Turner syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Turner syndrome was first described in 1938 by Henry Turner when he noticed a triad of short stature, cubitus valgus and pterygium colli. Other scientists went to to discover the pathophysiology of the 45 XO karyotype and the presence of streaked ovaries.

There is no established system for the classification of Turner syndrome.

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Loss the paternally or maternally derived X chromosome would lead to the class 45 XO karyotype. Sometimes, an individual may have two cells lines with different genetic makeups. The percentage of this mosaicism is said to determine the severity of the phenotype in the patient. Structural abnormalities such as the formation of a ring chromosome or an isochromosome and other mechanisms such as lyonization or imprinting also play a role in the pathophysiology of Turner Syndrome.

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Females normally have two of the same sex chromosomes, written as XX. Males have an X and a Y chromosome (written as XY). In Turner syndrome, cells are missing all or part of an X chromosome. The condition only occurs in females. Most commonly, the female patient has only one X chromosome. Others may have two X chromosomes, but one of them is incomplete. Sometimes, a female has some cells with two X chromosomes, but other cells have only one.

Turner’s syndrome must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormality is Noonan’s syndrome.

The incidence rate of Turner is 1 of 2500 live births. Turner Syndrome patients have a higher mortality rate compared to the general population.

There is currently no known cause for Turner syndrome, though there are several theories surrounding the subject.

Screening for complications of Turner syndrome starts as early as a prenatal visit. Abnormal maternal serum screening tests or an ultrasound detecting structural anomalies such shortned limbs, cystic hygromas, congenital heart defects or increased swelling of the hands or feet may point towards a diagnosis of Turner syndrome. As the years progress, screening involves a multidisciplinary combination of lab investigations (such as serum gonadotrophins,liver function tests, renal function tests, etc), referral to other departments (cardiology, endocrinology, ophthalmology, etc) and tools such as DEXA scans, X-rays, echocardiography, etc.

Natural history of the patient would depend on the age of the diagnoses and what complications have developed by the time the patients presents to the physician. Congenital lymphedema may take several years to decrease. The patient experiences low self esteem due to their short stature, decreased visual spatial functioning, hyperactivity, poor facial recognition and preference for social isolation. As soon as the patient is capable of understanding, counseling regarding the risks and benefits of Turner syndrome should be explained. When compared to the general population, Turner syndrome patients have an increased mortality rate.

The diagnostic study of choice for the diagnosis of Turner syndrome is karyotype analysis of 30 blood lymphocytes. Examination of additional cells , polymerase chain reaction, fluorescent in situ hybridization, Southern blotting, restricted fragment length polymorphisms and new generation gene sequencing techniques may be employed following the interpretation of the initial karyotype.

Natural history of the patient would depend on the age of the diagnoses and what complications have developed by the time the patients presents to the physician. Congenital lymphedema may take several years to decrease. The patient experiences low self esteem due to their short stature, decreased visual spatial functioning, hyperactivity, poor facial recognition and preference for social isolation. As soon as the patient is capable of understanding, counseling regaridng the risks and benefits of Turner syndrome should be explained.

Physical examination may be suggestive of thyroid dysfunction, congenital heart defects, inflammatory bowel disease, characteristic skeletal deformities and body habitus/skin manifestations.

Laboratory investigations serve as important screening tools for thyroid dysfunction, renal dysfunction, liver dysfunction, new onset diabetes mellitus,vitamin D deficiency and ovarian reserve.

An electrocardiogram is not employed in the diagnosis of Turner syndrome.

A x-ray may be used to diagnose cardiac and skeletal abnormalities.

Prenatal ultrasounds my show a left-sided cardiac defect, renal anomalies, growth retardation, relatively short limbs, fetal edema, cystic hygroma, polyhydramnios and brachycephaly. Echocardiographies and renal ultrasounds help detect structural defects.

Simple CTs or CT angiographies are helpful in screening/detecting the following cardiac abnormalities.

Cardiac MRIs are helpful in screening/detecting the following cardiac abnormalities and functional MRIs have been used to study neural pathways responsible for poor visual spatial skills and executive function.

There are no other imaging findings associated with Turner syndrome.

The diagnostic study of choice for the diagnosis of Turner syndrome is karyotype analysis of 30 blood lymphocytes. Findings may include the classic 45 XO karyotype, mosaicism and structural anomalies like isochromosomes or ring chromosomes.

