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Lipodermoid in a patient with Emanuel syndrome
Lipodermoid in a patient with Emanuel syndrome Tanya S. Glaser, BA,a Katherine A. Rauen, MD, PhD,b Linda J. B. Jeng, MD, PhD,c and Alejandra G. de Alba Campomanes, MD, MPHa
We report an 8-month-old boy with Emanuel syndrome who also had the clinical features of Goldenhar syndrome. At birth, he was observed to have bilateral microtia with multiple auricular pits, retrognathia, and a unilateral lipodermoid. Further testing revealed cardiac defects. The finding of a lipodermoid in Emanuel syndrome demonstrates phenotypic overlap between Goldenhar and Emanuel syndromes and suggests a role for genetic analysis in all patients with clinical features that include ear anomalies and lipodermoids. Correct identification of patients with Emanuel syndrome is important for determining whether there is risk of long-term neurodevelopmental disability, and genetic testing can determine parental carrier status to aid in family planning.
Case Report
A
n 8-month-old boy born at full term presented at the University of California–San Francisco for ophthalmological evaluation. His delivery had been complicated by prolonged rupture of membranes and hypoxic-ischemic injury. At birth, the patient was noted to have multiple craniofacial anomalies, including bilateral absence of the ear canals, with microtia and lowset ears, multiple auricular pits, retrognathia, mandibular hypoplasia, and right facial hemiparesis. Testing revealed conductive hearing loss. Echocardiogram demonstrated a patent ductus arteriosus, an atrial septal defect, and small ventricular septal defect. Ophthalmological examination was notable for a superotemporal conjunctival lipodermoid in the right eye (Figure 1A). A high-resolution karyotype revealed a normal male child with a supernumerary marker chromosome in every cell examined (Figure 1B). A diagnosis of Emanuel syndrome was confirmed by array-based comparative genomic hybridization analysis (Figure 2). The parents have not yet undergone the recommended genetic analysis to test for carrier status.
Discussion Emanuel syndrome (OMIM 609029), also known as supernumerary der(22)t(11; 22) syndrome, is associated with a supernumerary chromosome, the derivative 22 Author affiliations: Departments of aOphthalmology, bPediatrics, and cLaboratory Medicine, University of California–San Francisco, San Francisco, California Submitted June 29, 2012. Revision accepted November 14, 2012. Published online March 25, 2013. Correspondence: Alejandra G. de Alba Campomanes, MD, MPH, 10 Koret Way, Room K301, University of California, San Francisco, CA 94143 (email: [email protected]). J AAPOS 2013;17:211-213. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.11.011
Journal of AAPOS
(der(22)) chromosome, which consists of redundant genetic material from chromosomes 11 and 22 in addition to 2 normal copies of chromosomes 11 and 22. Emanuel syndrome is associated with multiple congenital anomalies, craniofacial dysmorphism, and significant developmental delay. A review of 63 patients with this syndrome found that the most common anomalies are ear pits, followed by micrognathia, heart malformations, cleft palate, preauricular tags, and microtia.1 Frequently encountered ocular complications include the development of myopia, strabismus, astigmatism, and ptosis, but no congenital ocular anomalies or lipodermoids have been reported in association with Emanuel syndrome.1 By comparison, oculo-auriculo-vertebral spectrum (OMIM 164210), which includes Goldenhar syndrome, is classically associated with a triad of congenital anomalies comprising epibulbar dermoids, preauricular appendages, and vertebral abnormalities.2,3 In a cohort of 18 patients with oculo-auriculo-vertebral spectrum disorders, the most common malformations included ear abnormalities, followed by ocular malformations, vertebral deformities, cerebral anomalies, and congenital heart defects (ventricular septal defect, tetralogy of fallot, and aortic coarctation).4 A total of 61% of patients also had lipodermoids, of which 72% occurred in combination with epibulbar dermoids. Emanuel and oculo-auriculo-vertebral spectrum overlap phenotypically with the presence of ear abnormalities, mandibular hypoplasia, and cardiac defects; to our knowledge, lipodermoids have not been previously described in Emanuel syndrome but do occur frequently in oculo-auriculo-vertebral spectrum disorders. The finding of a lipodermoid associated with Emanuel syndrome suggests that a diagnosis of Emanuel syndrome should be considered in addition to oculo-auriculo-vertebral spectrum in patients who present with ear abnormalities, mandibular hypoplasia, cardiac defects, and ocular choristomas. Proper diagnosis of Emanuel syndrome in patients with the aforementioned clinical features has important prognostic implications for long-term neurodevelopmental outcomes. A study of patients with oculo-auriculovertebral spectrum disorders found that 58% of patients scored below the mean in at least one domain of development, whereas the mean IQ was only slightly low in comparison with the normal population.5 In contrast, global delay was seen in 100% of patients with Emanuel syndrome.1 The vast majority of patients required special education and attended classes and schools for disabled children. Proper diagnosis of Emanuel syndrome may permit better anticipation of future needs and early therapeutic and educational interventions.
