Branchio-oculo-facial syndrome (BOFS) and congenital heart defects

Abstracts

Relatamos aqui o caso de um menino com 43 dias de vida, apresentando síndrome brânquio-óculo-facial (BOFS) e cardiopatia congênita. Na avaliação clínica, ele possuía retardo de crescimento, pregas epicânticas, fendas palpebrais pequenas, telecanto, base nasal alargada, fenda labial falsa (pseudocleft), micrognatia, orelhas displásicas e rotadas posteriormente, fendas branquiais, pescoço curto e alado, mamilo extranumerário, hipotonia e reflexos tendinosos profundos diminuídos. A ecocardiografia verificou presença de um defeito do septo atrioventricular completo do tipo A e persistência do canal arterial. Essa descrição fortalece a possibilidade de que defeitos cardíacos congênitos possam fazer parte do espectro de anormalidades observado na BOFS.

Síndrome brânquio-otorrenal; cardiopatias congênitas

Relatamos en este estudio el caso de un niño con 43 días de vida, que presentaba síndrome branquio óculo facial (BOFS) y cardiopatía congénita. En la evaluación clínica, revelaba retardo de crecimiento, pliegues epicánticos, hendiduras palpebrales pequeñas, telecanto, base nasal ensanchada, hendidura labial falsa (pseudocleft), micrognatia, orejas displásicas y rotadas posteriormente, hendiduras branquiales, cuello corto y alado, pezón extranumerario, hipotonía y reflejos tendinosos profundos diminuidos. La ecocardiografía verificó la presencia de un defecto del septo atrioventricular completo del tipo A y conducto arterial persistente. Dicha descripción fortalece la posibilidad de que defectos cardiacos congénitos puedan forman parte del espectro de anormalidades observado en la BOFS.

Síndrome branquio otorrenal; cardiopatías congénitas

CASE REPORT

Branchio-oculo-facial syndrome (BOFS) and congenital heart defects

Rafael Fabiano Machado Rosa; Paulo Ricardo Gazzola Zen; Carla Graziadio; Giorgio Adriano Paskulin

Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) and Santa Casa de Porto Alegre Hospital Complex (CHSCPA), Porto Alegre, RS – Brazil

Mailing address

ABSTRACT

We report the case of a 43-day-old boy with branchio-oculo-facial syndrome (BOFS) and congenital heart defect. On clinical examination, he presented growth retardation, epicanthal folds, small palpebral fissures, telecanthus, broadened nasal bridge, lip pseudocleft, micrognathia, dysplastic and posteriorly-rotated ears, branchial clefts, short and webbed neck, supernumerary nipple, hypotonia and decreased deep tendon reflexes. Echocardiography showed the presence of a type-A complete atrioventricular septal defect and patent ductus arteriosus. This description strengthens the possibility of congenital heart defects being part of the spectrum of anomalies seen in BOFS.

Key Words: Oto-renal-syndrome; heart defects, congenital.

We report the case of a 43-day-old boy with branchio-oculo-facial syndrome (BOFS) and congenital heart defect. On clinical examination, he presented growth retardation, epicanthal folds, small palpebral fissures, telecanthus, broadened nasal bridge, lip pseudocleft, micrognathia, dysplastic and posteriorly-rotated ears, branchial clefts, short and webbed neck, supernumerary nipple, hypotonia and decreased deep tendon reflexes. Echocardiography showed the presence of a type-A complete atrioventricular septal defect and patent ductus arteriosus. This description strengthens the possibility of congenital heart defects being part of the spectrum of anomalies seen in BOFS.

Introduction

Branchio-oculo-facial syndrome (BOFS) (MIM 113620)¹, first named in 1987 by Fujimoto et al², is a rare autosomal disease with a highly variable expressivity³. Mutations in genes of the EYA-DACH-SIX-PAX pathway, initially considered candidates for the syndrome because of their relationship with the development of some oro-facial-cervical structures and diseases overlapping with BOFS, such as the branchio-oto-renal syndrome (BOR; MIM 113650) and Townes-Brocks syndrome (TB; MIM 107480), have not been identified in BOFS patients. However, more recently, Milunsky et al⁴ studied a sample of BOFS patients and verified the presence of mutation in the TFAP2A gene, which is located in chromosome 6 (region 6p24) and previously related to the development of the anterior chamber of the eye^1,4. Despite these findings, the authors concluded that more patients should be studied to exclude possible genetic heterogeneity⁴. The syndrome is clinically characterized by the presence of branchial defects covered by a portion of normal skin, associated or not with pre-auricular or auricular pits; microphtalmia; coloboma; nasolacrimal duct obstruction; lip pseudoclefts (abnormal upper lip and filtrum resembling a poorly repaired cleft lip); partial or total clefts of upper lip, and premature graying of hair^2,3.

Although renal malformations are frequent in patients with the syndrome, the involvement of other organs, particularly congenital heart defects (CHD) have been rarely described^3,5. We report a rare case of BOFS associated with CHD.