Medical therapies include growth hormone, estrogen replacement therapy, oxandrolone (if growth hormone achieves suboptimal height), vitamin D supplementation, oral hypoglycemic agents and anti-hypertensives.

Psycosocial interventions aimed at treating ][visual spatial and executive function]] deficits along with in vitro fertilization (for infertility) are the interventions commonly used in Turner syndrome.

Surgery is indicated for craniofacial anomalies, to decrease the risk of aortic dissection and for congenital pterygium colli.

There are no established measures for the primary prevention of Turner syndrome.

There are no established measures for the secondary prevention of Turner Syndrome. Secondary prevention is aimed at preventing complications of Turner syndrome. This involves frequent screening of complications.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Turner syndrome was first described in 1938 by Henry Turner when he noticed a triad of short stature, cubitus valgus and pterygium colli. Other scientists went to to discover the pathophysiology of the45 XO karyotype and the presence of streaked ovaries.

• Turner syndrome was first described by Henry Turner, an Oklahoma endocrinologist in 1938 as a patient with short stature, sexual infantilism, cubitus valgus and pterygium colli. “Turner Syndrome – StatPearls – NCBI Bookshelf”.
• Ulrich (in 1930) and Bonnevie (in 1934) described similar findings in a young girl and mouse.
• Ovarian failure and streaked gonads were noted in 1944 by Henry Silver and Kaiser who found elevated gonadotrophins in a 32 month old child. “OVARIAN AGENESIS (CONGENITAL APLASTIC OVARIES) IN CHILDREN | JAMA Pediatrics | JAMA Network”.
• C.E Ford et al first described the pathophysiology of 45 XO in 1959 at Harwell, Oxfordshire and Guy’s Hospital in London.[2] It was found in a 14-year-old girl with signs of Turner syndrome. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

There is no established system for the classification of Turner syndrome.

There is no established system for the classification of Turner syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Loss the paternally or maternally derived X chromosome would lead to the class 45 XO karyotype. Sometimes, an individual may have two cells lines with different genetic makeups. The percentage of this mosaicism is said to determine the severity of the phenotype in the patient. Structural abnormalities such as the formation of a ring chromosome or an isochromosome and other mechanisms such as lyonization or imprinting also play a role in the pathophysiology of Turner Syndrome.

• The normal karyotype of a female and male is 46 XX and 46 XY respectively.
• Loss of the Y chromosome would mean an absence of the sex determining region of Y and therefore, the absence of testis determining factor (responsible for the process that converts dihydrotestosterone to testosterone and thereby the development of male genitalia).
• Karyotype abnormalities may take place during the formation of reproductive cells (45 XO) or during cell division processes responsible for fetal development (mosaicism).
• Turner syndrome is not an inherited condition.
• Therefore the physical manifestations of Turner’s syndrome are due to aneuploidy, absence of two normal sex chromosomes or haploinsufficiency (presence of 1 set of genes in the cell instead of 2 ) of genes present in the Y chromosome.
• Distal to Xq24, small deletions of the long arm of the X-chromosome are not included in the diagnosis of TS. ^[1]
• Females with short stature and deletion of the distal region of the paternal X chromosome including the SHOX gene are generally not diagnosed with Turner syndrome.
• Similarly, individuals with deletions of Xq24, with primary or secondary amenorrhea and without short stature are diagnosed as premature ovarian failure.
• Small deletions of the long arm of the X-chromosome distal to Xq24 are not included in the diagnosis of Turner syndrome.
• A study of 67 Turner syndrome in China found 50 percent of the patients with the classic 45 X karyotype followed by the mosaic pattern, a chromosomal structural abnormality (isochromosome or ring chromosome) and a Y chromosomal structural abnormality. ^[2]

Nondisjunction

• During meiosis in either parent, a nondisjunction event can occur that leaves the gamete, either oocyte or spermatocyte, with neither X nor Y chromosome.
• When this gamete combines with a gamete from the other parent (with a normal X chromosome), the embryo lacks the normal two chromosomes.
• This leaves the embryo with 45 chromosomes and a single X chromosome, denoted 45,X (or, sometimes 45,XO, where the “O” is used as a placeholder). This is found in 50% of individuals with Turner syndrome.

