Acta Neuropathologica

Acta Neuropathol. (Berl.) 48, 59-61 (1979)

'9 Springer-Verlag I979

Apert's Syndrome with Central Nervous System Anomalies J. A. M a k s e m a n d U. R o e s s m a n n Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA

Summary. The

p a t h o l o g i c a n a t o m y o f the central nervous system is described in a p a t i e n t with A p e r t ' s syndrome. Multiple d e v e l o p m e n t a l anomalies of the b r a i n were n o t e d i n c l u d i n g disturbances of rhinencephalic organization. The association between maldevelopm e n t of the r h i n e n c e p h a l o n a n d the face is well k n o w n . C r a n i a l vault m a l f o r m a t i o n s m a y also be associated with m a l d e v e l o p m e n t of the r h i n e n c e p h a l o n .

footling breech presentation to a 36-year-old mother with a tongstanding history of infertility. There were no signs of fetal distress. Membranes ruptured at delivery with the expulsion of clear fluid. Apgar scores were 4 at I rain and 8 at 5 rain. On physical examination at the time of delivery the infant had frontal bossing, a wide and anteroposed sagittal suture, and fused coronal sutures bilaterally. Respiratory distress was noted soon after birth and was treated with only partial sucess until hypoxia progressed and could not be corrected. The infant was pronounced dead 1l h after birth.

Key words: A p e r t ' s

Autopsy Findings

Craniosynostosis -

s y n d r o m e - Craniostenosis Rhinencephalon

A p e r t ' s s y n d r o m e is a constellation of a n a t o m i c findings characterized by craniostenosis secondary to variable a n d irregular early o b l i t e r a t i o n of cranial sutures with symmetrical syndactyly of the h a n d s a n d feet. The disorder is seen in from 1 in 100,000 to 1 in 160,000 live births (Cohen, 1975). Early fusion of cranial sutures usually involves the c o r o n a l sutures a n d results in a n t e r o p o s i t i o n of the a n t e r i o r fontanelle. Other craniofacial a n d visceral anomalies are recorded b u t are i n c o n s t a n t . Central n e r v o u s system anomalies do n o t appear c o m m o n . Ventricular d i l a t a t i o n was reported in eight patients with A p e r t ' s s y n d r o m e ( F i s h m a n et al., 1971 ; H o g a n a n d B a u m a n , 1971). P o s t m o r t e m exami n a t i o n in two of the cases showed a q u e d u c t a l atresia with cortical t h i n n i n g in one a n d absence of the corpus c a l l o s u m posteriorly with p a t e n c y of the a q u e d u c t of Sylvius in the other. The i n f a n t presented in this report h a d A p e r t ' s s y n d r o m e associated with visceral anomalies a n d multiple congenital m a l f o r m a t i o n s of the central nervous system.

Case Report Clinical History A 2,350 g white female infant, 31 - 3 2 weeks by dates, 33- 34 weeks by physicalexamination, was deliveredby cesarean section because of

The postmortem examination disclosed synostis of the coronal sutures bilaterally, abnormal facies, and symmetrical syndactyly of upper digits 2 - 5 and lower digits 1-5. Visceral anomalies included incomplete lobation of the right lung, accessory spleen, and malrotation of the bowel with malposition-posterior placement of the colon and hypogastric placement of the appendix-cecum. Hyaline membrane formation with bacteria deposition, vascular congestion, and wide distention of the respiratory bronchioles were found on microscopic examination. Lung cultures were positive for /% hemolytic streptococci of Lancefield GroupB. No demonstrable chromosomal abnormalities were observed in cultured fibroblasts. Dissection of the calvarium and base of skull confirmed synostosis of coronal sutures bilaterally. Crista galli was rudimentary and the cribriform plate was imperforate. The middle cranial fossae, receiving the temporal lobes of the brain, were deep and angulated inferiorly. The brain weighed 300 g. Olfactory bulbs and tracts were not present. The interhemispheric fissure was bridged by what appeared to be a cortical gyrus in its inferior part just rostral to the optic chiasm. The remainder of the interhemispheric fissure was normal, and beyond the point of cortical fusion there was no further evidence of abnormal interhemispheric communications. Corpus callosnm was normal. Septum pellucidum was present. Both fornices were in their proper location. The olfactory tubercle was prominent and extended laterad from the interhemispheric bridge. On microscopic examination it was characterized by a simplenonlayered cortex which extended to the insula where more typical neocortex was seen (Fig. 1). Caudad it extended to the temporal lobe, far beyond the diagonal band of Broca. The nucleus of the diagonal band of Broca was marked by a dense band of primitive neuroepithelial cells, and islets of small matrix cells were scattered in dense clumps under the entire limbic zone (Fig. i). The hippocampal structures were straightened out and greatly shortened (Fig. 2). There was extreme limitation of fascia denta and marked diminution in number of the pyramidal neurons of the endplate. Resistant sector and Sommer sector were hypoplastic. The

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Acta Neuropathol. (Berl.) 48 (1979)

Fig. 3. Entorhinal cortex is subdivided into four layers. Cresyl violet; x 22

Fig. 1. Section through the brain at the level of the foramen of Monroe (a). The temporal lobe tip did not reach this level and a large part of the insular cortex is exposed. The base is lined by single-layer cortex of the olfactory tubercle extending to the insula, where a transition to the six-layer neocor tex is seen (arrow). Dense collections of small neuroepithelial cells in the region of the diagonal band of Broca are noted (b), Hematoxylin and eosin; x 4

