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Bilateral orbito-palpebral cysts in a case of cryptophthalmos associated with Fraser syndrome
Bilateral orbito-palpebral cysts in a case of cryptophthalmos associated with Fraser syndrome Mehmet C. Mocan, MD,a Burce Ozgen, MD,b and Murat Irkec, MDa
A 15-month-old girl was referred for evaluation of congenital absence of both eyelids. Clinical evaluation revealed bilateral total cryptophthalmos and enlarged globes in addition to genitourinary anomalies, umbilical hernia, renal agenesis, and facial anomalies. The clinical findings were consistent with Fraser syndrome. Magnetic resonance imaging of the orbits revealed dysplastic globes that were characterized by cystic expansions that extended laterally anterior to the lateral orbital rim. Bilateral orbito-palpebral cysts that communicate with a dysplastic globe and extend beyond the orbital cavity may be a rare presenting feature of Fraser syndrome.
C
ryptophthalmos refers to the congenital absence of eyelids and is a cardinal component of Fraser syndrome (OMIM#219000), a rare autosomal-recessive disorder characterized by genitourinary anomalies, syndactyly, and a family history of consanguinity in association with various craniofacial, gastrointestinal, and musculoskeletal abnormalities.1,2 In addition to cryptophthalmos, eyelid coloboma, microphthalmos, absence of eyelashes/ eyebrows, and anterior segment anomalies are common ocular findings in Fraser syndrome.2 We report a case with Fraser syndrome presenting with cryptophthalmos and bilateral orbitopalpebral cysts, which communicated with the globes and extended laterally along the lateral orbital rim.
Case Report A fifteen-month-old girl was referred for evaluation of absence of both eyelids noticed at birth. Her past medical history was unremarkable. She was the first child of unrelated parents. Upon examination, the patient reacted to very bright light and intermittently rubbed her globes with her hands, recapitulating the oculodigital sign. Bilateral total cryptophthalmos and a palpable mass protruding from the orbit and extending laterally along the lateral orbital rim were detected (Figure 1). Orbital ultrasonography of both orbits revealed cysts posterior to the skin covering the orbits. In the systemic evaluation of the
Author affiliations: aDepartment of Ophthalmology and bDepartment of Radiology, Hacettepe University School of Medicine, Ankara, Turkey The authors have no proprietary interest in any of the materials used in this study. Submitted June 20, 2007. Revision accepted August 23, 2007. Published online December 14, 2007. ¨ niversitesi, Göz Hastalıkları Reprint requests: Murat Irkec, MD, Hacettepe U Anabilim Dalı, Sıhhiye, 06100, Ankara, Turkey (email: [email protected]). J AAPOS 2008;12:210-211. Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2007.09.009
210
FIG 1. Bilateral cryptophthalmos and orbito-palpebral cysts extending on to the lateral orbital rims.
patient, significant clinical findings that supported the diagnosis of Fraser syndrome were the presence of ambiguous genitalia, vaginal atresia, displaced anus, umbilical hernia, low-set ears, a broad nasal bridge, the absence of eyebrows, and a broad forehead. Syndactyly of hands or feet and skeletal defects were not present. Abdominal ultrasonography revealed unilateral renal agenesis. Magnetic resonance imaging (MRI) of the orbits revealed dysplastic globes that were characterized by cystic expansions, which extended laterally anterior to the lateral orbital rim (Figure 2). The cystic expansions communicated with the dysplastic globes on both sides. The anterior segment structures were indiscernible; however, the optic nerve, posterior segment structures, and extraocular muscles were found to be present and unaffected. A cranial MRI of the patient was unremarkable for her age group. Genetic testing was not performed on the patient.
