Most cases of Cri-du-chat syndrome are not the result of an inherited problem. Cri-du-chat syndrome result from a deletion in the DNA molecule that makes up a chromosome. In most cases, this chromosome break will occur in the developing egg or sperm. When this gamete is fertilized, the child will develop cri-du-chat syndrome. The parents, however, do not have the break themselves in any of their other cells. In fact, the break is usually such a rare and random event that it is very unlikely to happen again if the parent has another child. Thus affected people typically have no history of the disorder in their family. Nevertheless, it is possible for a child to inherit a broken chromosome from a parent who also had the disorder.

About 10 percent of individuals with Cri-du-chat syndrome will inherit the chromosome abnormality from an unaffected parent. In these cases, the parent carries a chromosomal rearrangement called a balanced translocation, in which no genetic material is gained or lost. Balanced translocations usually do not cause any health problems; however, they can become unbalanced as they are passed to the next generation. Children who inherit an unbalanced translocation can have a chromosomal rearrangement with extra or missing genetic material. Individuals with cri-du-chat syndrome who inherit an unbalanced translocation are missing genetic material from the short arm of chromosome 5, which results in the intellectual disability and health problems characteristic of this disorder. It is estimated that most cri-du-chat syndrome cases are the result of de novo deletions (about 80%), some derive from a familial rearrangement (12%), and only a few show other rare cytogenetic aberrations, such as mosaicism (3%), rings (2.4%), and de novo translocations (3%).

Gene(s) responsible or implicated in the disorder

Cri-du-chat syndrome is quite a rare disorder. It was first identified by the geneticist Jerome Lejeune in 1963 who also discovered the genetic abnormality that causes Down syndrome. Cri-du-chat syndrome is the result of a genetic deletion on chromosome 5. It is believed that this disorder is the result of a faulty mechanism during the development of the egg or sperm. Curiously, in 80 percent of the cases, the chromosome carrying the deletion comes from the father’s sperm rather than the mother’s egg.

When deletions occur during the formation of an egg or sperm, it is caused by unequal recombination during meiosis. Recombination normally occurs between pairs of chromosomes during meiosis while they are lined up at the metaphase plate. If the pairs of chromosomes don’t line up correctly, or if the chromosome breaks aren’t repaired properly, the structure of the chromosome can be altered. When unequal recombination occurs at this location on chromosome 5, it causes cri-du-chat syndrome.

Generally, (80-85%) are due to sporadic de novo deletion of 5p (15.3 → 15.2). Approximately 10-15% of cases are the result of the unequal segregation of the parental translocation in which the 5p monosomy is often accompanied by a trisomic portion of the genome. The phenotypes in these individuals may be more severe than in those with isolated monosomy of 5p because of this additional trisomic portion of the genome. In most cases they involve terminal deletions with 30-60% loss of 5p material. Fewer than 10% of patients have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).  A minority of cases result from one parent carrying a rearrangement of chromosome 5 called a translocation and passing this on to the baby. The occurrence of mosaicism is also a very rare finding, with frequency estimated at about 3% of patients. Chromosomal mosaicism involves a cell line with a 5p deletion and a cell line with a normal karyotype or a 5p deletion with rearranged cell lines

Genotype-phenotype studies in cri-du-chat syndrome led to the identification of two separate chromosomal regions, hemizygosity that is associated with specific phenotypes. A deletion of 5p15.3 results in the manifestation of a catlike cry, whereas a deletion of 5p15.2 results in the presentation of the other major clinical features of the syndrome. Moreover, a region for speech delay in 5p15.3 has been identified.

Population genetics

Cri-du-chat is one of the most common syndromes caused by a chromosomal deletion. It affects between 1 in 20,000 and 1 in 50,000 babies

The name of this syndrome is French for “cry of the cat,” referring to the distinctive cry of children with this disorder. The cry is caused by abnormal larynx development, one of the many symptoms associated with this disorder. It usually becomes less noticeable as the baby gets older, making it difficult for doctors to diagnose cri-du-chat after age two. Cri-du-chat is caused by a deletion (the length of which may vary) on the short arm of chromosome 5. Multiple genes are missing as a result of this deletion, and each may contribute to the symptoms of the disorder. One of the deleted genes known to be involved is TERT (telomerase reverse transcriptase). This gene is important during cell division because it helps to keep the tips of chromosomes (telomeres) intact. This disorder does not seem to be influenced by race or age of the mother. However, a significant female predominance is observed in affected newborns, with a male-to-female ratio of 0.72:1.

Clinical features

Babies with cri-du-chat usually are small at birth, and may have respiratory problems. Often, the larynx doesn’t develop correctly, which causes the signature cat-like cry. The characteristic cry is perceptually and acoustically similar to the mewing of kittens. This unusual cry is due to both structural abnormalities of the larynx – laryngeal hypoplasia – and to CNS dysfunction. The appearance of the laryngeal may be normal or may exhibit a range of anatomical abnormalities such as floppy epiglottis, small larynx, and asymmetric vocal cords. However, the cause of this characteristic cry cannot entirely be ascribed to the larynx. It seems that a problem in the brain development – most likely at the cranial base – play a role in the development of the signature cry of the syndrome. This cat like cry is not a permanent feature, indeed, it usually disappears over time.

Furthermore, distinctive external features are generally present too. Patients may have microcephaly, an unusually round face, widely set eyes, a small chin, folds of skin over the eyes, and a small bridge of the nose. There are also several problems that occur inside the body too. A small number of children are born with heart defects, muscular or skeletal problems, hearing or sight problems, and/or poor muscle tone. As they grow, people with cri-du-chat usually have difficulty walking and talking correctly. They may have behavior problems (such as hyperactivity or aggression), and severe mental retardation. If no major organ defects or other critical medical conditions exist, life expectancy is normal. Indeed, with contemporary interventions, the chance of survival to adulthood is possible. Currently, the mortality rate of cri-du-chat syndrome is 6-8% in the overall population. Pneumonia, congenital heart defects, and respiratory distress syndrome are the most common causes of death.

Pathogenesis (if known)

There is no known risk factors that can contribute to the development of this disorder. Doctors most often identify cri-du-chat by the infant’s cat-like cry. Other signs are microcephaly, poor muscle tone, and mental retardation. However, it is possible to test for cri-du-chat (and other chromosomal abnormalitites) while the baby is still in the womb. There are two ways of doing so. Doctors can either test a tiny sample of tissue from outside the sac where the baby develops (chorionic villus sampling (CVS)), or test a sample of the amniotic fluid (amniocentesis).

Optional: Other important section(s) for your disorder

Although there is no real treatment for cri-du-chat syndrome, children with the disorder can go through therapy to improve their language skills, motor skills, and to help them develop as normally as possible.