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Year : 2012  |  Volume : 55  |  Issue : 4  |  Page : 501-505
Cri du chat syndrome: A series of five cases

1 Cytogenetics Unit, Christian Medical College, Vellore, India
2 Developmental Paediatrics Unit, Christian Medical College, Vellore, India
3 Unipath Specialty Laboratory, Ahmedabad, India
4 Department of Neurology, Christian Medical College, Vellore, India
5 Clinical Genetics Unit, Christian Medical College, Vellore, India

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Date of Web Publication4-Mar-2013


The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome associated with a partial deletion of the short (p) arm of chromosome 5. We describe five children who were diagnosed to have CdCS by conventional cytogenetic analysis. The deletion was at 5p15 in four patients, whereas the fifth had a larger, more proximal deletion at 5p14. Fluorescence in situ hybridization (FISH) analysis confirmed the deletion of the CdCS critical region at 5p15.2. All five children had global developmental delay and dysmorphism with microcephaly. The other clinical features were variable. Since the clinical diagnosis of CdCS may not always be evident because of the phenotypic heterogeneity, cytogenetic analysis is necessary to establish the diagnosis and confirm that the deletion involves the CdCS critical region. This will enable early intervention which plays an important role in improving the outcome.

Keywords: Cri du chat syndrome, cytogenetics, deletion 5p, developmental delay

How to cite this article:
Dangare HM, Oommen SP, Sheth AN, Koshy B, Roshan R, Thomas MM, Danda S, Srivastava VM. Cri du chat syndrome: A series of five cases. Indian J Pathol Microbiol 2012;55:501-5

How to cite this URL:
Dangare HM, Oommen SP, Sheth AN, Koshy B, Roshan R, Thomas MM, Danda S, Srivastava VM. Cri du chat syndrome: A series of five cases. Indian J Pathol Microbiol [serial online] 2012 [cited 2022 Aug 11];55:501-5. Available from: https://www.ijpmonline.org/text.asp?2012/55/4/501/107791

   Introduction Top

Chromosomal abnormalities are an important cause of developmental delay and mental retardation in children. The cri du chat syndrome (CdCS) is a chromosomal deletion syndrome caused by a deletion of the short (p) arm of chromosome 5 which may be visible or submicroscopic. Children with CdCS have a cry resembling the mewing of a cat in infancy, global developmental delay (IQ of 50 or below), and dysmorphism. [1],[2] The dysmorphic features include micrognathia, down-slanting palpebral fissures, hypertelorism, and low-set ears. Pre-auricular tags, syndactyly, abnormal dermatoglyphics, cryptorchidism, hypospadias and cardiac, renal, gastrointestinal tract, and neurological abnormalities may also be present. [2],[3] Despite being one of the commonest deletion syndromes, there are only a few reports of CdCS from India. [4],[5]

   Subjects and Methods Top

We describe the clinical features and cytogenetic findings of five children with cytogenetically visible deletions of chromosome 5p between 2001 and 2011 at a tertiary hospital. Conventional cytogenetic analysis of phytohemagglutinin-stimulated peripheral blood cultures was performed using standard protocols. [6] For each patient, 20 G-banded metaphases at 400-550 band resolution were studied at ×1000 magnification using a Zeiss Axioskop 40 microscope. Fluorescence in situ hybridization (FISH) analysis was performed using a locus-specific probe for the CdCS critical region at 5p15.2 (Abbott Laboratories, Abbott Park, Illinois, U.S.A.) as per the manufacturer's instructions. The probe details are as follows: 5p15.2, green signal (D5S23:D5S721 locus); 5q31, internal control, red signal (EGR1 locus). At least 100 interphase cells and 10 metaphases were counted from each sample at ×1000 magnification using a Zeiss Axioskop 2 Mot fluorescence microscope. Ikaros software was used for karyotyping and Isis software for FISH (MetaSystems, GmBH, Altlussheim, Germany). Results were recorded using the International System for Human Cytogenetic Nomenclature (ISCN). [7]

   Results Top

The children ranged in age from 3 months to 6 years. Four of them were female children. All the five children had microcephaly and global developmental delay. The other clinical features were heterogeneous. Four children had hypertelorism and mouth and palatal abnormalities. Three had epicanthal folds, muscle hypotonia, and clinodactyly. Two had anti-mongoloid slant of the palpebral fissures, synophrys, squint, mild deafness, and increased muscle tone. One child had laryngomalacia. Cryptorchidism was present in the only male child. Only one child had an associated congenital heart disease (patent ductus arteriosus). Four children had evidence of early behavioral abnormalities. Two were hyperactive and two had features of social withdrawal. Since all children had gross developmental delay, we could not score them on standard developmental assessments. Therefore, we had to rely on subjective observations and parental reports to calculate the developmental age except for patient 5 who could complete the Vineland Adaptive Behaviour Scales at 6 years of age. Standard deviations (SD) are calculated using the WHO Anthopometry software WHO Anthro (version 3.2.2, January 2011). [8] *Since the software can be used only for children less than 5 years, standard deviations for patient 5 have been calculated from her height, weight and head circumference at 3 years of age.