Discussion Fraser syndrome is caused by genetic mutations of the FRAS1 gene (4q21) or the FREM2 gene (13q13.3) that code for an extracellular matrix protein, the mutation of which leads to subepidermal blisters.3,4 Animal experiments suggest that the mutation is believed to result in loss of epidermal adhesion and defective interactions between the epidermal and the mesenchymal tissues.4 Cryptophthalmos develops secondary to a defect in the formation of eyelid folds at the fourth week of intrauterine life.5 Although a variety of ocular and periocular abnormalities have been reported in association with Fraser syndrome,2 congenital orbitopalpebral cysts have been rarely observed; only 3 previous reports have been published in English literature.5-7 Amrith et al5 described a patient with
Journal of AAPOS
Volume 12 Number 2 / April 2008
FIG 2. Axial fat suppressed T2-weighted MRI of the orbits demonstrate the dysplastic-cystic appearance of both globes (arrows) the dysplasia being more prominent on the patient’s left side. Optic nerves appear to be bilaterally present (double arrows).
a unilateral orbitopalpebral cyst that communicated with the abortive globe. The removal and histopathological examination of that globe revealed an anteriorly located cyst, the wall of which was lined by a single layer of epithelium and a relatively well-developed posterior segment with a normal-appearing optic nerve. On the basis of these findings, Amrith et al5 hypothesized that orbitopalpebral cysts represented a surface ectodermal anomaly rather than the failure of normal invagination of the primary optic cup, which results in an anomaly referred to as the congenital cystic eye.8 Failure of invagination leads to the formation of a cystic globe lined instead by neuroglial and retinal elements.5,8 Butler et al6 reported the findings of a three-year-old boy with unilateral orbital cyst associated with anophthalmia in a case of bilateral cryptophthalmos together with congenital nose and ear anomalies but without syndactyly and renal anomalies. The report by Ehlers7 described a case of bilateral orbito-palpebral cysts in conjunction with total cryptophthalmos. Our report is the fourth to describe
Journal of AAPOS
Mocan et al
211
the presence of orbital cysts in the setting of Fraser syndrome and the second to feature the bilateral nature of the cysts. Removal of the orbitopalpebral cyst in a case with cryptophthalmos has been previously described.5 Although a preliminary surgical plan to selectively aspirate the cystic structures located along the lateral orbital rim was initially considered to improve cosmesis in the present case, the communicating nature of the cysts with the dysplastic globe and the presence of light perception precluded this approach. Light perception is important for the maintenance of circadian rhythm and is better preserved whenever possible.9 Although favorable surgical outcomes have been reported with incomplete cryptophthalmos,10 eyelid construction in the setting of total cryptophthalmos is generally associated with a poor outcome because of the absence of all layers of the eyelid. The findings of our case affirm that orbito-palpebral cysts that originate from the dysplastic globe may present as a rare ocular finding in Fraser syndrome. The communicating nature of the cysts with a globe that can be minimally functional warrants careful clinical and radiological evaluation before surgical removal. References 1. Fraser GR. Our genetical “load”: A review of some aspects of genetical variation. Ann Hum Genet 1962;25:387-415. 2. Slavotinek AM, Tifft CJ. Fraser syndrome and cryptophthalmos: Review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 2002;39:623-33. 3. Vrontou S, Petrou P, Meyer BI, Galanopoulos VK, Imai K, Yanagi M, et al. Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nat Genet 2003;34:209-14. 4. Smyth I, Scambler P. The genetics of Fraser syndrome and the blebs mouse mutants. Hum Mol Genet 2005;14:R269-74. 5. Amrith S, Lee Y, Lee J, Liew G, Leo S, Khoo B. Congenital orbito-palpebral cyst in a case of Fraser syndrome. Orbit 2003;22: 279-83. 6. Butler MG, Eisen JD, Henry J. Cryptophthalmos with an orbital cyst and profound mental and motor retardation. J Pediatr Ophthalmol Strabismus 1978;15:233-5. 7. Ehlers N. Cryptophthalmos with orbito-palpebral cyst and microphthalmos (report of a bilateral case). Acta Ophthalmol (Copenh) 1966;44:84-94. 8. Guthoff R, Klein R, Lieb WE. Congenital cystic eye. Graefes Arch Clin Exp Ophthalmol 2004;242:268-71. 9. Zisapel N. Circadian rhythm sleep disorders: Pathophysiology and potential approaches to management. CNS Drugs 2001;15:311-28. 10. Bergwerk K, Schorr N, Rabinowitz YS. Visual function in an 11 year old with Fraser cryptophthalmos syndrome. Am J Ophthalmol 2004; 137:591-3.
