Fragile X Syndrome

Epidemiology and Genetics

Epidemiology

• Most common inherited cause of intellectual disability and 2nd-most common genetic cause (behind Down’s syndrome)
• Incidence of classic Fragile X syndrome:
  • 1 in 3,600–4,000 live births in boys 
  • 1 in 4,000–6,000 live births in girls

Genetics

Fragile X syndrome (FXS) occurs due to a loss of function mutation in the fragile X mental retardation 1 (FMR1) gene on the X chromosome. FMR1 codes for fragile X mental retardation protein (FMRP), which is important in brain and gonadal (testes and ovaries) development.

More than 99% of cases are due to unstable trinucleotide (CGG) repeat expansion in the promoter region of the FMR1 gene:

• Classic fragile X phenotype (full mutation) results from > 200 repeats → abnormal methylation → silencing of the FMR1 gene → reduced/loss of FMRP
• Approximately 50–200 repeats is considered a premutation (normal < 40 repeats) → leads to a functional FMR1 gene with production of FMRP, although not fully normal
  • Less severe clinical manifestations present.
  • Allele is unstable and may become a full mutation in future offspring/generations.
• Length/size of the repeat expansion correlates with the severity of clinical manifestations (↑ expansion repeat → higher severity of condition)

The inheritance pattern is X-linked dominant:

• Boys more severely affected than girls due to boys only having 1 X chromosome
• Girls may have > 200 repeats on 1 allele on 1 X chromosome but not the other
• In girls’ cells, 1 X chromosome is inactivated, potentially limiting the effects of the mutation.

Clinical Presentation

Girls and those with premutations have variable and often less severe clinical manifestations. The following are the clinical features of patients with classic FXS (full mutation).

Clinical phenotype in boys

• Outer appearance: 
  • Tall stature
  • Macrocephaly (large head) with increased brain volume
  • Prominent facial features: long face, prominent forehead, prominent chin
  • Large ears
  • High arched palate 
  • Flat feet
  • Macroorchidism (enlarged testes, albeit with normal function) occurs after onset of puberty.
  • Hyperextensible joints, particularly thumbs and finger
  • Low muscle tone in infancy
  • Noticeable motor delay
• Cognition/intelligence:
  • Global developmental delay
  • Intellectual disability: IQ worsens with increase in age.
  • Learning disabilities, particularly with math/quantitative skills and visuospatial abilities
  • Delay in language development 
    • More difficulty with expressive than receptive language skills
    • Articulation poor, speech repetitive 
    • Approximately 10% remain nonverbal.
  • Decline in executive functioning and memory compared with peers worsens over time.
• Behavioral abnormalities:
  • Attention deficit hyperactivity disorder (ADHD)–like symptoms
    • Hyperactivity/impulsivity
    • Inattention/short attention span
  • Anxiety symptoms
    • Social anxiety
    • Panic attacks
    • Obsessive-compulsive disorder–like activities/obsessions
  • Autism spectrum disorder
    • 18%–67% meet criteria for autism spectrum disorders.
    • Boys with FXS and autism have greater cognitive and behavioral disabilities than those with FXS alone.
    • Characterized by:
      • Difficulty with social interactions, understanding social cues, and forming peer relationships
      • Gaze aversion and poor eye contact
      • Repetitive motor patterns (e.g., hand flapping, rocking, toe walking)
      • Echolalia/repetition of words and sounds
      • Hypersensitivity to environmental stimuli
      • Self-injurious behaviors (e.g., head banging, nail-biting)

Clinical phenotype in girls

• Approximately 50% with full mutation have normal intellect, remainder have borderline to mild intellectual disability.
• Approximately 50% have similar yet milder physical and behavioral features to boys, as seen above.

