Cri du Chat Syndrome

Since the description of the first three cases of the 'cri du chat' syndrome by Lejeune, Lafourcade, Berger, Vialatte, Boeswillwald, Seringe, and Turpin (1963), 12 patients have been reported on in whom part of the short arms of a chromosome in the 4-5 group were absent (Lejeune, Lafourcade, de Grouchy, and Berger, 1964b; Punnett, Carpenter, and DiGeorge, 1964; Book, Atkins, and Santesson, 1963; de Grouchy, Arthuis, Salmon, Lamy, and Thieffry, 1964; Dumars, Gaskill, and Kitzmiller, 1964; Macintyre, Staples, LaPolla, and Hempel, 1964; McCracken and Gordon, 1965; Hijmans and Shearin, 1965; Dyggve and Mikkelsen, 1965). The clinical features have all been similar; with characteristic cry, severe mental retardation, microcephaly, moon face, hypertelorism, epicanthus, antimongoloid slant of palpebral fissures, low-set ears, and abnormal dermatoglyphics.


First description and alternative names
First described by Lejeune in 1963, Cri du Chat Syndrome (CdCS), which takes its name from the 'cat-like cry', is often referred to as Deletion 5p-syndrome and chromosome five short arm deletion.

Incidence/prevalence
The prevalence of CdCS 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 (Niebuhr, 1978;Van Buggenhout et al., 2000;Dykens et al, 2000).

Genetics and Molecular Biology
CdCS is predominantly caused by a partial deletion on the tip of the short-arm of chromosome 5 (with a critical region of 5p15).The size of the deletion ranges from the entire short arm to the region 5p15 (Overhauser et al., 1994).A de novo deletion is present in 85% of cases; 10 to 15% are familial with more than 90% due to a parental translocation and 5% due to an inversion of 5p (Van Buggenhout et al., 2000).Neibuhr first identified the specific chromosomal region implicated in the syndrome as 5p15.1-5p15.3, using cytogenetic analysis (Niebuhr, 1978).More recent work has mapped specific critical areas within this region as being responsible for the expression of the core clinical features of the syndrome.For example, the characteristic high pitched 'cat-like' cry from which the syndrome derives its name has been mapped to the proximal part of 5p15.3, the speech delay to the distal part of 5p15.3 and severe intellectual impairment to 5p15.2 (Overhauser et al., 1994).This distinctive cry is considered the most prominent clinical diagnostic feature of the syndrome (Mainardi et al. 2006).Though relatively rare, CdCS represents the most common deletion syndrome in humans (Cornish et al, 2001).

Physical features and natural history
The distinctive cat-cry is a core feature of the syndrome and is still regarded as an important early clinical diagnostic feature in most but not all individuals (Mainardi et al.2006).The cry is thought to be caused by anomalies of the larynx (small, narrow and diamond shaped) and of the epiglottis that is usually small and hypotonic (Neibuhr, 1978) It has however been found that oral stimulation interventions in newborns with CdCS are beneficial to their development, improving oxygen saturation and preventing hypoxia, which shortens hospital stay at the beginning of life (Kim & Kim, 2018).Many infants tend to be of low birth weight and low weight usually persists in the first two years of life for both sexes (Marinescu et al., 2000).Feeding difficulties are common and the associated failure to thrive may be the initial clinical presentation.Some infants may require tube feeding, a process which may have to continue for several years.Gastroesophageal reflux is common in CdCS during the first years of life.Other health problems include respiratory tract infections, otitis media and dental problems.Many individuals with CdCS are prone to developing a curvature of the spine (congenital scoliosis) and this can become more apparent with advancing age.Some of the most frequently cited physically defining features of CdCS are facial characteristics including microcephaly, rounded face, widely spaced eyes, downward slanting of palpebral fissures, low set ears, broad nasal ridge and short neck (Dykens et al., 2000;Marinescu et al., 1999).Studies indicate that facial features change over time, specifically, lengthening of the face and coarsening of features (Mainardi et al. 2006).

Behavioural characteristics
Sleep difficulties are a significant problem in this group, occurring in between 30 to 50% of individuals (Maas et al., 2009).Repetitive behaviours are generally less common in CdCS than inother 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% of individuals, the frequency of this behaviour is significantly higher in CdCS than in other genetic syndromes including and in comparison to individuals with intellectual disability of heterogeneous cause.This behaviour differs from that commonly seen in autism spectrum disorder as it is typically focussed on one specific item (as opposed to a class of items) and the item may change over time.Additionally, the behaviour tends to become less marked with age.
Self-injurious and aggressive behaviours are a common behavioural feature of CdCS ( (Arron et al., 2011).The most common topographies are reported to be hitting, pulling hair, biting and pinching (Collins & Cornish, 2002).
Hyperactivity is a commonly reported feature of CdCS.Findings vary from reports of no increase in level of activity (Baird et al, 2001) to 90% prevalence rates of hyperactivity (Cornish et al,1998) with clinical hyperactivity (ADHD) reported to be more prevalent in CdCS than in an intellectual disability comparison group (Cornish & Bramble, 2002).The available literature documents the contrast between high prevalence of Attention Deficit Hyperactivity Disorder (ADHD) and the commonly identified immobility and severe motor delay (Cornish & Bramble, 2002).The reported high prevalence of ADHD like phenomena has raised concerns regarding both the restrictions this may place on cognitive and emotional development (Cornish et al., 1998) and its role in determining familial stress (Cornish & Bramble, 2002).This highlights a need to clarify prevalence as recommendations are often made for a relatively low threshold for medication in treating hyperactivity in these individuals (Dykens & Clarke, 1997) even though there is some evidence identifying intensive behaviour modification as the most effective intervention (Wilkins et al., 1983).ASD characteristics are not considered to be strongly associated with the CdCS (Moss et al., 2008) and have been reported to be less severe relative to a matched control group (Claro et al., 2011).In fact, several studies report social interaction skills as being a relative strength of individuals with CdCS (Carlin, 1990; Cornish & Pigram, 1996).Specifically, Moss et al., (2013) report that communication skills used to solicit social interaction (indicative of social motivation) occurred significantly more frequently in individuals with CdCS relative to matched contrast groups of individuals with Cornelia de Lange and Angelman syndromes during structured social observations.Receptive language was also noted to improve across the lifespan whilst other skills remained stable (Cochran et al., 2019).
Delayed but not deviant speech patterns, particularly in gestural and lexical fields, are also found to be a common characteristic in individuals with CdCS (Kristofferson, 2020).Intelligibility of speech may also be reduced due to difficulty producing consonants (Kristofferson et al., 2014).This is consistent with indications that children with CdCS and difficulties articulating may recall more detailed representations of words than they are capable of expressing (Garmann et al., 2017).

Neuropsychological characteristics
Early reports on CdCS suggested that profound intellectual disability was a common feature of the syndrome (Niebuhr, 1978).More recent, albeit limited, research data indicate that there is a wider range of cognitive ability (Cornish, 1996;Cornish et al, 1999).Progression in motor development is delayed and adaptive behaviour within the domains of socialisation, 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).Marinescu et al. (1999) found no association between the size of the genetic deletion on 5p and scores 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 & Clarke, 1997; Mainardi et al. 2006;Sarimski, 2003).