Clinical characteristics of a sample of patients with cat eye syndrome

Abstracts

OBJECTIVE: The cat eye syndrome is considered a rare chromosomal disease and a phenotypically quite variable condition. The objective of this study was to describe the clinical characteristics of a sample of patients with the syndrome evaluated in our Service. METHODS: Six patients with diagnosis of cat eye syndrome were retrospectively evaluated. All presented a karyotype with presence of an additional chromosome marker, inv dup(22)(pter->q11.2::q11.2->pter). One of them still had a mosaicism with a lineage with a normal chromosomal constitution. Clinical and evolution data were collected from their medical records. Fisher exact test (P<0.05) was used for comparison between the frequencies found in our study and literature. RESULTS: The main abnormalities found were preauricular skin tags/pits and imperforate anus (both observed in 83% of cases). Iris coloboma, an important feature of the syndrome was verified in 2 cases (33%). Congenital heart defect observed in 4 patients (67%), with the atrial septal defect (75%) as the most observed. Uncommon features included the hemifacial microsomia associated to microtia, besides biliary atresia. In relation to the evolution, only one of the patients died and this occurred secondary to quilothorax and sepsis. CONCLUSION: The phenotype observed in the cat eye syndrome is very variable and may overlap with that of oculo-auriculo-vertebral spectrum. Despite the good prognosis usually presented by the individuals, also from the neurological point of view, we believe that all patients with the syndrome should be evaluated as early as possible for presence of heart, biliary and anorectal malformations. This should avoid possible complications, including death.

Chromosomes, human, pair 22; Mosaicism; Goldenhar syndrome; Facial asymmetry

OBJETIVO: A síndrome do olho do gato é considerada uma doença cromossômica rara e fenotipicamente bastante variável. O objetivo deste trabalho foi descrever as características clínicas de uma amostra de pacientes com a síndrome avaliada em nosso serviço. MÉTODOS: Foram analisados, retrospectivamente, seis pacientes com diagnóstico de síndrome do olho do gato. Todos eles apresentavam cariótipo com a presença de um cromossomo marcador adicional, inv dup(22)(pter->q11.2::q11.2->pter). Um deles, ainda, possuía mosacismo com uma linhagem com constituição cromossômica normal. A partir dos prontuários médicos foram coletados dados clínicos e de evolução dos pacientes. Para comparação entre as frequências encontradas em nosso estudo e a literatura foi utilizado o teste exato de Fisher (P<0,05). RESULTADOS: As principais anormalidades encontradas foram os apêndices/fossetas pré-auriculares e a imperfuração anal (ambas observadas em 83% dos casos). O coloboma de íris, um achado importante da síndrome, foi verificado em dois casos (33%). Cardiopatia congênita, por sua vez, foi observada em quatro pacientes (67%), sendo o principal defeito a comunicação interatrial (75%). Achados incomuns incluíram a microssomia hemifacial associada à microtia, além da atresia de vias biliares. Quanto à evolução clínica, apenas um dos pacientes foi a óbito, sendo que este ocorreu secundário a um quadro de quilotórax e sepse. CONCLUSÃO: O fenótipo observado na síndrome do olho do gato é bastante variável e pode se sobrepor àquele do espectro óculo-aurículo-vertebral. Apesar dos indivíduos apresentarem usualmente um bom prognóstico, incluindo do ponto de vista neurológico, acreditamos que todo paciente com a síndrome deveria ser precocemente avaliado quanto à presença de malformações cardíacas, biliares e anorretais. Isto evitaria possíveis complicações, incluindo o óbito.

Cromossomos Humanos par 22; Mosaicismo; Síndrome de goldenhar; Assimetria facial

ORIGINAL ARTICLE

Clinical characteristics of a sample of patients with cat eye syndrome

Rafael Fabiano Machado Rosa^I; Rômulo Mombach^II; Paulo Ricardo Gazzola Zen^III; Carla Graziadio^IV; Giorgio Adriano Paskulin^III,*

^IMestrado em patologia - Doutorando pelo Programa de Pós-Graduação em Patologia da Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) e Médico Geneticista da UFCSPA e Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, RS

^IIMédico geneticista da Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) e Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA), Porto Alegre, RS

^IIIProfessor Doutor; Médico geneticista da Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) e Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA); Professor da Disciplina de Genética Clínica e do Programa de Pós-Graduação em Patologia da UFCSPA, Porto Alegre, RS

^IVProfessora e Mestre - Médica geneticista da Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) e Complexo Hospitalar Santa Casa de Porto Alegre (CHSCPA) e Professora da Disciplina de Genética Clínica da UFCSPA, Porto Alegre, RS

ABSTRACT

OBJECTIVE: cat eye syndrome is considered a rare chromosome disease with a highly variable phenotype. the objective of this paper was to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service.

