CHAPTER
3: COMMON SYNDROMES AND GENETIC DISORDERS
DAVID CLARKE
Some
of the basic concepts about genetic disorders have been discussed in chapter 2.
It is useful to look at the more common genetic disorders associated with
learning disabilities in some detail. Terms used in describing how common
diseases are include incidence and prevalence. The incidence of a disease is the
rate of occurrence of new cases in a defined population over a given period
of time, while prevalence is the proportion of a defined population that
has the disease at a given point in time or period of time. The birth defect
rate is the proportion of live births that has a given disease and is a type of
prevalence.
Syndromes
A
syndrome is a characteristic pattern of clinical features. Clinical features
include signs which a clinician can see or otherwise ascertain, such as a rash
or heart murmur and symptoms which a patient may experience such as pain or low
mood. This chapter deals with syndromes that cause, or that may cause, learning
disability. Such disorders include Down syndrome and Fragile-X syndrome, the two
commonest chromosomal disorders associated with learning disability. People with
learning disability may have other syndromes, such as Beçet’s syndrome, a
combination of oral and genital ulceration, believed to result from
immunological abnormalities, but these syndromes are coincidental or secondary
rather than causal.
Some
professionals are unhappy about the medical "labelling" of people with
disabilities, but the diagnosis of a syndrome has many benefits for the person
concerned and their carers. These include an explanation of the cause of the
person's disabilities or of their pattern of strengths and weaknesses,
improved knowledge regarding the risk of recurrence of the disorder among
relatives if a syndrome is of genetic origin, and the prediction of other
features that may not be apparent to the person concerned or their carers but
may be medically or educationally important. These might include the likelihood
of heart disease, or of a discrepancy between verbal and non-verbal cognitive
ability. Other advantages include the prediction of features that may develop in
the future. This is particularly important when treatment can alleviate the
problem, such as the thyroid gland disorders to which people with Down syndrome
are vulnerable. They may also be important to allow relatives to plan for the
future, for example knowledge of the increased risk of dementia of Alzheimer
type associated with Down syndrome.
Diagnosis
also provides access to support groups. People with syndromes and their carers
may increase their knowledge and ability to access services through membership
of such a group. Parents and carers often feel less isolated when they know that
other people face similar problems, and they may find practical solutions to
their difficulties of which professionals are not aware.
Accurate
diagnosis is also important when conducting research. In the field of learning
disability, research is often hampered by heterogeneity in study samples. If all
the people in a study have the same cause for their learning disability, much
more can be deduced about the influence of the syndrome itself, about the
influence of associated problems such as the severity of the intellectual
disability and about environmental factors which may cause particular problems.
Behavioural phenotypes
Behavioural
and cognitive aspects are so striking and characteristic a feature of some
syndromes that they may be used to prompt diagnostic assessment. Examples
include the abnormal movements and unusual and severe self-injury associated
with Lesch-Nyhan syndrome where affected men typically bite their fingers and
lips, but try to resist the urge to do so by restraining themselves, and the
hand-biting seen in some men with fragile-X syndrome when they become anxious.
Children with Smith-Magenis syndrome have a vulnerability to a number of
maladaptive behaviours including sleep problems. In Prader-Willi syndrome ,
there is a change in the pattern of characteristic behaviours with development.
New born babies feed very poorly, usually requiring tube feeding. During
childhood there is a switch to very marked over-eating, and adults with the
syndrome may be morbidly obese. In adult life there is a tendency to self-injure
through picking or scratching at spots on the skin, sleep abnormalities, and a
proneness to temper "tantrums" and obsessional behaviours.
Cognitively, adults with Prader-Willi syndrome seem to have particular problems
processing information given verbally. Men with Fragile-X syndrome have problems
with absorbing information presented in a sequential format e.g. "go
upstairs and get your winter coat from the wardrobe in the front room and put it
in the car". In both syndromes, information presented as a whole story
picture is more readily understood. Adults with Prader-Willi syndrome are often
described as "stubborn", and this may be the result of the auditory
information processing disorder associated with the syndrome i.e. the
information is not absorbed or acted on and the person appears stubborn or
repeatedly asks the same question.
These
patterns of vulnerability to particular behaviours associated with biologically
determined syndromes have been called Behavioural Phenotypes. Environmental
factors may interact with the vulnerability to a particular behaviour to
determine whether or not it occurs in a given setting, and this interaction may
be important for determining effective treatments.
Common and rare
syndromes
The
two commonest aetiological syndromes are Down syndrome and Fragile-X syndrome.
Almost everyone working with people with learning disability will meet someone
with these disorders. The other disorders are much less common, but it may be
very important to have access to a summary of clinical features. People who have
syndromes associated with heart defects, for example, need antibiotic cover for
some forms of dental work.
Genetics
A
summary of terms and concepts
applicable to human genetics is given in Chapter 2. Genetics is one of the most
rapidly-expanding areas of science. Many disorders associated with learning
disability that were previously of unknown origin are now known to have a
genetic basis in at least a proportion of cases. Advances in technology have
allowed very small deletions (missing portions) of chromosomes to be identified
in disorders such as Rubinstein-Taybi syndrome
and Williams syndrome.
SYNDROME DESCRIPTIONS
Down syndrome
J.
