Animal Development and Reproduction

Research Paper: Cri-Du-Chat Syndrome

Taylor M. Moore

Cri Du Chat Syndrome

First described by Jerome Lejeune in 1963, a French geneticist, cri du chat syndrome
(CdCS), also known as 5p syndrome, or is French for cat cry syndrome which takes its name
from the cat-like-cry, is often referred to as 5p deletion. Cri-du-chat syndrome is a rare genetic
condition that is caused by the deletion of a missing piece of genetic material on the small arm
(the p arm) of chromosome 5. The cause of this rare chromosome deletion is unknown. The
chromosomal change is written as 5p-. The size of the deletion varies among the affected
individuals. Some studies suggested that a larger deletion tends to result in more severe
intellectual disabilities and developmental delays than smaller deletions. Some researchers
believe the loss of a specific gene CTNND2 is associated with severe intellectual disability in
some people with this condition. The official name of CTNND2 gene is catenin (cadherinassociated protein) delta 2. The normal function of CTNND2 gene is to provide instruction for
making a protein called delta catenin. This protein is active in the nervous system, where it helps
cells to stick together and also plays a role in cell movement. In the developing brain, it may help
to guide nerve cells to the proper position as part of a process known as neuronal migration. In
mature nerve cells, delta-catenin is located in specialized outgrowths called dendrites. Dendrites
branch out from the cell and receive information from nearby cells. This information is relayed
across synapses, which are junctions between nerve cells where cell to cell communication will
occur. Delta-catenin appears to play a crucial role in the function of the synapses. The CTNND2
gene is located in a region of chromosome 5 that is often deleted in people with cri-du-chat
syndrome. As a result of this deletion, many people with this condition are missing a one copy of
CTNND2 gene in each cell. The loss of this gene may cause intellectual disabilities in some
affected infants. Researchers suspect that intellectual disabilities could result from a disruption of
neuronal migration during development of the nervous system. However, infants with cri-du-chat

syndrome who do not have a deletion of the CTNND2 gene tend to have milder intellectual
disabilities or normal intelligence.

Another possibility is that a deletion is caused by a break in a DNA molecule that makes
up a chromosome. In most cases, the chromosome break occurs while the sperm or egg cell is
developing. When the gamete is fertilized ( the male or female gamete), the child will develop
cri-du-chat syndrome. The parent, however, does not have the break in any other cells of the
body and does not actually have the syndrome. In fact the breaks are so rare that it is unlikely to
happen again if the parent has another child. However, it is possible for a child to inherit a
broken chromosome from a parent who also has the disorder. In 80 percent of the cases, the
chromosome carrying the deletion comes from the fathers sperm rather than the mothers egg.
Also the deletion during the formation of egg or sperm, are caused by unequal recombination
during meiosis. Recombination normally occurs between pairs of chromosomes while they are
lined up correctly, or if the chromosome breaks and are not repaired, properly, the chromosome
can actually gain or lose pieces. Unequal recombinations at a certain location on chromosome 5
causes cri-du-chat as well. The prevalence has been estimated at 1 in 50,000 live births and
although the exact gender ratio is unknown the syndrome is thought to be approximately twice as
prevalent in females as in males (Dykens et al., 2000; Niebuhr, 1978; Van Buggenhout et al,
2000). Although cri-du-chat syndrome is relatively rare it represents the most common deletion
syndrome in humans (Cornish et al., 2001).

Infants with this condition often have a high-pitched cry that sounds like that of a cat.
This distinctive cat cry is the core feature of the syndrome and is still regarded as an important
early diagnostic feature in most but not all individuals (Mainardi et al., 2006). The cry is thought

