present resulting in a milder presentation . 3 , 5 However , up to 30 % of females with the full mutation may | |||||||
still present with borderline range | |||||||
intellectual ability , with 25 % being | |||||||
affected by low intellectual ability ( IQ ). 8 The phenotype in females is usually less severe but more frequently | |||||||
associated with learning disabilities , | |||||||
socio-emotional difficulties and mental | |||||||
health issues . 5 | |||||||
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EPIDEMIOLOGY
THE prevalence of full mutation FXS
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is approximately 1:5000 in the general population . 1 Estimates vary widely , but FXS is thought to occur in 1.4 | |||||||
per 10,000 males and 0.9 per 10,000 | |||||||
females , making it the most common | |||||||
inheritable cause of intellectual | |||||||
disability . 4 | |||||||
However , the prevalence of premutation | |||||||
carriers is far more common , | |||||||
affecting up to 1:300-450 males and | |||||||
1:150-200 females . 2 |
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DIAGNOSIS
Physical symptoms
IT is difficult to make a diagnosis of
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Figure 1 . Chromosome in fragile X syndrome . |
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FXS at birth , as most signs and symptoms develop later . The newborn may present with hypotonia and feeding problems , which may include sucking or latching difficulties with breastfeeding , and reflux . 2 , 3
Delays in gross motor skills such as sitting , crawling and walking because of hypotonia may be a presenting feature before two years of age . 2 The cause of the hypotonia appears to be due to a generalised CNS dysfunction that occurs in FXS .
After the age of two years , speech and language delay become noticeable , especially in males . As these children get older , global developmental delay , specific learning disabilities and
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Unaffected father
XY
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Carrier mother
XX
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Box 1 . Physical features of FXS may include
• Large ears often present in prepubertal males .
• Long and narrow face .
• Prominent forehead and chin .
• High arched palate ( see figure 8 ).
• Flat feet .
• Hyperflexible joints .
• Hypotonia .
• Heart murmurs : mitral valve prolapse .
• Macro-orchidism in males ( often only present in adolescence ).
• Seizures .
• Recurrent otitis media .
• Gastrointestinal disturbances .
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behavioural presentations , including |
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sensory disorders , anxiety , autism and |
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ADHD , may become evident . 9
The signs and symptoms in
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Box 2 . Behavioural issues |
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box 1 may alert the GP to test for FXS . A definitive diagnosis is made on DNA testing on blood taken from the affected child .
Physically , the classical features of a long and narrow face and prominent ears are not always present prepubertally . They become more obvious as the child gets older ( see figures 3 , 4 and 5 ). A long face is clinically noticeable in 80 % of adult males with a full
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XY |
XX |
XX |
XY |
• Hand flapping and / or biting .
• Gaze avoidance .
• Hyperarousal to sensory stimuli .
• Impulsivity .
• Aggression .
• Social anxiety .
• Mood disorders .
• Shyness .
• Sleep issues .
• Significant anxiety .
• Hyperactivity .
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mutation . 9 |
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A high arched palate is a common sign of FXS , and these children may present with malocclusion and dental crowding . 9 Macro-orchidism occurs in 80 % of adolescent and adult males . |
Unaffected son |
Unaffected daughter |
Carrier or affected daughter |
Affected son |
common manifestations . 6 , 8 Behavioural markers which may indicate anxiety , include eye gaze avoidance , fidgeting or physical discomfort , hand |
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Although men with FXS are fertile , their behavioural issues and low IQ generally prevent the occurrence of frequent sexual encounters . 9 |
Figure 2 . There is a 50 % chance of a mother passing on her affected X chromosome equally to her sons and daughters . |
biting , fleeing from or refusal to be part of the situation and behavioural distress . 6 The condition is often debilitating , with care givers reporting anx- |
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Hypermobility , flat feet ( see figure 6 ), mitral valve prolapse and hernias are more common in FXS . These are thought to be the result of disordered collagen resulting in connective tissue problems . 10 If a click or murmur is heard on cardiac auscultation , refer for an echocardiogram and cardiac assessment to confirm / exclude mitral valve prolapse . 10
Otitis media ( see figure 7 ) occurs more frequently in children with FXS
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neurological abnormality in FXS . These usually occur before the age of five years and are more common in males ( 16 %) than females ( 5 %). 10 Most seizures begin in childhood or adolescence and cease before adulthood . Although generalised seizures may occur in some children with FXS , partial seizures are more common . 9 Routine EEGs are not recommended . 9
Strabismus is seen in around 30 % of patients . Treatment may include
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may occur in female carriers with the premutation ( see Therapy Update : Loss of ovarian function in younger women ). Evaluate females under age 40 who have amenorrhoea , menstrual dysfunction or infertility , often associated with anxiety , depression or sleep disturbances , for FXS . 11
Behavioural symptoms
Behavioural symptoms usually present
in early childhood ( see box 2 ).
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affect . 4 Anxiety , avoidance and arousal are the behavioural issues most commonly encountered . 5
There is a close correlation between the presence of FXS , ASD and ADHD . More than 60 % of boys with FXS are diagnosed with concomitant ADHD , ASD or both . 8 The DSM-5-TR diagnostic criteria for ASD are met in 60 % of males with FXS and 20 % of females . 7 An important difference between children with ASD alone and
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iety as the most disabling problem for individuals with FXS . 11 Shyness and social anxiety are especially common in children with FXS and more noticeable as they grow older . 2 The social anxiety impacts all areas of functioning for the individual and family , including education , daily activities and socialisation . 2 Even though females with FXS are more highly functioning both cognitively and verbally , the spectrum of anxiety-related |
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and is more common under the age of three years . 1 , 10 It is important that these infections are detected and |
patching to strengthen the weak eye , or surgery . 1
Hypertension has been noted in
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These symptoms are usually more severe in males than in females . 2
Individuals with FXS exhibit a
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those with both ASD and FXS is the anxiety component , with those diagnosed with both ASD and FXS showing |
behaviours is overall quite similar in both sexes . 5
Social avoidance can begin from
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treated , to prevent conductive hearing |
men with FXS ; this is thought to occur |
range of developmental and psychi- |
heightened signs of anxiety . 1 |
as early as four months of age , and |
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loss and further speech and language |
because of their anxiety . Evaluate per- |
atric symptoms , including anxiety |
Anxiety occurs in up to 80 % of |
increase in severity through child- |
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issues . 9 , 10 Seizures are a common |
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