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Sebaceous nevus syndrome: Report of two cases
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Sebaceous Nevus Syndrome: Report of Two Cases Eugenio V. Bonioli, MD*, Antonella Bertola, MD*, Antonio Di Stefano, MD*, and Carlo Bellini, MD, PhD* Sebaceous nevus (SN) syndrome is a neurocutaneous disorder characterized by a distinctive skin lesion in association with epilepsy and mental retardation. In one group of patients, brain lesions may be consequent to vascular abnormalities ("vascular variant"); another group of SN patients presents ipsilateral hemimegalencephaly, gyral anomalies, and facial hemihypertrophy ("neurologic variant" or "SN with hemimegalencephaly"). In the latter group, facial hemihypertrophy does not appear to be a constant feature and was not present in our 2 SN patients with hemimegalencephaly. Considering that about half of the SN patients with hemimegalencephaly described so far do not have facial asymmetry, we suggest the existence of a separate subgroup of SN patients with hemimegalencephaly and without facial hemihypertrophy. In these patients, the only clinical diagnostic clue is a nevus that is barely visible until puberty. © 1997 by Elsevier Science Inc. All rights reserved. Bonioli EV, Bertola A, Di Stefano A, Bellini C. S e b a c e o u s nevus syndrome: Report o f two cases. Pediatr Neurol 1997; 17:77-79.
Introduction E p i d e r m a l nevi (EN) arise f r o m the pluripotential germinal cells in the basal layer o f the e m b r y o n i c e p i d e r m i s and are c o n s i d e r e d a f a m i l y o f congenital h a m a r t o m a t o u s m a l f o r m a t i o n s , including different skin lesions, such as linear nevus sebaceous (of Jadassohn) [1], n e v u s verrucosus, ichthyosis hystrix, n e v u s unius lateralis, and localized
From the *Istituto di Clinica Pediatrica "G. Gaslini" and *Puericultura e Medicina Neonatale "L. Gaslini"; Universith di Genova; Genova, Italy.
© 1997 by Elsevier Science Inc. All rights reserved. PII S0887-8994(97)00008-8 ° 0887-8994/97/$17.00
acanthosis nigricans [2,3]. As m a n y as one third o f patients with E N m a y h a v e associated anomalies, m o s t often i n v o l v i n g brain and eyes, and the generic term E N s y n d r o m e has been used to e n c o m p a s s t h e m all. O w i n g to the h e t e r o g e n e i t y o f the skin lesions and o f the associated anomalies, the E N s y n d r o m e cannot be c o n s i d e r e d a single clinical entity, and m a n y distinct birth c[efects h a v e been l u m p e d together under this definition [4,5]. A m o n g these defects, m o s t investigators include the s y n d r o m e w h i c h Feuerstein and M i r e s [6] first described in 2 unrelated patients with linear nevus sebaceous o f the face, midline, associated with e p i l e p s y and mental retardation. This triad has been termed sebaceous nevus (SN) syndrome, or J a d a s s o h n s y n d r o m e , for the d e r m a t o l o g i s t w h o first described the cutaneous lesion in 1895. Similar cases have subsequently been described under various s y n o n y m s and, as a c o n s e q u e n c e o f the c o n f u s i n g n o s o g r a p h y and/or nomenclature, S N s y n d r o m e has two entries in the M c K u sick catalog (163200 and 165630) [7].