Associated conditions

• Vision: refractive errors, strabismus, and amblyopia
• Neurological: Seizures occur in 10%–20% of FXS cases.
  • Most common types: simple or complex partial seizures
  • Predominantly present in early childhood, then spontaneously resolve
• Cardiac: mitral valve prolapse, mitral regurgitation

Diagnosis

Prenatal diagnosis

• Amniocentesis
• Chorionic villus sampling

Postnatal diagnosis

• History and clinical examination
• Genetic testing:
  • Count CGG repeats on the X chromosome: > 200 repeats on 1 allele marks the diagnosis in girls.
  • Recommended in children who have characteristic physical or behavioral features and present with the following:
    • Developmental delay
    • Borderline intellectual abilities/disability
    • Diagnosis of autism without specific etiology
  • Recommended in adults who present with the following:
    • Physical features and unspecified intellectual disability
    • Women with premature ovarian failure (ovaries stop working before 40 years of age)
    • Patients > 50 years of age with progressive cerebellar ataxia and intention tremor
• Additional testing: echocardiogram (echo) to evaluate for mitral valve prolapse

Management

There is no curative treatment for FXS. Treatment is tailored to the symptoms present. Supportive therapy includes the following:

Educational treatment

• Early intervention
• Special education
• Speech and language therapy
• Vocational training
• Avoidance of stimulants, which trigger hypersensitivity and specific behaviors

Medical treatment

• Stimulants for ADHD, under strict monitoring
• Selective serotonin reuptake inhibitors (SSRIs) for anxiety and mood swings
• Anticonvulsants to control seizures and alleviate mood issues
• Antidepressants and antipsychotics to treat self-injurious and aggressive behaviors

Other

• Strabismus correction
• Genetic counseling

Clinical Relevance

Differential diagnosis

The following conditions are differential diagnoses of FXS:

• Prader-Willi syndrome (PWS): a genetic condition that is rarely inherited and is caused by a loss of functional genes on chromosome 15. Patients have similar physical, cognitive, and behavioral features as FXS; however, these patients display hyperphagia (overeating) and obesity. Approximately 10% of boys with FXS have a Prader-Willi phenotype, but not the genetic changes seen with PWS. Genetic testing aids in diagnosis. Treatment is supportive.  
• Klinefelter syndrome: a genetic condition affecting boys, characterized by the presence of 1 or more extra X chromosomes, most commonly leading to the karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Affected persons are typically tall and have small testes, decreased body hair, gynecomastia, and infertility. Treatment consists of life-long testosterone replacement therapy. 
• Sotos syndrome: also known as cerebral gigantism, a rarely familial genetic condition typically caused by a sporadic gene mutation. Patients have similar facial features as well as cognitive and behavioral abnormalities as in FXS. However, they have extreme growth in early childhood followed by premature epiphyseal fusion (growth plate closure) and advanced bone age. Diagnosis is made through genetic testing. Treatment is supportive. 
• Autism spectrum disorder: a neurodevelopmental disorder with early-childhood onset, characterized by poor communication and social skills as well as repetitive and stereotyped behaviors. Intellect is variable and may even be advanced. No association with specific physical features. Diagnosis is clinical based on history and behaviors. Testing may be done to evaluate for underlying or coexisting conditions. Early diagnosis and supportive therapies are important to improve the outcome. May occur with or without concurrent diagnosis of FXS.
• ADHD: a mental health disorder characterized by hyperactivity/impulsivity and inattentiveness that affects cognitive, behavioral, and social functioning. The disorder is not associated with any specific physical features. Diagnosis is clinical with extensive multifaceted medical, behavioral, emotional, and educational evaluations. Treatment involves stimulant medications, psychotherapy, and behavioral and educational interventions. May occur with or without concurrent diagnosis of FXS.

Related conditions

The following are conditions of concern for those with premutations for FXS.

• Premature ovarian failure: hypogonadotropic hypogonadism in women before the age of 40. Associated with menstrual irregularities, symptoms of estrogen deficiency (e.g., hot flashes, vaginal dryness, and osteoporosis), and, possibly, difficulty conceiving. Laboratory testing of hormone levels aids in diagnosis. As premature ovarian failure is associated with an FXS premutation, genetic testing for FXS premutation is warranted. Management involves hormone replacement therapy and addressing reproductive and associated mental health issues. 
• Tremor/ataxia syndrome: a progressive neurodegenerative disorder seen in individuals over 50 years of age with a premutation for FSX. Men are affected more than women. Clinical features include early-onset dementia or cognitive decline, late-onset ataxia (difficulty with movements such as walking), postural tremors, proximal lower limb weakness, and peripheral neuropathy. Genetic testing confirms the diagnosis. Treatment is supportive, with medications and therapy. There is no cure for the syndrome.