Case Report

The patient was a white boy, the first child of healthy nonconsanguineous young parents. His family history was negative for any congenital defect or genetic disease. He was born at the 36th week gestation, by cesarean section, in breech presentation. His birth weight was 2870 g (10-50th percentile), his height was 45 cm (10-50th percentile) and the 5-minute Apgar score was 9. On clinical examination at 43 days of age, his weight was 2590 g (< 3rd percentile), his height was 46 cm (< 3rd percentile), head circumference of 34 cm (< 2nd percentile), and he presented epicanthal folds, small palpebral fissures, telecanthus, broadened nasal bridge, lip pseudocleft, migrognathia, dysplastic and posteriorly-rotated ears, branchial clefts (areas of aplasia cutis) in the neck below the ears, short and webbed neck, and supranumerary nipple in right side of the chest (Figure 1).

The neurological examination revealed hypotonia and decreased deep tendon reflexes. Brain ultrasonography showed prominent lateral ventricles. Abdominal ultrasonography, eye examination and high-resolution GTG-banding karyotype were normal.

An echocardiography performed soon after birth showed the presence of an atrioventricular septal defect (AVSD) and patent ductus arteriosus (PDA).

Although cardiac surgery had been performed on the first month of life, the child progressed with hemodynamic and respiratory instability due to the heart condition, and died in the tenth month of life. Autopsy was not performed.

Discussion

The presence of some specific craniofacial anomalies in our patient, particularly telecanthus, broadened nasal bridge, lip pseudocleft, dysplastic and posteriorly-rotated ears associated with branchial clefts, which are considered possibly pathognomonic of BOFS³, supported the diagnosis. In medical databases such as OMIM¹ and LMD (London Medical Database)⁶, there is no description of the association between BOFS and congenital heart defects. However, in our review, we found four confirmed cases of BOFS presenting CHD which included: ostium secundum atrial septal defect (two cases)^3,7, tetralogy of Fallot (one case)⁵ and pulmonary valve stenosis (one case)⁸ (Table 1). All patients presented facial findings characteristic of BOFS associated with branchial defects^1,3,5,8. The present report is the first description of a patient with both BOFS and AVSD, one of the CHD more frequently associated with extracardiac anomalies, especially with Down syndrome⁹. Hing et al¹⁰ described a patient presenting multiple malformations and AVSD resembling BOFS. He presented some atypical findings such as holoprosencephaly and meningoencephalocele. The authors suggested that this patient could present a lethal variant of BOFS, or, alternatively, a syndrome not previously reported¹⁰. This case was reevaluated by Lin et al³, who considered it atypical, probably unaffected³. Although conotruncal heart defects – malformations related to the abnormal migration of cells from the neural crest into the branchial arches, are frequently found in other syndromes with branchial arch anomalies³, Bennaceur et al⁵ were the only authors to describe a patient with BOFS presenting this type of CHD (a patient with tetralogy of Fallot)⁵. The other reports included heart defects pathogenetically classified in the group of intracardiac blood flow defects^3,7,8 and extracellular matrix anomalies (the present case) (Table 1). Thus, this new BOFS report strengthens the possibility of congenital heart defects being part of the spectrum of anomalies observed in this syndrome.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any post-graduation program.

References

• ¹
  OMIM (TM). On line Mendelian Inheritance in man (TM). Baltimore: Center for Medical Genetics of the Johns Hopkins University; 2000. [Acessed in 2008 June 12]. Available from: http://www.3.ncbi.nlm.nih.gov:80/htbin-post/omnin/dispmin?229300
• 2. Fujimoto A, Lipson M, Lacro RV, Shinno NW, Boelter W, Jones KL, et al. New autosomal dominant branchio-oculo-facial syndrome. Am J Med Genet. 1987; 27: 943-51.
• 3. Lin AE, Gorlin RJ, Lurie IW, Brunner HG, van der Burgt I, Naumchik IV, et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet. 1995; 56: 42-59.
• 4. Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, et al. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet. 2008; 82: 1171-7.
• 5. Bennaceur S, Buisson T, Bertolus C, Couly G. Branchio-oculo-facial syndrome with cleft lip and bilateral dermal thymus. Cleft Palate Craniofac J. 1998; 35: 454-9.
• 6. Winter R, Baraitser M. Winter-Baraitser Dysmorphology Database (WBDD). In: London Medical Database (LMD) Version 1.0. London: Oxford University Press; 2005.
• 7. Verret DJ, Murray AD, Hobar PC. Branchio-oculo-facial syndrome with ectodermal parathyroid tissue. Otolaryngol Head Neck Surg. 2005; 133: 983-4.
• 8. Kapoor S, Kapur N. Branchio-oculo-facial syndrome with valvular pulmonic stenosis. Indian Pediatr. 2004; 41: 1180-1.
• 9. Marino B, Digilio MC. Congenital heart disease and genetic syndromes: specific correlation between cardiac phenotype and genotype. Cardiovasc Pathol. 2000; 9: 303-15.
• 10. Hing AV, Torack R, Dowton SB. A lethal syndrome resembling branchio-oculo-facial syndrome. Clin Genet. 1992; 41: 74-8.

Publication Dates

• Publication in this collection
  06 Apr 2009
• Date of issue
  Feb 2009

History

• Received
  16 June 2008
• Reviewed
  10 July 2008
• Accepted
  10 July 2008