The clinical features are summarized in [Table 1] and [Table 2].
Table 1: Antenatal, perinatal and developmental features of five children with cri du chat syndrome

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Table 2: Clinical features of five children with cri du chat syndrome

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All five patients had visible terminal deletions involving band 5p15 in four and band 5p14 in one. FISH analysis confirmed the loss of 5p15.2, the CdCS critical region, in all five patients. Only one family underwent parental karyotyping, which showed no abnormality. The partial G-banded karyotype, and FISH images are shown in [Figure 1].
Figure 1: (a) Idiogram of chromosome 5p [7]: Cri-du-chat syndrome (CdCS) critical region arrowed. (b) Partial karyotype of deletion 5p15. (c) Fluorescence in situ hybridization analysis of deletion 5p15.2: One green signal (5p15.2); two red signals (5q31, control)

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   Discussion Top

Chromosomal abnormalities are present in nearly 1% of live-born children, [10] and their effects are devastating. CdCS is among the better known chromosomal deletion syndromes [11] and has an estimated incidence of 1 in 15,000 [12] to 1 in 50,000 [11] live births with a slightly higher incidence in female births. [11] Fewer than 10 patients have been reported from India. [4],[5]

CdCS occurs when there is a partial deletion of the short (p) arm of chromosome 5 which may be terminal or, less commonly, interstitial. The deletions are de novo in 80% of patients and inherited from a parental balanced translocation or other rearrangement in the remaining patients. [13] Deletions of 5p vary in size, and may be visible, or submicroscopic, detectable only by FISH. Reported breakpoints range from 5p13 to 5p15.2. [13] Molecular studies have identified a small, but critical deleted region at 5p15.2. [11] The region for the "cat-like cry" has been localized to 5p15.3. [14],[15] CdCS is associated with haploinsufficiency of multiple genes on 5p which include the human semaphorin F (SEMAF) gene [16] and the human δ-catenin (CTNND2) gene in the CdCS critical region at 5p15.2 and the human telomerase reverse transcriptase (hTERT) gene at 5p15.33. [17],[18]

The clinical features are also variable. There is a positive correlation between the severity of the clinical features and the size of the deletion. Only those deletions of 5p which involve the critical region at 5p15.2 can be called CdCS. Although the features of CdCS are well-known, a clinical diagnosis is often difficult because of the heterogeneous phenotype which changes with age. The typical cry may normalize as early as 2 years. The round face becomes long and narrow, even asymmetric, because of greater growth of facial structures relative to that of the cranial vault. Facial dysmorphism also changes with age. Muscle hypotonia is replaced by hypertonia. Microcephaly becomes more evident as the child grows older. [2],[3] No association with prenatal events, age of parents, or birth order within the family has been established. [19]

We, too, noted heterogeneity in the dysmorphic features and the behavioral phenotype, therefore CdCS was suspected clinically in only two of the five children. The only consistent features seen in all our patients were global developmental delay and microcephaly. The diagnosis was established in all five children using conventional cytogenetic analysis as part of the work-up of developmental delay and dysmorphism. FISH was performed subsequently for confirmation of deletion of the CdCS critical region. All our patients had visible terminal deletions. None of the other mechanisms of deletions such as unbalanced translocations, inversions, or ring chromosomes were seen. There was no mosaicism.

If the clinical suspicion of CdCS is high, and the karyotype is normal, FISH analysis using locus- specific and/or subtelomeric probes is recommended to exclude submicroscopic deletions or cryptic translocations involving chromosome 5. [12],[20] Other methods that can be used instead of cytogenetic analysis and FISH include multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH); however, both these tests are not yet widely available in our country, and the latter is very expensive. If a deletion is present, karyotyping of parents is recommended to exclude a balanced rearrangement that could have resulted in a deletion in the child. Children who have 5p deletion inherited from a parental translocation involving chromosome 5 have more severe defects than those with de novo deletions. [11] In a parent with a balanced translocation, the risk of recurrence in a subsequent pregnancy has been computed to be 8.7-18.8% by Cerruti-Mainardi et al. [2] The risk of recurrence is low with de novo deletions. [2]

A correct diagnosis will allow for early intervention which plays a critical role in improving outcome. This is important because CdCS is not associated with a shortened life span. Affected patients have been reported to survive more than 50 years. [2] It is unlikely that children with CdCS will be able to live independently as adults. However, with early interventions followed by consistent behavioral and physical therapy, some adults have been able to attain communication abilities and daily living skills equivalent to the social and psychomotor level of normal five to six year olds. [2],[20]

   Conclusion Top

Cytogenetic analysis is necessary to establish the diagnosis of CdCS because of the variability in clinical presentation. An accurate diagnosis is important for several reasons. It will help to counsel families, and alleviate parental anxiety regarding the child's diagnosis. It also helps the physician to provide anticipatory guidance about the child's care. Thus, families will be enabled to make informed decisions regarding the child's future care and planning on subsequent pregnancies.

