Linear Nevus Sebaceous Syndrome: Megalencephaly and Heterotopic Gray Matter Brian C. Hager, DO*, I. Zachary Dyme, MD*, Stephen R. Guertin, MD*, Robert J. Tyler, MD~, Eugene W. Tryciecky, DO:~, and Jonathan D. Fratkin, MD +
Figure I. This ImJp.~3' of the fiwial nevus reveals hnger Ilair J'ollich.s in the deep dermis, nttmerotts hair follicles, and occasional sebaceous ghmds in the superficial det'mis. The latter ~lt'e small and poorly developed (hemato.o.lin stain, original m~l,tllli]tCtltioll A ]5 ).
Introduction Linear nevus sebaceous syndrome (LNSS) was originally described in the United States by Feuerstein and Mires in 1962 [1 ]. LNSS provides a strong association between
A 3-month-old white nmle with linear nevus sebaceous syndrome (LNSS), facial deformities, brain malformations, and cortical blindness is presented. Facial deformities included left ear hypertrophy and a left-sided h a m a r t o m a t o u s neck mass. Magnetic resonance imaging suggested that a central nervous system (CNS) abnormality, involving gray and white matter, should be linked with LNSS. Magnetic resonance imaging was more useful than computed t o m o g r a p h y in demonstrating the full spectrum of CNS anomalies, including unilateral lissencephaly, a paucity of white matter, excessive and heterotopic gray matter, a p p a r e n t left schizencephaly, and unilateral left colpocephaly (dilation of atrium and posterior horn of lateral ventricle). P o s t m o r t e m e x a m i n a t i o n revealed left hemisphere megalencephaly with a dilated posterior horn of the lateral ventricle. The impressive gray matter heterotopias likely were the source of the patient's seizures and perhaps the ultimate cause of death. Megalencephaly and other deviations of neuronal migration should be considered as a dramatic component of LNSS. Hager BC, Dyme IZ, Guertin SR, Tyler R J, Tryciecky EW, Fratkin JD. Linear nevus sebaceous syndrome: Megalencephaly and heterotopic gray matter. Pediatr Neurol 1991:7:45-9.
From the Department of *Pediatrics and Human Development; '~Department of Pathology(Neuropathology);¢Department of Radiology: Michigan State University; East Lansing. Michigan: ~Department of Pathology(Dennatopathology); E.W. Sparrow Hospital: Lansing. Michig~m.
Figure 2. Unenhanced CT demonstrates extensive mass effect on the h'J7 side and a shunt catheter draining what appears to he a porencephalic cyst.
Comn3unicationsshould be addressed to: Dr. Hager; Department of Pediatrics: Cook County Hospital: 700 South Wood Street: Chicago, IL 60612. Received February 22, 1990:accepted August 13. 1990.
Hager et al: Linear Nevus SebaceousSyndrome 45
A
B
Figure 3. (A) Bahmced (3.500/40) and (BI heavily T~_-wcighted (3.500/1001 axi, d MRI reveal left lissene~Thaly and heminwgalenc¢TJhaly. There is a paucity of white matter and poor gray-white d~]i'rentiation. Within the dilated posterior horll of'the h~/t lateral ventricle is the tip ¢!/the ventriculolwritoneal shltllt catheter.
skin and central nervous system lesions, as in the phakomatoses. In this syndrome, patients with midline cutaneous nevi are mentally retarded and have seizures. Nevertheless, the specific brain maltbrmations linked to skin abnormalities of LNSS have been infrequently discussed. Conventional computed tomography (CT) revealed asymmetric lateral ventricles, unilateral cerebral atrophy, and even calcification of the globes and optic nerves. We report a 3-month-old white male whose magnetic resonance imaging (MRI) scan revealed unilateral lissencephaly and colpocephaly (dilation of the atrium and posterior horn of the lateral ventricle), with apparent schizencephaly I21. In addition, the child also had hemihypertrophy of the left ear, and a hamartomatous neck mass. The MRI findings, clarified at autopsy, verified the proposed mechanism of seizure activity observed in these children. Case Report The patient presented at 3 months of age with epileptic seizures. He had been having seizures approximately once an hour for 48 hours. The seizures consisted of neck flexion with blinking, chev.,ing, and fisting motions of the hands: the episodes persisted for as long as 30 sec and occasionally were associated with apnea. The child's mother was an 18-year-old white primigravida whose pregnancy was complicated by alcohol abuse. A prenatal ultrasound examination demonstrated cephalopelvic disproportion believed secondar3, to hydrocephalus. He was delivered by cesarean section at 38 weeks gestation :rod required ventilation for 48 hours. Cranial ultrasound was reported as abnormal. The abnormal findings were confirmed by CT and the child required the placement of a ventriculoperitoneal shunt (see Radiographic Studies).