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FIG 1. A, Lipodermoid in the right eye. B, Karyotype analysis demonstrating the presence of a supernumerary marker chromosome (black arrow).
FIG 2. Array-based comparative genomic hybridization identifying the marker chromosome as the t(11,22) associated with Emanuel syndrome. Green bars highlight gains of 11q23.3q25 (chr11:116,227,351-134,432,295, hg18) and 22q11.1q11.21(chr22:15,777,528-18,587,100, hg18), which is consistent with a reciprocal translocation seen in Emanuel syndrome. The array used was a 105K-feature whole-genome microarray (ISCA v2 Clinical Design; Agilent Technologies, Santa Clara, CA).
An additional benefit of early diagnosis of Emanuel syndrome is the ability to offer genetic testing and counseling to families. Whereas oculo-auriculo-vertebral spectrum disorders are genetically heterogeneous, the genetic predisposition for Emanuel syndrome is both known and predictable in its outcome. The t(11; 22) is the most frequently identified familial reciprocal translocation, and if chromosomal nondisjunction occurs during gametogenesis in a parent who carries this balanced reciprocal translocation, it may result in offspring with the der(22) chromosome and Emanuel syndrome.6 Although either parent can be the carrier, a review found that the mother was the carrier of the balanced translocation in 90% of cases.1 Carriers with the balanced translocation have a 10% chance of conceiving and carrying to term a child with Emanuel syndrome.7
Information on the genetics of lipodermoids is limited, and there are no known associations between the genes in the areas of genetic copy gains and lipodermoid formation. Review of genes in the supernumerary chromosome has identified several genes that have been shown to be involved in ocular development. Depletion of the gene armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) is associated with eye and craniofacial defects in Xenopus laevis.8 The homeodomain transcription factor BARX homeobox 2 (Barx2) is highly expressed in conjunctiva, eyelid, and ocular gland tissue and overexpression of the Drosophila melanogaster homeobox gene equivalent results in eye malformations.9,10 Mutations in Cbl protooncogene, E3 ubiquitin protein ligase (CBL) has been shown to result in phenotypic characteristics similar to Noonan syndrome.11 Finally, membrane frizzle-related
Journal of AAPOS
Volume 17 Number 2 / April 2013 protein (MFRP) is thought to play a role in eye development because mutations in MFRP have been associated with nanophthalmos, retinitis pigmentosa, foveaschisis, and optic disk drusen.12 It is possible that the finding of a lipodermoid in our patient is coincidental and unrelated; however, the finding remains clinically relevant given that there is already significant phenotypic overlap between Emanuel syndrome and ocular-auriculo-vertebral spectrum disorders.
Literature Search A systematic literature search of the English-language PubMed database was performed through March 2012 using the following search terms revealed 43 articles: Emanuel syndrome, Emanuel AND syndrome, Supernumary der(22) syndrome, Supernumary der(22)t(11;22) syndrome, and Supernumary derivative 22 chromosome syndrome. Review of these articles found no discussion of lipodermoids. To confirm, the above query was further refined by the addition of lipodermoid, dermoid, or ocular. Only 1 article remained, which, on review, did not identify a lipodermoid in Emanuel syndrome. References 1. Carter MT, St Pierre SA, Zackai EH, Emanuel BS, Boycott KM. Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals. Am J Med Genet A 2009;149A:1712-21.
