Clinical description of 41 Brazilian patients with oculo-auriculo-vertebral dysplasia

Displasia óculo-aurículo-vertebral: aspectos clínicos de 41 pacientes brasileiros

José Roberto Mendes Pegler Diogo Cordeiro de Queiroz Soares Caio Robledo D’Angioli Costa Quaio Natalia Fernandes Luiz Antonio Nunes de Oliveira Rachel Sayuri Honjo Debora Romeo Bertola Chong Ae Kim About the authors

SUMMARY

Objective:

To describe the most prominent clinical features of a cohort of patients with oculo-auriculo-vertebral (OAV) dysplasia in Brazil.

Method:

A review of medical records of patients with diagnosis of OAV from 1990 to 2010 was performed in a medical genetics center.

Results:

41 patients were included in the study. Their average age at diagnosis was 2y 10mo (34,4±48,8 months) and the female proportion was 53.7%. Mean maternal age at patient’s birth was 28.5y (min: 17, max: 46y) for mothers and 31.4y (min: 21, max: 51y) for fathers. Most patients (97.5%) had auricular involvement, with facial manifestation in 90.2%, spinal in 65.9%, ocular in 53.7%, 36.6% with cardiovascular involvement, 29.3% urogenital, and 17% of the cases with central nervous system (CNS) involvement. The classic OAV triad was present in only 34%. All patients except one had concomitant problems in other organs or systems.

Conclusion:

Since the diagnosis of OAV dysplasia relies only on a comprehensive medical evaluation, it is imperative that clinicians be aware of the most common presentation of the syndrome. Once suspected, every patient should undergo a complete medical evaluation of multiple systems including complementary exams. Treatment of these patients is based on surgical correction of malformations and rehabilitation.

Keywords
Goldenhar syndrome; facial asymmetry; craniofacial abnormalities

RESUMO

Objetivo:

descrever os principais achados clínicos de uma coorte de pacientes com a displasia óculo-aurículo-vertebral (OAV).

Método:

revisão de prontuários médicos dos pacientes com diagnóstico de OAV no período de 1990 a 2010, acompanhados em um centro de genética médica.

Resultados:

foram incluídos no estudo 41 pacientes. A média de idade ao diagnóstico foi de 2 anos e 10 meses (34,4±48,8 meses) e a proporção de pacientes do sexo feminino foi de 53,7%. A média de idade dos pais ao nascimento do paciente foi de 28,5±6,9 anos para as mães e 31,4±7,4 anos para os pais. A maioria dos indivíduos (97,5%) possuía acometimento auricular, 90,2% tinham manifestações faciais, 65,9%, vertebrais, 53,7%, oculares, 36,6%, cardiovasculares, 29,3%, urogenitais e 17%, no sistema nervoso central. Além disso, 34% dos pacientes apresentavam a tríade clássica óculo-aurículo-vertebral, e todos os pacientes exceto um apresentavam concomitantemente problemas em outros órgãos ou sistemas.

Conclusão:

já que o diagnóstico desta entidade é eminentemente clínico, é imprescindível que os médicos das mais diversas especialidades conheçam os achados mais frequentes na OAV. Diante de um paciente com suspeita diagnóstica, deve ser realizada avaliação detalhada de outros órgãos, tanto clínica como por meio de exames complementares. O tratamento é baseado na correção cirúrgica das malformações e na reabilitação.

Palavras-chave
síndrome de Goldenhar; assimetria facial; anormalidades craniofaciais

INTRODUCTION

The Goldenhar syndrome was described in 1845 by Carl Ferdinand von Arlt and recognized as a clinical entity in 1952 by Maurice Goldenhar who described it in a child, as reported Salvitti et al.11 Salvitti C, Azulay RD, Heringer ML, Almeida de Faria LA. [Oculo-auriculo-vertebral dysplasia: presentation of a case and attempt at organizing the symptomatology]. Rev Ass Med Bras. 1978; 24(5):160-2. It has been known as first branchial arch syndrome, Gorlin’s syndrome and hemifacial microsomia (OMIM 164210), but currently it is best known as oculo-auriculo-vertebral (OAV) dysplasia, a nomenclature given by Gorlin et al.22 Gorlin RL. Branchial arch and oro-acral disorders. In: Gorlin JJ, Cohen Jr MM, Hennekam RC (eds.). Syndromes of the head and neck. London: Oxford University Press, 2001. p.790-97. and Sugar.33 Sugar HS. The oculoauriculovertebral dysplasia syndrome of Goldenhar. Am J Ophthalmol. 1966; 62(4):678.