Langdon Down originally described the syndrome in 1887. Trisomy 21 was first
reported in association with Down syndrome by Lejeune and colleagues in 1958.
About 1 in 600 live born children have Down syndrome. The rate increases with
increasing
There
is usually "floppiness" or muscular hypotonia at birth which usually
improves with development. Most adults are of short stature, with a
characteristic facial appearance. The eyes seem to slope upwards and outwards as
a result of alterations in the structure of the surrounding tissues. The nose
has a wide bridge, and the head, an
unusual shape being broader than long (brachycephaly). Limb abnormalities
include a single transverse crease on the palm, a large cleft between the first
and second toes, and relatively short upper arms. People with Down syndrome are
prone to abnormalities of the thyroid gland with 15% developing hypothyroidism
during childhood or adolescence. About 50% have a heart defect, about 15% having
an atrio-ventricular septal defect or a "hole in the heart".
Abnormalities of the gastro-intestinal tract occur in a significant minority.
Life expectancy has improved markedly over the past 50 years, largely as a
result of antibiotic treatment of respiratory tract infections. Survival into
the 8th decade is unusual but not extraordinary. The presence of an atrio-ventricular
septal defect often leads to heart and lung failure in early adult life. Adults
with Down syndrome are much more likely to develop dementia of Alzheimer type
than the general population. On post-mortem examination, almost all adults with
Down syndrome over the age of 35
have the brain changes characteristic of dementia of Alzheimer type, but only
about 45% of those over 45 years of age have clinically apparent dementia.
Although changes in blood cells are relatively common, leukaemia is not
particularly common affecting about 1%.
The
stereotype of people with Down syndrome as happy, placid individuals with a gift
for mimicry is not borne out by recent behavioural research. Stubbornness and
obsessional features seem to be over-represented, and many people with Down
syndrome react adversely in situations involving conflict. Autism occurs more
commonly than would be expected by chance alone.
Most
adults with Down syndrome have a moderate learning disability. About 10% have
low-normal intelligence, i.e. cognitive impairments that are not so severe as to
be classifiable as a learning disability. Almost all children with Down syndrome
have a relatively specific speech and language delay. About 25% have features of
attention deficit disorder. Cognitive abilities tend to be greater among people
whose Down syndrome is caused by mosaicism for trisomy 21.
Fragile-X syndrome
The
syndrome was by originally described by Martin and Bell in 1943. The
characteristic "fragile" site on the X chromosome was identified by
Lubs in 1969. All ethnic groups are affected equally, with a frequency of 0.3-1
per 1,000 in men and 0.2-0.6 per 1,000 in women. Fragile-X syndrome is the most
common inherited cause of learning disability.
Fragile-X
syndrome is an X-linked disorder, but has a very unusual pattern of inheritance.
X-linked disorders such as haemophilia are usually manifested in men who have
one X chromosome and transmitted by unaffected women carriers who have two X
chromosomes. Fragile-X syndrome is characterised by a bias to affected men but
with some affected women and some unaffected men who transmit the abnormality to
their daughters who then have affected sons. When peripheral blood lymphocytes
from affected individuals are grown in certain culture conditions e.g. with lack
of folic acid, a fragile site becomes evident on the long (q) arm of the X
chromosome at Xq27.3 (fragile site A). Fragile sites may not be seen in some
unaffected men who transmit the abnormality to their carrier daughters. These
men are termed "normal transmitting males". The probability that a
child with a fragile X chromosome will have learning disability depends on the
sex and intellect of the parent from whom the chromosome was inherited.
The
"fragility" of the X chromosome is now known to be associated with an
unstable region of DNA within the fragile-X mental retardation (FMR-1) gene.
This region of unstable DNA gradually increases in length and degree of
instability in successive generations (a pre-mutation) until a critical point is
reached and the gene no longer functions (a full mutation). The instability is
caused by an increase in CGG (cytosine-guanine-guanine) repeats from the 50 or
so repeats that are usual to 50-100 repeats (pre-mutation) to
over 200 repeats (full mutation). The chance of a child inheriting a
lengthened gene is proportional to the length of the unstable region in the
carrier mother. An increase does not occur in the children of normal
transmitting males. Modern genetic testing for fragile-X involves analysing the
relevant portion of DNA for CGG repeats (rather than looking for fragile sites).
The severity of intellectual disability and other fragile-X related phenomena in
women probably depends on the proportion of cells in which the abnormal
chromosome is inactivated as they "use" one copy of their two X
chromosomes, inactivation being random. Variants
of Fragile-X syndrome (FraX-A) have now been identified, with DNA expansions
nearer to the tip of the X chromosome's long arm. These include FraX-E and FraX-F.
Physical
features are variable. 96% of affected men have large testes but this is not
apparent until after puberty. Those with the syndrome tend to have a long face
with a large forehead, large simple ears, a large lower jaw and high-arched
palate. There is a connective tissue disorder, which may lead to tissue laxity,
hyper-extensible joints, flat feet, heart defects especially valve
abnormalities, and ear infections as the eustachian tube connecting the ear to
the respiratory tract closes easily. Visual problems such as cataracts occur.