Case Reports Patient 1. A female was born at 36 weeks gestational age after a normal pregnancy and labor, weighing 2,750 g (under the 3rd percentile); Apgar scores were 8/9; there were no prenatal complications, and family history was negative (Fig 1). Twenty hours after birth, she developed recurrent, generalized seizures. She was referred to our clinic on day 50 of life. At the time of examination, her weight was 4,100 g (25th percentile), length was 53 cm (10th to 25th percentile), and occipitofrontal circumference was 38 cm (75th percentile). The anterior fontanelle was normally tense, spanning 2 × 2 cm; a small, sharply demarcated, yellow-orange elevated plaque was evident on the face between the right zygomatic region and the nose. Neurologic examination did not reveal asymmetry or focal signs. The patient was unable to follow the movement of objects, and there was no interaction with the mother. Fundus oculi was normal. No other pathologic data were obtained from clinical examination. The patient presented frequent, symmetrical generalized seizures, each lasting 15 to 20 minutes. EEG revealed virtually continuous seizure activity arising from the right hemisphere, characterized by frequent bursts of irregular paroxysmal activity and single spike and wave complexes. Electrocardiogram and ultrasound cardiac evaluation, karyotype (highresolution chromosome analysis), routine laboratory investigations of blood and urine, organic acids and amino acids, as well as ammonia, mucopolysaccharides, and oligosaccharides were normal. TORCH studies were also normal. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans (Fig 2) demonstrated enlargement of right cerebral hemisphere, peduncle, and thalamus. The right sylvian fissure was open due to underdevelopment of the opercula. In the affected hemisphere, pachygyria was evident, with relative paucity of the white matter as
Communications should be addressed to: Professor Bonioli; Istituto di Clinica Pediatrica "G. Gaslini"; Largo G. Gaslini, 5; 16147 Genova, Italy. Received October 16, 1996; accepted January 7. 1997.
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Figure 1. Patient 1. Sebaceous nevus is evideut between the zygomatic region and the nose.
Figure 2. Patient L MRI: T~ (TR = 600 ms; TE - 20 ms) coronal. Hemimegalencephaly. Enlargement of the right cerebral hemisphere with pachygyria and thickening of the affected cortex is evident. The right silvian fissure is open due to underdevelopment of the opercula.
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Figure 3. Patient 2. A close-up shows the linear sebaceous nevus extending from the median and paramedian frontal region toward the right. compared with gray (reverse myelin pattern) but without heterotopia. Results of CT and MRI scans of the left hemisphere were within normal range. Treatment with a combination of phenobarbital (PB) and valproate (VPA) provided good seizure control for about 1 year. The patient now experiences frequent (daily) seizures and is severely mentally retarded. Patient 2. A female whose parents are healthy and nonconsanguineous was delivered by cesarean section after a normal term pregnancy. Her birth weight was 3,780 g, and her length was 51 cm; her occipitofrontal circumference was 38 cm (more than 95th percentile), (Fig 3). Neonatal hypoxia was evident, and resuscitation was successfully perfornled (Apgar scores were 1/9). Immediately after birth, she presented generalized seizures. The patient has never been seizure-free notwithstanding therapy with various antiepileptic drugs (PB and VPA). On day 23 of life, the patient was referred to our clinic. Her weight and height were at 90th percentile, and head circumference was 41 cm (more than 95th percentile). The forehead was prominent and the anterior fontanelle was 4.5 × 5 cm. A 0.5 × 0.5-cm "caf~-au-lait" spot was localized on the right knee, and a 3 × l-cm hemangioma planum was evident on the left thigh. A sharply demarcated and slightly elevated yellow-brown lesion, extending from the median and paramedian frontal region toward the right was present (linear sebaceous nevus of Jadassohn). Neurologic examination revealed no focal signs or asymmetry; muscle tone and power were normal. Neither nystagmus nor clonus was evident. The patient was unable to fixate on objects visually or to follow the movement of these objects. Severe mental retardation was evident. Fundus examination and visual evoked potentials were normal. Results of EKG and ultrasound cardiac evaluation, karyotype (high-resolution chromosome analysis), and routine laboratory investigations in blood and urine, organic acids and amino acids, as well as ammonia, mucopolysaccharides, and oligosaccharides were normal. TORCH studies were normal.
Figure 4. Patient 2. MRI: T 1 (TR = 600 ms; TE = 20 ms) coronal. Hemimegalencephaly associated with lateral ventricle enlargement. Pachygyric cortex and cortical thickening are evident on the affected side. The lateral ventricle is enlarged in proportion to the enlargement (~[ the qffected hernisphere.
