitoral hypertrophy, the presence of clitoris penis for some, presence of
normal penis for others.In
addition, echography revealed a lack of female internal genitalia (P2, P3), and
a presence of testicles (P3, P4, P5). Genetic analysis (chromosomal and
molecular) showed a karyotype 46, XX SRY (+) for all patients. New mutations
were found c.246 T>A, p.82 Asn82Lys and c.171
G>C, p.57 Gln57His.Conclusion: In our
study, we were able to correlate each
References
[1]
Cools, M., Nordenstrom, A., Robeva, R., Hall, J., Westerveld, P., Flück, C., et al. (2018) Caring for Individuals with a Difference of Sex Development (DSD): A Consensus Statement. Nature Reviews Endocrinology, 14, 415-429. https://doi.org/10.1038/s41574-018-0010-8
[2]
Hughes, A., Houk, C., Ahmed, S.F. and Lee, P.A. (2006) Consensus Statement on Management of Intersex Disorders. Archives of Disease in Childhood, 91, 554-563. https://doi.org/10.1136/adc.2006.098319
[3]
Rolston, A.M., Gardner, M., van Leeuwen, K., Mohnach, L., Keegan, C., Délot, E., et al. (2017) Disorders of Sex Development (DSD): Clinical Service Delivery in the United States. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175, 268-278. https://doi.org/10.1002/ajmg.c.31558
[4]
Lee, P.A., Houk, C.P., Ahmed, S.F., Hughes, I.A., International Consensus Conference on Intersex Organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology (2006) Consensus Statement on Management of Intersex Disorders. International Consensus Conference on Intersex. Pediatrics, 118, e488-e500. https://doi.org/10.1542/peds.2006-0738
[5]
Ahmad, A., Siddiqui, M.A., Goyal, A. and Wangnoo, S.K. (2012) Is 46 XX Karyotype always a Female? BMJ Case Reports, 2012, bcr2012006223. https://doi.org/10.1136/bcr-2012-006223
[6]
McElreavey, K., Rappaport, R., Vilain, E., Abbas, N., Richaud, F., Lortat-Jacob, S., et al. (1992) A Minority of 46, XX True Hermaphrodites Are Positive for the Y-DNA Sequence Including SRY. Human Genetics, 90, 121-125. https://doi.org/10.1007/BF00210754
[7]
McElreavey, K., Vilain, E., Abbas, N., Herskowitz, I. and Fellous, M. (1993) A Regulatory Cascade Hypothesis for Mammalian Sex Determination: SRY Represses a Negative Regulator of Male Development. Proceedings of the National Academy of Sciences of the United States of America, 90, 3368-3372. https://doi.org/10.1073/pnas.90.8.3368
[8]
Boucekkine, C., Toublanc, J.E., Abbas, N., Chaabouni, S., Ouahid, S., Semrouni, M., et al. (1994) Clinical and Anatomical Spectrum in XX Sex Reversed Patients. Relationship to the Presence of Y Specific DNA-Sequences. Clinical Endocrinology, 40, 733-742. https://doi.org/10.1111/j.1365-2265.1994.tb02506.x
[9]
Délot, E.C., Papp, J.C., Sandberg, D.E. and Vilain, E. (2017) Genetics of Disorders of Sex Development. Endocrinology and Metabolism Clinics of North America, 46, 519-537. https://doi.org/10.1016/j.ecl.2017.01.015
[10]
Anik, A., Catli, G., Abaci, A. and Bober, E. (2013) 46, XX Male Disorder of Sexual Development: A Case Report. Journal of Clinical Research in Pediatric Endocrinology, 5, 258-260. https://doi.org/10.4274/Jcrpe.1098
[11]
Alkhzouz, C., Bucerzan, S., Miclaus, M., Mirea, A.-M. and Miclea, D. (2021) 46, XX DSD: Developmental, Clinical and Genetic Aspects. Diagnostics, 11, Article 1379. https://doi.org/10.3390/diagnostics11081379
[12]
Sinclair, A.H., Berta, P., et al. (1990) A Gene from the Human Sex-Determining Region Encodes a Protein with Homology to a Conserved DNA-Binding Motif. Nature, 346, 240-244. https://doi.org/10.1038/346240a0
[13]
Faye, O., Azza, S., Adil, B., Doudou, D., Berthé, M.A., Ndiaye, M., et al. (2007) [Diagnostic Interest of Barr Chromatin Test in Sex Determination: About One Case of Male Pseudohermaphroditism]. Dakar Medical, 52, 204-208. (In French)
[14]
Dia, F. (2015) Contribution de la cytogénétique au diagnostic des anomalies de la différenciation sexuelle et des aneuploidies à l’hopital Aristide Le Dantec. [Mémoire de Diplome de Master en Biologie Animale, Spécialité Genetique des Populations, 238:47]. Universite Cheikh Anta Diop de Dakar, Faculte des Sciences et Techniques.