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Glaser et al
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2. Baum JL, Feingold M. Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 1973;75:250-57. 3. Gorlin RJ, Jue KL, Jacobsen U, Goldschmidt E. Oculoauriculovertebral Dysplasia. J Pediatr 1963;63:991-9. 4. Stromland K, Miller M, Sjogreen L, et al. Oculo-auriculo-vertebral spectrum: Associated anomalies, functional deficits and possible developmental risk factors. Am J Med Genet A 2007;143A:1317-25. 5. Cohen MS, Samango-Sprouse CA, Stern HJ, et al. Neurodevelopmental profile of infants and toddlers with oculo-auriculo-vertebral spectrum and the correlation of prognosis with physical findings. Am J Med Genet 1995;60:535-40. 6. Kurahashi H, Inagaki H, Ohye T, et al. The constitutional t(11;22): Implications for a novel mechanism responsible for gross chromosomal rearrangements. Clin Genet 2010;78:299-309. 7. Zackai EH, Emanuel BS. Site-specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction. Am J Med Genet 1980;7:507-21. 8. Cho K, Lee M, Gu D, et al. Kazrin, and its binding partners ARVCFand delta-catenin, are required for Xenopus laevis craniofacial development. Dev Dyn 2011;240:2601-12. 9. Tsau C, Ito M, Gromova A, Hoffman MP, Meech R, Makarenkova HP. Barx2 and Fgf10 regulate ocular glands branching morphogenesis by controlling extracellular matrix remodeling. Development 2011;138:3307-17. 10. Kojima T, Sone M, Michiue T, Saigo K. Mechanism of induction of Bar-like eye malformation by transient overexpression of Bar homeobox genes in Drosophila melanogaster. Genetica 1993;88:85-91. 11. Martinelli S, De Luca A, Stellacci E, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome–like phenotype. Am J Hum Genet 2010;87:250-57. 12. Crespi J, Buil JA, Bassaganyas F, et al. A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen. Am J Ophthalmol 2008; 146:323-8.
We report an 8-month-old boy with Emanuel syndrome who also had the clinical features of Goldenhar syndrome. At birth, he was observed to have bilateral microtia with multiple auricular pits, retrognathia, and a unilateral lipodermoid. Further testing revealed cardiac defects. The finding of a lipodermoid in Emanuel syndrome demonstrates phenotypic overlap between Goldenhar and Emanuel syndromes and suggests a role for genetic analysis in all patients with clinical features that include ear anomalies and lipodermoids. Correct identification of patients with Emanuel syndrome is important for determining whether there is risk of long-term neurodevelopmental disability, and genetic testing can determine parental carrier status to aid in family planning.
Case Report
A
n 8-month-old boy born at full term presented at the University of California–San Francisco for ophthalmological evaluation. His delivery had been complicated by prolonged rupture of membranes and hypoxic-ischemic injury. At birth, the patient was noted to have multiple craniofacial anomalies, including bilateral absence of the ear canals, with microtia and lowset ears, multiple auricular pits, retrognathia, mandibular hypoplasia, and right facial hemiparesis. Testing revealed conductive hearing loss. Echocardiogram demonstrated a patent ductus arteriosus, an atrial septal defect, and small ventricular septal defect. Ophthalmological examination was notable for a superotemporal conjunctival lipodermoid in the right eye (Figure 1A). A high-resolution karyotype revealed a normal male child with a supernumerary marker chromosome in every cell examined (Figure 1B). A diagnosis of Emanuel syndrome was confirmed by array-based comparative genomic hybridization analysis (Figure 2). The parents have not yet undergone the recommended genetic analysis to test for carrier status.