to be caused by anomalies of the larynx which is small, narrow and diamond shaped and the
epiglottis is usually small and hypotonic (Niebuhr, 1978). The high- pitched cat-like cry from
which the syndrome gets its name has been mapped on the 5p15.3 site Overhauser et al., 1994).
The sound of the cry usually becomes less noticeable as the baby gets older, making it it a lot
more difficult for doctors to diagnose after age 2. This disorder is also characterized intellectual
disabilities and delayed development by microcephaly which is small head size, low birth
weights usually persisting the first two years of life for both sexes (Marinescu et al., 2000). On a
typical growth chart you will most likely find a baby with cri-du-chat syndrome in the 50th
percentile or lower. Feeding difficulties are common and the associated failure to thrive may be
in the initial clinical presentation. Some infants may require a feeding tube, this being a process
that could continue for several years. Gastro-oesophageal reflux is common in cri-du-chat
syndrome during the first years of life (Collins and Eaton-Evans, 2011).Feeding difficulties and
gastro-oesophageal reflux during feeding could play a possible role in accounting for slow
growth. As the child grows, other symptoms may occur such as small hands and feet. Other
health problems include respiratory tract infections, otitis media and dental problems. Many
individuals with cri-du-chat syndrome are prone to developing a curvature of the spine which is
known as cogential scoliosis and can become much more apparent with advancing of age. Some
of the most frequently cited physically defining features of cri-du-chat syndrome are facial
features, including microcephaly, round face, widely spaced eyes, downward slanting of
palpebral fissures, low set ears, broad nasal bridge and short neck (Dykens et al., 2000:
Marinescu et al., 1999). Studies however, indicate that facial features change overtime.
Specifically, in lengthening of the face and coarsening of features (Mainardi et al., 2006). Some
children with cri-du-chat syndrome are born with heart defects. While a small amount of infants

are born with serious organ defects and other life threatening medical conditions. Most
individuals who have cri-du-chat syndrome have difficulty with language. Half of children learn
sufficient verbal skills to communicate. Some learn to use short sentences, while others express
themselves with a few basic words using gestures or sign language. The speech delay is been
mapped on a proximal part of 5p15.3 and intellectual impairment is found on 5p15.2 site.

Early reports on cri-du-chat syndrome suggested that profound intellectual disability was
a common feature for the syndrome (Niebuhr, 1978). More recent research data had indicated
that there is a wider range of cognitive ability (Cornish, 1996; Cornish et al., 1999). Progression
in motor development is delayed and adaptive behavior within the domains of socialization,
communication, daily living skills and motor skills does not appear to show any significant
strengths or weakness, although no contrast groups have been employed in research studies
(Cornish et al., 1998). Mainescu et al., (1999) found no association between the size of the
genetic deletion on the 5p site and on the Vineland Adaptive Behavior Scales. However,
individuals with translocations have been found to have a more severe developmental delay,
heightened social withdrawal and more autistic-like features than those with deletions (Dykens
and Clarke, 1997; Mainardi et al., 2006; Sarimski, 2003).
Most individuals with cri-du-chat syndrome have minimal or no speech (Cornish et al.,
1999), whereas receptive language tends to be significantly more developed than expressive and
written skills. According to Sohner and Mitchell (1991), indicators of compromised expressive
communication are present prior to speech development and are present prior to speech
development and can be evidenced by a delayed pattern of babbling development during infancy.
Some researchers have suggested that the delay in the development of verbal communication is a
result of cogential abnormalties of the larynx and delay in motor skills. It seems likely that

problems in expressive language in cri-du-chat syndrome are related physical abnormalities in

the larynx and delayed motor skill development (Manning, 1977; Niehbur, 1978; Sohner and
Mitchell, 1991). Receptive language skills are considered a marked strength within the cognitive
profile of cri-du-chat syndrome (Cornish and Munir, 1998; Cornish et al, 1998). Although
language development is significant delayed, a number of studies have demonstrated that there is
potential for verbal and nonverbal communication to develop in affected individuals. Wilkins et
al. (1980) reported that of 65 individuals with cri-du-chat syndrome, 16.9 percent had a
vocabulary of more than 100 words and were able to form sentences of three or more words. A
further 36.9 percent had limited but useful single-word vocabularies.According to Cornish and
Pigram (1996), only 25.9 percent of 27 individuals with cri-du-chat syndrome used speech to
communicate their needs, whereas 55 percent were able to communicate using non-verbal
methods. Importantly, Sarimskli (2002) has demonstrated that in addition on using verbal and
nonverbal communication to indicate their needs, individuals with cri0du-chat syndrome engage
in a significantly more socially directed communication than individuals with Cornelia de Lange
syndrome, performing at a level that is similar to individuals with Down syndrome. However,
Cornish and Pigram (1996) reported that only 7.4 percent of individuals use any formal signs, the
majority using idiosyncratic gestures. The findings demonstrate a clear capacity and motivation
to engage in communication in individuals with cri-du-chat syndrome, and stress the importance
of early intervention and introduction of sign language in order to further encourage the
development of communication in individuals with cri-du-chat syndrome. Social interaction
skills are considered to be a relative strength of individuals with cri-du-chat syndrome (Carlin,
1983), who are often noted to have a friendly and happy demeanor. However, empirical
evidence for this is inconsistent. In a sample 20 individuals with cri-du-chat syndrome, no

