MOLECULAR MEDICINE REPORTS 11: 1933-1938, 2015 When Cri du chat syndrome meets Edwards syndrome YINGJUN XIE1*, YI ZHOU1*, JIANZHU WU1, YUNXIA SUN2, YONGZHEN CHEN1 and BAOJIANG CHEN1 1Department of Prenatal Diagnosis, The First Affiliated Hospital of Sun Yat‑sen University;2 Department of Neonatology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, P.R. China Received January 6, 2014; Accepted October 24, 2014 DOI: 10.3892/mmr.2014.2920 Abstract. It has been well established that the 5p deletion typically characterized by the occurrence of a high-pitched, causes Cri du chat syndrome, typically characterized by cat-like cry, though this is lacking in certain cases (2). a cat-like cry, and that duplication of 18q causes Edwards Therefore, the phenotype of CdCS may be divided into two syndrome; the two are rare genetic abnormalities that sepa- categories, one for the typical cat-like cry and another for the rately lead to physical and mental impairments. However, the other clinical traits. In principle, these two distinct phenotypes severity of the clinicopathological characteristics that arise imply the existence of more than one critical region in 5p (3); when these two aberrations occur in one patient is unknown. differences in the sizes of deletions spanning these regions are Here, the first case in our knowledge of a single patient (a likely responsible for some of the variability of CdCS. two-year-old female) with 5p partial monosomy and 18q While ~90% of cases are attributed to a sporadic or de partial trisomy is described. In the present study, chromo- novo deletion with random occurrence, a few arise from the some microarray analysis was performed, which identified malsegregation of a balanced translocation in the parental the imbalance of chromosomes 5 and 18 in the patient. The karyotype (4). Under this condition, the 5p monosomy tends chromosome aberrations were further confirmed by fluores- to be accompanied by a partial trisomy of the genome. A cence in situ hybridization. By comparing the phenotypes priori, these patients may exhibit more severe phenotypes than of combined case with those of the individual syndromes, those with only monosomy of 5p. In the case presented here, a severe clinical phenotypes of the 5p (5p15.33-p13.3) deletion trisomic portion was identified at chromosome 18. were confirmed, however, the net effect of the duplication Trisomy 18, or Edwards syndrome, is the second most of 18q22.3-q23 was not determined, as this duplication only common autosomal trisomy syndrome following trisomy 21 appeared to have a weak effect on the patient's phenotypes. (Downs syndrome), and it results from full, mosaic, or partial The correlation between these chromosomal aberrations and trisomy of 18q. This syndrome has a very high mortality rate their clinical features has implications for the identification of due to heart abnormalities, kidney malformations and other critical regions of 5p and 18q, particularly for the functional internal organ disorders. While full trisomy of 18q is the most mapping of chromosome 18. prevalent form (5-8), partial trisomy of the terminal region of 18q is a very rare form that may present nonspecific abnormal- Introduction ities, including intrauterine growth restriction, microcephaly, a prominent forehead, hypertelorism, a short neck, mental Cri du chat syndrome (CdCS), which stems from a partial dele- retardation, seizure, laryngomalacia, atrial stenosis and club tion of the short arm of chromosome 5 (5p-), is a rare genetic foot (9-12). disorder occuring in ~1/15,000 to 1/50,000 live births (1), The deletion of 5p and partial 18q trisomy are rare though it is more commonly identified in patients with mental occurances. The purpose of current study was to report an retardation (~1/350) (1). As suggested by the name, CdCS is example of this unique combination in a female patient with an unbalanced translocation, giving rise to 5p deletion and 18q duplication, in addition to determining whether this case may assist in confirming critical regions of 5p that have previously been reported to cause typical CdCS, and whether Correspondence to: Professor Baojiang Chen, Department partial trisomy of 18q influences the clinical characteristics, of Prenatal Diagnosis, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan No. 2 Road, Guangzhou, even though the CdCS phenotype prevails. To address these Guangdong 510080, P.R. China issues, the karyotype and phenotype of the patient and her E-mail: [email protected] parents were assessed using G-banding techniques, chromo- some microarray analysis (CMA), and fluorescence in situ *Contributed equally hybridization (FISH). The regions involved in or the extent of the 5p deletion and 18q duplication are good candidates for Key words: Cri du chat syndrome, Edwards syndrome, partial mapping the phenotypic disruptions associated with CdCS trisomy 18q, genotype-phenotype correlation and Edwards syndrome. Therefore, determining which region has the genetic disorder in this case is of great clinical and etiological value. 