Discussion Emanuel syndrome (OMIM 609029), also known as supernumerary der(22)t(11; 22) syndrome, is associated with a supernumerary chromosome, the derivative 22 Author affiliations: Departments of aOphthalmology, bPediatrics, and cLaboratory Medicine, University of California–San Francisco, San Francisco, California Submitted June 29, 2012. Revision accepted November 14, 2012. Published online March 25, 2013. Correspondence: Alejandra G. de Alba Campomanes, MD, MPH, 10 Koret Way, Room K301, University of California, San Francisco, CA 94143 (email: [email protected]). J AAPOS 2013;17:211-213. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2012.11.011
Journal of AAPOS
(der(22)) chromosome, which consists of redundant genetic material from chromosomes 11 and 22 in addition to 2 normal copies of chromosomes 11 and 22. Emanuel syndrome is associated with multiple congenital anomalies, craniofacial dysmorphism, and significant developmental delay. A review of 63 patients with this syndrome found that the most common anomalies are ear pits, followed by micrognathia, heart malformations, cleft palate, preauricular tags, and microtia.1 Frequently encountered ocular complications include the development of myopia, strabismus, astigmatism, and ptosis, but no congenital ocular anomalies or lipodermoids have been reported in association with Emanuel syndrome.1 By comparison, oculo-auriculo-vertebral spectrum (OMIM 164210), which includes Goldenhar syndrome, is classically associated with a triad of congenital anomalies comprising epibulbar dermoids, preauricular appendages, and vertebral abnormalities.2,3 In a cohort of 18 patients with oculo-auriculo-vertebral spectrum disorders, the most common malformations included ear abnormalities, followed by ocular malformations, vertebral deformities, cerebral anomalies, and congenital heart defects (ventricular septal defect, tetralogy of fallot, and aortic coarctation).4 A total of 61% of patients also had lipodermoids, of which 72% occurred in combination with epibulbar dermoids. Emanuel and oculo-auriculo-vertebral spectrum overlap phenotypically with the presence of ear abnormalities, mandibular hypoplasia, and cardiac defects; to our knowledge, lipodermoids have not been previously described in Emanuel syndrome but do occur frequently in oculo-auriculo-vertebral spectrum disorders. The finding of a lipodermoid associated with Emanuel syndrome suggests that a diagnosis of Emanuel syndrome should be considered in addition to oculo-auriculo-vertebral spectrum in patients who present with ear abnormalities, mandibular hypoplasia, cardiac defects, and ocular choristomas. Proper diagnosis of Emanuel syndrome in patients with the aforementioned clinical features has important prognostic implications for long-term neurodevelopmental outcomes. A study of patients with oculo-auriculovertebral spectrum disorders found that 58% of patients scored below the mean in at least one domain of development, whereas the mean IQ was only slightly low in comparison with the normal population.5 In contrast, global delay was seen in 100% of patients with Emanuel syndrome.1 The vast majority of patients required special education and attended classes and schools for disabled children. Proper diagnosis of Emanuel syndrome may permit better anticipation of future needs and early therapeutic and educational interventions.
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Volume 17 Number 2 / April 2013
FIG 1. A, Lipodermoid in the right eye. B, Karyotype analysis demonstrating the presence of a supernumerary marker chromosome (black arrow).
FIG 2. Array-based comparative genomic hybridization identifying the marker chromosome as the t(11,22) associated with Emanuel syndrome. Green bars highlight gains of 11q23.3q25 (chr11:116,227,351-134,432,295, hg18) and 22q11.1q11.21(chr22:15,777,528-18,587,100, hg18), which is consistent with a reciprocal translocation seen in Emanuel syndrome. The array used was a 105K-feature whole-genome microarray (ISCA v2 Clinical Design; Agilent Technologies, Santa Clara, CA).