significant differences were identified between scores on the socialization domain of the
Vineland Adaptive Behavior Scales compared to communication, motor and self-help domains
(Cornish et al., 1998). These scores were in line with global mental age equivalent scores. Using
the same assessment with a larger sample of 100 individuals with cri-du-chat syndrome, Dykens,
Hoadapp, and Rosner (1999; cited in Dykens et al., 2000) demonstrated that scores on the
remaining three domains. Specifically, Dykens et al., (1999) reported that over 80 percent of
individuals with the syndrome show an interest in their peers and the actions of other people.

Repetitive behaviors are generally less common in cri-du-chat syndrome than in other
genetic syndromes. However, Moss et al., (2009) report that an attachment to specific objects is a
marked characteristic of the syndrome. Occurring at a clinically significant level in over 67
percent of individuals, the frequency of this behavior is significantly higher in cri-du-chat
syndrome than in four other genetic syndromes, compromising Angleman, Cornelia de Lange,
fragile X and Prader-Willi syndromes, and in comparison to individuals with intellectual
disability of heterogenous cause. This behavior differs from that commonly seen in ASD as it is
usually focused on one specific item as opposed to a class of items and the item may change over
time and the behaviour tends to become less marked with age. Although self-injurious and
aggressive behavior appears to be common behavioural features of cri-du-chat (Collins and
Cornish, 2002; Cornish and Pigram, 1996; Cornish et al., 1998; Dykens and Clarke, 1997), there
are very few studies examining prevalence and phenomenology. Using a questionnaire study to
examine the prevalence of self-injury in children and young adults, Collins and Cornish (2002)
found that 92 percent of the sample (n=66) exhibited some form of self-injurious behaviour.
Other questionnaire studies have found prevalence rates of self-injury to be approximately 70
percent (Cornish and Pigram, 1996; Dykens and Clarke, 1997). Collion and Cornish (2002)

found the most common forms of self-injurious behaviour to be head bangning, hitting head
against body parts and self-biting. In a recent questionnaire study, Arron et al., (in review) found
self-injurious behavior to be present in 76.8 percent of their sample and common topographies
including pulling self, hitting self with objects, hitting self with body and rubbing or scratching
themselves. Analysis of specific behaviors related to sleep disturbance demonstrated that head
banging during sleep or when going off to sleep, the need for security objects, gagging or
choking and appears more active during daytime. However, a small number of research studies
and anecdotal reports suggest that sleep difficulties are a significant problem. Cornish and
Pigram (1996) reported that sleep problems were reported that 30 percent of 20 children with cridu-chat syndrome had an irregular sleep pattern. In a larger study, Cornish et al., (2003) reported
that sleep problems were reported by parents to be severe cause of concern in 50 percent of
individuals. More recently, Maas et al., (2009) reported that nine out of 30 individuals with cridu-chat syndrome fulfilled the criteria for either a mild or severe sleep problem.

Hyperactivity is also commonly reported feature of cri-du-chat. Findings vary from

reports of no increase in level of activity (Baird et al., 2001) 90 prevalence rates of hyperactivity
(Cornish et al., 1998), with clinical hyperactivity reported to be more prevalent than an
intellectual disability comparison group (Cornish and Bramble, 2002). Of the studies assessing
behavior empirically, only two studies incorporated rating scales (Aberrant Behavior CHecklist)
normed on a population of people with intellectual disabilities (Clarke and Boer, 1998; Dkyens
and Clarke, 1997) and most frequently used measure, although not consistently used measure,
and not consistently in its entirety, the Vineland Adaptive Behavior Scales, which listed overly
active, poor concentration and attention and too impulsive within the Externalizing Behavior
factor. Only two studies have included comparison groups of different genetic syndromes and

data from other studies of community and institutionally residing individuals (Clarke and Boer,
1998) and published normative data from two heterogeneous groups (Dykens and Clarke, 1997)
reducing comparable data.

The diagnosis of cri-du-chat syndrome is generally made in the hospital at birth.