About 50% of affected men have epilepsy. Life expectancy depends on the severity
of associated features such as epilepsy, heart problems, etc but is probably
near normal.
There
is usually some degree of social impairment, with social anxiety and avoidance
of eye-to-eye contact, but with social responsiveness. Men with Fragile-X are
usually affectionate, and do not have the aloof quality typical of autism.
Self-injury is relatively
The
learning disability is usually mild to moderate. Verbal intelligence scores
exceed performance scores among populations of affected men and non-disabled
women carriers. Some studies have found that the rate of intellectual
development diminishes with age after puberty. Simultaneous information
processing abilities are greater than sequential processing skills. Speech and
language development is delayed with dysfluent conversation, incomplete
sentences, echolalia and verbal perseveration which is an inability to move on
from the subject being discussed. Speech is often disorganised, with poor topic
maintenance and tangential comments. It may be rapid, or include peculiar
"litany-like" changes in pitch. There may be problems with attention
and concentration which are
disproportionate to the severity of learning disability. Hyperactivity may be
the presenting feature among boys with Fragile-X who do not have learning
disability.
Angelman syndrome
The
prevalence of this syndrome is
estimated at 1 in 30,000 births. Most cases are sporadic, and associated with
deletions within 15q11q13 of maternal origin (c.f. Prader-Willi syndrome).
Angelman syndrome is occasionally associated with paternal uniparental disomy
(i.e. both the chromosome 15s are of paternal origin, so that the maternal
chromosome 15 has been “deleted”) but this seems to be less common than in
Prader-Willi syndrome. A gene responsible for the Angleman syndrome phenotype
has recently been described (Kishino et al, 1997).
Physical
characteristics include small head,
characteristic face with wide mouth, "hooked" nose, prominent lower
jaw, widely spaced teeth and tongue protrusion. Many affected children are
hypopigmented compared to first degree relatives. Voluntary movements are jerky
and the gait ataxic with stiff legs. About 80% develop epilepsy, and the EEG is
highly characteristic. There is no data available at the present time about
their life expectancy but this is probably potentially normal.
Behavioural
characteristics which include sudden bursts of laughter and the physical
features led to the term "happy puppet" syndrome being employed in the
1960s and 70s. The children enjoy social and physical contact, and mouthing
objects. Many are fascinated by water. They have severe learning disabilities
and delayed motor milestones. There
is little speech development (no reported person has more than 6 words), but
understanding of language may be better. Overactivity is often associated with a
short attention span.
Apert syndrome
The
prevalence is approximately 15 cases
per 1,000,000 live born infants. It is an autosomal dominant condition but most cases arise as new mutations i.e.
with unaffected parents.
Physical
features include high, prominent forehead, often with midline swelling; small
flattened nose; under development of the middle portion of the face and
abnormalities of the oral cavity and lower jaw leading to feeding, breathing or
speech problems, shallow eye sockets and large prominent eyes, set widely apart;
low set ears ,often with conductive hearing impairment and
hydrocephalus in some cases. Hand malformations
Coffin-Lowry syndrome
Incidence
and prevalence are unknown but more than 100 cases have been reported. This
X-linked syndrome has been ascribed to a locus in the Xp22.1-p22.2 region.
Physical features include short stature, coarse facial appearance with slanting
eye fissures, prominent forehead, short broad nose, forward facing nostrils,
large ears, large open mouth and small, widely spaced teeth. Increased fatty
tissue in forearms, large hands and tapering fingers, lax ligaments leading to
flat feet and spinal and chest abnormalities occur. Life expectancy is probably
near normal. Behavioural characteristics are largely unknown. Depression and
schizophrenia have been reported in association with the disorder and in female
carriers. The affected men have severe learning disabilities.
Coffin Siris syndrome
This
is an autosomal recessive condition. Physical features include sparse scalp hair
and hirsutism affecting other parts of the body, especially the face and the
back. Eye brows may be joined and other facial features include thick lips, flat
nasal bridge and large mouth. Abnormalities
of finger and toe nails especially the fifth finger, occasionally shortening of
digits, hypotonia and joint laxity may also occur. The physical features
vary in severity from individual to individual. Life expectancy depends
largely on the severity of physical features. Situation-specific maladaptive
behaviours and autistic disorders have been reported, but there is no clear
pattern of associated behaviours.
Cornelia de Lange
syndrome ( Brachman-de Lange syndrome)
This
syndrome is considered to occur about once in 60,000 live births, although some
authors believe it to be more common. Some families appear to show autosomal
dominant transmission. There is phenotypic overlap with a disorder arising from
duplication of 3q. Some authors suggest a gene located at 3q26.3 may be
responsible.
Affected
individuals show growth retardation; distinctive facial features consisting of
well defined arched eyebrows which meet in the middle, long curled eyelashes,
small nose with forward-facing nostrils and down-turned mouth with thin lips and
limb abnormalities such as small or shortened limbs, especially arms. Hearing
impairments, gut malformations and congenital heart defects also occur. Early
mortality is high because of feeding problems with regurgitation and vomiting
leading to aspiration pneumonia in some cases. One study reported people in
their 5th decade.
Self-injury,
autistic features and pleasurable responses to vestibular stimulation,e.g.
spinning in a chair have been reported as part of behavioural repertoire. The
degree of learning disability is usually severe, and speech is often very
limited. However, some affected people have IQs within the normal range.