An additional benefit of early diagnosis of Emanuel syndrome is the ability to offer genetic testing and counseling to families. Whereas oculo-auriculo-vertebral spectrum disorders are genetically heterogeneous, the genetic predisposition for Emanuel syndrome is both known and predictable in its outcome. The t(11; 22) is the most frequently identified familial reciprocal translocation, and if chromosomal nondisjunction occurs during gametogenesis in a parent who carries this balanced reciprocal translocation, it may result in offspring with the der(22) chromosome and Emanuel syndrome.6 Although either parent can be the carrier, a review found that the mother was the carrier of the balanced translocation in 90% of cases.1 Carriers with the balanced translocation have a 10% chance of conceiving and carrying to term a child with Emanuel syndrome.7
Information on the genetics of lipodermoids is limited, and there are no known associations between the genes in the areas of genetic copy gains and lipodermoid formation. Review of genes in the supernumerary chromosome has identified several genes that have been shown to be involved in ocular development. Depletion of the gene armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) is associated with eye and craniofacial defects in Xenopus laevis.8 The homeodomain transcription factor BARX homeobox 2 (Barx2) is highly expressed in conjunctiva, eyelid, and ocular gland tissue and overexpression of the Drosophila melanogaster homeobox gene equivalent results in eye malformations.9,10 Mutations in Cbl protooncogene, E3 ubiquitin protein ligase (CBL) has been shown to result in phenotypic characteristics similar to Noonan syndrome.11 Finally, membrane frizzle-related
Journal of AAPOS
Volume 17 Number 2 / April 2013 protein (MFRP) is thought to play a role in eye development because mutations in MFRP have been associated with nanophthalmos, retinitis pigmentosa, foveaschisis, and optic disk drusen.12 It is possible that the finding of a lipodermoid in our patient is coincidental and unrelated; however, the finding remains clinically relevant given that there is already significant phenotypic overlap between Emanuel syndrome and ocular-auriculo-vertebral spectrum disorders.
Literature Search A systematic literature search of the English-language PubMed database was performed through March 2012 using the following search terms revealed 43 articles: Emanuel syndrome, Emanuel AND syndrome, Supernumary der(22) syndrome, Supernumary der(22)t(11;22) syndrome, and Supernumary derivative 22 chromosome syndrome. Review of these articles found no discussion of lipodermoids. To confirm, the above query was further refined by the addition of lipodermoid, dermoid, or ocular. Only 1 article remained, which, on review, did not identify a lipodermoid in Emanuel syndrome. References 1. Carter MT, St Pierre SA, Zackai EH, Emanuel BS, Boycott KM. Phenotypic delineation of Emanuel syndrome (supernumerary derivative 22 syndrome): Clinical features of 63 individuals. Am J Med Genet A 2009;149A:1712-21.
Journal of AAPOS
Glaser et al
213
2. Baum JL, Feingold M. Ocular aspects of Goldenhar’s syndrome. Am J Ophthalmol 1973;75:250-57. 3. Gorlin RJ, Jue KL, Jacobsen U, Goldschmidt E. Oculoauriculovertebral Dysplasia. J Pediatr 1963;63:991-9. 4. Stromland K, Miller M, Sjogreen L, et al. Oculo-auriculo-vertebral spectrum: Associated anomalies, functional deficits and possible developmental risk factors. Am J Med Genet A 2007;143A:1317-25. 5. Cohen MS, Samango-Sprouse CA, Stern HJ, et al. Neurodevelopmental profile of infants and toddlers with oculo-auriculo-vertebral spectrum and the correlation of prognosis with physical findings. Am J Med Genet 1995;60:535-40. 6. Kurahashi H, Inagaki H, Ohye T, et al. The constitutional t(11;22): Implications for a novel mechanism responsible for gross chromosomal rearrangements. Clin Genet 2010;78:299-309. 7. Zackai EH, Emanuel BS. Site-specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction. Am J Med Genet 1980;7:507-21. 8. Cho K, Lee M, Gu D, et al. Kazrin, and its binding partners ARVCFand delta-catenin, are required for Xenopus laevis craniofacial development. Dev Dyn 2011;240:2601-12. 9. Tsau C, Ito M, Gromova A, Hoffman MP, Meech R, Makarenkova HP. Barx2 and Fgf10 regulate ocular glands branching morphogenesis by controlling extracellular matrix remodeling. Development 2011;138:3307-17. 10. Kojima T, Sone M, Michiue T, Saigo K. Mechanism of induction of Bar-like eye malformation by transient overexpression of Bar homeobox genes in Drosophila melanogaster. Genetica 1993;88:85-91. 11. Martinelli S, De Luca A, Stellacci E, et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome–like phenotype. Am J Hum Genet 2010;87:250-57. 12. Crespi J, Buil JA, Bassaganyas F, et al. A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen. Am J Ophthalmol 2008; 146:323-8.