46
PEDIATRIC N E U R O L O G Y
Vol. 7 No. I
"Fhe infant I~gan having infantile spasms. Elcctrocnccphalography (EEG) revealed hypsarrllylhnlia: phent~barl'fital and valproic acid were administered. He had persistent, recurrent seizures ass(~:iated with apnea and bradycardia and had been on an apnea monitor at home lor 2 months. There was no family history of seizures, skin lesions, or menial retardation. The child failed-to-thrive and was evaluated for shunt infection numerous times. At approxim:ltely I year of age the child died at Ii~,~tlle. At autc~psy, significant findings were restricted to tile skin ~md nervous system. Physical Examination. At 3 months of age, the child*s weight was 2,,~91 gm (< 5th percentile), length 55 cm (< ,51)1 percentile), and head circumference 40.5 cm (50th percentile). A midline yellow, raised, plaque-like skin lesion, consisting o1" tiny papules, extended from a patch on the ft~rchead across the glabella and then down the left side of the nose. This plaque reached the left nasolabial Ibid. There was a similar patch measuring 2 × 4 cm on the left side of the neck. The left ear, set 1.5 cm lower than the right, was Iwice the thickness and diameter of the right ear. A mass, which involved the left side of the neck. had tile consistency of subcutaneous fat; it was neither cystic nor well-circumscribed. The cranial sutures were 5 mm wide. tuld the anterior fontanel was 3 × 4 cm, soft, and flat. He was alert and startled normally to a hand clap. There was no "'social" smile. The fundi were nonna]; pupils were equal and reactive to light. Eye movements were at times conjugate and at other times disconjugate. The eyes roved freely and would not follow light. Muscle tone generally was decreased and the child had no head control. Deep tendon reflexes were brisk at the knees: however, other rellexes were absent. Suck and sw:dlow coordination ,.,,,ere adequate. The remainder of tile examination was unremarkable. At 3 months of age. the Ibllowing test results ,,','ere normal: complete blood count, sodium, potassium, chloride, bicarbonate, glucose, bun. creatinine, LDH, SGOT, SGPT. CK, total protein, albumin, total bilirubin, direct bilirubin, cholesterol, triglycerides, calcium, phosphorus, magnesium. ~md urinalysis. A skin biopsy of the frontal facial lesion revealed moderately enlarged sebaceous glands. The density of small,
IIIIIIIIIIIIIIIIIIIIIHIIIHLtlIIlIlIIIIII:ILI/LIIIklIH~hHIII:,~H
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Figure 4. (A) Coronal section of the brain documents massive enlargement of the left frontal lobe; the right hemisphere is of normal size. Tire demarcation between gray and white matter is less disthwt on the left. (B) The posterior horn of the left lateral ventricle is markedly dilated in these coronal sections of tire occipital lobes. This ventricular expansion, which can invoh,e the atrium, is termed colpocephaly. poorly formed hair follicles was increased. The epidermis was unremarkable (Fig 1). EEG disclosed hypsarrhythmia; high-amplitude delta slowing and multifocal spike-and-sharp-wave activity were most prominent in the left hemisphere. Visual evoked potentials demonstrated a retinal response, but no reproducible cortical response. Radiographic Studies. At 3 months of age, MRI (GE Signa, 1.5 T) was performed using the spin-echo technique. T~-weighted sagittal images were obtained using a repetition time (TR) of 500 msec and an
echo time (TE) of 925 msec. A 4-echo train of balanced and progressively greater T2-weighted axial images were obtained with TR 3,500 msec and TE 40, 80, 120, and 160 msec (3,500/40, 80, 120, 160). In addition to colpocephaly, these images demonstrated enla~ement of the left cerebral hemisphere, poor gray-white differentiation, and gross thickening of the cerebral cortex. The widespread loss of gyral architecture indicated severe cortical disorganization on the left side. There were many gray matter heterotopias scattered throughout the left oere-
Hager et al: Linear Nevus Sebaceous Syndrome 47
Figure 5. No well-formed suh'i are observed in this micrograph .~'om the left hemisphere. Demarcation ~" gray fi'om white matter cannot be discerned (LFB/cresyl vioh't, original magnification x~O).
