Turner Syndrome And Autoimmune Diseases

Introduction

What is turner syndrome?

Turner syndrome (TS) is a rare genetic condition that affects only people assigned female at birth (AFAB). It involves a chromosomal abnormality where there is a complete or partial loss of one of the two X chromosomes (sex chromosomes). This condition occurs in approximately 1 in every 2,000 AFAB births.¹

What are autoimmune diseases?

Autoimmune diseases occur when your immune system, which typically fights infections, mistakenly attacks your body's healthy cells. This leads to diverse patterns of inflammation and organ dysfunction and can affect individuals of any age. Common types of autoimmune diseases include rheumatoid arthritis and lupus.⁸

Overview of turner syndrome

Genetic characteristics: causes of turner syndrome

Typically, both genders have 23 pairs of chromosomes, totalling 46 chromosomes in each cell. One pair of these chromosomes, the sex chromosomes, determines the baby's gender. People with AFAB have two X chromosomes, while individuals that are assigned male at birth (AMAB) have one X and one Y chromosome.² 

TS is caused by an abnormality of the sex chromosomes in babies in the womb after conception. TS can be described in two main forms:

• Monosomy TS - About half of the AFAB population with TS have monosomy. This means that the people AFAB are missing one whole X chromosome. Instead of the 46 chromosomes in an AFAB person without TS, an AFAB person with monosomy TS has 45 chromosomes, with one missing in their 23^rd chromosome pair^1,3
• Mosaic TS -The other half of the AFAB population with TS have mosaicism. Mosaicism in AFAB people with TS involves chromosome changes in some cells. While some cells may have the usual two complete X chromosomes, other cells will have only one X chromosome or two X chromosomes with one of the two being partially missing or incomplete^1,4

In most cases, TS is often not inherited; rather, it is typically caused by a random event during the formation of reproductive cells.¹

Common physical and medical characteristics of turner syndrome

TS may present with distinctive physical characteristics and associated medical conditions. Features can vary for each AFAB person with TS and may develop at different times over their life, depending on the form of TS and which part of the X chromosome is missing.

Physical features 

General features include

• Short stature - AFAB people with TS tend to develop a shorter stature compared to their peers
• Shield chest - Characterised by a broad chest with widely spaced nipples
• Gonadal dysgenesis - AFAB people with TS may have underdeveloped ovaries leading to ovarian insufficiency(inability of the ovaries to produce eggs) and infertility

Head and neck features include

• Narrow and high-arched palate - A narrower mouth with a high-arched roof of the mouth
• Webbed neck - Their neck appears particularly short and wide with skin folds on the sides
• Lower hairline at the base of the neck
• Low-set ears

Hand and foot features include

• Lymphoedema - Swelling of the hands and feet present mostly at birth
• Nail dysplasia - Nails are small and spoon-shaped
• Short fourth metacarpals/metatarsals - The fourth finger or toe bones are shorter than normal

Arm and wrist features include

• Cubitus valgus - The arms turn out slightly at the elbows. This is also known as a ‘wide ‘carrying angle’
• Madelung deformity - Deformity of the forearm and wrist leading to wrist abnormalities^1,5,6

Associated health issues of turner syndrome

People with TS have a higher likelihood of developing certain health conditions, although not everyone with TS will encounter these issues. Some commonly associated health conditions include: ^1,3,6,7 

• Neurocognitive and behavioural problems - Problems such as visual-spatial perception, executive functioning, and understanding maths. However, individuals often have strong language skills
• Heart and blood vessel problems - A higher risk of congenital heart defects such as bicuspid aortic valve, coarctation of the aorta, aortic valve stenosis, and others
• Urinary tract abnormalities - Structural problems in the kidney-urinary system are common in TS, including kidney hypoplasia, kidney agenesis, or horseshoe kidney. These issues can increase your risk of developing urinary tract infections (UTIs)
• Autoimmune conditions - TS increases the risk of certain autoimmune conditions

Turner syndrome and autoimmune diseases

An AFAB person with TS is at an increased risk of developing autoimmune diseases compared to the general AFAB population. The likelihood of developing autoimmune conditions rises with age, and they may experience multiple autoimmune diseases simultaneously.⁹