Cri du Chat syndrome
The
prevalence is about 1 in 50,000 births. The short arm of chromosome 5 has a
terminal deletion. Deletions vary in size, but the critical region for
Cri-du-Chat syndrome is thought to be 5p15.2. 85% of deletions arise
spontaneously, and the majority are of paternal origin. 15% of affected people
have an unbalanced translocation, and in these cases the clinical features
depend on the other chromosome involved. Less that 1% of cases are due to
inherited deletions, which are usually very small.
Round
face, widely spaced slanting eyes, small head, a broad flat nose, small lower
jaw and ear abnormalities are characteristic. Larger deletions are associated
with more pronounced clinical
features such as lower intelligence, smaller stature, lower weight and smaller
head as do translocations The face often lengthens with development. and may be
asymmetrical. Cleft lip or palate, curved fingers, hernias and orthopaedic
abnormalities may occur. Older individuals often have premature greying of the
hair. Life expectancy depends on the severity of the condition.
In
infancy there are feeding difficulties and the cry is abnormally high pitched
(cat-like, hence "cri-du-chat"), but this is not an invariable or
pathognomonic feature. Unpublished work carried out by the author and E. Dykens
suggests that hyperactivity is a problem for a substantial proportion. Language
development is often markedly delayed. The IQ associated with the syndrome in
one study varied from 6 to 85.
Duchenne muscular
dystrophy
Prevalence
at birth is about 1 in 4,000 male births. This is an X linked recessive
condition in which deletions, duplications and mutations at Xp21 lead to failure
to produce dystrophin, a protein component of muscle tissue. New mutations
account for about 30% of cases. The syndrome is characterised by progressive
limb girdle and later respiratory muscle weakness. Heart muscle abnormalities
may occur too. The disease is usually more severe in the lower limbs and trunk
initially, with later involvement of the arms and respiratory muscles. The
affected individual may need a wheelchair usually at around 11 years, with death
in early adult life, in the mid twenties. Low mood, anxiety and social
abnormalities are often problems, and may become more prominent as the disorder
advances. These features may be normal reactions to a chronic and progressive
physical disease. Specific learning disabilities are common, especially specific
reading disorder. About 25% of those affected have a learning disability.
Performance IQ is typically higher than verbal IQ.
18q- syndrome
More
than 100 cases of people with the syndrome have been described. The ratio of
occurrence between men and women is 2 to 3 .The deletion occurs spontaneously in
about 80% of cases and the break point is often at 18q21.2
Physical
features include abnormally shaped skull, underdevelopment of the middle portion
of the face, lip and nose abnormalities, small teeth and ear and eye
abnormalities, typically squint and/or abnormal eye movements. Kyphosis,
scoliosis, dimples over joints and underdeveloped sexual organs in males have
also been reported. In about 10% of cases death occurs within months of birth.
Most affected people live to adulthood. Hyperactivity and aggressive behaviours
have been reported, as have autistic and psychotic disorders. A husky voice is
frequently reported.
Lesch-Nyhan syndrome
Prevalence
at birth is estimated to be between 1 in 100,000 to 1 in 1,000,000 births. This
is an X linked syndrome . The disease results from a deficiency of a purine
salvage enzyme, hypoxanthine-guanine phosphoribosyl transferase or HGPRT leading
to hyperuricaemia and neurological disorder. Partial HGPRT deficiency results in
gout. HGPRT is a 217 amino acid peptide coded for by one gene divided into nine
exons, located on the X chromosome at Xq26q27. Many different genetic lesions
can cause HGPRT deficiency : several
complete and partial deletions, insertions and duplication of exons have been
reported. Most lesions appear to be point mutations. Affected males may have had
spontaneous mutations or inherited mutations from asymptomatic female carriers.
Carrier detection and prenatal diagnosis are possible.
Neurological
features include athetoid and other abnormal movements and spasticity. Growth
retardation is usual. The presentation is usually with hypotonia and motor delay
at about 4 months. Extrapyramidal signs (such as spasticity and choreo-athetoid
movements) develop at about 9 months. Hyper-reflexia and clonus appear at about
1 year. Dystonic movements may also develop. Dysarthria is common. Affected
individuals may survive to 2nd or 3rd decade. Death is usually due to kidney
failure secondary to uric acid deposition or infection.
Compulsive
severe self-injury occurs in over 85% of cases, and usually consists of finger
and lip biting, with self-splinting in an attempt to prevent the behaviour. Other compulsive behaviours occur,
including apparently compulsive aggressive acts. The mean age at onset of
self-injury is 3.5 years, with wide variation. The IQ is usually between 40 and
80, but dysarthria and neurological
problems limit the validity of standard IQ tests.
Mucopolysaccharidoses
The
mucopolysaccharide group of disorders have names: Hunter syndrome, Hurler
syndrome, Sanfillipo syndrome, Morquio syndrome and Schie syndrome and numerical
designations: MPS IIA/B, MPS IH, MPS IIIA/B/C/D, MPS IVA/B and MPS IS
respectively. The disorders result from deficiencies in enzyme systems involved
in the degradation of glycosaminoglycans with accumulation of abnormal metabolic
products.