[15]
Gueye, M.V., Ndiaye, A., Diop, N., Faye, O., et al. (2014) Etude cytogénétique des anomalies chromosomiques par la chromatine de Barr et le caryotype au service d’histologie-embryologie-cytogénétique de Dakar: A propos de 100 cas. Journal de La Société de Biolocgie Clinique Du Bénin, 25, 90-95.
[16]
Faye, O., Ndiaye, A., Gueye, M.V., Dia, F., Gueye, F.D. and Sembène, M.P. (2016) Caractérisation des aneuploidies recues au Laboratoire de Cytogénétique du CHU Aristide Le Dantec: A propos de 12 cas. JAMO, 7, 6-11.
[17]
Gueye, F.D., Dia, F., Ndiaye, A., Diallo, A.D., Gueye, M.V., Diop, N., et al. (2023) Contribution of Cytogenetic and Molecular Biology in Disorders of Sex Development Diagnosis: About 55 Cases. International Journal of Genetics and Molecular Biology, 15, 1-12. https://doi.org/10.5897/IJGMB2022.0223
[18]
Settin, A., Elsobky, E., Hammad, A. and Al-Erany, A. (2008) Rapid Sex Determination Using PCR Technique Compared to Classic Cytogenetics. International Journal of Health Sciences, 2, 49-52.
[19]
Gunter, C., Paradee, W., Crawford, D.C., Meadows, K.A., Newman, J., Kunst, C.B., et al. (1998) Re-Examination of Factors Associated with Expansion of CGG Repeats Using a Single Nucleotide Polymorphism in FMR1. Human Molecular Genetics, 7, 1935-1946. https://doi.org/10.1093/hmg/7.12.1935
[20]
Erdal, M.E. and Barlas, I.O. (2000) Detection of the SRY Gene in a 46, XY Phenotypic Female by the PCR-SSCP Method. Turkish Journal of Medical Sciences, 30, 501-504.
[21]
Mohammed, F. and Tayel, S.M. (2005) Sex Identification of Normal Persons and Sex Reverse Cases from Bloodstains Using FISH and PCR. Journal of Clinical Forensic Medicine, 12, 122-127. https://doi.org/10.1016/j.jcfm.2004.08.007
[22]
Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., et al. (2010) A Method and Server for Predicting Damaging Missense Mutations. Nature Methods, 7, 248-249. https://doi.org/10.1038/nmeth0410-248
[23]
Salgado, D., Desvignes, J., Rai, G., Blanchard, A., Miltgen, M., Pinard, A., et al. (2016) UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution. Human Mutation, 37, 439-446. https://doi.org/10.1002/humu.22965
[24]
Choi, Y. and Chan, A.P. (2015) PROVEAN Web Server: A Tool to Predict the Functional Effect of Amino Acid Substitutions and Indels. Bioinformatics, 31, 2745-2747. https://doi.org/10.1093/bioinformatics/btv195
[25]
Mbacké, S.S. (2018) Apport de la recherche du gene sry dans le diagnostic des anomalies de la differenciation sexuel. Ph.D. Thesis, Université Cheikh Anta Diop de Dakar, Dakar.
