Oculo-auriculo-vertebral spectrum and cardiac malformations

Rosa, Rafael Fabiano Machado; Dall'Agnol, Lisiane; Zen, Paulo Ricardo Gazzola; Pereira, Vera Lúcia Berenstein; Graziadio, Carla; Paskulin, Giorgio Adriano

doi:10.1590/S0104-42302010000100018

Abstracts

OBJECTIVE: To verify the frequency and types of congenital heart defects in a sample of patients with oculo-auriculo-vertebral spectrum (OAVS), in an effort to correlate presence of these defects with other clinical characteristics and evolution. METHODS: The sample comprised 33 subjects, all attended in the same center, between January 1975 and December 2007. Twenty two of them were male and eleven female and their ages ranged from 1 day to 17 years. All presented normal karyotype by GTG-Banding. A data collection related to their clinical history, physical examination and result of complementary evaluations was performed. RESULTS: Cardiac abnormalities were observed in 13 patients (39.4%). Of these defects, 5 (38.5%) were conotruncal, tetralogy of Fallot being the main malformation (n=2). Unusual anomalies identified included cor triatriatum and double inlet left ventricle. Significant differences among the clinical characteristics of the group with and without heart defect were only verified in relation to age at first evaluation that was lower in subjects with cardiac malformations. Five patients died, four of them, bearers of congenital heart defects. CONCLUSION: Cardiac malformations, mainly conotruncal and septal defects, are frequent among patients with OAVS. Frequency found in our study was statistically similar to the majority of works described in literature where it ranged from 18 to 58%. Congenital heart defects also represent the main cause of death of these subjects. Thus, a cardiac evaluation should always be performed in these patients, especially at an early age.

Goldenhar Syndrome; Facial Asymmetry; Congenital Heart Defects

OBJETIVO: Verificar a frequência e tipos de cardiopatias congênitas em uma amostra de pacientes portadores de espectro óculo-aurículo-vertebral (EOAV), tentando correlacionar a presença desta malformação com suas demais características clínicas e evolução. MÉTODOS: A amostra foi composta por 33 indivíduos, todos atendidos em um mesmo centro, no período de janeiro de 1975 a dezembro de 2007. Vinte e dois deles eram do sexo masculino e 11 do feminino e suas idades variaram de 1 dia a 17 anos. Todos apresentavam avaliação cariotípica normal por bandas GTG. Realizou-se uma coleta de dados referentes à sua história clínica, exame físico e resultado de avaliações complementares. RESULTADOS: Anormalidades cardíacas foram observadas em 13 pacientes (39,4%). Dessas, cinco (38,5%) eram do tipo conotruncal, sendo o principal defeito a tetralogia de Fallot (n=2). Malformações não usuais identificadas incluíram o cor triatriatum e a dupla via de entrada de ventrículo esquerdo. Diferenças significativas entre as características clínicas do grupo com e sem cardiopatia foram verificadas somente em relação à idade na primeira avaliação, que foi mais baixa naqueles com malformações cardíacas. Cinco indivíduos foram a óbito, quatro deles portadores desses defeitos. CONCLUSÃO: Malformações cardíacas, em especial dos tipos conotruncal e septal, são frequentes entre pacientes com EOAV. A frequência encontrada em nosso estudo foi estatisticamente similar à da maior parte dos trabalhos descritos na literatura, que oscila de 18% a 58%. As cardiopatias congênitas também representam a principal causa de óbito desses indivíduos. Portanto, uma avaliação cardiológica, especialmente precoce, deveria ser sempre realizada nesses pacientes.

Síndrome de Goldenhar; Assimetria facial; Cardiopatias congênitas

ORIGINAL ARTICLE

^IGeneticista Clínico e Doutorando pelo Programa de Pós-Graduação em Patologia da Universidade Federal de Ciências da Saúde de Porto Alegre -UFCSPA e Complexo Hospitalar Santa Casa de Porto Alegre -CHSCPA, Porto Alegre, RS

^IIAluna de Graduação do Curso de Medicina da Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA, Porto Alegre, RS

^IIIProfessores Doutores - Geneticista Clínico da Universidade Federal de Ciências da Saúde de Porto Alegre - UFCSPA e Complexo Hospitalar Santa Casa de Porto Alegre - CHSCPA; Professores da Disciplina de Genética Clínica e do Programa de Pós-Graduação em Patologia da Universidade Federal de Ciências Médicas da Saúde de Porto Alegre, UFCSPA, Porto Alegre, RS

^IVGraduação em Farmácia - Citogeneticista do Laboratório de Citogenética da Universidade Federal de Ciências Médicas da Saúde de Porto Alegre UFCSPA, Porto Alegre, RS

^VProfessora com mestrado - Geneticista Clínica da UFCSPA e CHSCPA, Professora da Disciplina de Genética Clínica da UFCSPA

ABSTRACT

OBJECTIVE: To verify the frequency and types of congenital heart defects in a sample of patients with oculo-auriculo-vertebral spectrum (OAVS), in order to correlate the presence of these defects with other clinical characteristics and evolution.