bral hemisphere (Figs 3A,3B). Uhrasonography of the neck n'lass revealed no fluid collections or focal masses. One month later, unenhanced CT (GE Quick Scanner: Fig 2) demnnstrated hypertrophy of the left cerebral henfisphere with shift of the midline structures to the right. An intraventricular catheter passed through a burr hole in the left occipital area and terminated in the dilated posterior horn of the left lateral ventricle. Neuropathologic EaYtmination. The fixed brain, 1,130 gin, demonstrafed pronounced asymmetry of the hemispheres. The left hemisphere was markedly enlarged and the left medial frontal lobe extended across the midline. The right hemisphere was slightly compressed by the bulky left hemibrain. In coronal sections, at the rostrum of the corpus callosum, the left lateral ventricle was obliterated (Fig 4A). Posteriorly, the left lateral ventricle was present and narrowed, in comparison to the slightly dilated right lateral ventricle; however, in the left occipital lobe the posterior horn of the left lateral ventricle was significantly enlarged (Fig 4B). There was no sclfizencephalic cleft. The left basal ganglia and thalanms were only moderately lager than the contralateral striate zmd diencephalic nuclei. Sections of brainstem and cerebellum were intact and not affected by unilateral hypertrophy. Microscopic sections of the relatively intact right hemisphere demonstrated sharp demarcation between gray and white matter. Although scattered neurons occasionally intruded into the superficial white matter, the border between neurons and myelinated fibers could be easily distinguished. In comparison, the expanded white matter of the left hemisphere blended with the gray matter (Fig 5). In 1 area the subcortical white matter exhibited a striking astrocytic proliferation: central myelination was poorly developed. Heterotopic regions of gray matter were located deep within the centrum semiovale. At higher magnification, sporadic, enlarged neurons were prominent as myelinated fibers swept around them (Fig 6). Gray and white matter had merged.
Discussion L N S S can involve a variety o f tissues of m e s e n c h y m a l and e c t o d e r m a l origin and in that sense resembles other n e u r o c u t a n e o u s syndromes, such as Sturge-Weber syndrome, tuberous sclerosis, and Von HippeI-Lindau disease. Our patient's M R I findings closely resemble those of an adolescent female with L N S S , reported by Sarwar and
48 PEDIATRIC NEUROLOGY
Vol. 7 No. 1
Schafer [3]. T h e y presunaed that tile concurrence of brain and facial lesions resulted from the close e m b r y o l o g i c relationship between the two. T h e y emphasized that the brain has a great modulating influence on the lhte of facial m e s o d e r m a l derivatives during the early developnaental stages, as o b s e r v e d in the facial a n g i o m a t o s e s o f the Stu,'ge-Weber s y n d r o m e 13]. Although Jadassohn sebaceous nevi are c o m m o n , L N S S , with its associated nervous system and somatic malfornaations, is rare. Mehregan and Pinkus r e v i e w e d the histopathology of 150 Jadassohn sebaceous nevi and elucidated the 3-stage natural history o f these lesions [4]. In inFancy the hair follicles, and frequently the sebaceous glands, are poorly developed. At puberty, the lesion achieves its most characteristic appearance; the s e b a c e o u s glands b e c o m e hyperplastic, the epidermis reveals papillomatous hyperplasia, ectopic apocrine glands may develop, and the hair follicles remain srnall. In adulthood, benign appendage tumors and/or basal cell c a r c i n o m a may o c c u r within lesions o f the nevus sebaceous. Other anomalies associated with L N S S include porencephaly and nonfunctioning major cerebral sinuses similar to those observed in Sturge-Weber syndrome [5]. Multiple hamartomas have been described [61. C o m m o n ocular disorders in this syndrome have included c o l o b o m a , l i p o d e m m i d s , corneal pannus formation, and focal calcification involving multiple layers o f the globe. Histologic immaturity of the eye has suggested ocular d e v e l o p m e n t a l arrest at 7-8 months gestation [7]. Teratoma and c o l o b o m a , c o m m o n ocular features in L N S S , are believed to be a result o f an e m b r y o l o g i c disturbance in cell differentiation and migration. The severe brain maltbrmations can be explained as disorders of neuronal migration. Heterotopic gray matter nodules and aberrant cortical architecture are the result. S o m e authors speculate that a teratogenic agent
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Figure 6. Several neurons (arrows), including 1 giant neuron (arrowhead), are sitrrounded by myelinated fibers. In this micrograph of the enlarged left hemisphere, the elements of gray and white matter blend to~ether (LFB/cresyl violet, original magnification x275).
