Symptoms And Characteristics Of Fragile X Syndrome In Girl

Overview

Fragile X syndrome is a group of conditions associated with changes occurring in the Fragile X gene, also known as the FMR1 on the X chromosome. Inheriting the mutated gene can result in genetic conditions in males and females. Fragile X Syndrome can cause physical, cognitive, behavioural and emotional symptoms in people. Read on to find out the symptoms of Fragile X syndrome in females, along with information on how to identify and manage the condition. 

A mutation in this gene, also known as the FMR1 present on the X chromosome, when inherited can result in Fragile X-associated Disorder (FXD) consisting of disorders that both males and females can inherit. 

Definition of fragile X syndrome (FXS)

Fragile X Syndrome (FXS) is a group of conditions caused by the full mutation of the FMR1 gene of the X chromosome. It can affect both males and females, though symptoms are more marked in the case of males, in intellectual, behavioural, and social development spheres.¹

The symptoms of Fragile X Syndrome present in females with a full mutation include a wide variety, and they are milder than males with a full mutation. The milder symptoms are attributed to the second unaffected X chromosome in females which can compensate for the mutation in the affected chromosome.¹ 

Females are less likely to present physical characteristics of Fragile X Syndrome, though common features include prominent ears, hyper-flexible joints or flat feet. They may experience mild to moderate learning difficulties related to visual-spatial, and executive functions (such as memory, thinking and processing thoughts). Social anxiety, difficulty in concentration or attention, and difficulty picking up social cues (which include body language, tone of voice and personal boundaries)  can be common behavioural characteristics, with an increased risk of experiencing anxiety.¹

Overview of fragile X syndrome

Genetic basis of FXS

Fragile X Syndrome is caused by a condition occurring in a gene known as the FMR1, found on the X chromosome. Did you know DNA (deoxyribonucleic acid) are the molecules that carry and transmit the genetic materials required for any organism to develop and grow? 

The DNA consists of chromosomes, thread-like structures that carry this genetic material, with 23 pairs. The FMR1 gene (also known as the Fragile X gene) is located on the X chromosome, and can undergo changes that affect a pattern of DNA called the CCG repeats when inherited.¹

An unaffected FRM1 gene carried by the majority population contains fewer than 55 repeats, while an intermediate range of 55-200 repeats is classified as a Fragile X premutation. Greater than 200 CCG repeats are classified as a full mutation of Fragile X Syndrome.¹  

In the case of a full mutation, the repeat region results in reduced production of the protein Fragile X Mental Retardation Protein (FMRP) causing the symptoms of Fragile X Syndrome. The protein is essential for synapses, which refers to the space between nerve cells needed for transmitting nerve impulses to develop. The condition is known as fragile X since a segment of the X chromosome appears broken or fragile under the microscope.¹

Prevalence and inheritance patterns

Fragile X Syndrome is a rare condition, expected to occur in one in every 2500-11,000 females and one in every 2500-7000 males. The severity of Fragile X is greater in males than in females, with different criteria of how it manifests in physical, mental, and behavioural characteristics.¹ 

Since the FMR1 gene is found on the X chromosome, sex differences are seen in the inheritance of Fragile X Syndrome. When males, possessing one X and Y chromosome, inherit the X chromosome with FMR1 full mutation from their mother, 100% of their X chromosomes are at risk of being fully affected. Females on the other hand have two X chromosomes, hence on inheriting the X chromosome with FMR full mutation from the mother and an unaffected X chromosome from their father, have only 50% of chromosomes potentially affected.¹   

The second unaffected chromosome allows for the production of some amount of FMRP, resulting in milder symptoms of the syndrome in females.¹  

Symptoms and characteristics of FXS in females

The symptoms of Fragile X Syndrome in females can be wide-ranging and affect various spheres of functioning. Symptoms are milder in females than males, though they can pose challenges if not managed. 

These symptoms can range from physical characteristics to cognitive and developmental issues, influencing behavioural characteristics and sensory issues. 