Chromosomal structure

• An X chromosome can form a ring chromosome for example by losing a portion of the smaller arm, enabling the end of the long arm to wrap around. This is detrimental for the X chromosome in two ways. **Either the lost portion itself makes the chromosome less functional.
  • Or it causes nondisjunction, as described above. Thus, the causes listed here are partly overlapping.
• When such a ring chromosome combines with another ring chromosome in fertilization, the pair is denoted as 46, XrXp-, where rXp- means a ring chromosome missing the small (p) arm of the chromosome.
• Another variant of abnormal chromosomal structure is chromosomes with two long arms of the X chromosomes attached, and are called isochromosomes.
• Variants of chromosomal structure occur in 30% of individuals with Turner syndrome.

Nonfunctional Y

• Very rarely, the embryo has a normal X chromosome and a portion of the Y chromosome.
• In these cases, the Y chromosome does not have a functional SRY (and so develops as a female), the diagnosis is XY gonadal dysgenesis.[1]
• It is possible that some Turner syndrome diagnosis is due to gonadal dysgenesis, particularly when it is caused by a large deletion of the Y chromosome.

Mosaicism

• Each of the causes mentioned above can occur as a mosaicism, that is, some of the cells carry the mutation and some don’t. That is, two cell lines of different genetic make ups exist.
• This happens if the error takes place in one cell after the very first divisions of the early embryo after fertilization.
• The exact mixture of the two different cell types depends on when the nondisjunction occurred. *However, if the nondisjunction occurs after enough divisions, the fraction of abnormal cells is probably not large enough to show any significant effects.
• For instance, such a 45,X/46,XY individual will develop as a male, without Turner syndrome.
  • It is hypothesized that lower the percentage of mosaicism, the lesser is the phenotype expression.
• Mosaicism is found in about 20% of individuals with Turner syndrome.

No single Y

• There is no equivalent syndrome which results in a Y chromosome with no X, as such a condition is fatal in utero.

Lyonization

• In a normal 46 XX female, a process called lyonization inactivates one of the X chromosomes to equalize the number of expressible genes in males and females.
• Some genes escape this inactivation and contribute to the pathophysiology in Turner Syndrome.
• Turner syndrome might be due to the partial or complete absence of these inactivated genes and the presence of functional homologues of the Y chromosome. ^[3]

Imprinting

• Imprinting is an alteration in the expression of a gene, depending on whether it has been inherited from the mother or father.
• In the case of imprinting, it is not known whether there is a specific correlation between retention of the maternal or paternal chromosome and expression of particular phenotype.

• Short Stature is said to be due to the haploinsufficiency of the short stature homeobox (SHOX gene) which is located on the pseudoautosomal region of the X chromosome.
  • The SHOX gene is also responsible for skeletal abnormalities such as high arched palate, abnormal auricular development, cubitus valgus, genu valgum, Madelung deformity and short metacarpals.

• Visuospatial deficits (visuo-spatial function, visuomotor learning and spatial working memory) in Turner syndrome is hypothesized to be independent of hormone deficiencies and due to abnormalities in parieto-occipital mechanisms/morphology along with volumetric differences in the superior parietal lobule and the postcentral gyrus. ^[3]
• Executive skill deficiencies are said to be due to abnormalities in the prefrontal-striatal pathways.
• Reduced white matter in the frontal parietal pathways and defects in neurodevelopment and connectivity in these regions are responsible for the inability of Turner syndrome patients to link visuo-spatial functioning with executive functioning when performing complex tasks.
  • The patient is able to compensate for this deficiency whilst performing simple tasks by recruiting fronto-parietal resources. This recruitment is not possible during complicated tasks.
• One study suggested that volumetric differences in the amygdala were responsible for poor facial recognition and judgement. Poor connectivity between the amygdala and fusiform and aberrant development in the orbitofrontal cortex and superior temporal sulcus further contribute to this.
• Premature ovarian failure is secondary to ovarian dysgenesis and early follicular apoptosis.
• Fractures are due to estrogen deficiency and X chromosomal abnormalities. ^[4]
• Increased susceptibility to gonadoblastomas are seen in those individuals with Y chromosomal abnormality karyotypes.
  • It is proposed that a gonadoblastoma susceptibility locus is located on the pericentromeric region of the Y chromosome.
• Presence of autoimmune diseases may be due to haploinsufficiency of X chromosome or due to proinflammatory cytokines such as IL-6, IL-8 and tumor necrosis factor alpha. ^[5]

