University of Central Oklahoma CRI-DU-CHAT SYNDROME By James Truby May 3, 2006 BIO 2233 Heredity Paper Assignment CRI-DU-CHAT SYNDROME (CDCS) Cri-du-chat syndrome (CDCS) refers to a unique combination of physical and mental characteristics associated with a loss of genetic material on the distal short arm of the fifth chromosome. This loss of genetic material is referred to as a deletion. CDCS is also called 5p- syndrome (5p-S), 5p monosomy, or Cat Cry syndrome which was first identified by Dr. Jerome Lejeune in 1963.
He named so because of the distinctive cry in infancy that resembles to the mewing of a cat. This characteristic cry in the infancy is caused by structural abnormalities of the larynx (such as laryngeal hypoplasia) and CNS dysfunction (Chen, 2005). The laryngeal appearance may be normal or may exhibit remarkable anatomical abnormalities such as floppy epiglottis, small larynx, and asymmetric vocal cords. In addition to that, developmental field connecting the brain and the affected clivus region of the cranial base with the laryngeal region from which the characteristic cry derives may exist (Chen 2005).
Its high-pitched, monochromatic cry usually makes a physician decide to obtain a chromosome study and the definitive test required to confirm the diagnosis of CDCS (Campbell, 2005). The characteristic cry usually disappears by the time they are aged two year. Other features evident in infancy include characteristic physical features such as a small moon-shaped face, epicanthic folds, wide spaced, down-slanting eyes, and a small mouth and chin (Campbell, 2005).
These infants also exhibit low muscle tone (hypotonia), slow growth, and significant developmental delays. As children with CDCS grow, the face usually elongates and becomes thinner and more triangular in shape with a broad forehead and a somewhat small pointed and receding lower jaw and chin.. The epicantal folds remain and the nasal bridge widens and remains flattened. Baby teeth are often delayed in erupting, are small, and have multiple spaces (diastemas).
The growth rate may be normal in the early months or years but frequently slows somewhat during the toddler and schools years resulting in growth parameters that are below average (Campbell, 2005). Developmental milestones usually emerge slowly and show increasing delays with both the increasing age of the child and the complexity of the task. As well as a delay in expressive language, high rates of hyperactivity and inattention are often noted clinically, and symptoms of attention deficit hyperactivity disorder are also found.
By looking at their behaviors, the majority of the individuals exhibited some form of self-injurious behavior such as predominantly head banging and vomiting or rumination). Sixty-five per cent were reported as displaying some form of aggressive behavior; for example, hitting others or pulling others’ hair (Sarimski, 2005). Almost 80-85% cases are caused by sporadic de novo deletion of 5p which are mostly paternal in origin (Chen, 2005). Most of the remaining cases result from unbalanced translocations, which may be either maternally or paternally derived.
According to the study of Anju et el, the telomerase reverse transcriptase (hTERT) gene which is localizing chromosome fifth is relating to CDCS. hTERT is responsible for the rate-limiting of telomerase activity that is essential for telomere-length maintenance and sustained cell proliferation (Anju et el, 2003). Anju et el found that the CDCS patients had shorter telomeres than age-matched unaffected individuals and had a reduction in replicative life span and a high rate of chromosome fusions in cultured patient’s fibroblasts.
Therefore Anju et el are hypothysing that “one allele of hTERT should be deleted in this syndrome, and, a deletion of one hTERT copy occurs with in CDCS, consequently allowing hTERT expression and causing haploinsufficiency for telomere maintenance in the affected patients”. Zhang et el mapped Genotype-phenotype correlations by using Array Comparative Genomic Hybridization. The results are as follows. Genotype-phenotype correlations localized the region associated with the cry to 1. 5 Mb in distal 5p15. 31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676; speech delay to 3. Mb in 5p15. 32-15. 33, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2. 4 Mb in 5p15. 2-15. 31, 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 (Zang et el, 2005). There is a clear increase in the severity of retardation with an increasing extent of deletion, but there are some significant exceptions.