(chemical or biologic) may be responsible. No pattern of inheritance has been identified. Heterotopic gray matter, as observed clearly in this patient's MRI and histologic sections, may arise from defective formation or destruction of radial glial fibers. These fibers ordinarily act as a franaework along which proliferating neurons migrate from the subependymal matrix to their ultimate cortical locations [8]. Because this process is disturbed, the cerebral cortex is thickened and simplified. Cerebral infolding, which nomaally allows a large cortical surface area to exist in the small space within the cranial vault, is inhibited• Most often affecting an entire cerebral hemisphere, the migrational anomalies associated with heterotopic gray matter include unilateral megalencephaly and schizencephaly. Focal abnormalities of sulcus formation, such as pachygyria and polymicrogyria, also are common. Gray matter heterotopias are clinically associated with epileptogenicity. Cytochemical analysis of a hypermegalic hemisphere with neuronal heterotopias revealed increased neuronal DNA, RNA, and protein. These findings suggested that heteroploidy of chromosomal DNA, with enhanced transcription and translation, brought about the grossly enlarged hemisphere. A defect in regulation of cell metabolism during a critical period of development may have accounted for the morphologic and clinical abnormalities [9]. Previously, radiographic studies of brain malformations in LNSS primarily consisted of pneumoencephalograms and conventional CT [10,1 1]. One previous MRI study of an LNSS patient demonstrated enlargement of 1 hemisphere (megalencephaly) and hypoplasia of the white matter. Deficient sulcus formation and pachygyria of the frontal lobe were observed as well [3]. Because it provides
superior gray/white matter contrast, MRI is best suited to elucidate these abnormalities. We found only 1 other report of an MRI study of an LNSS patient [3]. We believe that the definition of LNSS must emphasize the migrational anomalies and heterotopic gray matter, as depicted on MRI, as the source of seizures that characterize this entity. References [1] Feuerstein RC, Mims LC. Linearnevus sebaceous with convulsions and mentalretardation.Am J Dis Child 1962;104:675-9. 12] Byrd SE, Naidich TP. Common congenital brain anomalies. Radiol Clin North Am 1988;26:755-72. [3] Sarwar M, Schafer M. Brain malformations in linear nevus sebaceous syndrome:An MR study. J ComputAssist Tomogr 1988;12: 338-40. [4] Mehregan AH, Pinkus H. Life history of organoid nevi. Arch Dermatol 1965;91:574-88. 15] Chalhub EG, Volpe JJ, Mok'htar HG. Linear nevus sebaceous syndrome associated with porencephaly and nonfunctioning major cerebral sinuses.Neurology 1975;25:857-60. [6] Mimouni F, Han BK, Barnes L, et al. Multiple hamartomas associated with intracranial malformation. Pediatr Dermatol 1986;3: 219-25. [7] Shoehot Y, Romano A, Barishak YR, et al. Eye findingsin the linear nevus sebaceous syndrome:A possible clue to the pathogenesis. J CraniofacGenet Dev Biol 1982;2:289-94. [8] Pollei SR, Boyer RS, Crawford S, Harnsberger R, Barkovich AJ. Disorders of migration and sulcation. Semin Ultrasound CT MR 1988;9:231-46. [9] Manz HJ, PhillipsTM, RowdenG, McCulloughDC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronalhypertrophy, and heterotopia: Cytomorphometric, fluorometric cytochemical, and biochemical analyses.Acta Neuropathol 1979;45:97-103. [10] GooskinsRH, Veiga-Pires JA, van NieuwenhuizenO, Kaiser MC. CT of sebaceous nevus syndrome (Jadassohn disease). Am J Neuroradiol 1983;4:203-5. Ill] LeonidasJC, Wolpert SM, Feingold M, McCauley R. Radiographic features of the linear nevus sebaceous syndrome. AJR 1979; 132:277-9.
