Download the velocardiofacial syndrome

THE VELOCARDIOFACIAL SYNDROME
Clinical and behavioural phenotype
Velocardiofacial syndrome is the most frequent known interstitial deletion found in man with
an incidence of 1 in 4000 live births [12]. Most deletions are the result of a de novo event,
although probably 5-10% are inherited [11]. Several diagnostic labels have been used for this
syndrome including Di George syndrome (DGS) [13], Conotruncal anomaly face syndrome or
Takao syndrome [14]. Shprintzen syndrome [15] and 22q11deletion syndrome [16].
The structures primarily affected in VCFS include the thymus, parathyroid gland, aortic arch,
branchial arch arteries and face. These key clinical features are due to abnormal development
of the third and fourth pharyngeal pouches during embryogenesis and are therefore classified
as “the pharyngeal phenotype”. The other key clinical traits include learning difficulties,
cognitive deficits, attention deficit disorders and psychiatric disorders [10] and are classified
as “the neurobehavioral phenotype”. There is incomplete penetrance and therefore a marked
variability in clinical expression between the different patients, making early diagnosis
difficult [16]. The physical phenotype is characterised by facial dysmorphism, palatal
abnormalities, hypocalcemia, T-cell immunodeficiency and learning disabilities. Heart defects
are present in 50-75% of the patients and are usually diagnosed in early infancy. Minor
manifestations are usually associated including a history of polyhydramnios, signs of
velopharyngeal insufficiency, minor facial anomalies, slender appearance of the fingers,
constipation and hypotonia. Speech and language delay is one of the most consistent
manifestations of VCFS in part related to the velopharyngeal insufficiency. Recurrent upperairway and ear infections are common during infancy and early childhood. In adolescence
there is a high risk for development of obesity and scoliosis (10%) [17].
Recent studies of the cognitive and psychoeducational profiles of children with 22q11deletion
confirm a wide variation in intelligence, ranging from moderate mental retardation to average
intelligence, with a mean full-scale IQ of about 70 [18,19]. Severe mental retardation is rare.
The mean full-scale IQ in familial cases is lower compared to those with de novo cases
[19,20], a finding which can be explained at least in part by the multifaceted origin of
intelligence and by assortative mating. A possible relationship between 22q11deletion and a
non-verbal learning disorder was suggested [21,22]. Common behavioural and temperamental
characteristics include impulsiveness, disinhibition, shyness and withdrawal [19]. A wide
variety of child psychiatric disorders has been reported including attentions deficit disorder
and rapidly cycling bipolar disorder in late childhood and adolescence [23], childhood
schizophrenia [24,25] and mood disorders [26]. Current estimates are that +/- 35 % of patients
develop psychiatric disorders in adolescence or adulthood [27]. There is a higher than
expected rate of psychotic disorder, specifically schizophrenia, schizoaffective disorder and
bipolar disorder, among adult persons diagnosed with VCFS [23,28].
Molecular genetics
Genes within the deletion
Numerous genes have been identified within the most commonly deleted region of 22q11.2.
In their search for genes, investigators have also sought for genes that might have a role in
branchial arch or neural crest development [11]. Several candidate genes have received
particular attention (IDD/SEZI/LAN, GSCL, HIRA, UFD1L) but all proved to be negative for
mutations in VCFS patients without a 22q11 microdeletion. COMT, the gene encoding for
catechol-O-methyl transferase, has a crucial role in the metabolism of the neurotransmitter
dopamine. Abnormal function of the dopaminergic pathways is considered to play a major
role in schizophrenia [44]. As the gene coding for COMT maps to 22q11, the COMT gene is
considered a prime candidate gene for the etiology of schizophrenia in VCFS. It was therefore
suggested that the common functional genetic polymorphism in the COMT gene, which
results in a 3-to4-fold difference in COMT activity [45] may contribute to the etiology of
psychiatric disorders. Two studies reported that in a population of patients with VCFS, there
is an apparent association between the low-activity allele, COMT158met, on the non-deleted
chromosome and the development of a bipolar spectrum disorder and, in particular, a rapid
cycling form [45-47].
THE PRADER-WILLI SYNDROME AND THE ANGELMAN SYNDROME
Clinical and behavioural phenotype of the Prader-Willi syndrome
The Prader-Willi syndrome (PWS) is a complex multisystem disorder characterised by a
variety of clinical features [62]. The clinical phenotype is characterised by hyperphagia,
childhood-onset- obesity, severe muscle hypotonia, a typical facies, hypogonadism with
absence of a pubertal growth spurt, short stature, small hands and feet and delayed
developmental milestones. The typical facial features include a small forehead, almond
shaped eyes, micrognathia, a thin upper lip and down-turned corners of the mouth [63]. The
syndrome is now considered as a multistage disorder characterised by three different phases
[64].



The first, “the hypotonic phase”, is characterised by varying degrees of
hypotonia during the neonatal period and early infancy, a weak cry,
hypothermia, hypogenitalism and a poor suck reflex usually necessitating
gavage feeding [65]. During the first year, PWS children are defined as
friendly, easy going and affectionate [66].