   References Top

1.Lejeune J, Lafourcade J, Berger R, Vialatte J, Boeswillwald M, Seringe P, et al. 3 Cases of partial deletion of the short arm of a 5 chromosome. C R Hebd Seances Acad Sci 1963;257:3098-102.  Back to cited text no. 1
2.Cerruti Mainardi P. Cri du Chat syndrome. Orphanet J Rare Dis 2006;1:33-41.  Back to cited text no. 2
3.Wilkins LE, Brown JA, Nance WE, Wolf B. Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. J Pediatr 1983;102:528-33.  Back to cited text no. 3
4.Iyer SL, Duraiswamy A, Kher AS, Joshi S, Bharucha BA, Kanade S. Cri du chat syndrome. J Postgrad Med 1996;42:86-8.  Back to cited text no. 4
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5.Tullu MS, Muranjan MN, Sharma SV, Sahu DR, Swami SR, Deshmukh CT, et al. Cri-du-chat syndrome: Clinical profile and prenatal diagnosis. J Postgrad Med 1998;44:101-4.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
6.Knoll JH, Lichter P. In situ hybridization to metaphase chromosomes and interphase nuclei. In: Haines JL, editor. Current Protocols in Human Genetics. Hoboken, NJ: John Wiley and Sons, Inc.; 2005. p. 4.3.1-4.3.31.  Back to cited text no. 6
7.Schaffer L, Slovak M, Campbell L. In situ Hybridization. In: ISCN 2009: An International System for Human Cytogenetic Nomenclature. Basel: Karger; 2009.  Back to cited text no. 7
8.WHO Anthro (version 3.2.2, January 2011) and macros [Internet]. WHO Child growth standards: Methods and development. 2009 Inc. Available from: http://www.who.int/childgrowth/software/en/. [Last accessed on 2012 Aug 14].  Back to cited text no. 8
9.Sambamurty AVSS. Human Genetics. In: Genetics. 2 nd ed. New Delhi: Narosa Publishing House; 2005. p. 276-7.  Back to cited text no. 9
10.Nussbaum RL, McInnes RR, Willard HF. Principles of Clinical Cytogenetics. In: Thompson and Thompson Genetics in Medicine. 7 th ed. St. Louis: Saunders, Elsevier; 2009. p. 59.  Back to cited text no. 10
11.Niebuhr E. The Cri du Chat syndrome: Epidemiology, cytogenetics, and clinical features. Hum Genet 1978;44:227-75.  Back to cited text no. 11
12.Higurashi M, Oda M, Iijima K, Iijima S, Takeshita T, Watanabe N, et al. Livebirth prevalence and follow-up of malformation syndromes in 27,472 newborns. Brain Dev 1990;12:770-3.  Back to cited text no. 12
13.Mainardi PC, Perfumo C, Calì A, Coucourde G, Pastore G, Cavani S, et al. Clinical and molecular characterisation of 80 patients with 5p deletion: Genotype-phenotype correlation. J Med Genet 2001;38:151-8.  Back to cited text no. 13
14.Overhauser J, Huang X, Gersh M, Wilson W, McMahon J, Bengtsson U, et al. Molecular and phenotypic mapping of the short arm of chromosome 5: Sublocalization of the critical region for the cri-du-chat syndrome. Hum Mol Genet 1994;3:247-52.  Back to cited text no. 14
15.Goodart SA, Simmons AD, Grady D, Rojas K, Moyzis RK, Lovett M, et al. A yeast artificial chromosome contig of the critical region for cri-du-chat syndrome. Genomics 1994;24:63-8.  Back to cited text no. 15
16.Simmons AD, Püschel AW, McPherson JD, Overhauser J, Lovett M. Molecular cloning and mapping of human semaphorin F from the Cri-du-chat candidate interval. Biochem Biophys Res Commun 1998;242:685-91.  Back to cited text no. 16
17.Medina M, Marinescu RC, Overhauser J, Kosik KS. Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 2000;63:157-64.  Back to cited text no. 17
18.Zhang A, Zheng C, Hou M, Lindvall C, Li KJ, Erlandsson F, et al. Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome. Am J Hum Genet 2003;72:940-8.  Back to cited text no. 18
19.Breg WR, Steele MW, Miller OJ, Warburton D, DeCapoa A, Allderdice PW. The cri du chat syndrome in adolescents and adults: Clinical finding in 13 older patients with partial deletion of the short arm of chromosome No. 5 (5p-). J Pediatr 1970;77:782-91.  Back to cited text no. 19
20.Wilkins LE, Brown JA, Wolf B. Psychomotor development in 65 home-reared children with cri-du-chat syndrome. J Pediatr 1980;97:401-5.  Back to cited text no. 20

Correspondence Address:
Vivi M Srivastava
Cytogenetics Unit, Christian Medical College, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.107791

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  [Figure 1]

  [Table 1], [Table 2]

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