Fig. 4. Medulla oblongata at the proposed level of decussation. The pyramids are asymmetrical and separated by a deep groove. Hematoxylin and eosin; x 22

Fig. 2. Hippocampus. The structure is partially "unwound" and hypoplastic. Fascia dentata and the endplate are particularly small. Cresyl violet; x 22

Fig. 5. Spinal cord, mid cervical level, A large segment of the uncrossed cortico-spinal fibers is seen in the ventral column (pale area) while the crossed fibers run in irregular bundles extending almost to the midline across the dorsal horn (arrows). Hematoxylin and eosin; x 26

J. A. Maksem and U. Roessmann: Apert's Syndrome with Central Nervous System Anomalies entorhinal cortex appeared more extensive than usual and showed subdivision of each of its two layers (Fig. 3). The skull deformity resulted in misapposition of the cerebral hemispheric components. The temporal lobes were widely separated from the frontal lobes and angulated inferiorly. The frontal cortex was placed anteriorly and more superiorly than normal, leaving the insulae exposed bilaterally over most of their extent. Thus, coronal sectioning allowed definition of three distinct compartments : frontal cortex above, insulae with underlying basal ganglia and mid-position, and temporal lobe structures both lateral and below. The internal arrangement of the basal ganglia was disturbed, the hypothalamus and subthalamus being shifted posteriorly in relation of the corpus striatum and thalamus. Such rearrangement caused the internal capsule to be angled horizontally and to appear longer than usual. The corticospinal fibers were myelinated in the internal capsule and the aqueduct of Sylvius was patent. Corticospinal fibers running in basis pontis were normal. The pyramids were small and symmetrical. A deep fissure divided the pyramids at the point where the decussation of fibers should have been observed (Fig. 4). In sections of cervical cord the lateral columns were asymmetrical with left sided diminution. On the right side, corticospinal fibers were found in the ventral, uncrossed position as well as in the lateral, crossed position. The lateral tract extended almost to the midline, near the central canal (Fig. 5). At the base &the brain there was considerable glial heterotopia with marked gliat proliferation in the subarachnoid space.

Discussion

Patients with Apert's syndrome exhibit developmental disturbances of the calvarium, cranial base and maxilla. Bony anomalies of the brain base may be secondary to premature closure of the cranial sutures. With fusion of the coronal sutures, there is a diminution of the anteroposterior diameter of the calvarium and narrowing of its lateral dimension (Cohen, 1975). In our case, this resulted in realignment of the cerebral hemispheres with separation of the frontal and temporal lobes and exposure of the insulae. Of special interest is the abnormal olfactory complex which included absence of olfactory bulbs and tracts, fusion of the medial aspects of the olfactory tubercles and an apparent arrest in the development of the olfactory tubercle and hippocampal structure. These anomalies suggest absence or impairment of the "induction factor" responsible for the normal formation and organization of the rhinencephalon (Laroche, 1977). Regardless of the nature or

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location of such a "factor", this case serves to emphasize the close relationship between the developmental sequence of skeletal and central nervous system organization. Whereas the relationship between facial anomalies and more severe forms of the arhinencephaIic complex are well known (De Myer et al., 1964), it seems that cranial vault malformations may also be associated with maldevelopment of the rhinencephalon. Whether the incomplete decussation of the pyramidal tracts represents an independent malformation or whether it is consequent to malfunction of the same "induction factor" operative in rhinencephalic organization cannot be determined. There may have been misplacement of corticospinal fibers in the internal capsule which was shifted because of disturbed alignment of the precentral cortex and the basal ganglia. Further studies of similar and related malformations are needed in order to determine whether such causal relationships exist. Glial heterotopia is a common finding in central system malformation (Brun, 1965). Marked proliferation of glial tissue within the subarachnoid space in the base of the brain could account for impaired percolation of the cerebrospinal fluid along the base of the brain; this mechanism should be considered in cases where hydrocephalus is noted in the absence of aqueductal stenosis or atresia. References Brun, A.: Marginal glioneural heterotopias of the central nervous system. Acta Pathol. Microbiol. Scand. 65, 221-233 (1965) Cohen, M. M. : An etiologic and nosologic overview of craniosynostosis syndromes. Birth Defects 11, 137-189 (1975) De Meyer, W., Zeman, W., Palmer, C. G.: The face predicts the brain : Diagnostic significance of facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 34, 256-263 (1964) Fishman, M. A., Hogan, G. R., Dodge, P. R. : The concurrence of hydrocephalus and craniosynostosis. J. Neurosurg. 34, 621 - 629 (1971) Hogan, G. R., Baumann, M. L.: Hydrocephalus in Apert's syndrome. J. Pediatr. 79, 782-787 (1971) Laroche, J. D.: Developmental pathology of the neonate, p. 482. Amsterdam: Excerpta Medica 1977 Received May 14, 1979/Accepted May 30, 1979

Apert's syndrome with central nervous system anomalies.

Acta Neuropathologica Acta Neuropathol. (Berl.) 48, 59-61 (1979) '9 Springer-Verlag I979 Apert's Syndrome with Central Nervous System Anomalies J...
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