GTS5:Turner syndrome

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-style manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Kathleen M. 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

Related Terminology

Acceptable	45,X syndrome; Ullrich-Turner syndrome
Not Recommended	45,XO 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. 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. TS 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

G-banded chromosome analysis of a PHA-stimulated peripheral blood specimen from a patient with variant Turner syndrome and a karyotype of 46,X,i(X)(q10); 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,psu idic(X)(q13.2)/45,X; 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,del(X)(p21.1)/45,X; 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,del(X)(q21.3)/45,X; Courtesy of Wisconsin Diagnostics Laboratories

In 45,X females, ovarian tissue is generally replaced with streak gonads, and most TS individuals are thus infertile. While spontaneous pregnancies have been reported in ~2-8% of TS females, it has been speculated that a normal cell line is present in the gonads of such individuals. 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. Screening for Y chromosomal material, by fluorescence in situ hybridization (FISH) or a molecular method, is recommended in such cases.

Epidemiology/Prevalence

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

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. 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. Both males and females typically have two copies of the SHOX gene, as it escapes X chromosome inactivation.
SRY	Presence of Y chromosomal material	N/A	N/A	The presence of Y chromosomal material, specifically the sex-determining region Y (SRY) gene carries a risk of developing gonadoblastoma, with reported incidences ranging from 7% to 33%. The risk is higher with the presence of the testis-specific protein Y-linked 1 (TSPY1) gene, which promotes germ cell proliferation, increasing the risk for tumor development. TSPY1 expression can synergize with other tumor-promoting factors, such as octamer-binding transcription factor 4 (OCT4), KIT proto-oncogene, receptor tyrosine kinase (c-KIT), and KIT ligand (KITLG), maintaining germ cells in a proliferative, undifferentiated state.

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

N/A

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
N/A	N/A	N/A

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 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, chromosome analysis of a skin fibroblast culture may be indicated.

Metaphase fluorescence in situ hybridization (FISH) analysis for the X chromosome centromere (green) in an individual with non-mosaic Turner syndrome and a 45,X karyotype.

Interphase fluorescence in situ hybridization (FISH) analysis for the X chromosome centromere (green) in an individual with non-mosaic Turner syndrome and a 45,X karyotype.

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. 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), TSPY1 (testis-specific protein Y-encoded), or other Y-specific markers. This technique can identify even low levels of mosaicism, which might not be detectable by conventional karyotyping or FISH. FISH can also be used to screen for SRY. When Y chromosomal material is confirmed, preventive measures, such as gonadectomy, are typically recommended to reduce the risk of malignancy. 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.

Metaphase fluorescence in situ hybridization (FISH) analysis for SRY (red) and the X chromosome centromere (green) in an individual with Turner syndrome and a 45,X/46,XY karyotype.

Interphase fluorescence in situ hybridization (FISH) analysis for SRY (red) and the X chromosome centromere (green) in an individual with Turner syndrome and a 45,X/46,XY karyotype.

Additional Information

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Notes

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THIS IS WEHRE THE OLD TEMPLATE BEGINS

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type, which is based on current knowledge within the WHO classification books and using resources such as PubMed for the latest information. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Kathleen Bone, PhD, Medical College of Wisconsin

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. 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. Both males and females typically have two copies of the SHOX gene, as it escapes X chromosome inactivation.

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

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)

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. 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. 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. 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

Put your text here

Links

Put a link here or anywhere appropriate in this page (Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update by a new author, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.  Additional global feedback or concerns are also welcome.

Prior Author(s):