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Encephalocraniocutaneous lipomatosis: a neurocutaneous syndrome
Encephalocraniocutaneous Lipomatosis: A Neurocutaneous Syndrome Kim E. Brown, MD,a,b Scott M. Goldstein, MD,b Raymond S. Douglas, MD, PhD,b,c and James A. Katowitz, MDb The neurocutaneous pattern syndromes are a group of disorders characterized by congenital abnormalities involving both the skin and the nervous system for which no identifiable cause has been isolated.1 Ophthalmologic manifestations of these syndromes are common. These rare syndromes often have overlapping ophthalmic and systemic findings. Examples include encephalocraniocutaneous lipomatosis (ECCL), oculocerebrocutaneous syndrome (OCC), and linear nevus sebaceous syndrome (LNS). Clarifying the diagnostic criteria for these syndromes is a worthy goal because it will help elucidate the phenotypic spectrum of these poorly understood diseases as well as possibly facilitate genetic counseling.1 In this short report, a case of ECCL is used to illustrate the clinical manifestations of neurocutaneous syndromes. (J AAPOS 2003;7:148-149) CASE REPORT A 4.5-month-old girl presented in March 1996 for evaluation of limbal dermoids. She was the full-term product of a pregnancy complicated by nuchal cord and cesarean section. External examination showed a large lipomatous plaque on the frontotemporal scalp with overlying alopecia (Figure 1A). There were also multiple nodular lesions of the right eyelid tracking up into the brow area. The right eyelid was ptotic with decreased levator function and lagophthalmos. Bilateral corneoscleral dermoids were present; the right was larger than the left (Figure 1B). Cycloplegic refraction disclosed 8 diopters (D) of astigmatism in the right eye and 4 D in the left. Fundoscopic examination was normal bilaterally. Neuroimaging studies showed significant dysplasia of the right cerebral hemisphere and the scalp lipoma. Areas of cerebral atrophy and polymicrogyri—as well as dilatation of the right lateral ventricle, including a midline shift to the left—were noted on magnetic resonance imaging. An arachnoid cyst and cerebral calcifications were identified on computed axial tomography. Neurologically, she had global developmental delay, a seizure disorder, and mental retardation. Since birth she had undergone a variety of surgical procedures, including ventricular shunt placement, right ptosis repair,
From the Department of Ophthalmology, University of Illinois-Chicago,a Chicago, IL, USA; and the Department of Ophthalmology,b Children’s Hospital of Philadelphia and Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA; and the Department of Ophthalmology,c Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA Submitted December 17, 2002. Revisions accepted December 27, 2002. Reprint requests: Scott M. Goldstein, MD, Scheie Eye Institute, 51 N 39th Street, Philadelphia, PA 19104. J AAPOS 2003;7:148-149. Copyright © 2003 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2003/$35.00 ⫹ 0 doi:10.1016/S1091-8531(03)00012-0
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and reduction of the corneoscleral dermoids bilaterally. At age 5 months, her vision is 20/60 OD and 20/40 OS. She still has marked astigmatism, which is greater in the right eye than the left. The reconstructed eyelid has remained in good position.
DISCUSSION There are two groups of neurocutaneous syndromes. The phakomatoses are a group of disorders with multiple discrete lesions affecting at least two organ systems in which the genetic etiology is well established. This group includes neurofibromatosis and tuberous sclerosis. The other neurocutaneous pattern syndromes have a collection of neurological and cutaneous as well as ophthalmologic manifestations but no known etiology, such as the case of ECCL. Haberland and Perou2 first described ECCL in 1970. The most common skin manifestations are cutaneous and subcutaneous lipomas, angiofibromas, and connective tissue nevi. The majority of these lesions occur unilaterally in the scalp, brow, and periocular area.2 The lipomas are associated with overlying alopecia. A common ophthalmic finding is the epibulbar dermoid.3 These may result in amblyopia caused by induced astigmatism, corneal opacity, or both. Eyelid coloboma,2 optic nerve pallor, and severe myopia have also been reported.3 Frequently identified neurological abnormalities in ECCL include unilateral cerebral atrophy, dilated ventricles, cerebral calcifications, polymicrogyria, and arachnoid cysts.4 Lipomas involving the brain or spinal cord are also typical.3 Most patients also have mental retardation, seizures, and behavioral problems.5 It is believed that ECCL results from a disruption in neuroectoderm formation.6 It has also been hypothesized that ECCL results from an autosomal gene mosaicism.7 Journal of AAPOS
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FIG 1. A, Large lipomatous lesion with overlying alopecia on the right frontotemporal scalp. B, Epibulbar dermoid on the lateral limbal border. Connective tissue hamartomas and lipomatous lesions on the right eyebrow and upper eyelid are also shown.