Common autoimmune diseases associated with turner syndrome

• Hashimoto's thyroiditis - This is an autoimmune disorder where your immune system attacks the thyroid gland, leading to hypothyroidism (underactive thyroid)
• Type 1 diabetes - An autoimmune condition where your immune system destroys insulin-producing beta cells in the pancreas, resulting in high blood glucose levels
• Alopecia areata - An autoimmune disorder where your immune system attacks your hair follicles, leading to hair loss on the scalp and other parts of your body
• Vitiligo - An autoimmune condition where your immune system destroys melanocytes, the cells responsible for producing your skin pigment, resulting in white patches on your skin
• Coeliac disease - An autoimmune disorder where ingestion of gluten leads to damage in your small intestine
• Inflammatory bowel disease (IBD) - IBD encompasses conditions like Crohn's disease and ulcerative colitis, where your immune system attacks the gastrointestinal tract, causing inflammation^10,11

Mechanisms linking turner syndrome and autoimmune diseases

The underlying pathophysiological mechanisms contributing to the increased risk of autoimmune diseases in TS remain partially unknown. However, both genetic factors and hormonal changes are suspected to play significant roles in this heightened risk. These include: ¹¹

• Role of the X chromosome - The X chromosome contains several genes that are crucial for immune system regulation. In TS, the complete or partial absence of one X chromosome disrupts the normal function of these genes, potentially leading to immune dysregulation and an increased risk of autoimmune diseases
• Oestrogen deficiency - In TS, oestrogen deficiency due to ovarian insufficiency may alter the balance of immune regulation, contributing to the development of autoimmune diseases

Diagnosis of turner syndrome

TS is typically recognised in childhood or at puberty due to its distinctive physical features. Nonetheless, it can occasionally be detected before birth through prenatal testing. Diagnostic criteria for TS include:^7,12

• Genetic testing (Karyotyping) - Karyotyping is the definitive test for diagnosing chromosomal abnormalities such as TS. This test involves analysing the chromosomes in a sample of blood taken after birth or amniotic fluid taken from the womb through amniocentesis to detect the presence of a missing or structurally altered X chromosome
• Clinical evaluation - Physical examination can reveal characteristic features of TS, such as short stature, webbed neck, low-set ears, and delayed puberty. Additional tests, such as echocardiograms and renal ultrasounds, may be conducted to assess associated abnormalities

Management and treatment of turner syndrome 

Given the complexity of TS and the lack of a cure a multidisciplinary management team involving endocrinologists, cardiologists, nephrologists, and other specialists is needed. Although TS cannot be cured, many of the associated symptoms and associated health issues can be managed and treated through the following measures:

• Growth hormone therapy - To improve height in AFAB people with TS. This involves daily injections of growth hormone, typically starting in early childhood and continuing until the growth plates close
• Oestrogen replacement therapy - To induce and maintain secondary sexual characteristics( breast and armpit and pubic hair). Oestrogen therapy usually begins around the age of puberty and may continue into adulthood^6,13
• Regular monitoring for associated health issues such as echocardiograms and blood pressure checks to manage heart anomalies and hypertension, and periodic renal ultrasounds to detect kidney abnormalities
• Screening for and treating autoimmune diseases
  • Regular monitoring for signs of autoimmune diseases through blood tests and clinical evaluations
  • Specific treatments for autoimmune diseases include:
    • Hashimoto's thyroiditis treatment - Thyroid hormone replacement therapy to maintain normal thyroid hormone levels
    • Type 1 diabetes treatment - Insulin therapy to control blood glucose levels
    • Coeliac disease treatment - A strict gluten-free diet to prevent symptoms and intestinal damage
    • Crohn's disease and ulcerative colitis treatment - Such as anti-inflammatory drugs, immunosuppressants, and biologics to control inflammation and manage symptoms
    • Alopecia areata treatments - May include topical corticosteroids, immunotherapy, and other medications to promote hair regrowth
    • Vitiligo treatments - May include topical corticosteroids, phototherapy, and other therapies to restore skin pigmentation¹⁴

Summary

Turner syndrome is a rare genetic disorder affecting only AFAB people, characterised by the partial or complete absence of one X chromosome. This condition leads to various physical features, such as short stature and gonadal dysgenesis, and an increased risk of associated health issues, including autoimmune diseases. 

The genetic and hormonal imbalances in TS, contribute to the higher incidence of autoimmune conditions like Hashimoto's thyroiditis, type 1 diabetes, and others. 

Diagnosis typically involves genetic testing and clinical evaluation, while management requires a multidisciplinary approach to address symptoms and associated health issues. 

Though TS cannot be cured, effective management can significantly improve the quality of life for those affected.