1934 XIE et al: NET EFFECT OF CRI DU CHAT SYNDROME Materials and methods Patient data. The two-year-old female patient was born at 39 weeks. She presented with laryngomalacia, atrial septal defect, a downturned mouth, transverse flexion creases and hypotonia, all of which are typical phenotypes of CdCS. In addition, the patient displayed psychomotor retardation, developmental delay and a long face, phenotypes which become evident with developing CdCS, however, she also had almond-shaped eyes and a bulbous nose (Fig. 1). Parental karyotyping detected an apparent balanced translocation (46, XY, t(5;18)(p13;q22)) in the father and no evident chromosomal abnormalities in the mother. Samples and pictures from the patient and her family were Figure 1. Clinical features of the female patient. She presented with laryn- gomalacia, a downturned mouth, almond-shaped eyes and a bulbous nose. obtained following informed consent. This study was approved by the ethics committee of The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. abnormal genotypes, appearing in phenotypically normal Conventional cytogenetic analysis. A 5 ml blood sample males (15). was collected from the patient and each of her parents. Lymphocytes were cultured from each sample and used for FISH analysis. FISH analysis of the proband and her parents cytogenetic analysis according to the standard blood cytoge- confirmed the rearrangements and revealed that the partial netic protocol (13). Further routine cytogenetic analysis was monosomy of 5p and the partial trisomy of 18q were the result performed using G-banding at 550 band resolution (trypsin: of a reciprocal unbalanced malsegregation derived from her Amresco, Solon, OH, USA; giemsa stain: Sigma-Aldrich, father (Fig. 2C and D). St. Louis, MO, USA). Comparative clinical features. The clinical phenotypes CMA. CMA was performed using the Affymetrix cyto of the current patient, who carries these two rare genomic HD Array (Affymetrix, Santa Clara, CA, USA). DNA was imbalances, were compared with the phenotypes of patients amplified, labeled and hybridized to the CytoScan HD array carrying only one of these genomic imbalances. The results platform according to the manufacturer's instructions. The are summarized in Tables I and II. While mental retarda- array is specifically designed for cytogenetics research and tion or developmental delay was consistently observed in all offers >2 million markers across the genome, including single patients with partial 5p monosomy, the present patient also nucleotide polymorphism probes and probes to detect copy presented a number of physical features that are not frequently number variations (Cyto‑arrays). CEL files obtained by scan- observed in other patients, including hypotonia and a bulbous ning CytoScan arrays were analyzed with the Chromosome nose. Microcephaly was observed in certain patients and is a Analysis Suite software (Affymetrix), employing genome common phenotype of CdCS; however, it was not observed annotation data (version GRCH37, hg19). Only data achieving in the present case. In addition, the current study determined the manufacturer's quality cut-off levels were included in that the patient presented features that have not previously further analyses. Primarily, gains and losses that affected been described in other patients, such as transverse flexion a minimum of 50 markers within a 100 kbp length were creases, a downturned mouth, a long face and almond-shaped accepted. eyes. The more severe features observed in this patient may stem from the deletion at 5p15.33-p13.3, which is larger than FISH. The FISH test for confirming the der(5)t(5:18) of the deriv- deletions found in other patients. They may also be caused ative chromosome was conducted using the Vysis Cri-du-Chat by the presence of the 18q duplication. However, patients region probe (Vysis, Downers Groove, IL, USA) and a combina- with partial chromosome 18 trisomy alone did not exhibit the tion of the CEP18 probes and 18q subtelomere‑specific probes abnormalities observed in the current case, although mental (Vysis) as described in the manufacturer's protocol, using the retardation or developmental delay was a common feature in standard FISH protocol (14). those patients. This suggests that in the present case, the 18q duplication may have a weaker effect on the phenotype than Results the larger 5p deletion. CMA. The array detected two genomic anomalies in the Discussion patient's genome: a 32 Mb deletion at 5p15.33-p13.3 (chr 5: 1-32, 137, 848) (Fig. 2A) and a 6.6 Mb duplication at In the patient, a large (32 Mb) terminal deletion of 5p was 18q22.3q23 (chr 18: 71, 368, 578-78, 014, 123) (Fig. 2B). The detected, covering all the CdCS critical regions that had been deletion encompasses the complete terminal region of chro- reported to date (p15.3, p15.2, p15.1, p14 and p13). The dele- mosome 5 covering band 5p15.2 and band 5p15.3, which are tion of p15.3 is the direct cause of typical CdCS (16), while well established CdCS critical regions.