Many syndromes fit into the diagnostic category of neurocutaneous pattern syndrome. The neurocutaneous syndromes often share overlapping features, which makes the diagnosis difficult. For illustrative purposes, three representative disorders are discussed: ECCL, OCC, and LNS. These three neurocutaneous syndromes are characterized by epibulbar choristomas, eyelid coloboma, mental retardation, and seizure disorders. Unilateral scalp lipomas with overlying alopecia are seen primarily in ECCL. LNS presents a similar-appearing hairless yellow plaque on the scalp resulting from atrophic epithelium, decreased abnormal dermal appendages, and sebaceous gland hyperplasia.8 Each of these disorders has subtle but unique features that facilitate diagnosis. ECCL presents with both ipsilateral subcutaneous extracranial lipomas as well as lipomas involving the central nervous system. Furthermore, ECCL patients tend to have connective tissue nevi and cerebral calcifications as part of the neurocutaneous manifestations. OCC patients may have microphthalmia or anophthalmia, orbital cysts, hypoplasia/aplasia of the corpus callosum, and rib defects. These patients also have focal dermal hypoplasia and “punched-out” skin defects in contrast to the nevi seen in cases of ECCL and LNS. Linear nevus sebaceous syndrome patients have ocular motility disturbances, visceral anomalies, and midline and unilateral facial sebaceous nevi that coalesce into a linear pattern.9 Also, LNS patients tend to have cerebral dysplasia compared with the cerebral atrophy with adjacent dilated ventricles seen in cases of ECCL or OCC. The combination of systemic features and ophthalmologic findings in these patients may help to more clearly differentiate these rare conditions. The prognosis of these
patients is limited by the neurological deficits and the potential for amblyopia secondary to the ocular processes. Ultimately, these various syndromes with similar phenotypic features will possibly be found to have differing genetic etiologies or a similar disruption in embryogenesis. This will not change the natural history immediately, but molecular or gene therapy may one day prevent the recurrence of these neurocutaneous syndromes. References 1. Shprintzen RJ. Genetics, syndromes and communication disorders. San Diego: Singular Publishing, 1997. p. 316. 2. Nowaczyk MJM, Mernagh JR, Bourgeois JM, Thompson PJ, Jurriaans E. Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis. Am J Med Genet 2000;91:261-6. 3. Kodsi SR, Bloom KE, Egbert JE, Holland EJ, Cameron JD. Ocular and systemic manifestations of encephalocraniocutaneous lipomatosis. Am J Ophthalmol 1994;118:77-82. 4. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. 3rd ed. Oxford monographs on medical genetics. New York: Oxford University Press, 1990. 5. Parazzini C, Triulzi F, Russo G, Mastrangelo M, Scotti G. Encephalocraniocutaneous lipomatosis: Complete neuroradiologic evaluation and follow-up of two cases. Am J Neuroradiol 1999;20:173-6. 6. Hennekam RCM. Scalp lipomas and cerebral malformations: Overlap between encephalocutanous lipomatosis and oculocerebrocutaneous syndrome. Clin Dysmorphol 1994;3:87-9. 7. Hamm H. Cutaneous mosaicism of lethal mutations. Am J Med Genet 1999;85:342-5. 8. Wilkes SR, Campbell RJ, Waller RR. Ocular malformation in association with ipsilateral facial nevus of Jadassohn. Am J Ophthalmol 1981;92:344-52. 9. Prayson RA, Kotagal P, Wyllie E, Bingaman W. Linear epidermal nevus and nevus sebaceous syndromes. Arch Pathol Lab Med 1999; 123:301-5.
From the Department of Ophthalmology, University of Illinois-Chicago,a Chicago, IL, USA; and the Department of Ophthalmology,b Children’s Hospital of Philadelphia and Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA; and the Department of Ophthalmology,c Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA Submitted December 17, 2002. Revisions accepted December 27, 2002. Reprint requests: Scott M. Goldstein, MD, Scheie Eye Institute, 51 N 39th Street, Philadelphia, PA 19104. J AAPOS 2003;7:148-149. Copyright © 2003 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2003/$35.00 ⫹ 0 doi:10.1016/S1091-8531(03)00012-0
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and reduction of the corneoscleral dermoids bilaterally. At age 5 months, her vision is 20/60 OD and 20/40 OS. She still has marked astigmatism, which is greater in the right eye than the left. The reconstructed eyelid has remained in good position.