All
are rare disorders. The incidences among live born children are approximately
1in100,000 for Hunter and Hurler syndromes, 1in 200,000 for all types of
Sanfillipo syndrome and for Morquio syndrome and 1in 500,000 for Schie syndrome.
The transmission is autosomal recessive except in Hunter (IIA and IIB) which is
X linked. Physical features vary. Coarse facial
features ("gargoylism"), hepato-splenomegaly, joint stiffness, eye
abnormalities and short stature occur in many of the disorders. Life expectancy
varies from death in first decade in Hurler syndrome through survival into 2nd
or 3rd decade in Sanfillipo syndrome, to survival to adult life in Hunter
syndrome and Schie syndrome.
Sleep
problems and abnormal nocturnal behaviours, e.g., staying up all night,
laughing/singing, sudden crying out and chewing of bedclothes have been reported
in association with Sanfillipo syndrome, and have been shown to respond to
behavioural management strategies. Cognitive abilities vary from normal
intelligence in Schie syndrome to severe learning disability and progressive
cognitive deterioration in Hurler
Myotonic Dystrophy
Myotonic
dystrophy affects about 1 in 8,000 live born infants. This is an autosomal
dominant condition with genetic defect localised to chromosome 19, where there
is an increase in the cytosine thymine guanine (CTG) trinucleotide repeats
within the non-coding portion of the myoprotein kinase gene. Anticipation which
is an increase in severity of symptoms and an earlier age at onset has been
observed in many families, and probably results from an increase in the number of repeats (see Fragile X
syndrome).
Physical
features involve muscle weakness and wasting. Facial weakness
results in ptosis or drooping eyelids and a "slack" jaw. Men
often have a characteristic pattern of hair loss. A failure of muscle relaxation
after use causes speech and swallowing difficulties. Cataracts are common, as
are cardiac conduction problems. Particular care is needed if a general
anaesthetic is required. Average age at death is in the sixth decade.
Neurofibromatosis
Type 1 (von Recklinghausen’s disease)
This
autosomal dominant disorder occurs about once in 3,000 births. The gene
responsible is localised to 17q11.2. The gene product, neurofibromin, is thought
to suppress tumour formation by regulating cell division. A high spontaneous
mutation rate means that about a half of all cases arise in unaffected families.
Tumours
arise from the connective tissue of nerve sheaths. Two or more of the following
features are usually required for diagnosis: six or more cafe au lait (light
brown) skin lesions, two or more neurofibromas or one plexiform neurofibroma (tumours
of the nerve sheath); freckling of the groin or arm-pit; lisch nodules; an optic
nerve glioma (tumour); a bony lesion characteristic of neurofibromatosis , a
first degree relative with the disorder. Life expectancy depends on nature and
severity of clinical features.
About
50% of children have speech or language abnormalities. Distractibility and
impulsiveness may be problems. Learning disability is seen about 10% of those
affected . Specific developmental disorders such as difficulties with reading,
writing or numeracy affect about half of the children. Visuo-spatial
abnormalities and lack of co-ordination have also been described.
Phenylketonuria
Classical
Phenylketonuria or PKU affects about 1 in 10,000 live born children in the UK.
Other hyperphenylalaninaemias also occur. The disorder results from a
deficiency of the enzyme phenylalanine hydroxylase . The extent of the
deficiency varies, with a spectrum of resulting clinical conditions from
classical Phenylketonuria to benign hyperphenylalaninaemia. The gene regulating
phenylalanine hydroxylase is
located on the long arm of chromosome 12 at 12q22-24.1. It is subject to various
mutations. The classical form is inherited in an autosomal recessive manner.
Prenatal diagnosis and
Physical
features include blond hair, blue eyes, eczema, an unusual
"mouse-like" body odour, microcephaly in half the suffers, epilepsy in
a quarter and tremor and movement disorders or spasticity . Life expectancy
depends on response to dietary restriction of phenylalanine, presence of
complications, etc. In the UK all new-borns are screened for the disorder. A low
phenylalanine diet is usually
continued through childhood. There is debate about age at which it is
appropriate to lift or relax dietary restrictions. Amino-acid supplements may be
used to block phenylalanine uptake. Dietary control is essential when affected
women become pregnant as hyperphenylalaninaemia is toxic to the foetus leading
to learning disability, microcephaly, and facial and heart abnormalities.
Untreated
Phenylketonuria is associated with
a number of maladaptive behaviours and behavioural syndromes including
overactivity, self-injury and autism. Autism and many of the other features do
not occur in children managed with low phenylalanine diets. Those who have not been treated may have
moderate to profound learning disabilities, irritability and marked
social impairments. Inadequate dietary control is associated with deficits in
mathematical, visuo-spatial and language skills.
Prader-Willi Syndrome
The
incidence is estimated at 1 in 10,000 live born infants and prevalence at 12 per
100,000 population aged 0-25 years if "suspected" cases are included.
About 70% of those affected have a
deletion of the long arm of chromosome 15 (del 15q11q13), the deleted chromosome
being of paternal origin. About 29% have maternal uniparental disomy (i.e. both
the chromosome 15s are of maternal origin so that there is no paternal
chromosome 15) and about 1% may have an imprinting error. This condition is
thought to arise through the lack of a paternal contribution to an area within
15q11q13, and is an example of a disorder caused by genomic imprinting (see
Chapter 2 on Genetics).
