Turner Syndrome is hypogonadism in phenotypica females due to partial or complete absence of one X chromosome, leading to short stature, gonadal dysgenesis, biscuspid valve and coarctation of the aorta, as well as a spectrum of somatic features.
Description
Turner syndrome (monosomy 45, XO) is a chromosomal disorder that affects only females and is characterised by partial or complete loss of one of the two X chromosomes. This condition leads to a spectrum of developmental and medical problems, including short stature, gonadal dysgenesis leading to primary amenorrhea, and various somatic abnormalities.
Pathogenesis
The pathogenesis of Turner syndrome involves complete or partial deletion of the second sex chromosome. In 75% of cases the X chromosome is maternal in origin, suggesting that the primary defect may be in paternal gametogenesis. This lack of genetic material from the second X chromosome leads to a cascade of developmental and physiological abnormalities, including gonadal dysgenesis, growth hormone deficiency, and congenital heart defects, among others.
Epidemiology, Risk Factors & Associations
- Turner syndrome affects approximately 1 in 2,500 live female births.
- There are no known risk factors as the chromosomal abnormality appears to be random.
- Unrelated to maternal age.
- About 98% of pregnancies with Turner syndrome result in miscarriage or stillbirth.
- Commonly associated conditions include congenital heart defects (particularly coarctation of the aorta and bicuspid aortic valve), hearing loss, autoimmune disorders (particularly hypothyroidism), and renal abnormalities.
Clinical Features
- Short stature: Hallmark of Turner syndrome, due to loss of both (expressed) copies of the short stature homeobox gene (SHOX) on the X chromosome which affects height. This causes premature closure of growth plates, often first noticed in early childhood. Most do not undergo a normal growth spurt during adolescence.
- Gonadal dysgenesis: Primary amenorrhoea due to streak ovaries, leading to infertility and lack of secondary sexual characteristics. They may also have delayed puberty and primary amenorrhoea without hormone replacement therapy.
- Somatic features: Multiple physical features may be present, including webbed neck, low posterior hairline, broad chest with widely spaced nipples, and lymphoedema of the hands and feet at birth.
- Skeletal: Brachydactyly and cubitus valgus
- Cardiovascular: Congenital heart defects are common, the most frequent being coarctation of the aorta and bicuspid aortic valve. Increased risk of hypertension and even aortic dissection in adulthood. The mechanisms of the cardiac malformations are unknown.
- Renal: Kidney abnormalities occur in about a third of patients. The most common is horseshoe kidney, but other renal malformations may also be seen.
- Endocrine: Increased risk of autoimmune thyroid disease, leading to hypothyroidism.
- Learning difficulties: Difficulties with spatial and mathematical abilities. Autism spectrum disorder.
Complications
- Cardiovascular problems: Congenital heart defects, hypertension, and aortic dissection are significant complications and major causes of increased mortality in Turner syndrome.
- Endocrine problems: Hypothyroidism and impaired glucose tolerance or type 2 diabetes are more common in females with Turner syndrome.
- Infertility: Due to premature ovarian failure, most females with Turner syndrome are infertile.
Subtypes
There are several karyotypic subtypes of Turner syndrome, including:
- Classic Turner syndrome (45,X), where one entire X chromosome is missing.
- Mosaic Turner syndrome (45,X/46,XX or 45,X/46,XY), where some cells have two X chromosomes or one X and one Y chromosome, and others have only one X chromosome.
- Turner syndrome with structural chromosome abnormalities (46,X,i(Xq) or 46,X,r(X)), where one X chromosome has a deletion or other structural abnormality.
Pathological Features
Genetics
Turner syndrome is caused by the absence of all or part of one X chromosome. The most common karyotype is 45,X, seen in about half of all cases. The rest have mosaicism or structural abnormalities of the X chromosome.
Histopathology
- Morphology: Associated with short stature, a webbed neck, and a broad chest with widely spaced nipples. Some individuals also have a low hairline, high arched palate, and low-set ears.
- The ovaries are replaced by fibrous streaks (streak gonads), which do not produce sex hormones or eggs.
- Cardiovascular abnormalities may be present, including a bicuspid aortic valve or coarctation of the aorta.
Biochemistry
1st Trimester Combined Screening Test
- Elevated follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels due to the lack of negative feedback from estrogen and inhibin.
- Thyroid function tests may reveal hypothyroidism, particularly in older individuals with Turner syndrome.
Radiological Features
Antenatal
- Cystic hygroma – cervicofacial macrocystic lymphatic malformation with internal septations, particular posterior cervical triangle. Approximately 75% of fetuses with cystic hygromas have a chromosomal abnormality, with Turner syndrome being the cause in around 95% of these cases.
- Increased nuchal thickness and nuchal translucency
- Coarctation of the aorta: 15-20%
- Bicuspid aortic valve
- Omphalocele
- Horseshoe kidney / pelvic kidney
- Mild IUGR
- Hydrops fetalis
- Short foetal limbs
- Absent nasal bone
Musculoskeletal
- Madelung deformity of the wrist – decreased carpal angle
- Shield chest
- High-arched palate may be visible
- Short 4th metacarpal.
- Narrowing of the scapholunate angle
- Scoliosis
- Short stature
Cardiovascular
- Congenital heart defects, such as bicuspid aortic valve or coarctation of the aorta, can be seen on echocardiogram or MRI. Hypertension-related changes may also be observed in older patients.
- Aortic dissection
Genitourinary
- Renal: Horseshoe kidney or unilateral renal agenesis.
- Gonads: Streak ovaries – severe atrophic and fibrous ovaries
Grading and Staging
Turner syndrome is a genetic condition, so the concept of grading and staging is not typically applied. However, the severity of symptoms and associated conditions can vary widely among individuals.
Differential Diagnosis
- Noonan syndrome: Shares many physical characteristics with Turner syndrome, but occurs in males and females and is caused by autosomal gene mutations.
- Androgen insensitivity syndrome: Causes male to female sex reversal, leading to a phenotype that may resemble Turner syndrome, but karyotype reveals 46,XY.
- Short stature due to other causes: Many conditions can lead to short stature and delayed puberty, including growth hormone deficiency, hypothyroidism, and chronic diseases.
Management
- Endocrinologist referral: Given the endocrine abnormalities in Turner syndrome, management by an endocrinologist is often necessary. They can administer growth hormone therapy to increase adult height and hormone replacement therapy to induce puberty.
- Cardiologist referral: Regular cardiac follow-up is necessary due to the risk of congenital heart disease, aortic dilation, and dissection.
- Psychological and educational support: Cognitive and learning difficulties may require additional support in the educational setting.
- Fertility specialist referral: Women with Turner syndrome who desire pregnancy may explore options such as in vitro fertilisation with donor eggs.