Its prevalence has been estimated at about one case per 5,600 to 26,550 births,44 Grabb WC. The first and second branchial arch syndrome. Plast Reconstr Surg. 1965; 36(5):485-508.

5 Stoll C, Roth MP, Dott B, Bigel T. Discordance for skeletal and cardiac defect in monozygotic twins. Acta Genet Med Gemellol. 1984; 33(3):501-4.
-66 Melnick M. The etiology of external ear malformations and its relation to abnormalities of the middle ear, inner ear and other organ systems. Birth Defects Orig Artic Ser. 1980; 16(4):303-31. with greater involvement of males than females (in a ratio of about 3:2).77 Cohen Jr MM, Rollinck BR, Kaye CI. Oculoauriculoveretbral spectrum: an updated critique. Cleft Palate J. 1989; 26(4):276-86. The cases are mostly sporadic, but families with autosomal recessive or autosomal dominant inheritance have been described;88 Pearson A. Developmental anatomy of the ear. In: English M (ed.). Otolaryngology. New York: Harper and Row, 1978. p.1-68.,99 Scholtz AW, Fish III JH, Kammen-Jolly K, Ichiki H, Hussl B, Kreczy A, et al. Goldenhar’s syndrome: congenital hearing deficit of conductive or sensorineural origin? Temporal bone histopathologic study. Otol Neurotol. 2001; 22(4):501-5. thus, the hypothesis that there is no kind of genetic factor involved that would influence susceptibility to the disease has been ruled out.1010 Phelps PD, Lloyd GA, Poswillo DE. The ear deformities in craniofacial microsomia and oculo-auriculo-vertebral dysplasia. J Laryngol Otol. 1983; 97(11):995-1005. In this regard, reports of monozygotic twins,1111 Bisdas S, Lenarz M, Lenarz T, Becker H. Inner ear abnormalities in patients with Goldenhar syndrome. Otol Neurotol. 2005; 26(3):398-404. both dichorionic and monochorionic,1212 Strömland K, Miller M, Sjögreen L, Johansson M, Joelsson B-ME, Billstedt E, et al. Oculo-auriculo-vertebral spectrum: associated anomalies, functional deficits and possible development risk factors. Am J Med Genet. 2007; 143A(12):1317-25. discordant for the disease have been made, suggesting a correlation with a multifactorial inheritance pattern.

Moreover, there is evidence in the literature indicating that ingestion of certain drugs, such as thalidomide, retinoic acid, tamoxifen and cocaine during pregnancy can be related to the development of this condition. Other factors have been suggested as etiological factors include maternal diabetes, viral infections (e.g. rubella and influenza) and the abuse of alcohol during pregnancy as well.1313 Mehta B, Nayak C, Savant S, Amladi S. Goldenhar syndrome with unusal features. Indian J Venerol Dermatol Leprol. 2008; 74(3):254-6.

14 Nakajima H, Goto G, Tanaka N, Ashiya H, Ibukiyama C. Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J. 1998; 62(8):617-20.
-1515 Das A, Ray B, Das D. A case of Goldenhar-Gorlin syndrome with unusual association of hypoplastic thumb. Indian J Ophthamol. 2008; 56(2):150-2. Mounoud et al. reported a case of OAV dysplasia in a child whose mother had a history of hypervitaminosis A. It is known that daily doses of vitamin A higher than 25,000 IU have teratogenic effects. This teratogen has harmful effects in the formation of neural crest cells, which are essential for the formation of the pharyngeal arches.1616 Mounoud RL, Klein D, Weber F. [A case of Goldenhar syndrome: acute vitamin A intoxication in the mother during pregnancy]. J Genet Hum. 1975; 23(2):135-54.,1717 Maj V, Col R. Golden-har syndrome. Mjafi. 2000; 56:231-2.