Infants
are hypotonic or floppy and have feeding problems associated with a failure to
suck. Many have been tube fed. In
early childhood there is a switch to marked over eating. Affected adults are of
short stature, have small hands and feet and a characteristic
pattern of facial appearance, and a lack of sexual development . Many are
obese as a result of the relative lack of satiety leading to over eating . There
is an increased prevalence of curvature of the spine or scoliosis and other
orthopaedic abnormalities, and diabetes or heart failure may result from
obesity. Life expectancy depends on severity of obesity. Most of those affected
die before the sixth decade, but this may change with early diagnosis and
improved dietary management. A woman aged 71 with del 15q11q13 has been
reported. The commonest cause of death is heart failure.
Affected
individuals have an almost insatiable appetite. They may steal food and consume
"unpalatable" food such as rotting or frozen food or
pet food . A variety of sleep abnormalities and a lowering of the threshold for
loss of temper are seen in these people. About
80% pick or scratch their skin. Insistence on routines, obsessional behaviours
and psychoses have also been reported. Anecdotal reports suggest the pain
threshold may be raised.
About
5% of those with syndrome have overall cognitive abilities with IQs in excess of
85, 27% have borderline cognitive
abilities with IQs between 70 and
85, 34% have mild learning disabilities, 27% moderate, 5% severe, and less than
1% have profound learning disability. There are deficits in auditory information
processing, and relative strengths in visuo-spatial tasks.
Rett syndrome
Rett
syndrome which causes significant learning disabilities in women has a
prevalence estimated at 1 in 10,000 women. The cause is thought to be genetic
for the following reasons: 1) only women are affected, 2) identical twin pairs
have so far both had the disorder and 3) an affected woman has given birth to an
affected girl child. However, so far no cause has been proven.
The
affected child appears normal at birth. For the first twelve months no major
abnormalities are apparent though the child may be placid,
lack muscle tone and may be relatively immobile. She acquires skills to
about 1 year. But regression begins around 18 months, with loss of skills,
especially speech and use of hands. Physical disorders increase with age, and
include scoliosis, spasticity and leg deformities. Epilepsy is common.
Pathological changes include a reduction in brain size with reduced cortical
thickness, reduced neuronal branching, and depigmentation of the basal ganglia.
Many affected girls reach adulthood, but about 1% of them die each year with
early death more likely with increasing physical disability.
Sleep
disturbance, withdrawal and episodes of crying occur during the phase of
regression around 18 months of age. This phase is followed by a developmental
plateau, when extreme agitation and over-breathing interspersed with episodes of
cessation of breathing become apparent. The most prominent feature of the
behavioural phenotype is the presence of stereotyped movements, especially
midline "handwringing" movements. The affected women and girls usually
have profound learning disability.
Rubinstein-Taybi
syndrome
This
syndrome is one of the 25 most common multiple congenital anomaly syndromes seen
in genetic clinics in the USA and has an estimated incidence at 1in 125,000 live
born infants. Recent studies have found small deletions at 16p13.3 in about 25%
of cases. A few apparently familial cases have been reported, and 4 sets of
concordant monozygotic ie identical twins have been reported.
The
affected individuals are usually short, have a small head, a beaked or straight
nose and downward slanting eyes. They have a
stiff gait and their thumbs
and first toes have broad terminal phalanges (ends), often with an angulation
deformity. Other congenital anomalies are not uncommon. Inadequate weight gain
in infancy, congenital heart defects, urinary tract abnormalities and severe
constipation contribute to morbidity reflected in a hospitalisation rate 10
times higher than the general population. Affected people can live to the
seventh decade.
Findings
from postal questionnaire surveys in the USA and UK indicate that the people
with the syndrome have a friendly, happy disposition, a propensity to
self-stimulatory activities such as rocking and an intolerance of loud noises.
Rocking, spinning and hand flapping were common in the UK survey. A survey of
non-institutionalised children reported an average IQ of 51. Another report
stated that 75% had an IQ below 50.
Smith-Lemli-Opitz syndrome
The
syndrome is thought to occur about once in 30,000 live births. Mild cases may be
undiagnosed and the syndrome may be relatively common as it is said to be one of
the commonest autosomal recessive conditions affecting people of White European
origin in North America. It appears to be thrice as common in men as compared to
women , but this may be due to the fact that the sexual abnormalities are easier
to detect in men. It is an autosomal recessive condition where a deficiency of
the enzyme 7-dehydrocholesterol reductase results in elevated levels of a
cholesterol precursor.
During
pregnancy, the foetus may show growth retardation. The affected individuals have
small head, drooping eyelids , squint, forward-facing nostrils, small
lower jaw and finger abnormalities such as extra fingers and
joining together of fingers. Males have abnormalities of their external
genitalia such as small testes or penis, abnormal opening of the ureter, e.g.,
hypospadia, undescended testes and female
genitalia . Cleft palate and abnormalities of almost all major organ systems may
also occur. Life expectancy depends on severity of associated features. Some
severely affected infants die shortly after birth but mildly affected adults
probably have near-normal life expectancy.
