Summary
TS is one of the most common sex chromosomal abnormalities, caused by complete or partial absence of one X chromosome in a phenotypic female. The most common features of TS are short stature and premature ovarian insufficiency, but the phenotypic spectrum is widely variable in both presentation and severity.
10.1 Incidence and Chromosome Abnormalities
10.1.1 Incidence
Turner Syndrome (TS) is one of the most common sex chromosomal abnormalities, caused by complete or partial absence of one X chromosome in a phenotypic female. The most common features of TS are short stature and premature ovarian insufficiency, but the phenotypic spectrum is widely variable in both presentation and severity.
The incidence is approximately 1 in 2000 live-born females, while analysis of cytogenetic screening studies suggest that TS occurs in 1 in 200 gestations, but most are lost as early fetal miscarriage, commonly due to cardiovascular and lymphatic development abnormalities and other less-well-defined causes.
10.1.2 Chromosome Abnormalities
Approximately 45% of live-born TS patients have X chromosome monosomy, 45,X. Other karyotypes may include structural abnormalities of the X chromosome, such as deletions of the short arm and duplication of the long arm to form an isochromosome (isoXq), ring formation (rX) and deletion in the long or short arm (respectively, Xq and Xp). Mosaicism of a 45,X cell line with one or more additional cell lines, most commonly 45,X/46,XX, may occur (Table 10.1).
Table 10.1 Chromosome abnormalities in TS
| Karyotype | Frequency (%) | |
|---|---|---|
| Monosomy X | 45,X | 40–50 |
| Mosaicism | 45,X/46,XX | 15–25 |
| Mosaicism with triple X | 45,X/47,XXX – 45,X/46,XX/47,XXX | 3 |
| Isochromosome X | 45,X/46,X,i(Xq) – 46,X,i(Xq) | 10 |
| Deletions | 45,X/46,X,del(X) – 46,X,del(X) | 6 |
| Ring chromosomes | 45,X/46,X,r(X) | 3 |
| Presence of Y material | 45,X/46,XY – other with Y material | 10–12 |
Approximately 10% of women with TS have Y chromosome material; they constitute a unique category because of their increased risk of developing a gonadoblastoma, a pre-malignant germ cell tumour with risk of malignant transformation. Reported rates of gonadoblastoma range from 2% to 50% and malignant transformation is rare, typically occurring after the second decade of life. Thus, the current recommendation is for laparoscopic, prophylactic gonadectomy [Reference Gravholt, Andersen, Conway, Dekkers, Geffner and Klein1], although there is little evidence about the appropriate timing for the procedure.
The phenotypic severity of TS is typically associated with karyotype, with in general the most severe phenotype occurring in women with 45,X monosomy and a milder phenotype in 45,X/46,XX mosaicism. However, the genetic basis linking the karyotype to phenotype is far from being elucidated. Comparative analysis of the karyotypes and phenotypes in TS is difficult, also due to the uncertainty regarding the extent of mosaicism in different tissues as the karyotype is usually based on a single examination of 30 peripheral blood cells. It has been hypothesised that all 45,X individuals who survive to birth have some degree of ‘cryptic mosaicism’ for a normal cell line somewhere in the body.
A number of pseudo-autosomal genes are present on the X and Y chromosomes that escape X inactivation and may be required in biallelic expression for normal development. So far, the only confirmed example of this genetic mechanism involved in the TS phenotype is short stature related to haploinsufficiency for the SHOX (short stature homebox) gene. Mutations and microdeletions of this locus result in short stature and some TS-associated skeletal anomalies.
Furthermore, preliminary studies suggest that the origin of TS-associated comorbidities may depend on a complex relationship between genes, transcriptional and epigenetic factors affecting gene expression across the genome.
10.2 Clinical Features and Diagnosis
10.2.1 Clinical Features
There is a wide variation of clinical features seen in females with TS, ranging from the severe phenotype with short stature, gonadal dysgenesis, characteristic dysmorphic features and cardiovascular congenital abnormalities, to women with only a mild reduction in final height and/or presentation with premature ovarian insufficiency.
10.2.1.1 Short Stature
Short stature is an almost invariable finding in women with TS. It begins prenatally, with poor growth often evident within the first 3 years of life. If left untreated, adult height is on average 20 cm below expected norms.
There is no evidence that growth hormone deficiency is a cause of short stature in TS, although partial growth hormone insensitivity may be a factor. Indeed, the recommended treatment during childhood consists of recombinant human growth hormone therapy in supraphysiological doses.
10.2.1.2 Bone Abnormalities
Many of the physical stigmata of TS (Table 10.2) are a result of structural bone defects, which rarely cause disability. Bone abnormalities include a shield chest with widely spaced nipples appearance, a short neck, cubitus valgus (increased carrying angle of the elbow), short metacarpals and metatarsals and Madelung deformity (bayonet deformity of the wrist). An increased risk of kyphosis and scoliosis is reported in patients with TS. The characteristic TS facies is also primarily due to skeletal malformations. These result in micrognathia, a high arched palate and low-set ears.
| Short stature | >95% |
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| 30% |
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10.2.1.3 Osteoporosis
The risk of low bone mineral density and fractures is increased in girls and women with TS. Several factors probably contribute to these findings, including inadequate oestrogen exposure and intrinsic bony abnormalities.