A 15-month-old girl was referred for evaluation of congenital absence of both eyelids. Clinical evaluation revealed bilateral total cryptophthalmos and enlarged globes in addition to genitourinary anomalies, umbilical hernia, renal agenesis, and facial anomalies. The clinical findings were consistent with Fraser syndrome. Magnetic resonance imaging of the orbits revealed dysplastic globes that were characterized by cystic expansions that extended laterally anterior to the lateral orbital rim. Bilateral orbito-palpebral cysts that communicate with a dysplastic globe and extend beyond the orbital cavity may be a rare presenting feature of Fraser syndrome.
C
ryptophthalmos refers to the congenital absence of eyelids and is a cardinal component of Fraser syndrome (OMIM#219000), a rare autosomal-recessive disorder characterized by genitourinary anomalies, syndactyly, and a family history of consanguinity in association with various craniofacial, gastrointestinal, and musculoskeletal abnormalities.1,2 In addition to cryptophthalmos, eyelid coloboma, microphthalmos, absence of eyelashes/ eyebrows, and anterior segment anomalies are common ocular findings in Fraser syndrome.2 We report a case with Fraser syndrome presenting with cryptophthalmos and bilateral orbitopalpebral cysts, which communicated with the globes and extended laterally along the lateral orbital rim.
Case Report A fifteen-month-old girl was referred for evaluation of absence of both eyelids noticed at birth. Her past medical history was unremarkable. She was the first child of unrelated parents. Upon examination, the patient reacted to very bright light and intermittently rubbed her globes with her hands, recapitulating the oculodigital sign. Bilateral total cryptophthalmos and a palpable mass protruding from the orbit and extending laterally along the lateral orbital rim were detected (Figure 1). Orbital ultrasonography of both orbits revealed cysts posterior to the skin covering the orbits. In the systemic evaluation of the
Author affiliations: aDepartment of Ophthalmology and bDepartment of Radiology, Hacettepe University School of Medicine, Ankara, Turkey The authors have no proprietary interest in any of the materials used in this study. Submitted June 20, 2007. Revision accepted August 23, 2007. Published online December 14, 2007. ¨ niversitesi, Göz Hastalıkları Reprint requests: Murat Irkec, MD, Hacettepe U Anabilim Dalı, Sıhhiye, 06100, Ankara, Turkey (email: [email protected]). J AAPOS 2008;12:210-211. Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2007.09.009
210
FIG 1. Bilateral cryptophthalmos and orbito-palpebral cysts extending on to the lateral orbital rims.
patient, significant clinical findings that supported the diagnosis of Fraser syndrome were the presence of ambiguous genitalia, vaginal atresia, displaced anus, umbilical hernia, low-set ears, a broad nasal bridge, the absence of eyebrows, and a broad forehead. Syndactyly of hands or feet and skeletal defects were not present. Abdominal ultrasonography revealed unilateral renal agenesis. Magnetic resonance imaging (MRI) of the orbits revealed dysplastic globes that were characterized by cystic expansions, which extended laterally anterior to the lateral orbital rim (Figure 2). The cystic expansions communicated with the dysplastic globes on both sides. The anterior segment structures were indiscernible; however, the optic nerve, posterior segment structures, and extraocular muscles were found to be present and unaffected. A cranial MRI of the patient was unremarkable for her age group. Genetic testing was not performed on the patient.
