Turner Syndrome is a chromosomal disorder that only affects females and is characterised by the whole or partial loss of one X chromosome of the sex chromosomes. It goes beyond having a short stature. It includes a range of physical and developmental traits such as renal abnormalities, hearing loss, cardiac abnormalities like coarctation of the aorta, ovarian dysgenesis, and more. Growth hormone therapy is often used as an intervention to address this growth deficiency in affected individuals. It is also able to mitigate associated health risks such as osteoporosis and cardiovascular complications that come with Turner Syndrome. 

Introduction

Turner Syndrome (TS) is also known as congenital ovarian hypoplasia syndrome. It is a common sex chromosomal abnormality that is found exclusively in females.¹ The sex chromosome consists of two X chromosomes (XX) for females and one X and Y chromosome (XY) for males. TS occurs when one of the X chromosomes from the female is missing, either partially or completely. This abnormality occurs due to errors during the formation of gametes in the parents. 

The Human growth hormone is originally derived from the pituitary gland, but for those with growth hormone deficiency or short stature, growth hormone therapy (GHT) is administered. In the case of TS, there is haploinsufficiency of the short (p) arm, which has the short stature homeobox gene, causing people with TS to have a shorter build than average. GH is injected subcutaneously at night to mimic the innate secretion of GH, which usually peaks at night.2 Based on research, it can be noted that depending on the dose of GH and the age, recombinant human GH replacement has greatly improved the height potential of females with TS, albeit with varied results.³

Understanding Turner Syndrome

While the exact cause and occurrence of TS development can differ, it is most likely a random event of nondisjunction that causes an abnormal amount of reproductive chromosomes during the cell division stage of early foetal development. 

The probability of cases of TS are either:

• onosomy, which has one chromosome missing with 50% probability, or 
• mosaic chromosomal component with 50% probability. Some variations of mosaic chromosomal components are:
  • Isochromosome Xq (two copies of long (q) arm connected head to head) 
  • Ring chromosome (parts of short (p) and long (q) arm missing)
  • Xp or Xq deletion (parts of p and q arms deleted)

Unlike other more obvious conditions, the prevalence of TS is harder to determine due to people with milder phenotypes of TS having late diagnosis or no diagnosis.¹

TS looks different for each individual, but the following lists, the common features and symptoms that often appear:

• Shorter stature: In relation to their parents’ heights, they can be shorter by up to 20%. On average, it can reach 20 cm shorter than the average female height⁴
• Dysmorphic features: webbed neck, broad chest with widely spaced nipples, nail dysplasia, narrow and high-arched palate
• Lack of sexual characteristics: primary amenorrhoea (lack of menstruation), streak ovaries (impaired development of the gonads – ovaries), lack of secondary sexual characteristics (eg. breasts development)
• Cognitive functions: people with TS have normal intelligence but may have specific neurocognitive deficits that could impact learning abilities
• Cardiac malformations: coarctation of the aorta, aortic valve abnormalities, pulmonary venous anomalies
• Bone health: Elevated risk of fractures and inadequate bone mineral density
• Risk for comorbidities: Some possible comorbidities that could develop are Celiac disease, metabolic syndrome, autoimmune thyroiditis, gonadoblastoma, and more

The conditions of each individual differ; some may have a more severe case that consists of several features and symptoms, while others may have milder phenotypes that do not impact quality of life and health a lot. 

Role of growth hormone therapy

Growth hormone (GH) administration causes:

• A direct effect: where they bind to target cells to stimulate a growth response
• An indirect effect: where the increased GH binding to surface GH receptors causes stimulation and secretion of insulin-like growth factor-1 (IGF-I)

IGF-I is secreted in hepatocytes, and alongside GH, are responsible for promoting growth of bones and tissues.⁵

Due to haploinsufficiency (insufficient haploidy in chromosome) on the short stature homeobox gene, which is located on the short (p) arm of the X chromosome (also called SHOX), people with TS turn out shorter than usual. By utilising GHT, it is able to exacerbate growth retardation, and also stimulate linear growth. Not only benefiting from growth, but GH can also expose underlying scoliosis conditions when supporting body growth. Studies have shown differing results, where GH has been proven to be effective and ineffective. Through these studies, a conclusion can be made that the discrepancy in the results is dependent on several factors, such as the dose of GH, age of starting GHT, ethnic and genetic differences, and use of randomised untreated controls.⁶

Apart from inducing growth in tissues, GH also mitigates apoptosis (a type of cell death) and prolongs the lifespan of existing cells.⁵ GH stimulates an increased rate of gluconeogenesis (production of glucose from carbon skeletons), leading to an overall hyperglycemic state in the bloodstream due to the increased glucose uptake from cells. 

Clinical management of Turner syndrome with GHT

The diagnostic criteria for TS is dependent on the clinical presentation, and also the administration of genetic testing. Genetic testing is required in order to differentiate between TS and Noonan Syndrome, which display similar clinical presentation. 

Following the diagnosis of TS, the clinical management includes evaluation of abnormalities normally associated with TS, including cardiac anomalies, renal anomalies, and learning disabilities.¹ In addition, the benefits of GHT are evaluated per case as the needs of each person differ through tests like radiographic assessment of bone age and measurement of IGF-I levels. As TS affects so many different aspects of the body, a multidisciplinary approach can ensure quality and accurate care for all conditions. 

For those who are able to benefit from GHT, their dose of GH is also personalised. For children, their dose is dependent on their body weight and is often adjusted and determined by the doctor. The usual weekly dose in total is 0.375 mg per kg of body weight, which is then divided into smaller doses per day and administered subcutaneously at night.⁸ Throughout treatments (often not limited to GHT), the patient is monitored for presenting TS abnormalities such as possible scoliosis presentation, aortic coarctation, audiology evaluations, orthopaedic issues, eye abnormalities, and/or other complications.¹

Efficacy and safety considerations

Turner’s Syndrome is often a lifelong diagnosis and requires consistent care and support from healthcare and caretakers. On the physical aspect, TS needs a multidisciplinary approach including cardiology, endocrinology, ophthalmology, audiology, and nephrology. While TS is a biological condition that affects those with TS on the physical aspect, it still could cause psychosocial impairments that can decrease quality of life. People with TS also need support in the mental and emotional aspects. Patients with TS often have a negative psychosocial impact due to depression and low self-esteem.¹⁰ While studies have shown that this impact is also influenced by the socioeconomic status factor, it is still imperative that all patients with TS should have access to essential information and care. Such support services include access to psychiatric care and/or therapy, which allow patients to continue to seek a better quality of life with support and advice from professionals. 

Summary

Due to a sex chromosome defect, Turner syndrome, which is characterised by monosomy/mosaic chromosomal abnormalities, causes a variety of health issues. A method used to lessen these difficulties is GHT, which aims to enhance quality of life and guarantee physical safety. Other methods involving a multidisciplinary approach are essential. To fully address the various medical, psychological, and social elements of the illness, a diverse array of medical professionals and specialists is needed.

There is hope for better results and quality of life for those with Turner Syndrome, despite its complexity. Future research into the illness and the development of more potent treatments may benefit from the incorporation of genetic and molecular technologies. This hope emphasises how crucial it is to continue conducting research and using a multidisciplinary approach in order to provide patients with Turner syndrome with comprehensive care.