Cri-Du-Chat Syndrome

A number sign (#) is used with this entry because cri-du-chat syndrome is a well-described partial aneusomy resulting from deletion of the short arm of chromosome 5. There is a high probability that deletion of multiple genes is responsible for the phenotype as well as evidence that deletion of the telomerase reverse transcriptase gene (TERT; 187270) is specifically involved in the phenotypic changes of cri-du-chat syndrome.

Description

Cri-du-chat syndrome was first described by Lejeune et al. (1963) as a hereditary congenital syndrome associated with deletion of part of the short arm of chromosome 5. The deletions can vary in size from extremely small and involving only band 5p15.2 to the entire short arm. Although the majority of deletions arise as new mutations, approximately 12% result from unbalanced segregation of translocations or recombination involving a pericentric inversion in one of the parents.

Clinical Features

Cri-du-chat syndrome is characterized in young children by microcephaly, round face, hypertelorism, micrognathia, epicanthal folds, low-set ears, hypotonia, and severe psychomotor and mental retardation. One of the most characteristic features in newborns is a high-pitched cat-like cry that is usually considered diagnostic for the syndrome (see Overhauser et al., 1994); however, the characteristic cat-like cry without the typical dysmorphic and severe developmental features of the syndrome has been found in individuals with a deletion confined to 5p15.3 (see Overhauser et al., 1994 and Gersh et al., 1995).

Kjaer and Niebuhr (1999) studied profile radiographs of the cranial face in 23 patients with cri-du-chat syndrome collected in Denmark in the 1970s. Twenty-two patients had terminal deletions of chromosome 5, and 1 patient had an interstitial deletion. The cranial base angle was in most cases reduced and in no cases increased compared to age-related standards for normal individuals. Malformations in the bony contours of the sella turcica and the clivus occurred in cri-du-chat patients with terminal deletions. They pointed out that this specific cranial base region develops around the notochord at the location from where the rhombencephalic-derived brainstem, pons, and cerebellum develop dorsally, and from where the neurons to the larynx migrate ventrally. They suggested that a cranial developmental field, originating from the notochordal location, is involved in the manifestations of cri-du-chat syndrome.

Van Buggenhout et al. (2000) pointed out that with advancing age the clinical picture of the cri-du-chat syndrome becomes less striking. They presented 7 patients with 5p deletion syndrome, with ages ranging from 16 to 47 years. Some of the clinical characteristics, such as long face, macrostomia, and scoliosis, became more evident. All patients were severely or profoundly mentally retarded except for one who was mildly retarded. Diagnosis was difficult to make in some of the patients who were first seen at an older age. In some of them, the craniofacial appearance resembled that of Angelman syndrome (105830). Most patients had periods of destructive behavior, self mutilation, and aggression.

Fang et al. (2008) reported a 3-generation Chinese Han family in which 5 members had cri-du-chat syndrome. The proband was a 62-year-old woman who presented to a psychiatric ward with temper tantrums, self-injuries, aggressive behavior, and psychotic symptoms, including delusions of persecution, auditory hallucinations, self-talking, and self-laughing. She had a soft, high-pitched, cat-like voice. Her 41-year-old daughter had mental retardation and similar psychotic features, which are rare in cri-du-chat syndrome. She did not have a high-pitched voice. In contrast, the other 3 affected males had mild to moderate mental retardation without psychotic symptoms. All affected individuals were found to have a 10.5-Mb terminal deletion at chromosome 5p15.2, which was confirmed and characterized by karyotyping, FISH, array CGH, and quantitative PCR analyses. The ROPN1L gene (611756) was found to be disrupted by the breakpoint. Although the affected family members apparently shared deletions of the same size, the variation in mental symptoms within this family suggested that other factors besides the size and location of 5p deletions may modify the mental presentation of patients with cri-du-chat syndrome. Fang et al. (2008) noted that familial occurrence of this disorder is rare.

Clinical Variability

Ladekarl (1968) reported a patient with features of cri-du-chat syndrome and Goldenhar syndrome (164210) associated with a 5q deletion. Choong et al. (2003) reported a male infant, born of nonconsanguineous parents, who had clinical features of cri-du-chat syndrome and Goldenhar syndrome. At birth, he was noted to have dysmorphic facial features, including bilateral preauricular tags, rotated ears, epicanthal folds, a left epibulbar lipodermoid, and an accessory left nipple. He also had hearing loss and feeding difficulties due to esophageal atresia with tracheoesophageal fistula, and horseshoe kidney. In addition, he had a high-pitched, cat-like cry, characteristic of cri-du-chat syndrome. Cytogenetic analysis detected a terminal deletion of chromosome 5p14, consistent with the cri-du-chat locus. The association of Goldenhar syndrome and cri-du-chat syndrome in this patient suggested that the chromosome 5p14 locus may harbor a gene implicated with Goldenhar syndrome.

Population Genetics

The cri-du-chat syndrome appears to be one of the most common human deletion syndromes, with an incidence varying between 1 in 20,000 to 1 in 50,000 births (Niebuhr, 1978). The frequency in populations of profoundly retarded patients (IQ less than 20) is approximately 1% (Niebuhr, 1978).

Molecular Genetics

Overhauser et al. (1994) analyzed the 5p deletion breakpoints in 49 individuals using somatic cell hybrids. They used 5p-specific DNA probes to unambiguously order most of the chromosomal breakpoints present by hybridization to somatic cell hybrid DNA. Comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved in the high-pitched cry mapped to proximal 5p15.3 (probe D5S727), while the chromosomal region involved in the remaining features of the syndrome mapped to a small region within central 5p15.2 (probe D5S721). This latter region was estimated to be about 2 Mb in size. Deletions that did not include these 2 chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype.