Hager et al: LinearNevus SebaceousSyndrome 49
Figure I. This ImJp.~3' of the fiwial nevus reveals hnger Ilair J'ollich.s in the deep dermis, nttmerotts hair follicles, and occasional sebaceous ghmds in the superficial det'mis. The latter ~lt'e small and poorly developed (hemato.o.lin stain, original m~l,tllli]tCtltioll A ]5 ).
Introduction Linear nevus sebaceous syndrome (LNSS) was originally described in the United States by Feuerstein and Mires in 1962 [1 ]. LNSS provides a strong association between
A 3-month-old white nmle with linear nevus sebaceous syndrome (LNSS), facial deformities, brain malformations, and cortical blindness is presented. Facial deformities included left ear hypertrophy and a left-sided h a m a r t o m a t o u s neck mass. Magnetic resonance imaging suggested that a central nervous system (CNS) abnormality, involving gray and white matter, should be linked with LNSS. Magnetic resonance imaging was more useful than computed t o m o g r a p h y in demonstrating the full spectrum of CNS anomalies, including unilateral lissencephaly, a paucity of white matter, excessive and heterotopic gray matter, a p p a r e n t left schizencephaly, and unilateral left colpocephaly (dilation of atrium and posterior horn of lateral ventricle). P o s t m o r t e m e x a m i n a t i o n revealed left hemisphere megalencephaly with a dilated posterior horn of the lateral ventricle. The impressive gray matter heterotopias likely were the source of the patient's seizures and perhaps the ultimate cause of death. Megalencephaly and other deviations of neuronal migration should be considered as a dramatic component of LNSS. Hager BC, Dyme IZ, Guertin SR, Tyler R J, Tryciecky EW, Fratkin JD. Linear nevus sebaceous syndrome: Megalencephaly and heterotopic gray matter. Pediatr Neurol 1991:7:45-9.
From the Department of *Pediatrics and Human Development; '~Department of Pathology(Neuropathology);¢Department of Radiology: Michigan State University; East Lansing. Michigan: ~Department of Pathology(Dennatopathology); E.W. Sparrow Hospital: Lansing. Michig~m.
Figure 2. Unenhanced CT demonstrates extensive mass effect on the h'J7 side and a shunt catheter draining what appears to he a porencephalic cyst.
Comn3unicationsshould be addressed to: Dr. Hager; Department of Pediatrics: Cook County Hospital: 700 South Wood Street: Chicago, IL 60612. Received February 22, 1990:accepted August 13. 1990.
Hager et al: Linear Nevus SebaceousSyndrome 45
A
B
Figure 3. (A) Bahmced (3.500/40) and (BI heavily T~_-wcighted (3.500/1001 axi, d MRI reveal left lissene~Thaly and heminwgalenc¢TJhaly. There is a paucity of white matter and poor gray-white d~]i'rentiation. Within the dilated posterior horll of'the h~/t lateral ventricle is the tip ¢!/the ventriculolwritoneal shltllt catheter.
skin and central nervous system lesions, as in the phakomatoses. In this syndrome, patients with midline cutaneous nevi are mentally retarded and have seizures. Nevertheless, the specific brain maltbrmations linked to skin abnormalities of LNSS have been infrequently discussed. Conventional computed tomography (CT) revealed asymmetric lateral ventricles, unilateral cerebral atrophy, and even calcification of the globes and optic nerves. We report a 3-month-old white male whose magnetic resonance imaging (MRI) scan revealed unilateral lissencephaly and colpocephaly (dilation of the atrium and posterior horn of the lateral ventricle), with apparent schizencephaly I21. In addition, the child also had hemihypertrophy of the left ear, and a hamartomatous neck mass. The MRI findings, clarified at autopsy, verified the proposed mechanism of seizure activity observed in these children. Case Report The patient presented at 3 months of age with epileptic seizures. He had been having seizures approximately once an hour for 48 hours. The seizures consisted of neck flexion with blinking, chev.,ing, and fisting motions of the hands: the episodes persisted for as long as 30 sec and occasionally were associated with apnea. The child's mother was an 18-year-old white primigravida whose pregnancy was complicated by alcohol abuse. A prenatal ultrasound examination demonstrated cephalopelvic disproportion believed secondar3, to hydrocephalus. He was delivered by cesarean section at 38 weeks gestation :rod required ventilation for 48 hours. Cranial ultrasound was reported as abnormal. The abnormal findings were confirmed by CT and the child required the placement of a ventriculoperitoneal shunt (see Radiographic Studies).