Affected individuals may present: malar and/or mandibular hypoplasia, hypoplasia of the facial muscles, microtia, preauricular tags and outer ear dysplasia, hemivertebrae and hypoplasia of cervical thoracic or lumbar vertebrae, epibulbar dermoids, microphthalmia, cleft palate and/or lip, cardiac, kidney or central nervous system (CNS) anomalies.22 Gorlin RL. Branchial arch and oro-acral disorders. In: Gorlin JJ, Cohen Jr MM, Hennekam RC (eds.). Syndromes of the head and neck. London: Oxford University Press, 2001. p.790-97. In addition, there are reports on the association of OAV dysplasia with other conditions, such as genitourinary,1818 Ishitoya S, Arai Y, Okubo K, Suzuki Y. Left retrocaval ureter associated with the Goldenhar syndrome (branchial arch syndrome). J Urol. 1997; 158(2):572-3.,1919 Ritchey ML, Norbeck J, Huang C, Keating MA, Bloom DA. Urologic manifestations of Goldenhar syndrome. Urology. 1994; 43(1):88-91. cardiovascular,1414 Nakajima H, Goto G, Tanaka N, Ashiya H, Ibukiyama C. Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J. 1998; 62(8):617-20.,2020 Kumar A, Friedman JM, Taylor GP, Patterson MWH. Pattern of cardiac malformation in oculoauriculovertebral spectrum. Am J Med Genet. 1993; 46(3):423-6. or psychiatric2121 Brieger P, Bartel-Friederich S, Haring A, Marneros A. Oculo-auriculo-vertebral spectrum disorder (Goldenhar “syndrome”) coexisting with schizophreniform disorder. J Neurol Neurosurg Psychiatry. 1998; 65(1):135-6.,2222 Lleonart M, Sarduy A, Gil M, Lois L. Displasia oculoauriculovertebral o síndrome de Goldenhar: estudio multidisciplinario de un caso clínico. Rev Cubana Oftalmol. 2001; 14(1):42-6. changes, and obstructive sleep apnea.2323 Hoch B, Hochban W. Four-year-old girl with Goldenhar-sequence and severe obstructive sleep apnea, symptoms, diagnosis and therapy. Int J Pediatr Otorhinolaryngol. 1998; 43(3):277-81. However, due to clinical variability, some patients have minimal manifestations, predominantly facial asymmetry and dysplasia of the auricular pavilion.22 Gorlin RL. Branchial arch and oro-acral disorders. In: Gorlin JJ, Cohen Jr MM, Hennekam RC (eds.). Syndromes of the head and neck. London: Oxford University Press, 2001. p.790-97.

Based on the above, and considering the importance of the topic due to prevalence, wide spectrum of clinical manifestations and the lack of studies that describe a significant number of patients suffering from OAV dysplasia in our midst, we describe a case series of patients diagnosed with OAV dysplasia followed in our service over the past 20 years.

METHOD

The sample consisted of individuals followed in the Medical Genetics Unit at Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (ICr-HC-FMUSP), diagnosed with OAV dysplasia from 1990 to 2010. This study was approved by the Ethics Committee for Research Project Analysis – CAPPesq of HC-FMUSP (No. 0667-07).

Patients included in the study were those with normal G-banding karyotype and involvement of at least two of the following sites: 1) mouth, skull and face, 2) eyes, 3) ears and 4) vertebrae. This approach was consistent with that adopted by Strömland et al. (2007).1212 Strömland K, Miller M, Sjögreen L, Johansson M, Joelsson B-ME, Billstedt E, et al. Oculo-auriculo-vertebral spectrum: associated anomalies, functional deficits and possible development risk factors. Am J Med Genet. 2007; 143A(12):1317-25. Individuals with chromosomal abnormalities or incomplete medical records were excluded from the study.

We conducted a retrospective analysis, and collected data on clinical manifestations (ear, face, spine, eyes and more), demographics (gender, date of birth, age at first consultation, and age of parents) and results of additional tests. The affected side (right, left or bilateral) was that where microtia or facial microsomia was located, similarly to the method adopted by Rollnick et al. (1987).2424 Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculo auriculovertebral dysplasia and variants: phenotypic characteristic of 294 patients. Am J Med Genet. 1987; 26(2):361-75.

RESULTS

Among the 41 patients studied, 19 (46.3%) were male and 22 (53.7%) female. The mean age at first consultation was 2 years and 10 months (34.4±48.8 months). The mean age of parents at the birth of the child in cases where information was available (39/41 patients) was 28.5±6.9 years for the mothers and 31.4±7.4 years for the fathers.

With regard to clinical manifestations, 97.5% of the patients had some degree of ear involvement, 90.2% facial, 65.9% vertebral, and 53.7% ocular. 89% of children had involvement of other organs. The classic OAV triad was present in only 34% (15 children). All patients except one had concomitant problems in other organs or systems.

