Prominent characteristics of the syndrome include an elongated face and large or protruding ears. Most young children do not show any physical signs of<unk> . It is not until puberty that physical features of<unk>  begin to develop. Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with<unk>  also meet the diagnostic criteria for autism. Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of<unk> , while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal<unk>  chromosome. Females with<unk>  may have symptoms ranging from mild to severe, although they are generally less affected than males. Physical phenotype * Large, protruding ears (both) * Long face (vertical maxillary excess) * High-arched palate (related to the above) * Hyperextensible finger joints * Hyperextensible thumbs ('double-jointed') * Flat feet * Soft skin * Postpubescent macroorchidism (large testicles in men after puberty) * Hypotonia (low muscle tone) Intellectual development Individuals with<unk>  may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene. Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with<unk>  are with working and short-term memory, executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected. Data on intellectual development in<unk>  are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children. Individuals with<unk>  often demonstrated language and communicative problems. This may be related to muscle function of the mouth and frontal-lobe deficits. Autism<unk>  co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with<unk> , prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with<unk>  not meeting the DSM criteria for an ASD. Although individuals with<unk>  have difficulties in forming friendships, those with<unk>  and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in<unk> , with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD. When both autism and<unk>  are present, a greater language deficit and lower IQ is observed as compared to children with only<unk> . Genetic mouse models of<unk>  have also been shown to have autistic-like behaviors. Social interaction<unk>  is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with<unk> , with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. Social anxiety in individuals with<unk>  is related to challenges with face encoding, the ability to recognize a face that one has seen before. It appears that individuals with<unk>  are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder. Females with<unk>  frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety. Individuals with<unk>  show decreased activation in the prefrontal regions of the brain. Mental health Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with<unk>  and 30% of females, making it the most common psychiatric diagnosis in those with<unk> . Children with<unk> <unk>  have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong. Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with<unk> , with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. Children with<unk>  pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with<unk> . Behavioral therapy can be used to decrease the child's sensitivity in some cases. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety. Perseveration is a common communicative and behavioral characteristic in<unk> . Children with<unk>  may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches. Although only a minority of<unk>  cases will meet the criteria for obsessive–compulsive disorder (OCD), a significant majority will have symptoms of obsession. However, as individuals with<unk>  generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors. Mood symptoms in individuals with<unk>  rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression. Individuals with<unk> <unk> -associated tremor/ataxia syndrome (FXTAS) are likely to experience combinations of dementia, mood, and anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism. Vision Ophthalmologic problems include strabismus. This requires early identification to avoid amblyopia. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with<unk>  are also common. Neurology Individuals with<unk>  are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature. In larger study populations the frequency varies between 13% and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication. Individuals who are carriers of premutation alleles are at risk for developing<unk> <unk> -associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease. It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline. Working memory From their 40s onward, males with<unk>  begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory. Fertility About 20% of women who are carriers for the<unk> <unk>  premutation are affected by<unk> <unk> -related primary ovarian insufficiency (FXPOI), which is defined as early menopause, which is menopause occurring between 40 and 45 years of age (menopause normally occurs between 45 and 55 years old). The number of CGG repeats correlates with penetrance and age of onset. However premature
Fragile X syndrome
Trichothiodystrophy
Rett syndrome
Fragile X-associated tremor/ataxia syndrome
X-linked dystonia parkinsonism
Foster Kennedy syndrome
Krabbe disease
Joubert syndrome