46
PEDIATRIC N E U R O L O G Y
Vol. 7 No. I
"Fhe infant I~gan having infantile spasms. Elcctrocnccphalography (EEG) revealed hypsarrllylhnlia: phent~barl'fital and valproic acid were administered. He had persistent, recurrent seizures ass(~:iated with apnea and bradycardia and had been on an apnea monitor at home lor 2 months. There was no family history of seizures, skin lesions, or menial retardation. The child failed-to-thrive and was evaluated for shunt infection numerous times. At approxim:ltely I year of age the child died at Ii~,~tlle. At autc~psy, significant findings were restricted to tile skin ~md nervous system. Physical Examination. At 3 months of age, the child*s weight was 2,,~91 gm (< 5th percentile), length 55 cm (< ,51)1 percentile), and head circumference 40.5 cm (50th percentile). A midline yellow, raised, plaque-like skin lesion, consisting o1" tiny papules, extended from a patch on the ft~rchead across the glabella and then down the left side of the nose. This plaque reached the left nasolabial Ibid. There was a similar patch measuring 2 × 4 cm on the left side of the neck. The left ear, set 1.5 cm lower than the right, was Iwice the thickness and diameter of the right ear. A mass, which involved the left side of the neck. had tile consistency of subcutaneous fat; it was neither cystic nor well-circumscribed. The cranial sutures were 5 mm wide. tuld the anterior fontanel was 3 × 4 cm, soft, and flat. He was alert and startled normally to a hand clap. There was no "'social" smile. The fundi were nonna]; pupils were equal and reactive to light. Eye movements were at times conjugate and at other times disconjugate. The eyes roved freely and would not follow light. Muscle tone generally was decreased and the child had no head control. Deep tendon reflexes were brisk at the knees: however, other rellexes were absent. Suck and sw:dlow coordination ,.,,,ere adequate. The remainder of tile examination was unremarkable. At 3 months of age. the Ibllowing test results ,,','ere normal: complete blood count, sodium, potassium, chloride, bicarbonate, glucose, bun. creatinine, LDH, SGOT, SGPT. CK, total protein, albumin, total bilirubin, direct bilirubin, cholesterol, triglycerides, calcium, phosphorus, magnesium. ~md urinalysis. A skin biopsy of the frontal facial lesion revealed moderately enlarged sebaceous glands. The density of small,
IIIIIIIIIIIIIIIIIIIIIHIIIHLtlIIlIlIIIIII:ILI/LIIIklIH~hHIII:,~H
t~l/ll
'kt~,~HIIrN~l,
: ,:~P: ' J l
]
A
Figure 4. (A) Coronal section of the brain documents massive enlargement of the left frontal lobe; the right hemisphere is of normal size. Tire demarcation between gray and white matter is less disthwt on the left. (B) The posterior horn of the left lateral ventricle is markedly dilated in these coronal sections of tire occipital lobes. This ventricular expansion, which can invoh,e the atrium, is termed colpocephaly. poorly formed hair follicles was increased. The epidermis was unremarkable (Fig 1). EEG disclosed hypsarrhythmia; high-amplitude delta slowing and multifocal spike-and-sharp-wave activity were most prominent in the left hemisphere. Visual evoked potentials demonstrated a retinal response, but no reproducible cortical response. Radiographic Studies. At 3 months of age, MRI (GE Signa, 1.5 T) was performed using the spin-echo technique. T~-weighted sagittal images were obtained using a repetition time (TR) of 500 msec and an
echo time (TE) of 925 msec. A 4-echo train of balanced and progressively greater T2-weighted axial images were obtained with TR 3,500 msec and TE 40, 80, 120, and 160 msec (3,500/40, 80, 120, 160). In addition to colpocephaly, these images demonstrated enla~ement of the left cerebral hemisphere, poor gray-white differentiation, and gross thickening of the cerebral cortex. The widespread loss of gyral architecture indicated severe cortical disorganization on the left side. There were many gray matter heterotopias scattered throughout the left oere-
Hager et al: Linear Nevus Sebaceous Syndrome 47
Figure 5. No well-formed suh'i are observed in this micrograph .~'om the left hemisphere. Demarcation ~" gray fi'om white matter cannot be discerned (LFB/cresyl vioh't, original magnification x~O).