[26]
Frade, F., Peycelon, M., Houang, M., Hyon, C., Siffroi, J.-P. and Audry, G. (2015) Anomalies du développement sexuel: Les erreurs à ne pas faire à la maternité. Le dossier Prise en charge des malformations en maternité, cahier 1, 4.
[27]
Ergun-Longmire, B., Vinci, G., Alonso, L., Matthew, S., Tansil, S., Lin-Su, K., et al. (2005) Clinical, Hormonal and Cytogenetic Evaluation of 46, XX Males and Review of the Literature. Journal of Pediatric Endocrinology and Metabolism, 18, 739-748. https://doi.org/10.1515/JPEM.2005.18.8.739
[28]
Roucher, F., Morel, Y., Mallet, D., Plotton, I. and Tardy, V. (2015) Physiopathologie et classification des anomalies du développement génitosexuel. Revue de médecine périnatale, 7, 137-146. https://doi.org/10.1007/s12611-015-0336-6
[29]
Gunes, S., Asci, R., Okten, G., Atac, F., Onat, O.E., Ogur, G., et al. (2013) Two Males with SRY-Positive 46, XX Testicular Disorder of Sex Development. Systems Biology in Reproductive Medicine, 59, 42-47. https://doi.org/10.3109/19396368.2012.731624
[30]
Yue, F., Zhang, H., Xi, Q., Jiang, Y., Li, L., Liu, R., et al. (2019) Molecular Cytogenetic Analysis and Genetic Counseling: A Case Report of Eight 46, XX Males and a Literature Review. Molecular Cytogenetics, 12, Article No. 44. https://doi.org/10.1186/s13039-019-0456-y
[31]
Baizri, H., Tajir, M., Aithammou, H., Aboussair, N. (2014) Diagnostic et prise en charge de le syndrome 46, XX male: A propos d’un cas. Research. https://doi.org/10.13070/rs.fr.1.1259
[32]
Scarpa, M.-G., Grazia, M.D. and Tornese, G. (2017) 46, XY Ovotesticular Disorders of Sex Development: A Therapeutic Challenge. Pediatric Reports, 9, Article 7085. https://doi.org/10.4081/pr.2017.7085
[33]
Ortenberg, J., Oddoux, C., Craver, R., McElreavey, K., Salas-Cortes, L., Guillen-Navarro, E., et al. (2002) SRY Gene Expression in the Ovotestes of XX True Hermaphrodites. The Journal of Urology, 167, 1828-1831. https://doi.org/10.1016/S0022-5347(05)65242-1
[34]
Ozdemir, M., Kavak, R.P., Yalcinkaya, I. and Guresci, K. (2019) Ovotesticular Disorder of Sex Development: An Unusual Presentation. The Journal of Clinical Imaging Science, 9, 34. https://doi.org/10.25259/JCIS_45_2019
[35]
Kyriakou, A., Lucas-Herald, A., McGowan, R. and Ahmed, F. (2015) Disorders of Sex Development: Advances in Genetic Diagnosis and Challenges in Management. Advances in Genomics and Genetics, 5, 165-177. https://doi.org/10.2147/AGG.S53226
[36]
García-Acero, M., Moreno, O., Suárez, F. and Rojas, A. (2020) Disorders of Sexual Development: Current Status and Progress in the Diagnostic Approach. Current Urology, 13, 169-178. https://doi.org/10.1159/000499274
[37]
Dierks, C., Sieme, H., Piechotta, M., Lehner, S., Merkt, J.C., Uphaus, H., et al. (2015) Elevated Testosterone Levels in a Racing Horse due to an XY Testicular Disorder of Sexual Development. Berl Munch Tierarztl Wochenschr, 128, 335-339.
[38]
Gottlieb, B. and Trifiro, M.A. (2017) Androgen Insensitivity Syndrome. GeneReviews, 23.
[39]
DiNapoli, L. and Capel, B. (2008) SRY and the Standoff in Sex Determination. Molecular Endocrinology, 22, 1-9. https://doi.org/10.1210/me.2007-0250
