J Pediatr Genet 2023; 12(04): 263-272
DOI: 10.1055/s-0043-1770982
Review Article

Chromosomal Abnormalities of Interest in Turner Syndrome: An Update

1   Department of Genetics, “Dr. José Eleuterio González” University Hospital of the Autonomous University of Nuevo León, Monterrey, México
1   Department of Genetics, “Dr. José Eleuterio González” University Hospital of the Autonomous University of Nuevo León, Monterrey, México
1   Department of Genetics, “Dr. José Eleuterio González” University Hospital of the Autonomous University of Nuevo León, Monterrey, México
› Author Affiliations
Funding None.


Turner syndrome (TS) is caused by the total or partial loss of the second sex chromosome; it occurs in 1 every 2,500–3,000 live births. The clinical phenotype is highly variable and includes short stature and gonadal dysgenesis. In 1959, the chromosomal origin of the syndrome was recognized; patients had 45 chromosomes with a single X chromosome. TS presents numerical and structural abnormalities in the sex chromosomes, interestingly only 40% have a 45, X karyotype. The rest of the chromosomal abnormalities include mosaics, deletions of the short and long arms of the X chromosome, rings, and isochromosomes. Despite multiple studies to establish a relationship between the clinical characteristics and the different chromosomal variants in TS, a clear association cannot yet be established. Currently, different mechanisms involved in the phenotype have been explored. This review focuses to analyze the different chromosomal abnormalities and phenotypes in TS and discusses the possible mechanisms that lead to these abnormalities.

Publication History

Received: 28 March 2022

Accepted: 01 June 2023

Article published online:
21 July 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Sybert VP, McCauley E. Turner's syndrome. N Engl J Med 2004; 351 (12) 1227-1238
  • 2 Pinsker JE. Clinical review: Turner syndrome: updating the paradigm of clinical care. J Clin Endocrinol Metab 2012; 97 (06) E994-E1003
  • 3 Wiedemann HR, Glatzl J. Follow-up of Ullrich's original patient with “Ullrich-Turner” syndrome. Am J Med Genet 1991; 41 (01) 134-136
  • 4 Turner HH. A syndrome of ınfantılısm, congenıtal webbed neck, and cubıtus valgus. Endocrinology 1938; 23 (05) 566-574
  • 5 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): 711-713
  • 6 Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006; 91 (10) 3897-3902
  • 7 Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser 1990; 26 (04) 209-223
  • 8 Hook EB, Warburton D. Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. Hum Genet 2014; 133 (04) 417-424
  • 9 Cameron-Pimblett A, La Rosa C, King TFJ, Davies MC, Conway GS. The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan. Clin Endocrinol (Oxf) 2017; 87 (05) 532-538
  • 10 Uematsu A, Yorifuji T, Muroi J. et al. Parental origin of normal X chromosomes in Turner syndrome patients with various karyotypes: implications for the mechanism leading to generation of a 45,X karyotype. Am J Med Genet 2002; 111 (02) 134-139
  • 11 Jacobs P, Dalton P, James R. et al. Turner syndrome: a cytogenetic and molecular study. Ann Hum Genet 1997; 61 (Pt 6): 471-483
  • 12 Ranke MB, Saenger P. Turner's syndrome. Lancet 2001; 358 (9278): 309-314
  • 13 Saenger P, Wikland KA, Conway GS. et al; Fifth International Symposium on Turner Syndrome. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001; 86 (07) 3061-3069
  • 14 Beals RK. Orthopedic aspects of the XO (Turner's) syndrome. Clin Orthop Relat Res 1973; (97) 19-30