There
is little information available about behavioural and cognitive characteristics.
Intelligence varies from normal to severe learning disability. One report
describes aggressive and self-injurious behaviours in an affected girl.
Smith-Magenis syndrome
This
syndrome which occurs about once in 50,000 births is associated with deletions
at 17p11.2. Affected individuals have flattened mid-face, abnormally shaped
upper lip, short hands and feet, single transverse palmar crease, abnormally
shaped or placed ears and occasionally
high arched palate or protruding tongue. The facial features coarsen with
development. Ear and eye disorders such as otitis media and squint are
relatively common.
New
born babies with the syndrome are usually placid, "floppy" and feed
with difficulty. This changes to hyperactivity, self-injury, e.g. head banging,
pulling out finger and toe nails and the insertion of objects into body orifices
from about 18 months onwards. Self-hugging and mid-line hand clapping have been
reported in a series of cases. Sleep disorders are common with some children
waking repeatedly in a state of agitation. An absence of rapid eye movement or
REM sleep has been reported in some patients. Many affected children appear to
be relatively insensitive to pain. Those with the syndrome usually have moderate
learning disability. The severity of the cognitive impairment correlates with
the size of the 17p11 deletion. Speech delay is more pronounced than delay in
motor achievements.
Sotos syndrome
This
is a syndrome of unknown origin .About 200 cases have been reported so far which
include familial and sporadic cases. Those affected have distinctive facial
features consisting of round face and forehead, a prominent jaw, anteverted
nasal
Behavioural
problems are common in the cases reported, and include aggressive and
destructive behaviours, unhappiness and poor social relationships. Early feeding
problems with reluctance to chew have been described, as have
obsessive-compulsive symptoms, temper tantrums, pica, excessive eating and
obesity and sleep abnormalities. Some authors have suggested that behavioural
abnormalities are perceived as being more severe in children with Sotos syndrome
because of their large size. Cognitive abilities vary from above average
intelligence to severe learning disability. Some children have specific learning
problems. Speech abnormalities include echolalia and perseveration (inability to
"move on" in speech). Verbal IQs tend to increase with age, whereas
performance IQ tends to remain constant or decrease. Overactivity and attention
deficit have also been described.
Tuberous sclerosis
The
incidence is about 1 in 7,000. It is an autosomal dominant condition but up to
80% arise as a result of spontaneous mutations. The disorder is genetically
heterogeneous, with gene linkage to 9q34 and 16p13. Physical features are very
variable. The previously used "diagnostic triad" of epilepsy, mental
retardation and a characteristic facial skin lesion is no longer considered
helpful., as it is seen in only about 30% of people with the disease. The
disorder is a multi-system one, with hamartomatous tumours (arising from
primitive cells)affecting the brain in 90%, skin in 96%, kidneys in 60%, heart
in 50%, eyes in 47%, teeth, bones, lungs and other organs. About 80% of affected
people have epilepsy. Life expectancy depends on the location and the number of
lesions. Brain tumours and kidney lesions are common causes of death.
Tuberous
sclerosis is associated with autism and related disorders, hyperactivity and
attention deficit disorder, obsessive and ritualistic behaviours, sleep
problems, and occasionally self-injurious or aggressive behaviours. Less than
half of affected people have a learning disability. Attention-deficit is common.
Of those with learning disability, a high proportion have an IQ less than 30.
Velo-cardio-facial
syndrome
This
condition is associated with micro-deletions at 22q11. Physical features include
cardiac anomalies including
ventriculoseptal defects, pulmonary stenosis and cardiac outlet abnormalities ;
facial dysmorphology with a prominent nose with broad bridge and squared tip,
small head and/.or small lower jaw ; ocular abnormalities in a proportion of
cases and cleft palate, short stature and long, thin, hyperextensible fingers.
Life expectancy depends primarily on the severity of heart abnormalities.
Affected
individuals show abnormalities of social behaviour. A high prevalence of
personality disorders and psychotic disorders during adolescence and early adult
life has been reported in some studies. Over 90% have a learning disability and
language problems are common.
Williams syndrome
(Idiopathic infantile hypercalcaemia)
The
syndrome affects between 1 in 25,000 and 1 in 50,000 live born infants. The
aetiology is not known, but a congenital cause is likely as the new born infants
have an abnormal facial appearance. Most cases are sporadic though a few
familial cases have been reported. Infants have difficulties in feeding, are
irritable, have constipation and fail to thrive. Over 60% of children have high
levels of calcium which responds to treatment with low-calcium diet and vitamin
D restriction. The face is distinctive, with prominent cheeks, a wide mouth and
flat nasal bridge often described as "elfin-like". Kidney and heart
lesions (especially supravalvular aortic stenosis and peripheral pulmonary
artery stenosis) are common. Growth is usually retarded. Life expectancy is
related to metabolic and heart abnormalities.
Social
disinhibition with abnormal friendliness to strangers, overactivity, poor
concentration, eating and sleeping abnormalities, abnormal anxiety, poor peer
relationships and abnormally sensitive hearing have been reported. 95% of
children with the disorder have a moderate or severe learning disability. Verbal
abilities are better developed than visuo-spatial and motor skills. There is an
unusual command of language : expressive language is superficially fluent and
articulate, but verbose. Comprehension is far more limited.