METHODS: this is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome. all of these patients' karyotypes exhibited the presence of an additional marker chromosome, inv dup(22)(pter->q11.2::q11.2->pter). one patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution. clinical and follow-up data were collected from the patients' medical records. fisher's exact test was used to compare the frequencies observed in our study with figures given in the literature (P<0.05).

RESULTS: the main abnormalities observed were preauricular tags and/or pits and anal atresia (both observed in 83% of cases). coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). congenital heart disease was detected in four patients (67%) and the main defect found was interatrial communication (75%). uncommon findings included hemifacial microsomia combined with unilateral microtia and biliary atresia. just one of these patients died, from chylothorax and sepsis.

CONCLUSION: the phenotype observed in cat eye syndrome is highly variable and may be superimposed on the phenotype of the oculo-auriculo-vertebral spectrum. although these patients usually have good prognosis, including from a neurological point of view, we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations, which may avoid possible complications in the future, including patient deaths.

Key words: Human chromosome pair 22. Mosaicism. Goldenhar syndrome. Facial asymmetry.

INTRODUCTION

Cat eye syndrome, also known as Schmid-Fraccaro syndrome (OMIM 115470), is considered a rare chromosome disease with an estimated incidence of 1 in every 50,000-150,000 live births (Berends et al., 2001). It is caused by partial tetrasomy of chromosome 22 which is the result of a supernumerary dicentric marker chromosome with satellites at the ends, inv dup(22)(pter->q11.2::q11.2->pter). This, as its description states, involves duplication of the entire short arm of chromosome 22 (p) plus part of its long arm (q), as far as band 11. It is now known that this band contains regions of low copy repeats (LCRs) which predispose it to rearrangements, including the marker chromosome observed in cat eye syndrome (Heather et al., 2002). Clinically, the disease is characterized by the presence of multiple malformations, primarily involving the eyes, ears and anorectal and urogenital systems. Notwithstanding, the phenotype that has been observed is highly variable and includes descriptions of very mild cases (Berends et al., 2001; Rosias et al., 2001).

Therefore, in response to the scarcity of studies of the disease in Brazil (Belangero et al., 2009), the objective of this paper is to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service.

METHODS

This is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome who were referred to the Clinical Genetics Department because of anal atresia, preauricular tags and/or preauricular pits, associated with other malformations. All of these patients' karyotypes exhibited the presence of an additional marker chromosome, similar to the dicentric chromosome found in the partial tetrasomy 22: inv dup(22)(pter->q11.2::q11.2->pter) (see Figure 1). One patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution: 47,XX, inv dup(22)(pter-->q11.2::q11.2->pter)[30]/ 46,XX[14]. In three cases it was possible to karyotype the patients' mothers and in one case the father was karyotyped, with normal results in all four cases.

The following data were collected from patient records: age and sex, referring service, anthropometric measurements, parents' age at birth of patient, clinical characteristics observed on physical examination, results of supplementary tests and death/survival to date.

Fisher's exact test was used to compare the frequencies observed in our study with figures given in the literature, using PEPI to perform the calculations. Only results where p<0.05 were considered statistically significant.

The study was approved by the institution's Research Ethics Committee.

RESULTS

Four of the six patients in the sample were female and two were male. Their ages at initial presentation varied from 5 days to 2 years and 6 months (mean of 234 days). Four of them had been referred by the pediatric surgery department, one by pediatrics and one by the pediatric cardiology department. Paternal ages varied from 36 to 50 years (mean of 41.2 years) and maternal age varied from 31 to 39 years (mean of 36 years). Birth weights varied from 2,178 to 3,640 g (mean of 2,896 g), length from 44 to 51.5 cm (mean of 47.9 cm) and head circumference from 32 to 36 cm (mean of 33.9 cm).

The patients and their clinical characteristics can be observed in Figure 1 and Table 1. The main abnormalities found were preauricular tags and/or preauricular pits and anal atresia (both observed in 83% of cases). Coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). Congenital heart disease was detected in four patients (67%) and the main defect was interatrial communication (75%). In terms of clinical progression, only one patient had died at data collection (patient 5). This fatality was the result of postoperative complications after surgery for congenital heart disease, with chylothorax and sepsis.

DISCUSSION

Although the supernumerary marker chromosome derived from 22 can vary in molecular size, depending on the LCRs in the q11 region where the rearrangement occurs (whether they are more proximal or more distal), no direct correlation has yet been identified between cat eye syndrome phenotypes and the supernumerary region size (Mears et al., 1994; Berends et al., 2001).