Facial manifestations

Facial abnormalities were observed in 90.2% (37/41) of patients. Of these, 83.8% (31/37) had some degree of hemifacial microsomia. In 46% (17/37) of the cases, change in facial expression was observed, suggesting some degree of facial paralysis. We also found that 14% (6/37) of the cases had cleft palate and/or lip and 7% (3/37) had ocular hypertelorism.

Ocular manifestations

From the classic triad of changes described as OAV dysplasia, ocular changes were less frequent in our series, with about 53.7% (22/41) of patients presenting some involvement. Epibulbar dermoids or dermoid cysts were seen in 45.4% (10/22), representing the vast majority in the group of eye diseases, followed by the finding of epicanthus, present in 22.7% (5/22) and other epibulbar tumors, present in 13.6% (3/22). Other ocular manifestations found in our series at a lower prevalence (1 or 2 cases) are: coloboma, changes in the lacrimal gland, anophthalmia and amaurosis.

Auricular manifestations

In terms of location, 30% (12/40) of patients had involvement limited to the right side, 30% (12/40) had abnormalities only in the left side, and 40% (16/40) were affected bilaterally. The most commonly found malformation was that of auricular dysplasia to varying degrees in 73% (30/41). The presence of preauricular tags occurred in 51.2% (21/41) of cases. In 24.4% (10/41) of patients, these two manifestations were simultaneous. In 31.7% (13/41) of cases, some degree of functional hearing loss was reported. Other changes described, by order of prevalence, are: auditory canal stenosis in 14.6% (6/41), auditory canal agenesis in 12.2% (5/41), abnormal implantation of the pinna in 9.8% (4/41), and recurrent acute otitis media in 7.3% (3/41).

Vertebral manifestations

65.9% (27/41) of the patients had vertebral abnormalities. Of these, spinal axis changes were found most often including marked kyphosis and/or scoliosis in 48.2% (13/27) of cases. Localized vertebral involvements were also prevalent, including the finding of hemivertebrae in 37% (10/27) cases, most often in the thoracic segment with 25% (7/27) patients affected. Block or fused vertebrae were diagnosed in 33% (9/27) of cases, with greater involvement of the cervical spine, affected in 77.7% (7/9) of patients, as well as the presence of incomplete fusion of vertebral arches in 14.8% (4/27) of the patients. Other reports included: sacral dimples in 22% (6/27) of patients, spina bifida in 14.8% (4/27), and transitional vertebrae in 14.8% (4/27).

Other systemic manifestations

Cardiovascular system

Cardiovascular involvement was found in 36.6% (15/41) of the patients. The spectrum is quite heterogeneous, but the most frequent changes were communications between heart chambers, which were present in 36.6% of the patients with cardiac involvement. Interatrial communication was responsible for 40% (6/15) of the cases, and ventricular septal defects for 33.3% (5/15) of the cases. Complex congenital heart disease were seen in 26.7% (4/15) patients, the most common being the tetralogy of Fallot, present in 50% (2/4) of cases. Persistent arterial duct was found in 20% (3/15) of the patients.

Urogenital system

In our sample, 29.3% (12/41) of patients showed abnormalities in the urinary tract, of which 41.7% (5/12) had concomitant change in the cardiovascular system. Among the abnormalities found, pelvic kidneys and unilateral renal agenesis were the most prevalent occurrences, both present in 41.7% (5/12) patients each. Of note, among patients diagnosed with pelvic kidney, 80% (4/5) had ipsilateral ear involvement. Other changes less frequently observed (1 or 2 cases) were pyelocaliceal ectasia, pyeloureteral duplication, vesicoureteral reflux and hypospadias.

Central nervous system

17% (7/41) of the patients had CNS changes, especially expansion of the cerebral ventricles, found in 43% (03/07) of cases. 28.6% (2/7) of these cases had dysgenesis of the corpus callosum associated with ventriculomegaly, and 14.3% (1/7) showed absence of the septum pellucidum associated with ventriculomegaly. Occipital encephalocele associated with posterior parietal meningoencephalocele was less frequent alteration found in one patient.