She experienced several clusters of mixed infantile spasms daily. Treatment with valproic acid (VPA), diazepam, and vigabatrin led to partial control of the spasm frequency. An EEG at 1 month of age showed generalized, irregular, very high-voltage bursts associated with slow waves, sharp waves, and multifocal spikes arising from the left side. Burst suppression, diffusely slow background activity, and marked attenuation of activity were evident on EEG recorded during sleep. MR1 demonstrated enlargement of the left hemisphere with medioposterior dilatation of the left lateral ventricle without signs relating to intracranial hypertension /Fig 4).
Discussion
SN syndrome is appropriately classified as a neurocutaneous syndrome. The condition is sporadic and is considered the result of a lethal mutation that survives by mosaicism. Cells carrying the mutation have been suggested to be capable of surviving only in close proximity to normal cells [8]. All elements of the skin are represented in SN, although histologically it is characterized by an abundance of sebaceous glands [5]. The clinical appearance reflects not only the variable histologic pattern, but also hormonal and environmental influences [8], which explains why an SN may remain unrecognized early in infancy, when it ap-
pears as a slightly raised linear plaque, skin-colored and velvety. The lesion becomes more evident as the child grows older, usually during adolescence [5]. Because SN is considered a premalignant lesion, either long-term monitoring or radical excision before puberty is warranted. Pathologic and/or radiologic examination of the brain of some SN patients demonstrates infarcts, atrophy, porencephaly, and calcifications. These anomalies are considered acquired brain lesions, a consequence of vascular abnormalities (ischemia or hemorrhage due to blood vessel dysplasia), with secondary brain involvement. Such patients have been classified as having a "vascular" variant of SN syndrome [4,9]. In another group of SN patients, a definite "neurologic variant" (also termed SN with hemimegalencephaly) has been described as consisting of ipsilateral hemimegalencephaly, gyral anomalies, and facial hemihypertrophy [4,8]. Actually, facial hemihypertrophy does not appear to be a constant feature in this group of patients. Our 2 patients and almost half of the SN patients with hemimegalencephaly described in the literature have no facial asymmetry (bibliography available on request). We therefore hypothesize the existence of a separate subgroup of patients affected by SN syndrome with hemimegalencephaly but without facial hemihypertrophy, in whom the only diagnostic clue is a nevus that is barely visible until puberty. Early diagnosis of SN syndrome in this subgroup must be based on accurate clinical examination to detect the typical skin lesions.
References
[1] Jadassohn J. Bemerkungen zur Histologie der systematisierten Naevi und tiber "Talgdrtisen-Naevi". Arch Dermatol Syph 1895;33:355408. [2] Rogers M, McCrossing 1, Commens C. Epidermal nevi and the epidermal nevus syndrome. A review of 131 cases. J Am Acad Dermatol 1989;20:476-88. [3] Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol 1968;97:273-85. [4] Pavone L, Curatolo P, Rizzo R, et al. Epidermal nevus syndrome: A neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991 ;41:266-71. [5] Happle R. How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol 1991;25:550-6. [6] Fenerstein RC, Mims LC. Linear nevus sebaceous with convulsion and mental retardation. Am J Dis Child 1962;104:675-9. [7] McKusick VA. Mendelian inheritance in man. Catalogs of human genes and genetic disorders, l lth ed. Baltimore: The Johns Hopkins University Press, 1994. [8] Dodge NN, Dobyns WB. Agenesis of the corpus callosum and Dandy-Walker malformation associated with hemimegalencephaly in the sebaceous nevus syndrome. Am J Med Genet 1995;56:147-50. [9] Dobyns WB, Garg BP. Vascular abnormalities in epidermal nevus syndrome. Neurology 1991 ;41:276-8.
