Overview

Turner syndrome is a genetic condition affecting about 1 in 2000 people assigned female at birth (AFAB). Also known as 45, X syndrome, monosomy X, or congenital ovarian hypoplasia syndrome, it is considered the most common genetic disorder related to the sex chromosome in people with AFAB. The syndrome causes variable and complex symptoms, but the most common are short stature and ovarian dysfunction. The severity of Turner’s syndrome depends on how the sex chromosome is affected, and how much genetic material is missing. Severe cases can be discovered early, even before birth, because the foetus can present heart, kidney, and other problems visible on ultrasound examination. On the other hand, patients can also be mildly affected by this syndrome and discover they have it during adulthood, because of infertility problems.^1,2,3 

Turner syndrome can be identified clinically, considering its symptoms and key featuresDiagnosis is confirmed by a genetic test, called karyotype, but there are other alternatives. This article aims to briefly present this genetic condition and focus on the diagnosis methods available, depending on the patient’s age when the diagnosis is made.⁴

What is turner syndrome?

How frequent is turner syndrome?

Turner syndrome is probably the most common genetic condition in people with AFAB, but  99% of the cases (severe and mild) are miscarried. 1-2% of conceived embryos are affected, and only 1% of them are born. Maternal age is not an increased risk factor, and most cases happen randomly.^2,4

What is the genetic cause of turner syndrome?

The DNA holds all the information the body needs to function, and it is folded and packed in structures called chromosomes. Humans have 46 chromosomes in each cell: 44 autosomes, and 2 sex chromosomes (X and Y) The genetic “formula” for people assigned male at birth (AMAB) is 46, XY, and for people AFAB, is 46, XX.

Turner syndrome develops when the DNA from one of the X chromosomes in people AFAB, which could be due to:

• Complete loss: Monosomy X (45, X) happens in approximately 50% of the cases when an entire X chromosome is missing from all the cells of the body.
• Partial loss:  The rest of the cases have two X chromosomes, but one X chromosome can have missing parts
• Mosaicism: The body has a combination of two cell lines,  one with 45, X and the other with 46, XX.
• Abnormal structure of one of the X chromosomes, such as a circular form (ring chromosome) or with one arm duplicated and another missing (isochromosome). 

The symptoms of this syndrome arise because of the absence of developmental genes located on the X chromosome. In some rare cases, some cells have one X chromosome, and some cells have one X chromosome and part of the Y chromosome, but not enough to develop male features. However, the Y presence is linked to an increased risk of developing a type of cancer called gonadoblastoma, so the diagnosis process is focused on identifying the possible Y material.^1,2,3 

What are the symptoms of turner syndrome?

The most common symptoms encountered in the patients are short stature and premature ovarian failure, which results in the inability to attain puberty in adolescence, or infertility in adulthood. Congenital heart conditions affect about 50% of the patients, can be detected before or after birth, and some of the heart anomalies can be incompatible with life and result in miscarriages.⁵ Mortality rate is increased because of serious heart complications, such as aortic aneurysm and dissection, and hypertension, that can happen in childhood or adulthood. Thus, doctors screen for these complications for an early intervention.⁶ Patients also present problems and abnormalities with their kidneys, lymphatic system, immunity, bones, liver, thyroid, ears, hearing, eyes, and teeth, and can develop diabetes.^1,3,4,5,6

Distinctive physical features, besides the short stature, are given by a short, webbed neck with a low posterior hairline; low inserted, misshapen ears; a high-arched, narrow roof of the mouth, with crowded teeth; a broad chest known as “shield chest”, with increased space between the nipples; skeletal problems such as scoliosis; puffy hands and feet (probably lymphoedema). Turner patients have normal intelligence but can struggle at school in certain domains, such as maths.⁵ 

What are the diagnosis methods for turner syndrome? 

