12.4.6 Behavioural phenotypes and specific syndromes

What a behavioural phenotype is

• A behavioural phenotype is a pattern of behaviour linked to a syndrome at group level. It does not predict how each person will behave.

• Features vary within a syndrome and also occur outside it, so behaviour alone does not establish a genetic diagnosis.

• A phenotype guides surveillance. It does not justify automatic restrictions, and it does not replace the search for pain, illness or environmental causes of new behaviour.

Imprinting at 15q11-q13: Prader-Willi and Angelman syndromes

The same region of chromosome 15 gives two different syndromes, and the parent of origin decides which.

Prader-Willi syndrome

• In infancy the baby has neonatal hypotonia and poor feeding or failure to thrive.

• In childhood insatiable hyperphagia follows, with food seeking, foraging and hoarding.

• Skin picking is characteristic, together with temper outbursts and rigid insistence on routine.

• People have short stature and hypogonadism (micro-orchidism), not tall stature, and may have daytime sleepiness.

• Maternal uniparental disomy carries the highest risk of later psychosis, often affective, compared with paternal deletion.

• Hyperphagia risks choking, gastric dilatation, obesity and diabetes. Restricting access to food needs consent or another lawful basis, and it must be proportionate and reviewed.

Angelman syndrome

• Intellectual disability is typically severe to profound.

• The disposition is happy and excitable, with frequent, easily provoked laughter that is often out of context.

• Speech is absent or minimal, and understanding is better than speech.

• The gait is jerky, ataxic and wide-based, with the arms raised.

• Hand flapping, a fascination with water and poor sleep are typical.

• Acquired microcephaly means the head is a normal size at birth and then falls behind.

• The face has a wide mouth, widely spaced teeth and a protruding tongue.

• Epilepsy is commoner than in any other intellectual disability syndrome. It usually begins before age three, and atypical absences and myoclonic seizures are common.

Down syndrome

Physical features and karyotype

• Down syndrome (trisomy 21) is recognised at birth by upslanting palpebral fissures, epicanthic folds, hypotonia, a single palmar crease and a congenital heart defect.

• Developmental delay and intellectual disability emerge over infancy.

• Atrioventricular septal defect is the commonest heart defect in Down syndrome and the one most strongly tied to it.

• The hands are short and broad, with a single transverse palmar crease, fifth finger clinodactyly, syndactyly and altered dermatoglyphics.

• Mosaic trisomy 21, in which only some cells carry the extra chromosome 21, gives a milder phenotype and intelligence in the normal range.

• Free trisomy, Robertsonian translocation, isochromosome 21q and ring chromosome 21 do not carry this milder picture.

• Private speech, talking or mumbling to oneself, is a characteristic part of the behavioural phenotype.

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Alzheimer's disease

• Alzheimer-type neuropathology (amyloid plaques and neurofibrillary tangles) is near universal from the fifth decade.

• The extra copy of the amyloid precursor protein (APP) gene on chromosome 21 drives this pathology.

• Apolipoprotein E (APOE) genotype, and the family history that reflects it, changes the age at which dementia begins. Comorbidities, karyotype subtype and severity of intellectual disability do not.

• Dementia often first shows as frontal-type personality and behavioural change (apathy, withdrawal, irritability) rather than memory loss.

• In one cohort the median age was about 50 for prodromal disease and 54 for dementia.

• New apathy or lost skills can also come from thyroid disease, sleep apnoea, sensory loss or depression, and these causes are looked for.

• NICE recommends recording adaptive function as a baseline in adulthood, so that later decline can be measured against it.

Fragile X syndrome

Genetics

• Fragile X syndrome is an X-linked CGG repeat expansion in FMR1 that silences the gene.

• It passes through carrier women, so the family tree often shows an affected maternal uncle or great-uncle.

• Females are more mildly affected than males because they have a second X chromosome.

• Fragile X is the commonest inherited cause of intellectual disability.

• Premutation carriers can develop primary ovarian insufficiency (women) or fragile X-associated tremor ataxia syndrome (older men).

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Physical features

• The face is long, with a prominent jaw and large prominent ears.

• Lax finger joints, mitral valve prolapse and macro-orchidism after puberty are typical.

• The head is relatively large, whereas many intellectual disability syndromes carry microcephaly.

Behaviour and language

• Social anxiety is prominent: people are shy and avert their gaze even though they want social contact.

• Hand flapping, hand biting, hyperactivity and autistic features are common.

• Speech is rapid, cluttered and perseverative, with palilalia and echolalia.

• Syntax is relatively spared for mental age, while conversational use of language and auditory processing are impaired.

• Psychosis is uncommon, affecting fewer than one in ten people with the full mutation.

• Interviewers should not demand eye contact from someone who finds it distressing.

22q11.2 deletion syndrome

This is also called velocardiofacial or DiGeorge syndrome. It is the commonest human microdeletion syndrome, at roughly 1 in 2,000 to 4,000 births.

Its multisystem cluster is known as CATCH-22.

• About a quarter to a third of adults develop schizophrenia or another psychotic disorder, roughly twentyfold the population rate.

• Psychosis emerges in late adolescence or early adulthood.

• The deletion is the strongest single known genetic risk factor for schizophrenia.

Williams syndrome

• Williams syndrome is a contiguous gene microdeletion at 7q11.23 that includes the elastin gene, which explains the supravalvular aortic stenosis.

• Physical features are supravalvular aortic stenosis, infantile hypercalcaemia, elfin facies, full lips, periorbital fullness and a stellate iris.

• People are overfriendly and indiscriminately sociable towards strangers, which can make them vulnerable.