bral hemisphere (Figs 3A,3B). Uhrasonography of the neck n'lass revealed no fluid collections or focal masses. One month later, unenhanced CT (GE Quick Scanner: Fig 2) demnnstrated hypertrophy of the left cerebral henfisphere with shift of the midline structures to the right. An intraventricular catheter passed through a burr hole in the left occipital area and terminated in the dilated posterior horn of the left lateral ventricle. Neuropathologic EaYtmination. The fixed brain, 1,130 gin, demonstrafed pronounced asymmetry of the hemispheres. The left hemisphere was markedly enlarged and the left medial frontal lobe extended across the midline. The right hemisphere was slightly compressed by the bulky left hemibrain. In coronal sections, at the rostrum of the corpus callosum, the left lateral ventricle was obliterated (Fig 4A). Posteriorly, the left lateral ventricle was present and narrowed, in comparison to the slightly dilated right lateral ventricle; however, in the left occipital lobe the posterior horn of the left lateral ventricle was significantly enlarged (Fig 4B). There was no sclfizencephalic cleft. The left basal ganglia and thalanms were only moderately lager than the contralateral striate zmd diencephalic nuclei. Sections of brainstem and cerebellum were intact and not affected by unilateral hypertrophy. Microscopic sections of the relatively intact right hemisphere demonstrated sharp demarcation between gray and white matter. Although scattered neurons occasionally intruded into the superficial white matter, the border between neurons and myelinated fibers could be easily distinguished. In comparison, the expanded white matter of the left hemisphere blended with the gray matter (Fig 5). In 1 area the subcortical white matter exhibited a striking astrocytic proliferation: central myelination was poorly developed. Heterotopic regions of gray matter were located deep within the centrum semiovale. At higher magnification, sporadic, enlarged neurons were prominent as myelinated fibers swept around them (Fig 6). Gray and white matter had merged.
Discussion L N S S can involve a variety o f tissues of m e s e n c h y m a l and e c t o d e r m a l origin and in that sense resembles other n e u r o c u t a n e o u s syndromes, such as Sturge-Weber syndrome, tuberous sclerosis, and Von HippeI-Lindau disease. Our patient's M R I findings closely resemble those of an adolescent female with L N S S , reported by Sarwar and
48 PEDIATRIC NEUROLOGY
Vol. 7 No. 1
Schafer [3]. T h e y presunaed that tile concurrence of brain and facial lesions resulted from the close e m b r y o l o g i c relationship between the two. T h e y emphasized that the brain has a great modulating influence on the lhte of facial m e s o d e r m a l derivatives during the early developnaental stages, as o b s e r v e d in the facial a n g i o m a t o s e s o f the Stu,'ge-Weber s y n d r o m e 13]. Although Jadassohn sebaceous nevi are c o m m o n , L N S S , with its associated nervous system and somatic malfornaations, is rare. Mehregan and Pinkus r e v i e w e d the histopathology of 150 Jadassohn sebaceous nevi and elucidated the 3-stage natural history o f these lesions [4]. In inFancy the hair follicles, and frequently the sebaceous glands, are poorly developed. At puberty, the lesion achieves its most characteristic appearance; the s e b a c e o u s glands b e c o m e hyperplastic, the epidermis reveals papillomatous hyperplasia, ectopic apocrine glands may develop, and the hair follicles remain srnall. In adulthood, benign appendage tumors and/or basal cell c a r c i n o m a may o c c u r within lesions o f the nevus sebaceous. Other anomalies associated with L N S S include porencephaly and nonfunctioning major cerebral sinuses similar to those observed in Sturge-Weber syndrome [5]. Multiple hamartomas have been described [61. C o m m o n ocular disorders in this syndrome have included c o l o b o m a , l i p o d e m m i d s , corneal pannus formation, and focal calcification involving multiple layers o f the globe. Histologic immaturity of the eye has suggested ocular d e v e l o p m e n t a l arrest at 7-8 months gestation [7]. Teratoma and c o l o b o m a , c o m m o n ocular features in L N S S , are believed to be a result o f an e m b r y o l o g i c disturbance in cell differentiation and migration. The severe brain maltbrmations can be explained as disorders of neuronal migration. Heterotopic gray matter nodules and aberrant cortical architecture are the result. S o m e authors speculate that a teratogenic agent
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Figure 6. Several neurons (arrows), including 1 giant neuron (arrowhead), are sitrrounded by myelinated fibers. In this micrograph of the enlarged left hemisphere, the elements of gray and white matter blend to~ether (LFB/cresyl violet, original magnification x275).