• While phenotype-kartyotype correlations are unreliable in predicting clinical features in Turner syndrome, some studies have suggested the following: ^[1]
  1. Loss of short and long arm of X chromosome – decreased ovarian function, number and survival of oocytes.
  2. Loss of interstitial or terminal long arm of X chromosome – Short stature, primary or secondary ovarian failure
  3. Loss of short arm of paternally inherited X chromosome– Full phenotype
  4. Loss of a region at Xp22.3 – Neurocognitive problems
  5. Loss of a region at Xp11.4 – Critical for the development of lymphedema
  6. Presence of an isochromosome Xq – Increased risk of hypothyroidism and inflammatory bowel disease
  7. Presence of ring chromosome – Increased risk of mental retardation.
  8. Lack of the XIST locus – Phenotype with more severe mental retardation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Humans have 46 chromosomes. Chromosomes contain all of your genes and DNA, the building blocks of the body. Two of these chromosomes, the sex chromosomes, determine if you become a boy or a girl. Females normally have two of the same sex chromosomes, written as XX. Males have an X and a Y chromosome (written as XY).

In Turner syndrome, cells are missing all or part of an X chromosome. The condition only occurs in females. Most commonly, the female patient has only one X chromosome. Others may have two X chromosomes, but one of them is incomplete. Sometimes, a female has some cells with two X chromosomes, but other cells have only one.

Turner syndrome results from the following mechanisms.

Nondisjunction

• During meiosis in either parent, a nondisjunction event can occur that leaves the gamete, either oocyte or spermatocyte, with neither X nor Y chromosome.
• When this gamete combines with a gamete from the other parent (with a normal X chromosome), the embryo lacks the normal two chromosomes.
• This leaves the embryo with 45 chromosomes and a single X chromosome, denoted 45,X (or, sometimes 45,XO, where the “O” is used as a placeholder). This is found in 50% of individuals with Turner syndrome.

Chromosomal structure

• An X chromosome can form a ring chromosome for example by losing a portion of the smaller arm, enabling the end of the long arm to wrap around. This is detrimental for the X chromosome in two ways. **Either the lost portion itself makes the chromosome less functional.
  • Or it causes nondisjunction, as described above. Thus, the causes listed here are partly overlapping.
• When such a ring chromosome combines with another ring chromosome in fertilization, the pair is denoted as 46, XrXp-, where rXp- means a ring chromosome missing the small (p) arm of the chromosome.
• Another variant of abnormal chromosomal structure is chromosomes with two long arms of the X chromosomes attached, and are called isochromosomes.
• Variants of chromosomal structure occur in 30% of individuals with Turner syndrome.

Nonfunctional Y

• Very rarely, the embryo has a normal X chromosome and a portion of the Y chromosome.
• In these cases, the Y chromosome does not have a functional SRY (and so develops as a female), the diagnosis is XY gonadal dysgenesis.[1]
• It is possible that some Turner syndrome diagnosis is due to gonadal dysgenesis, particularly when it is caused by a large deletion of the Y chromosome.

Mosaicism

• Each of the causes mentioned above can occur as a mosaicism, that is, some of the cells carry the mutation and some don’t. That is, two cell lines of different genetic make ups exist.
• This happens if the error takes place in one cell after the very first divisions of the early embryo after fertilization.
• The exact mixture of the two different cell types depends on when the nondisjunction occurred. *However, if the nondisjunction occurs after enough divisions, the fraction of abnormal cells is probably not large enough to show any significant effects.
• For instance, such a 45,X/46,XY individual will develop as a male, without Turner syndrome.
  • It is hypothesized that lower the percentage of mosaicism, the lesser is the phenotype expression.
• Mosaicism is found in about 20% of individuals with Turner syndrome.

No single Y

• There is no equivalent syndrome which results in a Y chromosome with no X, as such a condition is fatal in utero.

Lyonization

• In a normal 46 XX female, a process called lyonization inactivates one of the X chromosomes to equalize the number of expressible genes in males and females.
• Some genes escape this inactivation and contribute to the pathophysiology in Turner Syndrome.
• Turner syndrome might be due to the partial or complete absence of these inactivated genes and the presence of functional homologues of the Y chromosome. ^[1]

Imprinting

• Imprinting is an alteration in the expression of a gene, depending on whether it has been inherited from the mother or father.
• In the case of imprinting, it is not known whether there is a specific correlation between retention of the maternal or paternal chromosome and expression of particular phenotype.