Diagnosis of Turner syndrome can be suspected after a clinical evaluation of the patient, and confirmed by laboratory testing. The golden standard is the karyotype, a blood test that analyses the chromosomes under the microscope and can identify the problems with the X chromosomes, including the abnormal structures. When mosaicism cases and the presence of the Y chromosome are suspected, additional testing methods are recommended.^6,7 In case the Y chromosome is present, surgery to remove the gonads, called gonadectomy will be necessary to prevent the risk of developing gonadoblastoma in the future.^4,,8,9 

Prenatal diagnosis methods

Screening of maternal blood for three/four substances (triple/quadruple screening test) or a prenatal ultrasound can raise the suspicion of Turner syndrome. The latter can reveal relevant clinical features, such as heart (aortic coarctation) or renal (horseshoe kidney) abnormalities, increased nuchal translucency, foetal oedema (foetal hydrops), foetal growth restriction, or abnormalities in the amniotic fluid.^6,7,8

Non-invasive prenatal screening tests (NIPT), which only require a blood sample and use next-generation sequencing technologies (NGS), have improved the early detection of Turner syndrome. However, they are limited to cases of mosaicism and samples can be contaminated maternal DNA.^6,7 

Diagnosis must be confirmed with the karyotype analysis, using a DNA sample obtained from amniocentesis or chorionic villus sampling. This method may fail to detect low levels of mosaicism, and the Y chromosome. In these cases, Fluorescence in situ hybridisation (FISH) analysis with X and Y probes will complete the diagnosis.⁸ Chromosomal microarray analysis (CMA) or polymerase chain reaction (PCR) can also be performed.^6,7,9 

Newborn diagnosis methods

A newborn with the following clinical characteristics will raise a strong suspicion of Turner syndrome: a heart and/or kidney malformation, especially aortic coarctation and/or horseshoe kidney, along with swollen, puffy hands and feet, a webbed neck aspect, abnormal nails, and a high-arched roof of the mouth.^1,2,5 A clinical team constituted by the doctor in charge, a clinical geneticist, and other specialities doctors, such as a paediatric cardiologist, will manage the case and perform a multidisciplinary evaluation (clinical examination, cardiac and renal ultrasound, blood tests, etc). A karyotype, together with FISH, PCR and CMA depending on the type of mutation, will confirm the diagnosis.^5,9 

Childhood diagnosis methods

A child suffering from Turner syndrome presents the following clinical signs: short stature, low growing rate, webbed neck, low posterior hairline, “shield chest” with wide-spaced nipples, widened carrying angle of the elbow joints, skeletal, heart, kidney problems, repeated ear infections, behavioural, emotional, and specific learning difficulties at school, despite having a normal IQ.^2,4,5

The diagnostic process is the same, including complex clinical evaluation and genetic testing methods. Early diagnosis is vital for preventing growth failure, hearing problems, heart and kidney complications and improving  long-term disease management.^5,8

Adolescence and adulthood diagnosis methods

Adolescents and adults with Turner syndrome present short stature and lack of puberty onset (absence of sexual secondary characteristics, such as breast development, and menstrual cycles). The latter will result in adult infertility. These reproductive-related problems are caused by primary ovary insufficiency because Turner patients have modified ovaries, called “streak gonads”. The characteristic clinical features would be present, but probably manifested in a milder form or undetected.^1,4,5,8

Diagnosis methods at these ages are based on the same principles, with a thorough clinical evaluation and genetic testing. A karyotype will be performed immediately if a patient has a suspicion of Turner syndrome. A clinical geneticist should always evaluate the case and recommend the best testing approach to have a complete diagnosis. TPreventive gonadectomy is recommended when the Y chromosome is detected.^1,2,5,8,10

Adolescence

Complete paediatric and endocrinological evaluation, bone age determination, and pelvic ultrasound (to assess the reproductive system), are necessary before medically inducing puberty with oestrogen replacement therapy. Previous hormonal growth treatment should be taken into consideration.^1,2,5

Adulthood

Complete evaluation and diagnosis are necessary before discussing infertility. Spontaneous pregnancies occur only in about 7% of the cases and doctors advise assisted reproduction with donated eggs. Patients need oestrogen replacement therapy continuously until they are expected to enter menopause.⁵

Summary

Turner syndrome is considered the most common genetic condition affecting people with AFAB. The clinical symptoms are caused by the absence of genetic material in the X chromosome. The genetic error can be variable, leading to different types of Turner syndrome, with different degrees of severity. Some cases are incompatible with life and miscarry in the first trimester of the pregnancy, others can go undetected until unknown infertility in adulthood.

Diagnosis is suspected after a clinical evaluation of the patient and confirmed by genetic testing. The golden standard test is the karyotype, but other tests are taken into consideration to obtain a complete diagnosis (FISH analysis with X and Y probes, PCR and CMA c Prenatally, non-invasive screening tests are performed to detect several genetic syndromes, but karyotype must be done for definitive diagnosis. A clinical geneticist should always be consulted regarding the diagnostic tests available and the best approach for the patient.