GTS5:Turner syndrome

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Primary Author(s)*

Kathleen Bone, PhD, Medical College of Wisconsin

WHO Classification of Disease

Structure Disease
Book Genetic Tumor Syndromes (5th ed.)
Category DNA repair and genomic instability
Family Chromosomal and non-dysjunction (aneuploidy) syndromes
Type N/A
Subtype(s) Turner Syndrome

Definition / Description of Disease

Turner Syndrome (TS) is a rare chromosomal disorder resulting from complete or partial loss of the second sex chromosome. The most common clinical manifestations include short stature, ovarian failure, primary or secondary amenorrhea associated with hypergonadotropic hypogonadism, congenital lymphedema of the hands and feet, Madelung deformity of the forearm and wrist, webbed neck, cardiac anomalies such as coarctation of the aorta, bicuspid aortic valves, mitral valve prolapse, hypertension, ischemic heart disease and arteriosclerosis, impaired glucose tolerance, thyroid disease and hearing loss.[1][2][3][4][5][6] Despite considerable phenotypic variability, short stature and gonadal dysgenesis are the most consistent findings. While individuals with TS may experience impairments in nonverbal developmental skills, they generally have normal intellectual ability.[7] Turner syndrome should be suspected prenatally when a prenatal ultrasound reveals fetal hydrops, cystic hygroma, or cardiac defects. Approximately 50% of TS patients have monosomy X (45,X), while the remaining 50% exhibit various structural abnormalities of the X chromosome or mosaicism with a normal female or normal male cell line.

G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with Turner Syndrome and a 45,X karyotype; Courtesy of Wisconsin Diagnostics Laboratories


G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with variant Turner syndrome and a karyotype of 46,X,r(X)(p21q22)/45,X; Courtesy of Wisconsin Diagnostics Laboratories


In individuals with mosaic TS and Y chromosomal material, external genitalia may vary from normal male to ambiguous to female with TS characteristics. The Y chromosome, if present, may also be structurally abnormal. A patient with TS showing evidence of virilization is more likely to be mosaic for a Y-containing cell line, which increases the risk for gonadoblastoma.[1][8] Molecular screening for Y chromosomal material is recommended in such cases.

Synonyms / Terminology

45,X Syndrome, Monosomy X, Variant Turner Syndrome, Mosaic Turner Syndrome, Congenital Ovarian Hypoplasia Syndrome (historical), Ullrich-Turner Syndrome (historical), Bonnevie-Ullrich syndrome (historical), 45,XO (historical, not recommended)

Epidemiology / Prevalence

TS and its variants occur in approximately 1 in 2000 to 1 in 2500 live-born females.[9][10] However, TS is among the most common chromosomal disorders, affecting 1–2% of conceptions, with approximately 99% of affected pregnancies resulting in pregnancy loss.[11] The true prevalence of TS is difficult to ascertain, as many individuals remain undiagnosed or are only diagnosed later in adulthood.[12]

Genetic Abnormalities: Germline

Gene Genetic Variant or Variant Type Molecular Pathogenesis Inheritance, Penetrance, Expressivity Notes
SHOX Whole or partial X chromosome loss encompassing gene Haploinsufficiency De novo, complete penetrance, complete expressivity The short stature homeobox (SHOX) gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) on the short arms of the X (Xp22.3) and Y (Yp11.3) chromosomes.[13] It plays a crucial role in skeletal development, particularly in the growth plates of bones, where it regulates the proliferation and differentiation of chondrocytes, the cells responsible for cartilage formation. SHOX is vital for normal bone growth and stature, and pathogenic variants or deletions in this gene are associated with TS and other syndromes, including Leri-Weill dyschondrosteosis, and idiopathic short stature.[14] Both males and females typically have two copies of the SHOX gene, as it escapes X chromosome inactivation.[14][15]

Genetic Abnormalities: Somatic

N/A

Gene Genetic Variant or Variant Type Molecular Pathogenesis Inheritance, Penetrance, Expressivity Notes
N/A N/A N/A N/A N/A

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations EXAMPLE: Histone modification, chromatin remodeling EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

TS can be diagnosed prenatally through chorionic villus sampling (CVS) or amniocentesis, followed by G-banded chromosome analysis or karyotyping. Postnatal confirmation requires chromosome analysis of a phytohemagglutinin (PHA)-stimulated peripheral blood (PB) specimen. In cases of mosaicism, the karyotype may appear normal, so additional diagnostic methods may be necessary.

If TS is strongly suspected, a fluorescence in situ hybridization (FISH) study using an X chromosome centromere probe may be performed alongside karyotyping. Furthermore, if clinical suspicion remains high despite normal results from chromosome analysis and FISH, a chromosome analysis of a skin fibroblast culture may be indicated.

In patients with TS who exhibit signs of virilization, the presence of Y chromosomal material is a significant concern, as it increases the risk for the development of gonadoblastoma, a type of germ cell tumor.[8] To detect Y chromosomal material, polymerase chain reaction (PCR) is a sensitive and specific molecular method used for screening. PCR involves amplifying DNA sequences specific to the Y chromosome, such as SRY (sex-determining region Y), TSPY (testis-specific protein Y-encoded), or other Y-specific markers.[16] This technique can identify even low levels of mosaicism, which might not be detectable by conventional karyotyping or FISH. When Y chromosomal material is confirmed, preventive measures, such as gonadectomy, are typically recommended to reduce the risk of malignancy.[8] PCR is particularly valuable in cases where clinical findings and standard cytogenetic testing are inconclusive but there is strong clinical suspicion of Y chromosomal mosaicism. This molecular approach complements cytogenetic methods, providing a comprehensive evaluation for patients with TS and virilization.