SEX CHROMOSOME ANOMALIES
Klinefelter syndrome
Prevalence
at birth is between 1 in 5,00 and 1 in 1000 live male births. This is a disorder
of surplus of X chromosomes in phenotypic males. Two-thirds have 47 XXY
chromosome complement. Height, weight and head circumference are below average
at birth. Increased growth, especially of legs occurs from 3 years of age
onwards. Affected men are usually taller than their fathers. Head size remains
small. Puberty normally occurs, but testosterone production falls in early adult
life. Affected adults have a normal sized penis but small testes. About 60% have
some breast enlargement. Life expectancy is thought to be normal.
Boys
with XXY are typically introverted and less assertive and sociable than other
children, with poorer school performance. Adults may have increased rates of
antisocial behaviour and impulsiveness. The IQ distribution is skewed downwards,
although measured full scale IQs run from the 60s to the 130s. Performance
scores usually exceed Verbal scores. Most affected children receive speech and
language therapy, and expressive language deficits are often more pronounced
than problems with receptive language.
Turner syndrome
This
syndrome affects about 1 in 2,500 live female births. The abnormality is much
more common at conception, but about 99% of affected foetuses are miscarried.
The genetic abnormality is the loss or abnormality of one X chromosome in women.
About 50% have an XO chromosome complement , although a very small proportion of
normal cell lines may be present, and about 40% have mosaicism. About 15% have a
45,XO/45XX karyotype.
Affected
children have a short stature in childhood. Ovarian failure occurs before birth,
and puberty does not occur naturally. Dysmorphic features include a webbed neck,
low hairline at the rear of the head, widely spaced nipples and multiple
pigmented naevi.
Hyperactivity
and distractibility are common in childhood. Poor social skills, and social
withdrawal, may be problems in later childhood and adolescence. Immaturity and
problems in peer relationships have also been reported. One study found that
about a quarter of girls with the syndrome had psychiatric disorders of a
severity comparable to cases referred for treatment. The women usually have
normal IQs, but specific cognitive abnormalities are frequently found, including
a relative deficit in performance skills, depression of Wechsler subtest scores
for items such as Block Design, Object Assembly, Arithmetic and Information.
Some verbal measures, such as verbal recognition and the use of advanced
vocabulary, are typically enhanced. This may lead to an over-estimation of
abilities. There is considerable variation in cognitive profile between affected
women.
XXX syndrome
The
XXX syndrome occurs about 1 in 1,000 female births. Most are not diagnosed.
There is a primary non-disjunction of a maternal or paternal X chromosome. 48
XXXX is much rarer, about 40 cases have been reported. New born babies have a
low birth weight and small head circumference . Height in adult life is usually
increased. Fertility is not impaired. There may be deficits in balance or fine
motor co-ordination. Life expectancy is thought to be normal.
Underactivity
and withdrawal have been reported. Emotional development may be slowed. Most
appear to adapt to adult life without difficulties. Women with the syndrome
usually have IQs between 80 and 90. Women with XXXX syndrome have lower IQs (55
to 75). An expressive language delay is typical. Some have a relatively poor
short-term auditory memory.
XYY syndrome
This
condition occurs about 1 in 1,000 live male births. There is a primary
non-disjunction of the Y chromosome. About 10% have mosaic 46,XY/47,XYY
chromosome complement. Offspring rarely have two Y chromosomes. Affected
individuals show increase in body and leg length between years 4 and 9. Most are
over 10cm taller than their fathers as adults. Sexual development and fertility
are unaffected. Balance and co-ordination may be minimally compromised. Life
expectancy is normal.
Distractibility,
hyperactivity and temper tantrums appear relatively common in childhood. Speech
and language problems are common. Overactivity and distractibility may lead to
educational problems. IQ is usually lower than siblings’ IQ, but only just
below population means.
FURTHER READING AND
SOURCES OF INFORMATION
The
Contact a Family (CaF) Directory (Contact a Family, 1995) is widely used for
basic information about characteristics and carer organisations. The support
organisations themselves often publish material for carers and professionals.
The
Society for the Study of Behavioural Phenotypes (SSBP) can provide information
about syndromes, including conference proceedings with syndrome summary sheets
and guides to the measurement of behaviours associated with learning disability.
SSBP Publications are available from Dr G. O'Brien, Northgate Hospital, Morpeth,
A
book on behavioural phenotypes published in 1995 provides an overview of
research in the area and detailed descriptions of many syndromes: O’ Brien, G.
& Yule, W. (eds) (1995) Behavioural Phenotypes. London: Mac Keith Press.
Information
is also available from the Internet, by typing in the relevant syndrome name
into a search engine such as Yahoo (http://www.yahoo.com) or by accessing a site
such as the Alliance of Genetic Support Groups (http://www.medhelp.org/www/agsg.htm)
ACKNOWLEDGEMENT
I
am grateful to the organisations and colleagues who contributed information used
in this chapter, including the Society for the Study of Behavioural Phenotypes,
John Corbett, Harm Boer, Elisabeth Dykens and Bob Hodapp, Geoff Marston, Barbara
Whitman and Pru Allington-Smith.
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