METHODS: The sample comprised 33 subjects, all attended in the same center, between January 1975 and December 2007. Twenty two of them were male and eleven female with ages ranging from 1 day to 17 years old. All presented normal karyotype by GTG-Banding. A data collection related to their clinical history, physical examination and result of complementary evaluations was performed.

RESULTS: Cardiac abnormalities were observed in 13 patients (39.4%). Of these, 5 (38.5%) were conotruncal, tetralogy of Fallot being the main malformation (n=2). Unusual anomalies identified included cor triatriatum and double inlet left ventricle. Significant differences among the clinical characteristics of the group with and without heart defect were only verified in relation to age at first evaluation that was lower in subjects with cardiac malformations. Five patients died, four of them carriers of congenital heart defects.

CONCLUSION: Cardiac malformations, mainly of the conotruncal and septal types, are frequent among patients with OAVS. The frequency found in our study was statistically similar to the one found in the majority of works described in literature, which ranges from 18 to 58%. Congenital heart defects also represent the main cause of death of these subjects. Thus, a cardiac evaluation should always be performed in these patients, especially at an early age.

Key words: Goldenhar syndrome. Facial asymmetry. Congenital heart defects.

INTRODUCTION

Oculo-auriculo-vertebral spectrum (OAVS), also known as Goldenhar syndrome and hemifacial microsomia (OMIM 164210),1 is an etiologically heterogeneous and phenotypically quite variable condition. Most cases occur in a sporadic manner; however, familial cases, suggesting a pattern of inheritance, both autosomal dominant and recessive, have also been described.2-4 OAVS presents an estimated prevalence that ranges from 1 to 5,600 in 45,000 of the live-born, and is considered the result of a blastogenesis defect that involves particularly the structures originated from the first branchial arches.2-7 Thus, its main findings are anomalies, generally asymmetric, involving ears (especially microtia and preauricular skin tags ), face (hemifacial microsomia), eyes (epibulbar dermoid), and spine (vertebra l alterations with fused vertebrae or hemivertebrae). However, its phenotypical spectrum is very broad, and involvement of other organs and systems is frequent.4,8-10 Cardiac malformations, on their turn, are common in OAVS individuals. However, its frequency has been shown to be very variable, oscillating between 5% and 58%.4-14

Thus, in face of the importance of the clinical characterization of these patients, and the paucity of related studies in our country,^15-17 our objective was to verify the frequency and types of congenital heart defects in a sample of patients with OAVS, correlating the presence of this malformation with other clinical characteristics and evolution.

METHODS

The sample was composed of individuals attended by the Clinical Genetics Service of the Universidade Federal de Ciências da Saúde de Porto Alegre/Complexo Hospitalar Santa Casa de Porto Alegre, Rio Grande do Sul, Brazil, diagnosed with OAVS from January 1975 to December 2007. This study was approved by the Ethics Committee of the Institution. This study included only patients submitted to chromosome evaluation through karyotype exam by GTG banding and who presented phenotypical abnormalities in at least two or the following regions: 1) orocraniofacial, 2) ocular, 3) auricular and 4) vertebral. This approach was in accordance with the one adopted by Strömland et al. (2007).⁴ Individuals carrying chromosome alterations or having incomplete medical files were excluded from the study.

A retrospective analysis with collection of data related to sex, age, reason for the referring, as well as clinical history, physical examination, and complementary evaluations result was performed. For evaluating anthropometrical measures, standard growth curves were used,¹⁸ and values two standard deviations higher or lower than the average, according to the age (with due correction for length/height), were considered abnormal. A delay in neuropsychomotor development was considered when the patient presented the description of starting walking alone only after 18 months old.⁹ The side affected presented by the syndrome (right, left, or bilateral) was determined according to microtia's and facial microsomia's localization, similarly to the method adopted by Rollnick et al. (1987).⁸

Thus, during this period, 42 patients fulfilled the clinical criteria for inclusion. However, six of them were excluded due to not having a karyotype evaluation. Out of the other 36, one did not have complete medical files and two had chromosome abnormalities. Thus, the final sample was constituted of 33 patients. Twenty two were male and 11, female, their ages at the first evaluation ranged from 1 day to 17 years old (69.7% of them presented less than 1 year). The majority was referred by pediatrics (n=21); out of the rest, four came referred by plastic surgery, two by pediatric surgery, two by cardiology, and four by other specialties. As for clinical characteristics presented by the patients, two had phenotypic alterations involving the four regions belonging to the study's inclusion criteria, 14 had 3 regions, and 17 had 2.

For statistic analysis, PEPI program was used, more specifically Fisher's exact test for comparing the frequencies found between the subgroups with and without cardiopathy in our sample and for comparing with other studies described in literature. Values of p <0.05 were considered significant.