• Short Stature is said to be due to the haploinsufficiency of the short stature homeobox (SHOX gene) which is located on the pseudoautosomal region of the X chromosome.
  • The SHOX gene is also responsible for skeletal abnormalities such as high arched palate, abnormal auricular development, cubitus valgus, genu valgum, Madelung deformity and short metacarpals.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2] Akash Daswaney, M.B.B.S[3]

Turner’s syndrome must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormality is Noonan’s syndrome.

• Turner’s syndrome must be differentiated from other diseases that cause latency in secondary sexual characteristics development, such as constitutional delay of puberty, hypopituitarism, delayed puberty, and chromosomal abnormalities. Chromosomal abnormality is Noonan’s syndrome.^[1]

Diseases		Laboratory Findings					Physical examinations				Other Findings
		GnRH	LH	FSH	Estradiol	Testosterone	Lack of secondary sexual characteristics	Amenorrhea	Webbed neck	Final height
Turner’s syndrome		↓	↑	↑	↓	–	+	+	+	↓	Bicuspid aortic valve
Delayed puberty	Primary hypogonadism	↑	↑	↑	↓	↓	+	+	–	↓	–
	Secondary hypogonadism	↓	↓	↓	↓	↓	+	+	–	↓	–
Constitutional delay of puberty		Nl	Nl	Nl	Nl	Nl	+	+	–	Nl	Normal puberty, finally
Hypopituitarism		↑	↓	↓	↓	↓	+	+	–	↓	–
Noonan’s syndrome		↓	↑	↑	–	↓	+	–	+	Nl	Mitral valve prolapse
Outflow tract obstruction (imperforate hymen or transverse vaginal septum)		Nl	Nl	Nl	Nl	Nl	–	+	–	Nl	Imperforate hymen Perirectal mass Bulging hymen with hematocolpos
Mayer-Rokitansky-Kuster-Hauser syndrome		Nl	Nl	Nl	Nl	Nl	–	+	–	Nl	Variable absence of Mullerian structures in pelvic ultrasound

Turner syndrome must be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, POEMS syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.^{[2][3][4][5][6]}

Disease	Addison’s disease	Type 1 diabetes mellitus	Hypothyroidism	Other disorders present
APS type 1	+	Less common	Less common	Hypoparathyroidism Candidiasis Hypogonadism
APS type 2	+	+	+	Hypogonadism Malabsorption
APS type 3	–	+	+	Malabsorption
Thymoma	+	–	+	Myasthenia gravis Cushing syndrome
Chromosomal abnormalities (Turner syndrome, Down’s syndrome)	–	+	+	Cardiac dysfunction
Kearns–Sayre syndrome	–	+	–	Myopathy Hypoparathyroidism Hypogonadism
Wolfram syndrome	–	+	–	Diabetes insipidus Optic atrophy Deafness
POEMS syndrome	–	+	–	Polyneuropathy Hypogonadism Plasma cell dyscrasias

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

The incidence rate of Turner syndrome is 1 of 2500 live births. Turner Syndrome patients have a higher mortality rate compared to the general population.

• The incidence rate of Turner syndrome is in 1 of 2500 live births. ^[1]
• 45 XO is the most common karyotype followed by mosaicism.
• Studies have shown that 30 percent of the time, Turner syndrome remains undiagnosed till adolescence. Therefore, it’s true prevalence rate cannot be estimated. “Turner Syndrome – StatPearls – NCBI Bookshelf”.
• The prenatal prevalence is much higher than the postnatal prevalence and the intrauterine mortality rate is higher when compared to the patients of the same age.
• Turner syndrome patients have a higher mortality rate when compared to the general population. ^[2]
• Approximately 98% of all fetuses with Turner syndrome spontaneously abort. Turner syndrome accounts for about 10% of the total number of spontaneous abortions in the United States.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

There is currently no known cause for Turner syndrome, though there are several theories surrounding the subject.