Notwithstanding the small size of our case series, the phenotypes observed among our patients were no different from those that have previously been described in the literature. While this syndrome is known as cat eye syndrome because of the appearance of the iris, caused by vertical coloboma of the iris and choroid (which resembles a cat's iris), the most commonly observed malformations with this disease are preauricular pits and/or tags and anorectal malformations (Rosias et al., 2001). These were the principal findings among our sample, both observed in 83% of cases. In contrast, some of the malformations observed in this sample, for example biliary atresia, have rarely been described in the syndrome. Four out of 48 cases (8%) in a series described by Rosias et al. (2001) had this abnormality.

We were unable to locate any other descriptions in the literature of patients with cat eye syndrome and hemifacial microsomia combined with unilateral microtia (patient 2). Taking all of this patient's findings together with the preauricular tags/pits, presentation was highly suggestive of a clinical diagnosis of oculo-auriculo-vertebral spectrum (OAVS), or Goldenhar syndrome (OMIM 164210) (Strömland et al., 2007; Engyz et al., 2007). Based on the results of our literature search, this is the first case description of a patient with cat eye syndrome and this phenotype. However, interestingly, we found a report in the literature of other patients with the OAVS phenotype and cytogenetic abnormalities involving the addition of part or the whole of chromosome 22. These included trisomy of chromosome 22 in mosaic (Pridjian et al., 1995), the supernumerary chromosome der(22)t(11;22) (Engiz et al., 2007) and duplication of the long arm of chromosome 22 (Hathout et al., 1998). Furthermore, in some of the cases described by Berends et al. (2001) there was facial asymmetry/hypoplasia of one hemiface. Notwithstanding, we cannot rule out the possibility that this finding is associated with the chromosomal mosaicism exhibited by the patient, in which areas of hyperplasia and hypoplasia may occur (Woods et al., 1994).

The frequency of heart defects observed in our sample (67%) was statistically similar to that of other series described in the literature, ranging from 50% to 63% (Berends et al., 2001; Rosias et al., 2001). However, as Rosias et al. (2001) and Berends et al. (2001) have rightly pointed out, these frequencies may have been affected by bias, since mildly affected patients may escape detection. The main heart defect described among people with cat eye syndrome is total anomalous pulmonary venous connection (29% to 43%), although this was only detected in one of the patients in our sample (25% of the cases with congenital heart disease). The most common malformation in our series was interatrial communication (75%), which has been described in around 30% of previous samples, and persistent ductus arteriosus, in 14% of the patients with the syndrome (Berends et al., 2001; Rosias et al., 2001). We observed persistence of the left superior vena cava in one of the patients in our sample, which is an uncommon finding (Berends et al., 2001). On the other hand, another common defect - tetralogy of Fallot - was absent from our series although it is described in around 8% to 14% of cases (Berends et al., 2001; Rosias et al., 2001). Rarer malformations include abnormalities of the aorta (such as interruption of the aortic arch), pulmonary stenosis, tricuspid atresia, hypoplastic left heart syndrome, mitral valve, atrial or ventricular hypoplasia and single ventricle (Berends et al., 2001; Rosias et al., 2001; Belangero et al., 2009).

With relation to neurological findings, structural anomalies of the central nervous system are observed with low frequency among people with cat eye syndrome. Examples include cerebral hypoplasia (present in patients 2 and 6 of our sample) and cerebellar atrophy and micropolygyria (Berends et al., 2001; Rosias et al., 2001). Delayed neuropsychomotor development is reported in around 50% of patients (Berends et al., 2001) and was observed in three of the five patients in our sample who were assessed (60%). In turn, mental development ranges from normal to severely impaired (Berends et al., 2001; Rosias et al., 2001). That feature cannot be adequately assessed for this sample because of the young ages of our patients.

Patients with cat eye syndrome usually have good prognosis. The complications primarily responsible for those deaths that do occur are heart failure, liver failure/biliary atresia, bronchopneumonia and sepsis (Rosias et al., 2001), as was observed in the only patient who died from our sample.

CONCLUSION

The phenotype observed in cat eye syndrome is highly variable and may be superimposed on the OAVS phenotype. Although these patients usually have good prognosis, including from a neurological point of view (when mental deficiencies are present they are usually mild to moderate) (Berends et al., 2001), we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations. Some of these may need early intervention and treatment which can avoid possible complications in the future, including patient deaths.

Conflicts of interest: No conflicts of interest declared concerning the publication of this article.

REFERENCES

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Publication Dates

• Publication in this collection
  12 Nov 2010
• Date of issue
  2010

History

• Received
  22 Mar 2010
• Accepted
  17 May 2010