• Expressive language is fluent, but visuospatial construction is markedly impaired. Fluent replies can outrun understanding, so understanding has to be checked.

• Hyperacusis (fear of loud noises), a love of music and anticipatory anxiety are typical.

• Among common genetic causes of intellectual disability, anxiety is most strongly linked to Williams syndrome, particularly specific phobia and generalised anxiety that persist into adulthood.

• Attention deficit hyperactivity disorder is also common.

Smith-Magenis syndrome

• Smith-Magenis syndrome follows an interstitial deletion at 17p11.2 involving the RAI1 gene, or a mutation of RAI1.

• The face is broad and square, with brachycephaly and a hoarse voice.

• The melatonin rhythm is inverted, peaking by day, which causes night waking, very early rising and daytime sleepiness.

• New self-injury still needs assessment for pain, sleep loss, medication effects, environmental change and unmet communication needs.

• Prolonged-release melatonin is licensed for children with neurogenetic disorders whose insomnia persists despite good sleep hygiene.

Lesch-Nyhan syndrome

• Lesch-Nyhan syndrome is an X-linked recessive deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT1, Xq26), so affected children are boys.

• The body overproduces uric acid, so urate crystals appear in the nappy, and kidney disease and gout can follow.

• The behavioural hallmark is compulsive, tissue-destroying self-biting of the lips, tongue and fingers.

• The self-injury is unwanted, so restraint brings relief, and some people ask for protection.

• Motor features are dystonia, choreoathetosis and spasticity.

• Simple extinction programmes are avoided, and management draws on neurological, behavioural and safety expertise.

Rett syndrome

• Rett syndrome results from mutation of the MECP2 gene at Xq28, usually a new mutation.

• It is X-linked dominant and seen almost only in girls, because hemizygous males rarely survive infancy.

• Early development is apparently normal and is followed by regression.

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• Other features are slowing head growth, irregular breathing while awake, and epilepsy.

• Night sleep is disturbed by difficulty settling and frequent waking, with excessive daytime sleepiness and napping.

Cri-du-chat syndrome

• Cri-du-chat syndrome is a deletion of the short arm of chromosome 5 (5p).

• Laryngeal anomalies give the infant a high-pitched, cat-like mewing cry.

• Other features are neonatal hypotonia, microcephaly, a round face, hypertelorism and severe intellectual disability.

• The behavioural phenotype includes hyperactivity, self-injury, stereotypies, sensitivity to noise, and understanding that runs ahead of speech.

Cornelia de Lange syndrome

• Cornelia de Lange syndrome is usually caused by a variant in NIPBL, a cohesin regulator.

• Hypertrichosis shows as synophrys, long lashes and body hirsutism.

• The face has a long smooth philtrum, a thin downturned upper lip and upturned nostrils, and limb reduction defects occur.

• Intellectual disability is severe.

• Growth is restricted from before birth, so microcephaly, small hands and feet and short stature are expected, not macrocephaly.

• Twirling on the spot, avoidance of other children, very limited speech and autistic features are typical.

• Self-injury worsens after meals and on lying down because reflux causes pain.

Tuberous sclerosis

• Tuberous sclerosis is autosomal dominant, caused by mutations in TSC1 (9q34) or TSC2 (16p13.3), whose products together hold mTOR in check.

• The classic Vogt triad is epilepsy, intellectual disability and facial angiofibromas.

• Other signs are infantile spasms, a shagreen patch and cardiac rhabdomyoma.

Foetal alcohol syndrome

• The facial triad is short palpebral fissures, a smooth philtrum and a thin upper lip.

• When all three facial features are present, the diagnosis stands even if drinking in pregnancy cannot be confirmed.

• Growth deficiency and neurodevelopmental impairment accompany the facial features.

• Microcephaly is characteristic because prenatal alcohol impairs brain growth.

• Corpus callosum abnormality (callosal dysgenesis) is the characteristic structural brain finding, and it impairs interhemispheric transfer, attention and executive function.

• Poor learning from consequences and weak working memory are typical.

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Other chromosomal syndromes

• Turner syndrome preserves general intelligence but brings visuospatial, executive and social-cognitive weakness.

• Turner syndrome is often recognised late because signs can be mild or absent, especially in mosaics, and girls are often karyotyped only when short stature or failed puberty prompts it.

• An excess among prisoners was attributed to 47,XYY, not to Klinefelter syndrome.

Metabolic and storage disorders

• In phenylketonuria, phenylalanine hydroxylase deficiency raises phenylalanine and lowers melanin synthesis.

• Untreated phenylketonuria, or a diet started at birth and then abandoned, causes intellectual disability, epilepsy, eczema, hyperactivity, outbursts and self-injury.

• Reduced pigmentation gives fair skin, hair and eyes, and there is a musty odour.

• Homocystinuria presents with venous thrombosis, a tall slim build with long fingers, fair colouring, malar flush and lenses displaced downwards and inwards.

Homocystinuria is told from Marfan syndrome by the lenses: in Marfan syndrome they usually slip upwards, and cognition is normal.

Epilepsy in intellectual disability

• Landau-Kleffner syndrome is acquired epileptic aphasia: established language is lost, beginning with failure to understand speech despite normal hearing.

• In Landau-Kleffner syndrome, seizures arise from sleep, spike-and-wave activity becomes almost continuous in slow-wave sleep, and non-verbal skills are spared.

• In Lennox-Gastaut syndrome, intellectual functioning deteriorates after onset rather than improving.

Patterns of inheritance

Other associations

• Pica in people with intellectual disability is most strongly associated with co-occurring autism spectrum disorder.

• Savant syndrome is a single area of exceptional ability against low general intellectual functioning, and it occurs most often in autism.