Bonioli et al: Sebaceous Nevus Syndrome
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Sebaceous Nevus Syndrome: Report of Two Cases Eugenio V. Bonioli, MD*, Antonella Bertola, MD*, Antonio Di Stefano, MD*, and Carlo Bellini, MD, PhD* Sebaceous nevus (SN) syndrome is a neurocutaneous disorder characterized by a distinctive skin lesion in association with epilepsy and mental retardation. In one group of patients, brain lesions may be consequent to vascular abnormalities ("vascular variant"); another group of SN patients presents ipsilateral hemimegalencephaly, gyral anomalies, and facial hemihypertrophy ("neurologic variant" or "SN with hemimegalencephaly"). In the latter group, facial hemihypertrophy does not appear to be a constant feature and was not present in our 2 SN patients with hemimegalencephaly. Considering that about half of the SN patients with hemimegalencephaly described so far do not have facial asymmetry, we suggest the existence of a separate subgroup of SN patients with hemimegalencephaly and without facial hemihypertrophy. In these patients, the only clinical diagnostic clue is a nevus that is barely visible until puberty. © 1997 by Elsevier Science Inc. All rights reserved. Bonioli EV, Bertola A, Di Stefano A, Bellini C. S e b a c e o u s nevus syndrome: Report o f two cases. Pediatr Neurol 1997; 17:77-79.
Introduction E p i d e r m a l nevi (EN) arise f r o m the pluripotential germinal cells in the basal layer o f the e m b r y o n i c e p i d e r m i s and are c o n s i d e r e d a f a m i l y o f congenital h a m a r t o m a t o u s m a l f o r m a t i o n s , including different skin lesions, such as linear nevus sebaceous (of Jadassohn) [1], n e v u s verrucosus, ichthyosis hystrix, n e v u s unius lateralis, and localized
From the *Istituto di Clinica Pediatrica "G. Gaslini" and *Puericultura e Medicina Neonatale "L. Gaslini"; Universith di Genova; Genova, Italy.
© 1997 by Elsevier Science Inc. All rights reserved. PII S0887-8994(97)00008-8 ° 0887-8994/97/$17.00
acanthosis nigricans [2,3]. As m a n y as one third o f patients with E N m a y h a v e associated anomalies, m o s t often i n v o l v i n g brain and eyes, and the generic term E N s y n d r o m e has been used to e n c o m p a s s t h e m all. O w i n g to the h e t e r o g e n e i t y o f the skin lesions and o f the associated anomalies, the E N s y n d r o m e cannot be c o n s i d e r e d a single clinical entity, and m a n y distinct birth c[efects h a v e been l u m p e d together under this definition [4,5]. A m o n g these defects, m o s t investigators include the s y n d r o m e w h i c h Feuerstein and M i r e s [6] first described in 2 unrelated patients with linear nevus sebaceous o f the face, midline, associated with e p i l e p s y and mental retardation. This triad has been termed sebaceous nevus (SN) syndrome, or J a d a s s o h n s y n d r o m e , for the d e r m a t o l o g i s t w h o first described the cutaneous lesion in 1895. Similar cases have subsequently been described under various s y n o n y m s and, as a c o n s e q u e n c e o f the c o n f u s i n g n o s o g r a p h y and/or nomenclature, S N s y n d r o m e has two entries in the M c K u sick catalog (163200 and 165630) [7].
