Turner Syndrome

Turner syndrome is a chromosomal condition in individuals with a female phenotype, resulting from complete or partial absence of one X chromosome. The classic karyotype is 45,X, though a substantial proportion of affected individuals have mosaicism or a structural X chromosome abnormality rather than complete monosomy. It is the commonest sex chromosome abnormality in females.

It has a distinctive constellation of features: short stature, ovarian insufficiency with pubertal failure and infertility, and variable congenital anomalies, particularly cardiovascular and renal. Turner syndrome must be actively excluded in any girl with unexplained short stature.

Structured, lifelong multidisciplinary surveillance is essential because of the broad range of associated comorbidities.

Pathophysiology and genetics

• Complete monosomy X (45,X) is loss of an entire sex chromosome, most commonly from a meiotic error during gamete formation. It accounts for a substantial proportion of confirmed cases.
• A significant additional proportion have mosaicism (a mixture of 45,X and normal 46,XX or, less commonly, 46,XY cell lines) or a structural abnormality of one X chromosome, including a ring chromosome or isochromosome.
• Karyotype has some relationship to phenotypic severity, with substantial individual variation even among individuals with an identical karyotype.
• Ovarian insufficiency reflects accelerated, premature follicular loss, typically occurring even before birth. Most girls with Turner syndrome enter puberty with a substantially depleted follicular reserve. This accounts for absent or incomplete spontaneous pubertal development and, in the substantial majority, infertility.
• A small proportion, particularly those with mosaic karyotypes, retain sufficient ovarian function for spontaneous puberty and, in a small minority, spontaneous fertility.
• Y chromosome material in a mosaic karyotype (45,X/46,XY) carries an increased risk of gonadoblastoma in the dysgenetic gonadal tissue. This warrants gonadal assessment and, in some cases, prophylactic gonadectomy.

• Short stature typically becomes apparent in childhood and is a near-universal feature.
• Characteristic but variably present physical features are a webbed neck, low posterior hairline, broad chest with widely spaced nipples, cubitus valgus (increased carrying angle at the elbow), and multiple pigmented naevi. The combination and severity vary substantially, and some individuals have few overt features beyond short stature.
• Lymphoedema of the hands and feet is present at birth in a proportion of affected infants. Increased nuchal translucency or cystic hygroma on antenatal ultrasound may identify some cases prenatally.
• Pubertal failure reflects ovarian insufficiency and presents as absent or incomplete spontaneous pubertal development. The substantial majority of affected girls need pubertal induction with exogenous oestrogen, and also have primary infertility.
• Congenital cardiovascular anomalies occur in a substantial proportion. Bicuspid aortic valve and coarctation of the aorta (see congenital heart disease) are particularly characteristic and common.
• There is also an increased risk of aortic dilation and, in a small proportion, aortic dissection, warranting structured, lifelong cardiovascular surveillance.
• Renal anomalies include horseshoe kidney and other structural variations (see congenital anomalies of the kidneys and urinary tract).
• Further associated comorbidities need lifelong surveillance: otitis media with hearing impairment, autoimmune thyroid disease (particularly hypothyroidism), and, in adulthood, increased risk of type 2 diabetes and osteoporosis.
• Cognitive function is generally within the normal range. A relative difficulty with visuospatial and certain mathematical skills is common and informs educational support planning. Global intellectual impairment is not a typical feature.

• Karyotype analysis gives definitive confirmation and identifies the pattern of X chromosome abnormality (complete monosomy, mosaicism, or structural abnormality). The karyotype informs, to some degree, anticipated phenotypic severity and associated risks, including the gonadoblastoma risk with Y chromosome material.
• Age and circumstance at diagnosis vary considerably, reflecting the phenotypic variability of the condition.
• Prenatal diagnosis follows invasive testing prompted by an antenatal ultrasound finding (increased nuchal translucency, cystic hygroma, or a structural cardiac or renal anomaly), or non-invasive prenatal testing.
• In infancy, diagnosis is prompted by characteristic physical features, including lymphoedema, or an identified congenital cardiac anomaly. In childhood it is prompted by evaluation of unexplained short stature. In adolescence it is prompted by evaluation of delayed or absent pubertal development.
• Baseline evaluation after diagnosis includes echocardiography, renal ultrasound, thyroid function testing, hearing assessment, and formal ophthalmological evaluation. Cardiac magnetic resonance imaging is added where indicated, for aortic assessment. These findings inform the lifelong surveillance programme.

• Growth hormone therapy is standard treatment for short stature, generally started in early to mid-childhood. Final adult height improves meaningfully when treatment starts at an appropriate age and continues consistently through the growth period.
• Pubertal induction uses low-dose, gradually increasing exogenous oestrogen, started at about the age of normal pubertal onset (generally around eleven to twelve years). The gradual escalation mimics normal pubertal progression as closely as possible.
• Therapy later changes to combined oestrogen and progestogen once uterine development is sufficiently established. Hormone replacement generally continues to the typical age of natural menopause. It supports bone health and cardiovascular wellbeing and manages symptoms of oestrogen deficiency.
• Fertility counselling is essential, because the substantial majority of affected individuals are infertile from ovarian insufficiency. Oocyte donation is the primary route to biological pregnancy for the great majority who wish to pursue it.
• For the minority with retained ovarian function, consider fertility preservation where clinically appropriate and desired. Counselling should be sensitive, because this is often a profoundly important part of life planning.
• Lifelong cardiovascular surveillance is critical given the substantial cardiovascular risk. It includes regular echocardiography, periodic cardiac magnetic resonance imaging of aortic dimensions (given the aortic dissection risk), blood pressure monitoring, and management of any hypertension.
• Pregnancy, through oocyte donation or, rarely, spontaneous conception, carries a substantially elevated risk of aortic dissection. It needs careful specialist cardiovascular assessment and monitoring.
• Surveillance and management of the wider comorbidities includes regular thyroid function testing, audiological assessment, and, in adulthood, screening for diabetes and osteoporosis.
• Provide educational support for the visuospatial and mathematical learning difficulty where relevant, and psychosocial support for the lifelong impact on the individual and family.
• Structured transition planning from paediatric to adult specialist services ensures continuity of lifelong multidisciplinary care.