The second phase, “the hyperphagic phase”, which usually starts between the
ages of one and two, is characterised by a voracious appetite, hyperphagia,
foraging for food, early onset of childhood obesity, physical inactivity,
decreased pain sensitivity, disturbed thermoregulation, psychomotor
retardation, speech articulation difficulties and cognitive dysfunction.
Simultaneously, with the change in eating pattern, PWS individuals show
significant maladaptive behavioural and emotional characteristics including
temper tantrums, inappropriate social behaviour, automutilation (skin picking),
stubbornness, mood lability, impulsivity, argumentativeness, anxiety and
obsessive compulsive symptoms [67,68].
The third phase ‘“adolescence and adulthood” is dominated by health
problems secondary to obesity. These include scoliosis, dental problems,
diabetes mellitus, hypertension, hypercholesterolemia, osteoporosis [69].
About 10% of the adolescents and adults develop major psychiatric problems
ranging from severe and agitated depression to psychotic episodes [70,71]. The
psychotic episodes in PWS patients have many features in common including
an acute onset, a polymorphous and fluctuating symptomatology with
anxieties, agitation, abnormal beliefs and auditory hallucinations. These
episodes are classified as acute cycloid psychosis [72].
Dysfunction of the hypothalamus may be the basis of a number of symptoms in the PraderWilli syndrome. The fetal hypothalamus plays a major role in labour and hypothalamic
dysfunction may explain the high proportion of children born prematurely or postmaturely.
Abnormal LSH-releasing hormones are thought to be responsible for the decreased levels of
sex hormones resulting in non-descended testes, undersized sex organs, amenorrhoea and
insufficient growth during puberty. Growth hormone deficiency due to hypothalamic
dysregulation contributes to the abnormal growth pattern, excess of body fat and deficit of
lean body mass with consequent reduced energy expenditure. Hypothalamic disturbances
cause aberrant control of body temperature and daytime hypersomnolence. The insatiable
hunger and hyperphagia is probably a consequence of the decreased number of oxytocine
neurones- the putative satiety neurones in the hypothalamic paraventricular nucleus [73].
Clinical and behavioural phenotype of the Angelman Syndrome
The typical facial features in Angelman syndrome (AS) include brachycephaly, microcephaly,
a large mouth with widely spaced teeth, mandibular prognatism, midfacial hypoplasia, deepset and blue eyes and hypopigmentation. This facial gestalt becomes apparent between the age
of one and four years and there is a facial coarsening with increasing age. AS patients show
truncal ataxia and hypotonia with hypertonia of the limbs and have a high risk for developing
scoliosis. All patients have severe mental retardation with little or no development of active
language. Jerky movements including tongue thrusting, mouthing and flapping when walking
become apparent in the first years of life. The gait is slow, ataxic and stiff-legged with the
characteristic posture of raised arms with flexed wrists and elbows. Paroxysms of easily
provoked, prolonged laughter may start as early as 10 weeks. Hyperactivity and sleep
disorders are common in childhood. AS individuals are fascinated by water, mirrors and
plastic. Epileptic seizures occur in 80% of the patients with an onset varying between one
month and 5 years. A diversity of seizures can be observed, ranging from atypical absence
seizures, tonic-clonic seizures, myoclonic seizures, and tonic seizures to status epilepticus.
They are difficult to control. The EEG patterns seen in AS are very characteristic and are seen
in patients with and without seizures and may play an important diagnostic role in the
appropriate clinical context [74]. Neuroimaging studies are normal. Cerebral atrophy and
ventricular dilatation are seen in a minority of the patients.
Molecular genetics of the Angelman and the Prader-Willi syndrome
PWS and AS result from loss of paternal or maternal expression, respectively, of genes
located on the human chromosome 15q11-13 region [75]. Different molecular mechanisms
leading to this loss of expression have been identified, including microdeletions, intragenic
mutations, uniparental disomy and imprinting defects:
A. Microdeletions in PWS and AS
75% of the PWS patients and 70% of the AS patients have large chromosomal deletions of +/4 Mb of the same chromosomal 15q11-13 region, the typically deleted region (TDR). In PWS
there is a deletion on the paternally inherited chromosome, while in Angelman there is a
deletion on the maternally inherited chromosome.
B. Single gene mutations in PWS and AS
There are no known PWS patients with a single gene mutation, suggesting that PWS is a
continuous gene syndrome. In 4 % of the cases, Angelman is caused by mutations in the
Ubiquitin ligase gene, UBE3A [76,77].
C. Uniparental disomy in PWS and AS
Uniparental disomy occurs in 24% of the PWS patients (maternal disomy) and in 3-5% of AS
patients (paternal disomy). The most likely explanation is trisomy 15 rescue, suggested by the
observation of trisomy 15 mosaicism in patients with unusual PWS manifestations [78-80]
D. Imprinting defects in PWS and AS
The imprinting centre (IC) regulates the erasure, establishment and maintenance of paternal
and maternal imprinted genes. It has been mapped to the SNURF-SNRPN locus and presents
with a bipartite structure overlapping the SNRPN promotor. The exon alpha SNRPN
promotor is found within a CpG island that is completely methylated on the maternal
chromosome and completely unmethylated on the paternal chromosome.