RESULTS

All the 33 patients included in the study were submitted to cardiac evaluation through clinical exam and complementary tests, such as thorax radiography and electrocardiogram. In 23 it was complemented through echocardiography. Cardiac abnormalities were observed in 13 patients (39.4%). Defects presented by them are exposed in Table 1. Conotruncal defects were present in 5 patients (38.5%), the most relevant of them being tetralogy of Fallot (n=2). One of the patients without cardiopathy had the description of an innocent murmur. Out of the 13 individuals with congenital heart defect, 4 died within the first two years of life, while in the group without cardiopathy only one presented a similar description (see Table 1).

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The other clinical characteristics observed in the 33 patients of the total sample are found in Table 2. A significant difference between the group with and without cardiopathy was seen only in relation to the age at first evaluation, lower among cardiac malformation carriers.

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DISCUSSION

Congenital heart defects are frequently observed among OAVS individuals. The prevalence of these conditions seen in our study (39%) was statistically similar to that of some reports (varying between 18% and 58%),^4-7,10-14 and different from others with values between 5% and 15%^8,9 (see Table 3). This variability is very probably due to the different inclusion criteria adopted and the varying sample sizes of the studies.⁶ For example, Rollnick et al. (1987),⁸ despite their big sample (n=294), included among their OAVS patients many subjects who presented only microtia and few with more severe abnormalities, as pointed by Kumar et al (1993),⁶ which may justify the low frequency of congenital cardiopathies found (5%). On the other hand, Greenwood et al. (1974)¹² attributed the high level of cardiac malformations observed in their study (58%) to a probable selection bias, as the researchers were more interested in patients with these defects and in the use of bigger medical centers as a source. Taking into consideration all the studies together (n=601), we observed that congenital heart defects frequency found was 17% (Table 3). Nevertheless, we believe that the true index of these defects may be higher, due to total value dilution provoked by the work of Rollnick et al. (1987).⁸ Apart from this study, the frequency of cardiac defects would go to 29%. Besides that, as in our study, the most works described in literature evaluated OAVS patients from tertiary centers, where individuals are frequently hospitalized for complications related to major abnormalities, such as congenital cardiopathies. Thus, we believe that this may also have some influence on the real frequency of cardiac malformations in these patients.

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Despite the variability of defects described in the syndrome, there seems to be a predominance of those of the conotruncal (involving the heart's outlets) and septal types among these patients.^4-12,16 Digilio et al. (2008)⁷ believe that this heterogeneity is related with the different pathogenic causes associated to the syndrome.

In our study, conotruncal and septal defects were also predominant, being observed in 39% and 23% of the patients, respectively. Among them, tetralogy of Fallot is highlighted,^{6,7,11,12,16,19} the main cardiac defect discovered in our sample (15%), and interventricular communication,^5-7,9,11,19 identified in one patient (8%). Defects concerning abnormal expected growth (such as total anomalous venous pulmonary return) and laterality (such as heterotaxy) have also been very common;^{6,7,10,15,16,19} however, none of our patients presented them. On the other hand, cor triatriatum and the double inlet of left ventricle, defects observed in our sample, are malformations usually not observed in individuals with OAVS. It is believed that the high frequency of defects of conotruncal type described among the patients with the syndrome may be related to the hypothesis that its etiology is related to an abnormality in neural crest cells, which would justify both cardiac phenotype and the other abnormalities related to ear, mandible, and neck presented by the patients.^2,4,6,20

As for the other clinical characteristics, we noticed that, in the whole sample, there was a predominance of male over female patients, with a proportion of 2:1. A similar finding has been described in literature, but with a slightly lower proportion, 3:2.^2,9 In relation to age at first evaluation, we believe it to be lower in cardiopathy carriers due to the fact that these malformations, because of their own severity, frequently require a special attention in an early age. In addition to that, almost all our patients were not born in our hospital, having been referred for evaluation to this center mainly due to its major findings (as congenital cardiopathy). In Bustamante et al.'s cases series (1989),¹⁶ for example, congenital cardiopathy's clinical repercussion was the main motive of hospital admission in the five evaluated patients. The side affected by the disease (right or left) was similar in both groups, with or without cardiopathy. Interestingly, we did not observe a significant difference in relation to the presence of neuropsychomotor delay, which is a common finding in individuals with congenital cardiopathy. In addition to that, hypotonia, a neurologic finding closely related with the acquisition of developmental marks, was present in a similar way in patients of both groups.

Congenital heart defects were the main cause of death in our patients (five of them died; four of these had cardiac defects, and three died due to clinical complications directly related to this malformation), which did agree with reports in literature.^3,5,12 It is known that conotruncal cardiac defects present a higher severity and are associated to a high mortality index, especially in face of the lack of early clinical and surgical care,²¹ happening in the first years of life.^3,5,12 Thus, congenital cardiopathies are very important in these individuals' clinical evolution and prognostics.

CONCLUSION

Congenital cardiac defects are frequent in OAVS patients, especially of the conotruncal and septal type. They also represent the main cause of death in these individuals, which occurs early in their lives.^3,5,12 Therefore, all the patients with OAVS diagnosis should be submitted early to cardiologic evaluation, aiming at identifying the presence of these defects and, consequently, try to lessen the possible complications resulting from them.

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

REFERENCES

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