(chemical or biologic) may be responsible. No pattern of inheritance has been identified. Heterotopic gray matter, as observed clearly in this patient's MRI and histologic sections, may arise from defective formation or destruction of radial glial fibers. These fibers ordinarily act as a franaework along which proliferating neurons migrate from the subependymal matrix to their ultimate cortical locations [8]. Because this process is disturbed, the cerebral cortex is thickened and simplified. Cerebral infolding, which nomaally allows a large cortical surface area to exist in the small space within the cranial vault, is inhibited• Most often affecting an entire cerebral hemisphere, the migrational anomalies associated with heterotopic gray matter include unilateral megalencephaly and schizencephaly. Focal abnormalities of sulcus formation, such as pachygyria and polymicrogyria, also are common. Gray matter heterotopias are clinically associated with epileptogenicity. Cytochemical analysis of a hypermegalic hemisphere with neuronal heterotopias revealed increased neuronal DNA, RNA, and protein. These findings suggested that heteroploidy of chromosomal DNA, with enhanced transcription and translation, brought about the grossly enlarged hemisphere. A defect in regulation of cell metabolism during a critical period of development may have accounted for the morphologic and clinical abnormalities [9]. Previously, radiographic studies of brain malformations in LNSS primarily consisted of pneumoencephalograms and conventional CT [10,1 1]. One previous MRI study of an LNSS patient demonstrated enlargement of 1 hemisphere (megalencephaly) and hypoplasia of the white matter. Deficient sulcus formation and pachygyria of the frontal lobe were observed as well [3]. Because it provides
superior gray/white matter contrast, MRI is best suited to elucidate these abnormalities. We found only 1 other report of an MRI study of an LNSS patient [3]. We believe that the definition of LNSS must emphasize the migrational anomalies and heterotopic gray matter, as depicted on MRI, as the source of seizures that characterize this entity. References [1] Feuerstein RC, Mims LC. Linearnevus sebaceous with convulsions and mentalretardation.Am J Dis Child 1962;104:675-9. 12] Byrd SE, Naidich TP. Common congenital brain anomalies. Radiol Clin North Am 1988;26:755-72. [3] Sarwar M, Schafer M. Brain malformations in linear nevus sebaceous syndrome:An MR study. J ComputAssist Tomogr 1988;12: 338-40. [4] Mehregan AH, Pinkus H. Life history of organoid nevi. Arch Dermatol 1965;91:574-88. 15] Chalhub EG, Volpe JJ, Mok'htar HG. Linear nevus sebaceous syndrome associated with porencephaly and nonfunctioning major cerebral sinuses.Neurology 1975;25:857-60. [6] Mimouni F, Han BK, Barnes L, et al. Multiple hamartomas associated with intracranial malformation. Pediatr Dermatol 1986;3: 219-25. [7] Shoehot Y, Romano A, Barishak YR, et al. Eye findingsin the linear nevus sebaceous syndrome:A possible clue to the pathogenesis. J CraniofacGenet Dev Biol 1982;2:289-94. [8] Pollei SR, Boyer RS, Crawford S, Harnsberger R, Barkovich AJ. Disorders of migration and sulcation. Semin Ultrasound CT MR 1988;9:231-46. [9] Manz HJ, PhillipsTM, RowdenG, McCulloughDC. Unilateral megalencephaly, cerebral cortical dysplasia, neuronalhypertrophy, and heterotopia: Cytomorphometric, fluorometric cytochemical, and biochemical analyses.Acta Neuropathol 1979;45:97-103. [10] GooskinsRH, Veiga-Pires JA, van NieuwenhuizenO, Kaiser MC. CT of sebaceous nevus syndrome (Jadassohn disease). Am J Neuroradiol 1983;4:203-5. Ill] LeonidasJC, Wolpert SM, Feingold M, McCauley R. Radiographic features of the linear nevus sebaceous syndrome. AJR 1979; 132:277-9.
Hager et al: LinearNevus SebaceousSyndrome 49