DISCUSSION

OAV dysplasia is a well-defined entity, characterized by unilateral or bilateral craniofacial anomalies, to a variable degree, involving the first and second branchial arches, and vertebral and eye abnormalities. Clinically, it varies from an isolated microtia, with or without mandibular hypoplasia, to a more complex phenotype involving skeletal, cardiac, renal, lung and CNS disorders.2424 Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculo auriculovertebral dysplasia and variants: phenotypic characteristic of 294 patients. Am J Med Genet. 1987; 26(2):361-75.,2525 Kelberman D, Tyson J, Chandler DC, McInerney AM, Slee J, Albert D, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet. 2001; 109(6):638-45.

As previously mentioned, much has been speculated about the etiological and pathogenic mechanisms that lead to the development of OAV dysplasia. In this sense, several studies have been performed to identify genetic changes that may be related to the phenotype displayed by patients with OAV, but so far such correlation could not be established.2626 Brosco KC, Zorzetto NL, Costa AR. [Audiology profile in patients with Goldenhar’s syndrome]. Rev Bras Otorrinolaringol. 2004; 70(5):645-9.

Our results reveal that 21 (48%) patients were male and 23 (52%) were female, a proportion similar to that found in a study conducted in the city of Bauru, state of São Paulo, 2727 Smith DW. Síndromes de malformações congênitas: aspectos genéticos, embriológicos e clínicos. 3.ed. São Paulo: Manole, 1985. and different from that observed in other studies that found male predominance with a ratio of 3:2.77 Cohen Jr MM, Rollinck BR, Kaye CI. Oculoauriculoveretbral spectrum: an updated critique. Cleft Palate J. 1989; 26(4):276-86.

Regarding the therapeutic approach, in less complex cases interventions vary according to the age and systemic involvement and are mainly intended to improve esthetics. In patients with mandibular hypoplasia, reconstructive surgery can be performed using bone grafts taken from the ribs and, in some instances, bone stretching. In cases where there is cleft lip and/or palate, surgical correction is usually performed followed by the use of orthodontic devices after correction of mandibular defects.

Reconstructive surgery to correct auricular malformation is usually performed at the age of 6 to 8 years. In patients with milder involvement, mandibular reconstruction surgery can be performed in early adolescence. Epibulbar dermoids must be removed surgically. Structural ocular anomalies and those of the outer ear should be corrected by plastic surgeons.

CONCLUSION

It is important to emphasize that individuals with OAV dysplasia often have psychosocial difficulties caused by stigma. Thus, the participation of a multidisciplinary team is crucial so that patients can be addressed globally for proper support. In general, the prognosis is good, especially in cases without systemic involvement. More severe cases of OAV dysplasia can affect many aspects of a patient’s life, and many require interventions shortly after birth.22 Gorlin RL. Branchial arch and oro-acral disorders. In: Gorlin JJ, Cohen Jr MM, Hennekam RC (eds.). Syndromes of the head and neck. London: Oxford University Press, 2001. p.790-97.,1414 Nakajima H, Goto G, Tanaka N, Ashiya H, Ibukiyama C. Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J. 1998; 62(8):617-20.

TABLE 1
Type and frequency of changes observed in patients with OAV dysplasia.