Case Reports Patient 1. A female was born at 36 weeks gestational age after a normal pregnancy and labor, weighing 2,750 g (under the 3rd percentile); Apgar scores were 8/9; there were no prenatal complications, and family history was negative (Fig 1). Twenty hours after birth, she developed recurrent, generalized seizures. She was referred to our clinic on day 50 of life. At the time of examination, her weight was 4,100 g (25th percentile), length was 53 cm (10th to 25th percentile), and occipitofrontal circumference was 38 cm (75th percentile). The anterior fontanelle was normally tense, spanning 2 × 2 cm; a small, sharply demarcated, yellow-orange elevated plaque was evident on the face between the right zygomatic region and the nose. Neurologic examination did not reveal asymmetry or focal signs. The patient was unable to follow the movement of objects, and there was no interaction with the mother. Fundus oculi was normal. No other pathologic data were obtained from clinical examination. The patient presented frequent, symmetrical generalized seizures, each lasting 15 to 20 minutes. EEG revealed virtually continuous seizure activity arising from the right hemisphere, characterized by frequent bursts of irregular paroxysmal activity and single spike and wave complexes. Electrocardiogram and ultrasound cardiac evaluation, karyotype (highresolution chromosome analysis), routine laboratory investigations of blood and urine, organic acids and amino acids, as well as ammonia, mucopolysaccharides, and oligosaccharides were normal. TORCH studies were also normal. Cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans (Fig 2) demonstrated enlargement of right cerebral hemisphere, peduncle, and thalamus. The right sylvian fissure was open due to underdevelopment of the opercula. In the affected hemisphere, pachygyria was evident, with relative paucity of the white matter as
Communications should be addressed to: Professor Bonioli; Istituto di Clinica Pediatrica "G. Gaslini"; Largo G. Gaslini, 5; 16147 Genova, Italy. Received October 16, 1996; accepted January 7. 1997.
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Figure 1. Patient 1. Sebaceous nevus is evideut between the zygomatic region and the nose.
Figure 2. Patient L MRI: T~ (TR = 600 ms; TE - 20 ms) coronal. Hemimegalencephaly. Enlargement of the right cerebral hemisphere with pachygyria and thickening of the affected cortex is evident. The right silvian fissure is open due to underdevelopment of the opercula.
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Figure 3. Patient 2. A close-up shows the linear sebaceous nevus extending from the median and paramedian frontal region toward the right. compared with gray (reverse myelin pattern) but without heterotopia. Results of CT and MRI scans of the left hemisphere were within normal range. Treatment with a combination of phenobarbital (PB) and valproate (VPA) provided good seizure control for about 1 year. The patient now experiences frequent (daily) seizures and is severely mentally retarded. Patient 2. A female whose parents are healthy and nonconsanguineous was delivered by cesarean section after a normal term pregnancy. Her birth weight was 3,780 g, and her length was 51 cm; her occipitofrontal circumference was 38 cm (more than 95th percentile), (Fig 3). Neonatal hypoxia was evident, and resuscitation was successfully perfornled (Apgar scores were 1/9). Immediately after birth, she presented generalized seizures. The patient has never been seizure-free notwithstanding therapy with various antiepileptic drugs (PB and VPA). On day 23 of life, the patient was referred to our clinic. Her weight and height were at 90th percentile, and head circumference was 41 cm (more than 95th percentile). The forehead was prominent and the anterior fontanelle was 4.5 × 5 cm. A 0.5 × 0.5-cm "caf~-au-lait" spot was localized on the right knee, and a 3 × l-cm hemangioma planum was evident on the left thigh. A sharply demarcated and slightly elevated yellow-brown lesion, extending from the median and paramedian frontal region toward the right was present (linear sebaceous nevus of Jadassohn). Neurologic examination revealed no focal signs or asymmetry; muscle tone and power were normal. Neither nystagmus nor clonus was evident. The patient was unable to fixate on objects visually or to follow the movement of these objects. Severe mental retardation was evident. Fundus examination and visual evoked potentials were normal. Results of EKG and ultrasound cardiac evaluation, karyotype (high-resolution chromosome analysis), and routine laboratory investigations in blood and urine, organic acids and amino acids, as well as ammonia, mucopolysaccharides, and oligosaccharides were normal. TORCH studies were normal.
Figure 4. Patient 2. MRI: T 1 (TR = 600 ms; TE = 20 ms) coronal. Hemimegalencephaly associated with lateral ventricle enlargement. Pachygyric cortex and cortical thickening are evident on the affected side. The lateral ventricle is enlarged in proportion to the enlargement (~[ the qffected hernisphere.