Discussion Fraser syndrome is caused by genetic mutations of the FRAS1 gene (4q21) or the FREM2 gene (13q13.3) that code for an extracellular matrix protein, the mutation of which leads to subepidermal blisters.3,4 Animal experiments suggest that the mutation is believed to result in loss of epidermal adhesion and defective interactions between the epidermal and the mesenchymal tissues.4 Cryptophthalmos develops secondary to a defect in the formation of eyelid folds at the fourth week of intrauterine life.5 Although a variety of ocular and periocular abnormalities have been reported in association with Fraser syndrome,2 congenital orbitopalpebral cysts have been rarely observed; only 3 previous reports have been published in English literature.5-7 Amrith et al5 described a patient with
Journal of AAPOS
Volume 12 Number 2 / April 2008
FIG 2. Axial fat suppressed T2-weighted MRI of the orbits demonstrate the dysplastic-cystic appearance of both globes (arrows) the dysplasia being more prominent on the patient’s left side. Optic nerves appear to be bilaterally present (double arrows).
a unilateral orbitopalpebral cyst that communicated with the abortive globe. The removal and histopathological examination of that globe revealed an anteriorly located cyst, the wall of which was lined by a single layer of epithelium and a relatively well-developed posterior segment with a normal-appearing optic nerve. On the basis of these findings, Amrith et al5 hypothesized that orbitopalpebral cysts represented a surface ectodermal anomaly rather than the failure of normal invagination of the primary optic cup, which results in an anomaly referred to as the congenital cystic eye.8 Failure of invagination leads to the formation of a cystic globe lined instead by neuroglial and retinal elements.5,8 Butler et al6 reported the findings of a three-year-old boy with unilateral orbital cyst associated with anophthalmia in a case of bilateral cryptophthalmos together with congenital nose and ear anomalies but without syndactyly and renal anomalies. The report by Ehlers7 described a case of bilateral orbito-palpebral cysts in conjunction with total cryptophthalmos. Our report is the fourth to describe
Journal of AAPOS
Mocan et al
211
the presence of orbital cysts in the setting of Fraser syndrome and the second to feature the bilateral nature of the cysts. Removal of the orbitopalpebral cyst in a case with cryptophthalmos has been previously described.5 Although a preliminary surgical plan to selectively aspirate the cystic structures located along the lateral orbital rim was initially considered to improve cosmesis in the present case, the communicating nature of the cysts with the dysplastic globe and the presence of light perception precluded this approach. Light perception is important for the maintenance of circadian rhythm and is better preserved whenever possible.9 Although favorable surgical outcomes have been reported with incomplete cryptophthalmos,10 eyelid construction in the setting of total cryptophthalmos is generally associated with a poor outcome because of the absence of all layers of the eyelid. The findings of our case affirm that orbito-palpebral cysts that originate from the dysplastic globe may present as a rare ocular finding in Fraser syndrome. The communicating nature of the cysts with a globe that can be minimally functional warrants careful clinical and radiological evaluation before surgical removal. References 1. Fraser GR. Our genetical “load”: A review of some aspects of genetical variation. Ann Hum Genet 1962;25:387-415. 2. Slavotinek AM, Tifft CJ. Fraser syndrome and cryptophthalmos: Review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J Med Genet 2002;39:623-33. 3. Vrontou S, Petrou P, Meyer BI, Galanopoulos VK, Imai K, Yanagi M, et al. Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nat Genet 2003;34:209-14. 4. Smyth I, Scambler P. The genetics of Fraser syndrome and the blebs mouse mutants. Hum Mol Genet 2005;14:R269-74. 5. Amrith S, Lee Y, Lee J, Liew G, Leo S, Khoo B. Congenital orbito-palpebral cyst in a case of Fraser syndrome. Orbit 2003;22: 279-83. 6. Butler MG, Eisen JD, Henry J. Cryptophthalmos with an orbital cyst and profound mental and motor retardation. J Pediatr Ophthalmol Strabismus 1978;15:233-5. 7. Ehlers N. Cryptophthalmos with orbito-palpebral cyst and microphthalmos (report of a bilateral case). Acta Ophthalmol (Copenh) 1966;44:84-94. 8. Guthoff R, Klein R, Lieb WE. Congenital cystic eye. Graefes Arch Clin Exp Ophthalmol 2004;242:268-71. 9. Zisapel N. Circadian rhythm sleep disorders: Pathophysiology and potential approaches to management. CNS Drugs 2001;15:311-28. 10. Bergwerk K, Schorr N, Rabinowitz YS. Visual function in an 11 year old with Fraser cryptophthalmos syndrome. Am J Ophthalmol 2004; 137:591-3.