• There is currently no known cause for Turner syndrome, though there are several theories surrounding the subject.
  • Nondisjunctions increase with maternal age, such as for Down syndrome, but that effect is not clear for Turner syndrome.
  • It is also unknown if there is a genetic predisposition present that causes the abnormality, though most researchers and doctors treating Turners women agree that this is highly unlikely.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Screening for complications of Turner syndrome starts as early as a prenatal visit. Abnormal maternal serum screening tests or an ultrasound detecting structural anomalies such shortened limbs, cystic hygromas, congenital heart defects or increased swelling of the hands or feet may point towards a diagnosis of Turner syndrome. As the years progress, screening involves a multidisciplinary combination of lab investigations (such as serum gonadotrophins, liver function tests, renal function tests, etc), referral to other departments (cardiology, endocrinology, ophthalmology, etc) and tools such as DEXA scans, X-rays, echocardiography, etc.

• The ‘Diagnostic study of choice’ page in this microchapter helps to integrate the below screening modalities in a clinical setting.
• In addition, frequent referral to departments such as cardiology, nephrology, embryology, genetics, endocrinology, otorhinolaryngology, ophthalmology, dermatology and rheumatology ensures that a detail physical examination can be done to catch early signs of associated conditions seen in Turner syndrome.
• Screening newborns usually first involves a bed side ultrasonography which may reveal nuchal translucency, structural abnormalities such as shortened limbs, lymphedema of hands and feed, cystic hygroma and cardiac defects.
• This is used along with a maternal serum screening test which detects high inhibin B, low unconjugated estriol, high human chorionic gonadotrophin and low alpha feto protein.
• Once a diagnosis has been established, screening is aimed at detecting complications.
• Individuals on growth hormone should be screened regularly with forward bend tests and X-rays as the therapy exposes underlying scoliosis.
• echocardiography for cardiac structural abnormalities especially aortic dilation that predisposes the individual to aortic dissection and sudden cardiac death.
  • The aortic severity index is a useful prognostic indicator when assessing for the risk of aortic dilatation. ^[1]
  • It is the aortic diameter corrected for body surface area and a score of more than 2.3 cm per metre square indicates a high risk of aortic dissection (2-2.3 cm per metre square is considered as moderate risk).
  • The advice offered to moderate risk patients is restriction of activities and that offered to high risk patients is that they should completely avoid competitive sports and intensive weight training.
• Renal ultrasound for structural abnormalities like duplication of the collecting system and horseshoe shaped kidney.
• Dual energy x-ray absorptiometry (DEXA) scans may be done to test bone mineral density.
• Audiology for sensorineural and conductive hearing loss.
• Multidisciplinary neuropsychiatric evaluation should be done at major transitional stages such preschool entry and high school entry. ^[2]
• ECGs should be performed as long QT syndrome frequently occurs secondary to medication used to treat complications of Turner syndrome.
• Individuals with a Y karyotypic abnormality should be screened with fluorescent insitu hybridization and polymerase chain reaction techniques, to detect the risk of developing a gonadoblastoma.

• Laboratory investigations that may help in screening include: ^[3]
  1. serum gonadotrophins and anti Mullerian hormone– ovarian reserve.
  2. renal function tests – renal failure secondary to structural abnormalities.
  3. Thyroid function tests – thyroiditis, hypothyroidism, hyperthyroidism
  4. liver function tests – focal nodular hyperplasia
  5. serum IgA, IgA anti endomysium antibodies and IgA antigliadin antibodies – Celiac disease
  6. Lipid profile – hyperlipidemia
  7. Oral glucose tolerance test and serum glycosylated hemoglobin – for type 2 diabetes mellitus.
  8. serum 25-hydroxyvitamin D- Vitamin D deficiency.

Class I

1.Women with Turner syndrome should be evaluated for bicuspid aortic valve, coarctation of the aorta, and enlargement of the ascending aorta. (Level of Evidence: B-NR)

Class IIa

1.Prophylactic replacement of the aortic root or ascending aorta in adults with Turner syndrome is reasonable when the aortic diameter is 2.5 cm/m2 or greater. (Level of Evidence: B-NR)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Akash Daswaney, M.B.B.S[2]

Natural history of the patient would depend on the age of the diagnoses and what complications have developed by the time the patients presents to the physician. Congenital lymphedema may take several years to decrease. The patient experiences low self esteem due to their short stature, decreased visual spatial functioning, hyperactivity, poor facial recognition and preference for social isolation. As soon as the patient is capable of understanding, counseling regarding the risks and benefits of Turner syndrome should be explained. When compared to the general population, Turner syndrome patients have an increased mortality rate.