IC defects are found in 2 % of the AS cases and in less than 1 % of the PWS cases.
Genes within the deletion for PWS
In PWS patients, the typically deleted region on the paternal chromosome is 4Mb and the
PWS-SRO (smallest region of overlap) is 4,3 kb .The common deletion includes a large
cluster of imprinted genes (2-3Mb) and a non-imprinted domain (1-2Mb) [89,97]. A cluster of
paternally expressed genes has been mapped to the PWS region: SNURF-SNRPN (small
ribonucleoprotein N upstream reading frame-small ribonucleoprotein N), MKRN3 (makorin
ring finger protein), IPW (imprinted gene in the PWS region gene), MAGEL2 (melanoma
antigen-like gene2), and NDN (necdin) [75,98]. It is not clear if PWS is caused by the loss of
expression of a single imprinted gene or multiple genes. Two strong candidates for PWS are
NDN and MAGEL2. The human NDN is a good candidate due to its expression in the
nervous system and the observation that it is absent in PWS patients [99]. MAGEL2 is
expressed predominantly in the brain and in several foetal tissues.
Genes within the deletion for AS
In AS patients, the common deletion on the maternal chromosome also spans a 4 Mb interval
and includes a cluster of imprinted and a non-imprinted domain [101]. The UBE3A gene
(ubiquitin ligase 3) was mapped to the AS critical region in 1994 and its role in AS was
corroborated by the observation that point mutations in UBE3A are present in a small (4-6%)
fraction of the AS patients [76,77,102-104].
Genotype/phenotype correlation
Genotypic / phenotypic correlations with these different genetic causes were identified.
Individuals with a deletion show the classic signs of AS [119]. A milder phenotype is found
among the cases with paternal UPD. These AS individuals have better growth, less
hypopigmentation, more subtle facial changes, walk at earlier ages, have less severe or
frequent seizure disorders, less ataxia and a greater facility with rudimentary communication
such as signing and gesturing [120,121]. AS patients with imprinting mutations have a less
severe seizure disorder, show milder microcephaly and less hypopigmentation. Milder
epilepsy is noted in AS with UBE3A mutations [122]. Further refinement of the phenotype/
genotype correlation will progressively improve the gene-behaviour understanding [123].
A correlation between psychiatric disorders in PWS and uniparental disomy has recently been
reported [124]. If this finding is confirmed, imprinted genes outside the typically deleted
region on the paternal or the maternal chromosome may contribute to the psychiatric
phenotype.
THE SMITH MAGENIS SYNDROME
Clinical and behavioural phenotype
Intelligence in SMS patients is varying from borderline to profound mental retardation. The
degree of retardation is mostly moderate. Children with SMS show a particular pattern of
behaviour that can be a useful clue to diagnosis. Infants are very sociable with appealing
smiles and need to be waked for feeding [121]. The most characteristic features in children
include neurobehavioral abnormalities such as aggressive and self-injurious behaviour (SIB)
and significant sleep disturbances and stereotypical behaviours [207]. Behaviour problems
include disobedience, hyperactivity, tantrums, attention seeking, sleep distortion, lability,
property destruction, impulsivity, bed wetting and argumentative behaviour [208]. SIB is
frequent and reported in 67 % to 92% of all patients and includes head banging, self-hitting
and hand, finger and wrist biting, nose or ear picking, onychotillomania,
polyembolokoilomania [209]. With increasing age and ability, the overall prevalence of SIB
as well as the number of different types of SIB are increasing [210]. Sleeping difficulties are
reported in 65% to 75% of the patients and include difficulties falling asleep, frequent
awakening, shortened sleep cycles and excessive daytime sleepiness [211]. Stereotypical
behaviours are an important clinical symptom in the diagnosis. Many SMS persons show selfhugging, behaviour and spasmodic upper body squeeze [210]. Autistic characteristics are also
reported [207,212,213]. The disturbed sleep pattern and behaviour problems correlate with a
disturbed circadian rhythm in melatonin [214,215]. The abnormalities in the circadian rhythm
of melatonin could be secondary to aberrations in the production, secretion, distribution or
metabolism of melatonin. It was suggested that haploinsufficiency for a circadian gene
mapping to chromosome 17p11.2 may cause the inversions of the circadian rhythm of
melatonin in SMS.
Molecular genetics
Mechanisms leading to the deletion [7]
Most patients have a 5 Mb common deletion of 17p11.2 [8]. The deletion in the 17p11.2 band
in SMS patients occurs between two flanking repeat gene clusters [216].
Genes within the deletion
It is still unclear if the SMS phenotype is caused by the fusion of different genes from the
flanking repeat gene clusters or by the loss of one or multiple genes in the context of a
contiguous gene syndrome [218].