For example, there are some patients with interstitial deletions on 5p who are either unaffected or minimally retarded, whereas others with smaller deletions in the same region are profoundly retarded. Many medical or health problems are common in children. Campbell, et al. (2005) reported 20% of the individuals with CDCS had some form of hearing loss. Cardiac complications are common with about 30% having heart malformations. In addition, an early onset or delayed puberty in females was also reported. Disorders of sleep, feeding problems, constipation (increases with age), infections, and behavior problems are fairly common.
Other medical problems include low birth weight, cleft lip and palate, respiratory complications including susceptibility to pneumonia, gastrointestinal structural differences such as intestinal malrotation, gastroesophageal reflux, susceptibility to middle ear fluid and infections, susceptibility to other infections, curvature of the spine (scoliosis), inguinal and abdominal hernias, orthopedic structural differences, slow growth rate, differences in various organ systems, laryngeal structural differences, colic, jaundice, susceptibility to dehydration, kidney and urinary tract problems, and abnormal urethral opening in male (hypospadias ) (Campbell, 2005). Individual with CDCS need medical attention from Clinical geneticist, Developmental pediatrician, Neurologist, Cardiologist, Ophthalmologist, Dentist, Orthopedist, Psychologist, Physical and occupational therapist, Speech language pathologist, and Audiologist, Urologist (Chen, 2005). Prior to the 1980’s, research on CDCS consisted primarily of medical studies of individuals who had lived in institutions. Most of these individuals did not have access to a loving family environment, education, or systematic medical care. Consequently, the prognosis for individuals with CDCS reported in early studies was very pessimistic.
Parents of children diagnosed early with significant disabilities in the United States were strongly encouraged to place them in institutions and forget them (Campbell, 2005). However current research on CDCS presents a more optimistic prognosis. When children are provided a positive home environment and access to early intervention programs a more favorable prognosis is expected (Campbell, 2005). CDCS is a relatively uncommon syndrome with an incidence rate of between one in 15,000 live births and one in 50,000. Interestingly enough, the incidence rate of one in 15,000 estimates emanates from a study of 27,472 live births in a large Tokyo hospital from 1972 to 1985 (Campbell, 2005). Because of the low incidences of CDCS, little information is available.
The cause of the dilation on chromosome fifth still remains unknown, but I guess that some kind of mutagens are affecting the chromosome and causing CDCS. I hope the more advance of chromosomal study that tells us the prevention and real treatment of CDCS. Reference Anju Zhang, Chengyun Zheng, Mi Hou, Charlotta Lindvall, Ke-Jun Li, Fredrik Erlandsson, Magnus Bjo? rkholm, Astrid Gruber, Elisabeth Blennow,and Dawei Xu. (2003). Deletion of the Telomerase Reverse Transcriptase Gene and Haploinsufficiency of Telomere Maintenance in Cri du Chat Syndrome. American Journal of Human Genetics, Vol. 72 Issue 4, p940, 9p Sarimski, K. (2003). Early play behaviour in children with 5p- (Cri-du-Chat) syndrome. Journal of Intellectual Disability Research. Vol. 47 (2) 113-120
Xiaoxiao Zhang, Antoine Snijders, Richard Segraves, Xiuqing Zhang, Anita Niebuhr, Donna Albertson, Huanming Yang, Joe Gray, Erik Niebuhr, Lars Bolund, and Dan Pinkel. (2005). High-Resolution Mapping of Genotype-Phenotype Relationships in Cri du Chat Syndrome Using Array Comparative Genomic Hybridization American Journal of Human Genetics. V. 73, pp. 312-326 Dennis J. Campbell, Mary Ester Carlin, Joseph E. Justen, and Samera M. Baird. (2005). Cri-du-chat Syndrome: A Topical Overview. Organization of Five Point Minus Society. Retrieved from http://www. fivepminus. org/cdc%20overview. pdf#search=’Lejeune%20et%20al%20cat%20cry’ Harold Chen. (2005). Cri-du-chat Syndrome. Emedicine. Retrieved from http://www. emedicine. com/ped/topic504. htm