DISCUSSION There are two groups of neurocutaneous syndromes. The phakomatoses are a group of disorders with multiple discrete lesions affecting at least two organ systems in which the genetic etiology is well established. This group includes neurofibromatosis and tuberous sclerosis. The other neurocutaneous pattern syndromes have a collection of neurological and cutaneous as well as ophthalmologic manifestations but no known etiology, such as the case of ECCL. Haberland and Perou2 first described ECCL in 1970. The most common skin manifestations are cutaneous and subcutaneous lipomas, angiofibromas, and connective tissue nevi. The majority of these lesions occur unilaterally in the scalp, brow, and periocular area.2 The lipomas are associated with overlying alopecia. A common ophthalmic finding is the epibulbar dermoid.3 These may result in amblyopia caused by induced astigmatism, corneal opacity, or both. Eyelid coloboma,2 optic nerve pallor, and severe myopia have also been reported.3 Frequently identified neurological abnormalities in ECCL include unilateral cerebral atrophy, dilated ventricles, cerebral calcifications, polymicrogyria, and arachnoid cysts.4 Lipomas involving the brain or spinal cord are also typical.3 Most patients also have mental retardation, seizures, and behavioral problems.5 It is believed that ECCL results from a disruption in neuroectoderm formation.6 It has also been hypothesized that ECCL results from an autosomal gene mosaicism.7 Journal of AAPOS
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FIG 1. A, Large lipomatous lesion with overlying alopecia on the right frontotemporal scalp. B, Epibulbar dermoid on the lateral limbal border. Connective tissue hamartomas and lipomatous lesions on the right eyebrow and upper eyelid are also shown.
Many syndromes fit into the diagnostic category of neurocutaneous pattern syndrome. The neurocutaneous syndromes often share overlapping features, which makes the diagnosis difficult. For illustrative purposes, three representative disorders are discussed: ECCL, OCC, and LNS. These three neurocutaneous syndromes are characterized by epibulbar choristomas, eyelid coloboma, mental retardation, and seizure disorders. Unilateral scalp lipomas with overlying alopecia are seen primarily in ECCL. LNS presents a similar-appearing hairless yellow plaque on the scalp resulting from atrophic epithelium, decreased abnormal dermal appendages, and sebaceous gland hyperplasia.8 Each of these disorders has subtle but unique features that facilitate diagnosis. ECCL presents with both ipsilateral subcutaneous extracranial lipomas as well as lipomas involving the central nervous system. Furthermore, ECCL patients tend to have connective tissue nevi and cerebral calcifications as part of the neurocutaneous manifestations. OCC patients may have microphthalmia or anophthalmia, orbital cysts, hypoplasia/aplasia of the corpus callosum, and rib defects. These patients also have focal dermal hypoplasia and “punched-out” skin defects in contrast to the nevi seen in cases of ECCL and LNS. Linear nevus sebaceous syndrome patients have ocular motility disturbances, visceral anomalies, and midline and unilateral facial sebaceous nevi that coalesce into a linear pattern.9 Also, LNS patients tend to have cerebral dysplasia compared with the cerebral atrophy with adjacent dilated ventricles seen in cases of ECCL or OCC. The combination of systemic features and ophthalmologic findings in these patients may help to more clearly differentiate these rare conditions. The prognosis of these
patients is limited by the neurological deficits and the potential for amblyopia secondary to the ocular processes. Ultimately, these various syndromes with similar phenotypic features will possibly be found to have differing genetic etiologies or a similar disruption in embryogenesis. This will not change the natural history immediately, but molecular or gene therapy may one day prevent the recurrence of these neurocutaneous syndromes. References 1. Shprintzen RJ. Genetics, syndromes and communication disorders. San Diego: Singular Publishing, 1997. p. 316. 2. Nowaczyk MJM, Mernagh JR, Bourgeois JM, Thompson PJ, Jurriaans E. Antenatal and postnatal findings in encephalocraniocutaneous lipomatosis. Am J Med Genet 2000;91:261-6. 3. Kodsi SR, Bloom KE, Egbert JE, Holland EJ, Cameron JD. Ocular and systemic manifestations of encephalocraniocutaneous lipomatosis. Am J Ophthalmol 1994;118:77-82. 4. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head and neck. 3rd ed. Oxford monographs on medical genetics. New York: Oxford University Press, 1990. 5. Parazzini C, Triulzi F, Russo G, Mastrangelo M, Scotti G. Encephalocraniocutaneous lipomatosis: Complete neuroradiologic evaluation and follow-up of two cases. Am J Neuroradiol 1999;20:173-6. 6. Hennekam RCM. Scalp lipomas and cerebral malformations: Overlap between encephalocutanous lipomatosis and oculocerebrocutaneous syndrome. Clin Dysmorphol 1994;3:87-9. 7. Hamm H. Cutaneous mosaicism of lethal mutations. Am J Med Genet 1999;85:342-5. 8. Wilkes SR, Campbell RJ, Waller RR. Ocular malformation in association with ipsilateral facial nevus of Jadassohn. Am J Ophthalmol 1981;92:344-52. 9. Prayson RA, Kotagal P, Wyllie E, Bingaman W. Linear epidermal nevus and nevus sebaceous syndromes. Arch Pathol Lab Med 1999; 123:301-5.