  • 15 Gravholt CH, Andersen NH, Conway GS. et al; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017; 177 (03) G1-G70
  • 16 Ferguson-Smith MA. karyotype-phenotype correlations in gonadal dysgenesis and their bearing on the pathogenesis of malformations. J Med Genet 1965; 2 (02) 142-155
  • 17 Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry. Circulation 2012; 126 (18) 2220-2226
  • 18 Gravholt CH, Viuff MH, Brun S, Stochholm K, Andersen NH. Turner syndrome: mechanisms and management. Nat Rev Endocrinol 2019; 15 (10) 601-614
  • 19 Donadille B, Christin-Maitre S. Heart and Turner syndrome. Ann Endocrinol (Paris) 2021; 82 (3-4): 135-140
  • 20 Klásková E, Zapletalová J, Kaprálová S. et al. Increased prevalence of bicuspid aortic valve in Turner syndrome links with karyotype: the crucial importance of detailed cardiovascular screening. J Pediatr Endocrinol Metab 2017; 30 (03) 319-325
  • 21 Donadille B, Tuffet S, Cholet C. et al. Prevalence and progression of aortic dilatation in adult patients with Turner syndrome: a cohort study. Eur J Endocrinol 2020; 183 (04) 463-470
  • 22 Landin-Wilhelmsen K, Bryman I, Wilhelmsen L. Cardiac malformations and hypertension, but not metabolic risk factors, are common in Turner syndrome. J Clin Endocrinol Metab 2001; 86 (09) 4166-4170
  • 23 Mortensen KH, Young L, De Backer J. et al. Cardiovascular imaging in Turner syndrome: state-of-the-art practice across the lifespan. Heart 2018; 104 (22) 1823-1831
  • 24 Tanaka T, Igarashi Y, Ozono K. et al. Frequencies of spontaneous breast development and spontaneous menarche in Turner syndrome in Japan. Clin Pediatr Endocrinol 2015; 24 (04) 167-173
  • 25 Bernard V, Donadille B, Zenaty D. et al; CMERC Center for Rare Disease. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod 2016; 31 (04) 782-788
  • 26 Mohamed SOO, Elkhidir IHE, Abuzied AIH, Noureddin AAMH, Ibrahim GAA, Mahmoud AAA. Prevalence of autoimmune thyroid diseases among the Turner Syndrome patients: meta-analysis of cross sectional studies. BMC Res Notes 2018; 11 (01) 842
  • 27 Bakalov VK, Cheng C, Zhou J, Bondy CA. X-chromosome gene dosage and the risk of diabetes in Turner syndrome. J Clin Endocrinol Metab 2009; 94 (09) 3289-3296
  • 28 Gravholt CH, Naeraa RW, Nyholm B. et al. Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner's syndrome. The impact of sex hormone replacement. Diabetes Care 1998; 21 (07) 1062-1070
  • 29 Fiot E, Zénaty D, Boizeau P, Haignere J, Dos Santos S, Léger J. French Turner Syndrome Study Group. X chromosome gene dosage as a determinant of congenital malformations and of age-related comorbidity risk in patients with Turner syndrome, from childhood to early adulthood. Eur J Endocrinol 2019; 180 (06) 397-406
  • 30 Hong DS, Reiss AL. Cognitive and neurological aspects of sex chromosome aneuploidies. Lancet Neurol 2014; 13 (03) 306-318
  • 31 Wolstencroft J, Skuse D. Social skills and relationships in Turner syndrome. Curr Opin Psychiatry 2019; 32 (02) 85-91
  • 32 Graff A, Donadille B, Morel H. et al. Added value of buccal cell FISH analysis in the diagnosis and management of Turner syndrome. Hum Reprod 2020; 35 (10) 2391-2398
  • 33 Tuke MA, Ruth KS, Wood AR. et al. Mosaic Turner syndrome shows reduced penetrance in an adult population study. Genet Med 2019; 21 (04) 877-886
  • 34 Kleczkowska A, Kubien E, Fryns JP, Van den Berghe H. Turner syndrome: the Leuven experience (1965-1989) in 478 patients. I. Patient's age at the time of diagnosis in relation to chromosomal findings. Genet Couns 1990; 1 (3-4): 235-240
  • 35 Sybert VP. Phenotypic effects of mosaicism for a 47,XXX cell line in Turner syndrome. J Med Genet 2002; 39 (03) 217-220