However, at birth it is not currently possible to predict how severely the infant is affected by cridu-chat syndrome. A health care provider may note the clinical symptoms. Doctors may also
perform an x-ray on the newborns head to detect abnormalities in the base of the skull. To
confirm the diagnosis, a chromosomal analysis may be used to help to detect small deletions. The
analysis of the individual's chromosomes may be performed. The missing portion (deletion) of
the short arm of chromosome 5 may be seen on a chromosome analysis. If not, a more detailed
type of genetic test called fluorescence in situ hybridization (FISH) analysis may be needed to
reveal the deletion. FISH analysis is a laboratory technique used to visualize where a particular
gene or DNA sequence is located within a person's genome. A clinical scientist will check for
specific chromosomal alterations which cause genetic conditions. The cells are then cultured in a
similar way to karyotype analysis being performed where the cells are cultured, harvested, and
prepared on a microscope slide.
The actual technique FISH can be carried out on dividing cells which is called metaphase
or where individual chromosomes can be distinguished or non-dividing cells this is called
interphase. Metaphase FISH studies are designed to detect changes in microdeletions or
microduplications associated with specific phenotypic findings and require specific and focused
clinical questions to be addressed through the appropriate DNA probe selection. Genetic
changes that are detected in metaphase chromosome preparations by this type of testing are
limited to position and copy number changes, primarily losses being deletions and, in some

instances, gains which would be duplications of the specific chromosomal regions for which the
employed DNA probes are localized. Repositioning of these DNA probes from their normal sites
must be determined in metaphase cell preparations ( translocations, insertions). Interphase FISH
Studies is the enumeration or rearrangements involving specific DNA probes are the only
information available from interphase FISH studies. However, additional inferences on the
chromosome constitution of cells utilized are not possible from interphase FISH studies.
The FISH technique will use a fluorescently labelled hybridization probe which will
attach to the exact part of DNA which the scientist wants to visualize.This makes it quicker to get
results than other techniques such as karyotyping. The hybridization probe is a short fragment of
DNA that has a fluorescent dye attached. A typical FISH probe would be 10 to 100 thousand base
pairs of DNA long. The probe is then added to a microscope slide where all the chromosomes
from a cell are spread out and have been treated so that their DNA is single stranded. If that
region of DNA is present in the patient sample the fluorescently labeled probe will attach to the
DNA and will be visible under a microscope. Even the smallest deletion around 3 to 5 million
base pair of DNA can be seen with FISH technique. If a matching sequence is present enabling
the probe to attach to the DNA from the cell, tiny fluorescent spots will then be seen on the
chromosome at that location. This will actually allow deletions to appear where no fluorescent
will be spotted at the expected position. The FISH technique can detect deletions as small as 200
to 500 base pairs of DNA. For the FISH analysis for a suspected cri-du-chat syndrome a blood
sample is required. 3 to 5 mL peripheral blood in sodium heparin for children and 1 to 2 mL
peripheral blood in sodium heparin for newborns. The blood taken is to be keep at room
temperature and to be taken to the laboratory as soon as it is taken. The test usually takes
anywhere for 5 to 12 days.

There is another testing method that is also used for detecting cri-du-chat syndrome it is
called Cytogenetic Analysis. Cytogenetic testing is commonly performed during pregnancy to
determine if a fetus is at risk for common aneuplodies ,which are syndromes caused by having
extra or missing chromosomes, syndromes caused by structural abnormalities like those of
unbalanced translocations or inversions, or to determine if extra or missing genetic material is
present through cytogenetic microarray testing. The same cytogenetic analyses can be performed
on a newborn or child with multiple anomalies or developmental delays to look for a potential
chromosomal abnormality. With the information provided by cytogenetic analyses, more
accurate diagnoses can be made, allowing for proper treatment of the child. Information gained
through cytogenetic testing is also valuable during reproductive discussions. Also if there is a
family history of cri-du-chat syndrome in the family, the doctor of the mother would suggest a
chromosome analysis or genetic testing while the child is still in the womb. The doctor will
either test a small sample of tissue from outside the sac where the child is developing. This
particular test is called Chorionic Villus Sampling also known as CVS or the doctor may also test
a sample of amniotic fluid known as Amniocentesis to determine whether the child has cri-duchat.

Unfortunately, there is no cure for cri-du-chat syndrome. But there are treatments for
children to reach their full potential. Physical therapy which can help to improve poor muscles.
Speech therapy which will help to stimulate the language ability. Occupational therapy which
will help children with cri-du-chat syndrome learn coping strategies and to obtain new skills.
Children born with cri-du-chat syndrome will require ongoing support from a team made up of
parents, therapist, and medical and educational professionals to help the children with cri-du-chat
syndrome are capable of reaching their fullest potential and can lead full meaningful lives.

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