REFERENCES

  • 1
    Salvitti C, Azulay RD, Heringer ML, Almeida de Faria LA. [Oculo-auriculo-vertebral dysplasia: presentation of a case and attempt at organizing the symptomatology]. Rev Ass Med Bras. 1978; 24(5):160-2.
  • 2
    Gorlin RL. Branchial arch and oro-acral disorders. In: Gorlin JJ, Cohen Jr MM, Hennekam RC (eds.). Syndromes of the head and neck. London: Oxford University Press, 2001. p.790-97.
  • 3
    Sugar HS. The oculoauriculovertebral dysplasia syndrome of Goldenhar. Am J Ophthalmol. 1966; 62(4):678.
  • 4
    Grabb WC. The first and second branchial arch syndrome. Plast Reconstr Surg. 1965; 36(5):485-508.
  • 5
    Stoll C, Roth MP, Dott B, Bigel T. Discordance for skeletal and cardiac defect in monozygotic twins. Acta Genet Med Gemellol. 1984; 33(3):501-4.
  • 6
    Melnick M. The etiology of external ear malformations and its relation to abnormalities of the middle ear, inner ear and other organ systems. Birth Defects Orig Artic Ser. 1980; 16(4):303-31.
  • 7
    Cohen Jr MM, Rollinck BR, Kaye CI. Oculoauriculoveretbral spectrum: an updated critique. Cleft Palate J. 1989; 26(4):276-86.
  • 8
    Pearson A. Developmental anatomy of the ear. In: English M (ed.). Otolaryngology. New York: Harper and Row, 1978. p.1-68.
  • 9
    Scholtz AW, Fish III JH, Kammen-Jolly K, Ichiki H, Hussl B, Kreczy A, et al. Goldenhar’s syndrome: congenital hearing deficit of conductive or sensorineural origin? Temporal bone histopathologic study. Otol Neurotol. 2001; 22(4):501-5.
  • 10
    Phelps PD, Lloyd GA, Poswillo DE. The ear deformities in craniofacial microsomia and oculo-auriculo-vertebral dysplasia. J Laryngol Otol. 1983; 97(11):995-1005.
  • 11
    Bisdas S, Lenarz M, Lenarz T, Becker H. Inner ear abnormalities in patients with Goldenhar syndrome. Otol Neurotol. 2005; 26(3):398-404.
  • 12
    Strömland K, Miller M, Sjögreen L, Johansson M, Joelsson B-ME, Billstedt E, et al. Oculo-auriculo-vertebral spectrum: associated anomalies, functional deficits and possible development risk factors. Am J Med Genet. 2007; 143A(12):1317-25.
  • 13
    Mehta B, Nayak C, Savant S, Amladi S. Goldenhar syndrome with unusal features. Indian J Venerol Dermatol Leprol. 2008; 74(3):254-6.
  • 14
    Nakajima H, Goto G, Tanaka N, Ashiya H, Ibukiyama C. Goldenhar syndrome associated with various cardiovascular malformations. Jpn Circ J. 1998; 62(8):617-20.
  • 15
    Das A, Ray B, Das D. A case of Goldenhar-Gorlin syndrome with unusual association of hypoplastic thumb. Indian J Ophthamol. 2008; 56(2):150-2.
  • 16
    Mounoud RL, Klein D, Weber F. [A case of Goldenhar syndrome: acute vitamin A intoxication in the mother during pregnancy]. J Genet Hum. 1975; 23(2):135-54.
  • 17
    Maj V, Col R. Golden-har syndrome. Mjafi. 2000; 56:231-2.
  • 18
    Ishitoya S, Arai Y, Okubo K, Suzuki Y. Left retrocaval ureter associated with the Goldenhar syndrome (branchial arch syndrome). J Urol. 1997; 158(2):572-3.
  • 19
    Ritchey ML, Norbeck J, Huang C, Keating MA, Bloom DA. Urologic manifestations of Goldenhar syndrome. Urology. 1994; 43(1):88-91.
  • 20
    Kumar A, Friedman JM, Taylor GP, Patterson MWH. Pattern of cardiac malformation in oculoauriculovertebral spectrum. Am J Med Genet. 1993; 46(3):423-6.
  • 21
    Brieger P, Bartel-Friederich S, Haring A, Marneros A. Oculo-auriculo-vertebral spectrum disorder (Goldenhar “syndrome”) coexisting with schizophreniform disorder. J Neurol Neurosurg Psychiatry. 1998; 65(1):135-6.
  • 22
    Lleonart M, Sarduy A, Gil M, Lois L. Displasia oculoauriculovertebral o síndrome de Goldenhar: estudio multidisciplinario de un caso clínico. Rev Cubana Oftalmol. 2001; 14(1):42-6.
  • 23
    Hoch B, Hochban W. Four-year-old girl with Goldenhar-sequence and severe obstructive sleep apnea, symptoms, diagnosis and therapy. Int J Pediatr Otorhinolaryngol. 1998; 43(3):277-81.
  • 24
    Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculo auriculovertebral dysplasia and variants: phenotypic characteristic of 294 patients. Am J Med Genet. 1987; 26(2):361-75.
  • 25
    Kelberman D, Tyson J, Chandler DC, McInerney AM, Slee J, Albert D, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet. 2001; 109(6):638-45.
  • 26
    Brosco KC, Zorzetto NL, Costa AR. [Audiology profile in patients with Goldenhar’s syndrome]. Rev Bras Otorrinolaringol. 2004; 70(5):645-9.
  • 27
    Smith DW. Síndromes de malformações congênitas: aspectos genéticos, embriológicos e clínicos. 3.ed. São Paulo: Manole, 1985.

Publication Dates

  • Publication in this collection
    May 2016

History

  • Received
    06 Aug 2014
  • Accepted
    24 Aug 2014
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