  • 36 Blair J, Tolmie J, Hollman AS, Donaldson MDC. Phenotype, ovarian function, and growth in patients with 45,X/47,XXX Turner mosaicism: implications for prenatal counseling and estrogen therapy at puberty. J Pediatr 2001; 139 (05) 724-728
  • 37 Tauchmanovà L, Rossi R, Pulcrano M, Tarantino L, Baldi C, Lombardi G. Turner's syndrome mosaicism 45X/47XXX: an interesting natural history. J Endocrinol Invest 2001; 24 (10) 811-815
  • 38 Bouchlariotou S, Tsikouras P, Dimitraki M. et al. Turner's syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review. J Matern Fetal Neonatal Med 2011; 24 (05) 668-672
  • 39 Hamerton JL, Canning N, Ray M, Smith S. A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet 1975; 8 (04) 223-243
  • 40 Lindhardt Johansen M, Hagen CP, Rajpert-De Meyts E. et al. 45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function—a retrospective longitudinal study. J Clin Endocrinol Metab 2012; 97 (08) E1540-E1549
  • 41 El-Mansoury M, Barrenäs ML, Bryman I. et al. Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in Turner syndrome. Clin Endocrinol (Oxf) 2007; 66 (05) 744-751
  • 42 Viuff MH, Just J, Brun S. et al. Women with Turner syndrome are both estrogen and androgen deficient: the impact of hormone replacement therapy. J Clin Endocrinol Metab 2022; 107 (07) 1983-1993
  • 43 Huang YC, Lee CT, Wu MZ. et al. The spectrum of 45,X/46,XY mosaicism in Taiwanese children: the experience of a single center. J Formos Med Assoc 2019; 118 (1 Pt 3): 450-456
  • 44 Grumbach MM, Van Wyk JJ, Wilkins L. Chromosomal sex in gonadal dysgenesis (ovarian agenesis): relationship to male pseudohermaphrodism and theories of human sex differentiation. J Clin Endocrinol Metab 1955; 15 (10) 1161-1193
  • 45 Tosson H, Rose SR, Gartner LA. Description of children with 45,X/46,XY karyotype. Eur J Pediatr 2012; 171 (03) 521-529
  • 46 Cools M, Looijenga LHJ, Wolffenbuttel KP, T'Sjoen G. Managing the risk of germ cell tumourigenesis in disorders of sex development patients. Endocr Dev 2014; 27: 185-196
  • 47 de Marqui ABT, da Silva-Grecco RL, Balarin MAS. [Prevalence of Y-chromosome sequences and gonadoblastoma in Turner syndrome]. Rev Paul Pediatr 2016; 34 (01) 114-121
  • 48 Silveri M, Grossi A, Bassani F, Orazi C, Camassei FD, Zaccara A. Ullrich-Turner syndrome and tumor risk: is there another chance to early gonadectomy in positive TSPY and SRY patients?. Eur J Pediatr Surg 2016; 26 (03) 273-276
  • 49 Karila D, Donadille B, Léger J. et al. Prevalence and characteristics of gonadoblastoma in a retrospective multi-center study with follow-up investigations of 70 patients with Turner syndrome and a 45,X/46,XY karyotype. Eur J Endocrinol 2022; 187 (06) 873-881
  • 50 Lorda-Sanchez I, Binkert F, Maechler M, Schinzel A. A molecular study of X isochromosomes: parental origin, centromeric structure, and mechanisms of formation. Am J Hum Genet 1991; 49 (05) 1034-1040
  • 51 Wolff DJ, Miller AP, Van Dyke DL, Schwartz S, Willard HF. Molecular definition of breakpoints associated with human Xq isochromosomes: implications for mechanisms of formation. Am J Hum Genet 1996; 58 (01) 154-160
  • 52 James RS, Dalton P, Gustashaw K. et al. Molecular characterization of isochromosomes of Xq. Ann Hum Genet 1997; 61 (Pt 6): 485-490
  • 53 Gardner RJM, Sutherland GR, Shaffer LG. Chromosome abnormalities and genetic counseling. Clin Med (Lond) 2011; 12 (03) 297
  • 54 Sen SK, Han K, Wang J. et al. Human genomic deletions mediated by recombination between Alu elements. Am J Hum Genet 2006; 79 (01) 41-53