• The natural history of Turner syndrome patients depends on the age of diagnosis .
  • The age of diagnosis would in turn determine when they present to the physician.
• A newborn would typically present with lymphedema of the hands and feet, pterygium colli (webbed neck), low posterior hairline, cubitus valgus, Madelung deformity and cyanosis secondary to congenital heart disease. ^[3]
  • A complete physical examination is necessary.
  • Key history findings such as poor feeding (secondary to weak sucking reflexes), irritability, lower extremity coldness (claudication) and diaphoresis should point to coarctation of aorta or heart failure.
• Children around 2 years of age begin to dip below the 5th percentile and exhibit weight loss due to feeding difficulties.
  • This progresses to complaints of hearing loss, behavioral difficulties, low self esteem due to short stature and obesity. “Turner Syndrome – StatPearls – NCBI Bookshelf”.
  • Visuospatial deficits would affect the child’s performance in school.
• As soon as the patient is capable of understanding, the physician should actively counsel explaining the risks, benefits and process of transitioning to adult care. ^[4]

System	Clinical features and Complications
Gonadal	Rudimentary uterus Streaked ovaries Primary or secondary amenorrhea Infertility Chronic estrogen deficiency and Androgen deficiency Gonadoblastoma Dysgerminoma Dyspareunia
Endocrine	Type 1 diabetes mellitus Type 2 diabetes mellitus Autoimmune thyroiditis – Hashimotos thyroiditis Short stature
Gastrointestinal and hepatic	Celiac disease Inflammatory bowel disease Feeding problems Failure to thrive Regenerative nodular hyperplasia Multiple focal nodular hyperplasia Non alcoholic liver disease
Ophthalmology	Red-green color blindness Myopia Prominent epicanthal folds Bilateral epicanthus Strabismus Ptosis Amblyopia Hypermetropia Cataract Nystagmus
Otorhinolayngology	Increased risk of otitis media Conductive hearing loss Sensorineural hearing loss External ear deformities Small eustachian tube Palatal] dysfunction
Neck	Pterygium colli Low posterior hair line Loose skin on the nape of newborns
Chest	Wide shield shaped chest with broadly spaced inverted nipples
Skin, hair and nail	Lymphedema of the hands and feet Toenail cellulitis Vitiligo Alopecia Nail hypoplasia Psoriasis Pigmented melanocytic nevi Hyperconvex nails Premature wrinkling of facial skin Keloid formation
Skeletal	Genu valgum Cubitus valgus deformity Congenital hip dysplasia Short 4th metacarpal Decreased bone mineral content Increased risk of fractures secondary to decreased bone mineral density Scoliosis Kyphosis Juvenile idiopathic arthritis
Cardiac	Coarctation of aorta Ventricular septal defect Bicuspid aortic valve Aortic dissection Aortal dilation Aortic aneurysm Ischemic heart disease Atherosclerosis Elongated transverse aortic arch Pulmonary venous anomalies Hypoplastic left heart syndrome Infective endocarditis Persistent left superior vena cava Patent ductus arteriosus
Renal	Horse shoe shaped kidney Duplicate ureter Renal hypoplasia Renal aplasia
Psychological	Visuo spatial deficits Hyperactivity Poor facial recognition Poor self-esteem

• Madelung deformity is secondary to SHOX haploinsufficiency. It is the chondrodysplasia of the distal radius epiphysis, typical of Leri Weill syndrome.
• Patients have normal global intellectual functioning.
• Studies have shown that Turner syndrome patient exhibit superior language and comprehension skills when compared to individuals their age. They understand less common words better and sometimes have better receptive vocabulary skills.
• Test of mental rotation, object assembly and facial recognition show significant deficits.
• Non verbal skills are poor.
• Visuospatial skills would affect right left orientation.
• Executive function skill deficits would include impairments in planning, organization, attention, concentration, processing speed and problem solving ability.
• Patients are impulsive and hyperactive. They have sleepless night and have problems maintaining relationships. They eventually become socially isolated. This affects their self-esteem.
• Associated conditions include autism, attention deficit hyperactive disorder, anxiety and depression.

• When compared to the general population, Turner syndrome patients have an increased mortality. ^[5]
• Atherosclerotic complications causing stroke and coronary artery disease and aortic dissection are leading causes of mortality.
• However, some Turner syndrome patients are satisfied with their lifestyle. “Turner Syndrome – StatPearls – NCBI Bookshelf”.
• Complications like gonadoblastoma have a good prognosis if detected and removed early. ^[6]

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