Gersh et al. (1995) studied 4 families in which patients with 5p deletions had only the characteristic cat-like cry, with normal to mildly delayed development. The precise location of the deletion in each family was determined by fluorescence in situ hybridization using lambda phage and cosmid clones. All of the deletion breakpoints mapped distal to a chromosomal region implicated with the facial features and severe mental and developmental delay in the cri-du-chat syndrome. The breakpoints were located distal to the 5p15.2 region and indicated to Gersh et al. (1995) that another genetic component of this contiguous gene syndrome is located in that area.

Simmons et al. (1997) isolated cDNAs from the cri-du-chat critical region by direct sequencing of a chromosome 5-specific cDNA library. A thrombospondin-like gene and 3 other cDNAs were considered candidate genes for the cri-du-chat contiguous gene deletion syndrome.

Cerruti Mainardi et al. (2001) studied 80 patients with cri-du-chat syndrome. Sixty-two had a 5p terminal deletion with breakpoints ranging from p13 to p15.2. Seven patients had a 5p interstitial deletion; 4 had a de novo translocation, and 3 had a familial translocation. Three had a de novo 5p anomaly involving 2 rearranged cell lines, and 1 had a 5p deletion arising from a paternal inversion. Cerruti Mainardi et al. (2001) identified a critical region at p15.2 for dysmorphism and mental retardation and a separate region at p15.3 for the cat-like cry, this region being bounded by the markers at D5S13 and D5S731. They also suggested a separate region at p15.3 for speech delay. The 62 patients were subdivided into 4 groups according to deletion size and a significant trend was identified, with increased severity of dysmorphism and developmental delay corresponding to increased size of deletion.

Medina et al. (2000) determined that the CTNND2 gene (604275) maps to a specific region in chromosome 5p15.2 implicated in the mental retardation phenotype of cri-du-chat syndrome. They characterized the breakpoints in patients with 5p terminal deletions with respect to the severity of mental retardation and the physical location of the CTNND2 gene and found a strong correlation between hemizygous loss of CTNND2 and severe mental retardation. Medina et al. (2000) concluded that these findings, and the properties of CTNND2 as a neuronal-specific protein, expressed early in development and involved in cell motility, supported its role in the mental retardation of cri-du-chat syndrome when present in only 1 copy.

The TERT gene is localized to the distal portion of chromosome 5p (viz., 5p15.33) and is the rate-limiting component for telomerase activity, which is essential for telomere length maintenance and sustained cell proliferation. Zhang et al. (2003) showed that a deletion of the TERT allele had occurred in all 10 patients with cri-du-chat syndrome whom they examined. Induction of TERT mRNA in proliferating lymphocytes derived from 5 of 7 patients was lower than that in unaffected control individuals. The patient lymphocytes exhibited shorter telomeres than age-matched unaffected individuals (P less than 0.0001). A reduction in replicative life span and a high rate of chromosome fusions were observed in cultured patient fibroblasts. Reconstitution of telomerase activity by ectopic expression of TERT extended the telomere length, increased the population doublings, and prevented the end-to-end fusion of chromosomes. Zhang et al. (2003) suggested that haploinsufficiency for telomere maintenance in vivo may be one genetic element contributing to the phenotypic changes in cri-du-chat syndrome.

Perfumo et al. (2000) reported 3 children with mosaic 5p rearrangements, 2 with a partial monosomic cell line and a partial monosomic/trisomic cell line and 1 with 2 different partial monosomic cell lines.

Zhang et al. (2005) used array comparative genomic hybridization to map DNA copy number changes in 94 patients with cri-du-chat syndrome who had been carefully evaluated for the presence of the characteristic cry, speech delay, facial dysmorphology, and level of mental retardation. Most subjects had simple deletions involving 5p; the deletion was terminal in 67 and interstitial in 12. Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between BACs containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.33-p15.32, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.31-p15.2, between BACs containing D5S208 and D5S2887. Mental retardation depended approximately on the 5p deletion size and location, but there were many cases in which the retardation was disproportionately severe, given the 5p deletion. All 15 of these cases, approximately two-thirds of the severely retarded patients, were found to have copy number aberrations in addition to the 5p deletion. Restriction of consideration to patients with only 5p deletions clarified the effect of such deletions and suggested the presence of 3 regions, referred as MR-I, MR-II, and MR-III, with differing effect on retardation. Deletions including MR-I, a 1.2-Mb region overlapping the previously defined cri-du-chat critical region but not including MR-II and MR-III, produced a moderate level of retardation. Deletions restricted to MR-II, located just proximal to MR-I, produced a milder level of retardation, whereas deletions restricted to the still more proximal MR-III produced no discernible phenotype. However, mental retardation increased as deletions that included MR-I extended progressively into MR-II and MR-III, and mental retardation became profound when all 3 regions were deleted.

South et al. (2006) reported a child with cri-du-chat syndrome and a terminal deletion 5p14.3 which microsatellite analysis confirmed was inherited from the mother. FISH analysis identified a paracentric inversion, inv(5)(p13.3p15.3), in the mother. South et al. (2006) noted that this was an unusual case because paracentric inversion carriers usually do not have liveborn children since recombination is predicted to result in unstable chromosomes that are embryonic lethal. South et al. (2006) proposed a mechanism involving dicentric chromosome formation with subsequent breakage and telomere healing during meiosis to explain the findings in this case.