Additional Information

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References

  1. ↑ 1.0 1.1 Gravholt, Claus H. (2005-11). "Clinical practice in Turner syndrome". Nature Clinical Practice. Endocrinology & Metabolism. 1 (1): 41–52. doi:10.1038/ncpendmet0024. ISSN 1745-8366. PMID 16929365. Check date values in: |date= (help)
  2. ↑ Bondy, Carolyn A.; et al. (2006-07). "Investigation of cardiac status and bone mineral density in Turner syndrome". Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society. 16 Suppl A: S103–108. doi:10.1016/j.ghir.2006.03.008. ISSN 1096-6374. PMID 16624607. Check date values in: |date= (help)
  3. ↑ Dhooge, Ingeborg J. M.; et al. (2005-03). "Otologic disease in turner syndrome". Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 26 (2): 145–150. doi:10.1097/00129492-200503000-00003. ISSN 1531-7129. PMID 15793396. Check date values in: |date= (help)
  4. ↑ Güngör, N.; et al. (2000-10). "High frequency hearing loss in Ullrich-Turner syndrome". European Journal of Pediatrics. 159 (10): 740–744. doi:10.1007/pl00008338. ISSN 0340-6199. PMID 11039128. Check date values in: |date= (help)
  5. ↑ Zinn, A. R.; et al. (1998-12). "Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1". American Journal of Human Genetics. 63 (6): 1757–1766. doi:10.1086/302152. ISSN 0002-9297. PMC 1377648. PMID 9837829. Check date values in: |date= (help)
  6. ↑ Sävendahl, L.; et al. (2000-10). "Delayed diagnoses of Turner's syndrome: proposed guidelines for change". The Journal of Pediatrics. 137 (4): 455–459. doi:10.1067/mpd.2000.107390. ISSN 0022-3476. PMID 11035820. Check date values in: |date= (help)
  7. ↑ Kesler, Shelli R. (2007-07). "Turner syndrome". Child and Adolescent Psychiatric Clinics of North America. 16 (3): 709–722. doi:10.1016/j.chc.2007.02.004. ISSN 1056-4993. PMC 2023872. PMID 17562588. Check date values in: |date= (help)
  8. ↑ 8.0 8.1 8.2 Gravholt, Claus H.; et al. (2024-06-05). "Clinical practice guidelines for the care of girls and women with Turner syndrome". European Journal of Endocrinology. 190 (6): G53–G151. doi:10.1093/ejendo/lvae050. ISSN 1479-683X. PMID 38748847 Check |pmid= value (help).
  9. ↑ Cui, Xiaoxiao; et al. (2018-11). "A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment". Intractable & Rare Diseases Research. 7 (4): 223–228. doi:10.5582/irdr.2017.01056. ISSN 2186-3644. PMC 6290843. PMID 30560013. Check date values in: |date= (help)
  10. ↑ Nielsen, J.; et al. (1991-05). "Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark". Human Genetics. 87 (1): 81–83. doi:10.1007/BF01213097. ISSN 0340-6717. PMID 2037286. Check date values in: |date= (help)
  11. ↑ Urbach, Achia; et al. (2009). "Studying early lethality of 45,XO (Turner's syndrome) embryos using human embryonic stem cells". PloS One. 4 (1): e4175. doi:10.1371/journal.pone.0004175. ISSN 1932-6203. PMC 2613558. PMID 19137066.
  12. ↑ Gunther, Daniel F.; et al. (2004-09). "Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life". Pediatrics. 114 (3): 640–644. doi:10.1542/peds.2003-1122-L. ISSN 1098-4275. PMID 15342833. Check date values in: |date= (help)
  13. ↑ Rao, E.; et al. (1997-05). "Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome". Nature Genetics. 16 (1): 54–63. doi:10.1038/ng0597-54. ISSN 1061-4036. PMID 9140395. Check date values in: |date= (help)
  14. ↑ 14.0 14.1 Binder, Gerhard (2011-02). "Short stature due to SHOX deficiency: genotype, phenotype, and therapy". Hormone Research in Paediatrics. 75 (2): 81–89. doi:10.1159/000324105. ISSN 1663-2826. PMID 21325865. Check date values in: |date= (help)
  15. ↑ Berletch, Joel B.; et al. (2011-08). "Genes that escape from X inactivation". Human Genetics. 130 (2): 237–245. doi:10.1007/s00439-011-1011-z. ISSN 1432-1203. PMC 3136209. PMID 21614513. Check date values in: |date= (help)
  16. ↑ Mendes, J. R.; et al. (1999-01). "Y-chromosome identification by PCR and gonadal histopathology in Turner's syndrome without overt Y-mosaicism". Clinical Endocrinology. 50 (1): 19–26. doi:10.1046/j.1365-2265.1999.00607.x. ISSN 0300-0664. PMID 10341852. Check date values in: |date= (help)

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