She experienced several clusters of mixed infantile spasms daily. Treatment with valproic acid (VPA), diazepam, and vigabatrin led to partial control of the spasm frequency. An EEG at 1 month of age showed generalized, irregular, very high-voltage bursts associated with slow waves, sharp waves, and multifocal spikes arising from the left side. Burst suppression, diffusely slow background activity, and marked attenuation of activity were evident on EEG recorded during sleep. MR1 demonstrated enlargement of the left hemisphere with medioposterior dilatation of the left lateral ventricle without signs relating to intracranial hypertension /Fig 4).
Discussion
SN syndrome is appropriately classified as a neurocutaneous syndrome. The condition is sporadic and is considered the result of a lethal mutation that survives by mosaicism. Cells carrying the mutation have been suggested to be capable of surviving only in close proximity to normal cells [8]. All elements of the skin are represented in SN, although histologically it is characterized by an abundance of sebaceous glands [5]. The clinical appearance reflects not only the variable histologic pattern, but also hormonal and environmental influences [8], which explains why an SN may remain unrecognized early in infancy, when it ap-
pears as a slightly raised linear plaque, skin-colored and velvety. The lesion becomes more evident as the child grows older, usually during adolescence [5]. Because SN is considered a premalignant lesion, either long-term monitoring or radical excision before puberty is warranted. Pathologic and/or radiologic examination of the brain of some SN patients demonstrates infarcts, atrophy, porencephaly, and calcifications. These anomalies are considered acquired brain lesions, a consequence of vascular abnormalities (ischemia or hemorrhage due to blood vessel dysplasia), with secondary brain involvement. Such patients have been classified as having a "vascular" variant of SN syndrome [4,9]. In another group of SN patients, a definite "neurologic variant" (also termed SN with hemimegalencephaly) has been described as consisting of ipsilateral hemimegalencephaly, gyral anomalies, and facial hemihypertrophy [4,8]. Actually, facial hemihypertrophy does not appear to be a constant feature in this group of patients. Our 2 patients and almost half of the SN patients with hemimegalencephaly described in the literature have no facial asymmetry (bibliography available on request). We therefore hypothesize the existence of a separate subgroup of patients affected by SN syndrome with hemimegalencephaly but without facial hemihypertrophy, in whom the only diagnostic clue is a nevus that is barely visible until puberty. Early diagnosis of SN syndrome in this subgroup must be based on accurate clinical examination to detect the typical skin lesions.
References
[1] Jadassohn J. Bemerkungen zur Histologie der systematisierten Naevi und tiber "Talgdrtisen-Naevi". Arch Dermatol Syph 1895;33:355408. [2] Rogers M, McCrossing 1, Commens C. Epidermal nevi and the epidermal nevus syndrome. A review of 131 cases. J Am Acad Dermatol 1989;20:476-88. [3] Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol 1968;97:273-85. [4] Pavone L, Curatolo P, Rizzo R, et al. Epidermal nevus syndrome: A neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. Neurology 1991 ;41:266-71. [5] Happle R. How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol 1991;25:550-6. [6] Fenerstein RC, Mims LC. Linear nevus sebaceous with convulsion and mental retardation. Am J Dis Child 1962;104:675-9. [7] McKusick VA. Mendelian inheritance in man. Catalogs of human genes and genetic disorders, l lth ed. Baltimore: The Johns Hopkins University Press, 1994. [8] Dodge NN, Dobyns WB. Agenesis of the corpus callosum and Dandy-Walker malformation associated with hemimegalencephaly in the sebaceous nevus syndrome. Am J Med Genet 1995;56:147-50. [9] Dobyns WB, Garg BP. Vascular abnormalities in epidermal nevus syndrome. Neurology 1991 ;41:276-8.
Bonioli et al: Sebaceous Nevus Syndrome
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