  • 55 Kim HM, Narayanan V, Mieczkowski PA. et al. Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J 2008; 27 (21) 2896-2906
  • 56 Bose P, Hermetz KE, Conneely KN, Rudd MK. Tandem repeats and G-rich sequences are enriched at human CNV breakpoints. PLoS One 2014; 9 (07) e101607
  • 57 Weckselblatt B, Rudd MK. Human structural variation: mechanisms of chromosome rearrangements. Trends Genet 2015; 31 (10) 587-599
  • 58 Rao E, Weiss B, Fukami M. et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997; 16 (01) 54-63
  • 59 Marchini A, Ogata T, Rappold GA. A track record on SHOX: from basic research to complex models and therapy. Endocr Rev 2016; 37 (04) 417-448
  • 60 Kosho T, Muroya K, Nagai T. et al. Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: implications for the development of Turner syndrome. J Clin Endocrinol Metab 1999; 84 (12) 4613-4621
  • 61 Ogata T, Muroya K, Matsuo N. et al. Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. J Clin Endocrinol Metab 2001; 86 (11) 5498-5508
  • 62 Adachi M, Tachibana K, Asakura Y, Muroya K, Ogata T. Del(X)(p21.1) in a mother and two daughters: genotype-phenotype correlation of Turner features. Hum Genet 2000; 106 (03) 306-310
  • 63 Ross JL, Roeltgen D, Kushner H, Wei F, Zinn AR. The Turner syndrome-associated neurocognitive phenotype maps to distal Xp. Am J Hum Genet 2000; 67 (03) 672-681
  • 64 Zinn AR, Roeltgen D, Stefanatos G. et al. A Turner syndrome neurocognitive phenotype maps to Xp22.3. Behav Brain Funct 2007; 3 (01) 24
  • 65 Mercer CL, Lachlan K, Karcanias A. et al. Detailed clinical and molecular study of 20 females with Xq deletions with special reference to menstruation and fertility. Eur J Med Genet 2013; 56 (01) 1-6
  • 66 Krauss CM, Turksoy RN, Atkins L, McLaughlin C, Brown LG, Page DC. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987; 317 (03) 125-131
  • 67 Sala C, Arrigo G, Torri G. et al. Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21. Genomics 1997; 40 (01) 123-131
  • 68 Guilherme RS, Meloni VFA, Kim CA. et al. Mechanisms of ring chromosome formation, ring instability and clinical consequences. BMC Med Genet 2011; 12: 171
  • 69 Sigurdardottir S, Goodman BK, Rutberg J, Thomas GH, Jabs EW, Geraghty MT. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of “complete ring” syndrome. Am J Med Genet 1999; 87 (05) 384-390
  • 70 Conlin LK, Kramer W, Hutchinson AL. et al. Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients. J Med Genet 2011; 48 (01) 1-9
  • 71 Vermeesch JR, Baten E, Fryns JP, Devriendt K. Ring syndrome caused by ring chromosome 7 without loss of subtelomeric sequences. Clin Genet 2002; 62 (05) 415-417
  • 72 Le Caignec C, Boceno M, Jacquemont S, Nguyen The Tich S, Rival JM, David A. Inherited ring chromosome 8 without loss of subtelomeric sequences. Ann Genet 2004; 47 (03) 289-296
  • 73 Seghezzi L, Maraschio P, Bozzola M. et al. Ring chromosome 9 with a 9p22.3-p24.3 duplication. Eur J Pediatr 1999; 158 (10) 791-793
  • 74 Knijnenburg J, van Haeringen A, Hansson KBM. et al. Ring chromosome formation as a novel escape mechanism in patients with inverted duplication and terminal deletion. Eur J Hum Genet 2007; 15 (05) 548-555
  • 75 Rossi E, Riegel M, Messa J. et al. Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation. J Med Genet 2008; 45 (03) 147-154
  • 76 Berkovitz G, Stamberg J, Plotnick LP, Lanes R. Turner syndrome patients with a ring X chromosome. Clin Genet 1983; 23 (06) 447-453
  • 77 Palmer CG, Reichmann A. Chromosomal and clinical findings in 110 females with Turner syndrome. Hum Genet 1976; 35 (01) 35-49