10.2.1.4 Other External Stigmata
Other specific features that might be present in a TS patient are pterygium colli (defined as webbed neck), irregular shape of the ears, low hairline at the back of the neck, ptosis, hypertelorism and epicanthal folds, and an increased number of melanocytic nevi (Table 10.2).
10.2.1.5 Premature Ovarian Insufficiency
TS is one of the most common causes of premature ovarian insufficiency failure. The gonads in TS differentiate normally until the third month of gestation, after which accelerated apoptosis of oocytes occurs along with an increase in ovarian stromal fibrosis. The pathogenesis of this process is yet to be determined. Pelvis ultrasound show that the majority of young TS have streak ovaries and, in many, the ovaries are too small to be identified. The uterus remains prepubertal in size if oestrogen treatment has not been started.
Approximately one-third of TS have spontaneous thelarche. Spontaneous menarche occurs in 5%–20%, most commonly in those having a mosaic karyotype. It is difficult to predict which girls with TS will have spontaneous menarche. Because of the ovarian insufficiency, many girls have elevated serum concentrations of follicle-stimulating hormone (FSH). However, measurement of anti-Müllerian hormone (AMH) may be more sensitive as a marker of pending ovarian failure than FSH [Reference Hankus, Soltysik, Szeliga, Antosz, Drosdzol-Cop and Wilk2].
Spontaneous pregnancy is rare and women with TS report infertility to be one of the greatest issues affecting their quality of life through all age groups [Reference Sutton, McInerney-Leo, Bondy, Gollust, King and Biesecker3]. Oocyte donation in vitro fertilisation (OD-IVF) and the recent techniques of fertility preservation increasingly offer the possibility of childbearing to TS women.
10.2.1.6 Cardiovascular Manifestations
Mortality is three-fold higher in TS women. TS-associated cardiovascular manifestations represent the most serious health problem for young and adult TS females and contribute to the increased morbidity and mortality seen in TS.
A bicuspid aortic valve is found in 30% of TS women compared with 1%–2% of the general population. This condition requires regular follow-up to exclude haemodynamically significant regurgitation and stenosis, where surgical intervention may be required.
Coarctation of the aorta is found in up to 17% compared with 0.04% in the general population. If left untreated, aortic coarctation may be complicated by severe hypertension, congestive heart failure and aortic dissection. It is commonly diagnosed during childhood when surgical intervention may be indicated.
Other congenital defects include elongated and kinked transverse aortic arch, aberrant right subclavian artery, partial anomalous pulmonary venous drainage, atrial and ventricular septal defects, and persistent left superior vena cava (Table 10.3) [Reference Mortensen, Andersen and Gravholt4].
| Cardiac congenital malformations | |
| Elongated transverse aortic arch | Up to 50% |
| Bicuspid aortic valve | Up to 30% |
| Aortic coarctation | Up to 17% |
| Pulmonary venous abnormalities | 15% |
| Persistent left superior vena cava | 10% |
| Atrial septal defects | 2% |
| Ventricular septal defects | 2% |
| Coronary arteries abnormalities | Up to 2% |
| Hypoplastic left heart | <1% |
| ECG abnormalities | |
| Prolonged QTc interval | Up to 35% |
| Hypertension | 30% |
In addition to the congenital cardiovascular defects, hypertension is common in young and adult women with TS and is often independent of cardiac or renal abnormalities and of obesity. Loss of the nocturnal dip in blood pressure is commonly seen, and whilst current guidelines have no specific cut-off for treatment, it is reasonable to check 24-hour blood pressure values and have a lower threshold for intervention (e.g. >130/80 mmHg) if there are other cardiac risk factors. Some studies suggest that a general vasculopathy, as reflected by an increased arterial stiffness in TS compared with controls, might be a contributing factor. Cardiac conduction defects are also common and in particular prolongation of the QTc.
Aortic dilatation is reported in up to 30% of TS women and is associated with hypertension, bicuspid aortic valve and aortic coarctation, although it may also occur in the absence of these risk factors.
Importantly, aortic dissection affects 1%–2% of TS women and can be rapidly fatal if it is not promptly diagnosed and surgically treated. Risk factors for aortic dissection are the presence of hypertension, the presence of bicuspid aortic valve, aortic coarctation and aortic dilatation. In addition, pregnancy is a further risk factor due to the increased cardiac output. However, in 10% of TS who dissect no risk factors are identified. Aortic dissection is almost 100-fold higher than for women in general and is seen at a much younger age. Therefore, it is crucial to consider a diagnosis of aortic dissection in adult and young TS women with chest and back pain. The use of a wallet card to show to emergency personnel highlighting the risk/action for aortic dissection has proven helpful (Figure 10.1).