Physical features

1. Facial features: Females with Fragile X Syndrome may exhibit distinctive facial features seen in males, such as a long face, prominent ears, and a high forehead, though they are less pronounced
2. Connective tissue issues: Hypermobility of fingers, wrists, elbows and joints and soft, velvety textured skin may be present
3. Macrocephaly: In some cases, individuals may have an abnormally large head size compared to the rest of their body, though it is more common in males
4. Hand and finger features: Long, slender fingers and a single crease across the palm (simian crease) may be present
5. Other features: Females with Fragile X Syndrome may also exhibit additional physical characteristics such as flat feet and low muscle tone, though these can vary in their presence and severity^1,2

Cognitive and developmental issues

Fragile X Syndrome can affect the cognitive functioning of a person. In the case of females, it may cause mild to moderate intellectual disability. They may present with challenges related to: 

• Executive functioning: a set of skills related to managing time, paying attention, planning and organising, remembering details and multi-tasking controlled by the frontal lobe of the brain 
• Spatial and visual reasoning: a set of skills related to the ability to visualise and manipulate shapes, patterns and visual stimuli in your mind
• Mathematical skills: skills related to understanding and manipulating numerical data 

The discrepancy in cognitive function between those assigned females at birth (AFABs) with Fragile X and their typically developing peers is larger for IQ than academic achievement scores. 

Studies have shown that the decline in executive functioning was associated more with a slowing rate of acquisition of new skills rather than a loss of existing skills. However, other aspects of intelligence like verbal fluency and spatial ability remained constant.^1,2

Socio-emotional characteristics  

Females with Fragile X Syndrome have been observed to have issues related to dysregulation of anxiety, avoidance and arousal behaviours. 

Studies have shown that females with Fragile X Syndrome are more vulnerable to social anxiety and avoidance, developing from shyness in childhood. The risk of developing anxiety and related disorders such as specific phobias, social phobias and selective mutism is greater.¹  

Moreover, they also tend to exhibit greater deficits in interpersonal and social skills compared to peers. A greater degree of gaze aversion, task avoidance and behavioural signs of distress is seen in females with Fragile X Syndrome compared to their same-sex typically developing siblings.¹ 

A higher probability of having attention deficit hyperactivity disorder (ADHD) and autism compared to peers has also been suggested.¹

Despite a higher extent of adaptive behaviours compared to male peers, these have been observed to decline throughout childhood. Though they exhibit functional skills, females with Fragile X Syndrome may face challenges related to communication in social settings.¹

Emotional issues 

Fragile X Syndrome can increase the risk of anxiety and mood issues, such as mood swings and depression in individuals. Females with Fragile X Syndrome are thus at a higher risk of having depression and related disorders.¹  

Diagnosis of fragile X syndrome in females

Since AFAB people with Fragile X Syndrome often do not exhibit or exhibit milder symptoms, diagnostic tests are required to identify whether a premutation or a full mutation exists. Different techniques can be used for diagnosis, such as: 

1. Clinical evaluation: A healthcare provider, such as a paediatrician or geneticist, will conduct a thorough clinical evaluation of the individual, looking for physical characteristics and developmental features that are associated with Fragile X Syndrome
2. Family history: Information about the individual's family history, especially regarding any relatives who may have intellectual disabilities or developmental delays, can provide important clues for diagnosis
3. Genetic testing: The primary method for diagnosing Fragile X Syndrome is through genetic testing, specifically a DNA test to analyze the FMR1 gene. This typically involves a blood sample or sometimes a saliva sample. There are two main types of genetic tests used:
   • FMR1 DNA test: This test detects the number of CGG repeats in the FMR1 gene. More than 200 repeats are usually diagnostic of Fragile X Syndrome
   • Molecular genetic testing: This test examines the DNA sequence of the FMR1 gene to confirm the presence of a mutation^1,2

Summary

Fragile X Syndrome manifests differently in males and females. Though the symptoms are milder and more manageable in females, they can still impact their lives. Hence, it is important to understand the different characteristics of Fragile X syndrome, the increased risk of developing specific disorders, as well as influence of adaptive skills. Adequate understanding of the condition and timely management can improve the quality of life of the individual.