  • 78 Uehara S, Nata M, Obara Y, Niinuma T, Funato T, Yajima A. A Turner syndrome woman with a ring X chromosome [45,X/46,X,r(X)(p22.3q27)] whose child also had a ring X chromosome. Fertil Steril 1997; 67 (03) 576-579
  • 79 Tomkins DJ, McDonald HL, Farrell SA, Brown CJ. Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay. Eur J Hum Genet 2002; 10 (01) 44-51
  • 80 Kubota T, Wakui K, Nakamura T. 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. Cytogenet Genome Res 2002; 99 (1-4): 276-284
  • 81 Knickmeyer RC, Davenport M. Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders. J Neurodev Disord 2011; 3 (04) 293-306
  • 82 Mazzaschi RLP, Taylor J, Robertson SP, Love DR, George AM. A turner syndrome patient carrying a mosaic distal x chromosome marker. Case Rep Genet 2014; 2014: 597314
  • 83 Hochstenbach R. Department of Genetics, University Medical Centre Utrecht, et al. Mechanisms of origin and clinical effects of multiple small supernumerary marker chromosomes, each derived from a different chromosome. OBM Genet 2017; 1 (01) 002
  • 84 Makroo RN, Chowdhry M, Sharma S. Identification and characterization of marker chromosome in Turner syndrome. Apollo Med 2013; 10 (02) 171-172
  • 85 Liehr T, Claussen U, Starke H. Small supernumerary marker chromosomes (sSMC) in humans. Cytogenet Genome Res 2004; 107 (1-2): 55-67
  • 86 Baldwin EL, May LF, Justice AN, Martin CL, Ledbetter DH. Mechanisms and consequences of small supernumerary marker chromosomes: from Barbara McClintock to modern genetic-counseling issues. Am J Hum Genet 2008; 82 (02) 398-410
  • 87 Álvarez-Nava F, Lanes R. Epigenetics in Turner syndrome. Clin Epigenetics 2018; 10: 45
  • 88 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 (01) 68-75
  • 89 Corbitt H, Morris SA, Gravholt CH. et al; GenTAC Registry Investigators. TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome. PLoS Genet 2018; 14 (10) e1007692
  • 90 Trolle C, Nielsen MM, Skakkebæk A. et al. Widespread DNA hypomethylation and differential gene expression in Turner syndrome. Sci Rep 2016; 6: 34220
  • 91 Abramowitz LK, Olivier-Van Stichelen S, Hanover JA. Chromosome imbalance as a driver of sex disparity in disease. J Genomics 2014; 2: 77-88
  • 92 Lepage JF, Hong DS, Hallmayer J, Reiss AL. Genomic imprinting effects on cognitive and social abilities in prepubertal girls with Turner syndrome. J Clin Endocrinol Metab 2012; 97 (03) E460-E464
  • 93 Helena Mangs A, Morris BJ. The human pseudoautosomal region (PAR): origin, function and future. Curr Genomics 2007; 8 (02) 129-136
  • 94 Lopes AM, Burgoyne PS, Ojarikre A. et al. Transcriptional changes in response to X chromosome dosage in the mouse: implications for X inactivation and the molecular basis of Turner Syndrome. BMC Genomics 2010; 11 (01) 82
  • 95 Ashworth A, Rastan S, Lovell-Badge R, Kay G. X-chromosome inactivation may explain the difference in viability of XO humans and mice. Nature 1991; 351 (6325): 406-408
  • 96 Zhang R, Hao L, Wang L. et al. Gene expression analysis of induced pluripotent stem cells from aneuploid chromosomal syndromes. BMC Genomics 2013; 14 (Suppl 5, Suppl 5): S8
  • 97 Rajpathak SN, Deobagkar DD. Evidence for epigenetic alterations in Turner syndrome opens up feasibility of new pharmaceutical interventions. Curr Pharm Des 2014; 20 (11) 1778-1785
  • 98 Massingham LJ, Johnson KL, Scholl TM, Slonim DK, Wick HC, Bianchi DW. Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome. Hum Genet 2014; 133 (09) 1075-1082
  • 99 Zhang X, Hong D, Ma S. 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; 117 (09) 4864-4873