STUDIES OF VERTEBRAL CORONAL CLEFT IN RHIZOMELIC CHONDRODYSPLASIA PUNCTATA
Theadis R. Wells, HT (ASCP), Benjamin H. Landing, MD, and F. Hines Bostwick, MD 0 Departments of Pathology and
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
Laboratory Medicine, Childrens Hospital Los Angeles and University of Southern California School of Medicine, Los Angeles, California
0 Dissection and serial section-reconstructton preparations from vertebrae with coronal cleft o f a 2%2year-old girl with rhizomelic chondrodysplasia punctata are described. The cartilage plate between the dorsal and ventral vertebral oss$cation centers, abnormal thickness o f which is the explanation of the radiologic coronal cleft, shows differences in thickness, with dorsal and ventral midline extensions and with small foci o f communication ofthe cancellous bone ofthe dorsal and ventral ossification centers ofthe vertebral body bilatmally. Although the process in coronal cleft is in some ways similar to that of radiologic “retarded epiphyseal closure,’’ the explanation o f the coronal clejs in rhizomelic chondrodysp h i a punctata appears to be overproduction o f cartilage in the zone between the dorsal and ventral vertebral body ossification centers, plus reduced removal of cartilage ce1lsJ;om this zone. No evidences of persistence of notochord cells were seen microscopically in sections of the coronal clefts.
KEY WORDS: vertebra, rhizomelic chondrodysplasia punctata.
INTRODUCTION So-called vertebral coronal cleft, seen in lateral spinal radiographs as a radiolucent band running superinferiorly through one or more vertebral bodies, ordinarily results not from a vertebral cleft but from persistence or retarded regression of the cartilage layer between the dorsal and ventral ossification centers of a vertebral body (1-4). Whether an alternative possible explanation for some instances of vertebral coronal cleft, in which the vertebral body would have, in the coronal plane, a figure-of-8 shape, comparable to that which produces in posterior-anterior radiographs the pattern called butterfly vertebra (5), ever occurs is not known. Coronal cleft can be demonstrated in one or more vertebral bodies, more often in the lumbar vertebrae, in up to 5% of newborns, more commonly the lower the gestational age and The authors are indebted to Mrs. Peggy C . Earhart for the preparation of this manuscript. Address reprint requests to: Benjamin H. Landing, M.D., Childrens Hospital of Los Angeles, Anatomic Pathology-Research Division, Box 103, P.O. Box 54700, Los Angeles, California 90054-0700.
Pediatric Patholou, 12:593-600, 1992 CopyrGht 0 1992 by Hemisphere Publishing Corporation
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more often in males. Vertebral coronal clefts have been particularly associated with the peroxisomal disorder rhizomelic chondrodysplasia punctata (4, 6, 7), and the lesion has also been reported with atelosteogenesis, trisomy 13, dyssegmental dysplasia, fibrochondrogenesis, humerospinal dysostosis, Kniest dysplasia, metatropic dysplasia, otospondylomegaepiphyseal dysplasia, and, in patients with imperforate anus, esophageal atresia-tracheoesophageal fistula or myelomeningocele (4-6, 8). This paper describes the anatomic features of vertebral coronal cleft shown by special dissection and serial sectionreconstruction studies in specimens from a 25/12-year-old girl with rhizomelic chondrodysplasia punctata. The clinical history and general pathologic findings of this patient have been reported by Sugarman (9), who also presented radiographs of vertebral sections in different planes. Radiographic, pathologic, and ultrastructural features of the disease have been reviewed by Gilbert et al. (6).
MATERIALS AND METHODS Vertebral bodies of the patient, removed at autopsy, were fixed in 10% formalin and processed as follows:
1. Sections of undecalcified vertebra 3-4 mm thick were cut with a jigsaw. Some of these were stained with toluidine blue at pH 2 and then cleared in methyl salicylate to show the distribution of cartilage in relation to the radiologic coronal cleft, and some were not stained. 2. A decalcified vertebra was embedded in paraffin and serial sections 10 mm thick were cut, stained with hematoxylin and eosin, and used for preparation of a wax plate serial section-reconstruction of a vertebra showing coronal cleft. 3. The cancellous bone was dissected from one undecalcified vertebra. The serial section-reconstruction was done by placing the hematoxylin and eosin-stained serial sections in a photographic enlarger and making prints of size calculated to ensure the same magnification in all three dimensions in the reconstruction. Translucent dental wax plates 1 mm thick were placed over the prints, and the outlines of the vertebral body and the cartilage bar of the coronal cleft were cut with a no. 11 surgical blade and stacked to produce the three-dimensional replica of the vertebral structures. The model was sealed with a heated spatula, and segmental cutaways were made to permit visualization of the coronal cleft in the coronal plane. Giemsa and toluidine blue stains of paraffin sections of decalcified lumbar vertebrae showing radiologic coronal clefts, from two patients with other anomaly syndromes, were
VERTEBRA IN CHONDRODYSPLASIA PUNCTATA
595
prepared for comparison with the sections from the 25/i2-year-oldpatient with rhizomelic chondrodysplasia punctata. The various preparations are illustrated in Figures 1-6.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
RESULTS Figure 1 shows the irregular shape of the cartilage bar of the coronal cleft, as frequently described (e.g., ref 1). Figure 2 , of cleared toluidine bluestained sections of vertebrae of the same patient, shows in (a) a cut in the parasagittal plane, the cartilage band corresponding to the radiologic coronal cleft, and, in (b) a cut in the transverse plane, a dorsal extension of the cartilage bar beneath the superior vertebral surface, indicating a degree of butterfly shape of the dorsal ossification center. The bases of the pedicles are seen on both lower sides of Fig. 2b. Figure 3 shows a specimen in which the bony tissue has been dissected from an undecalcified vertebral body to show the cartilage band of the coronal cleft between the dorsal (above) and ventral (below) embryonic vertebral ossification centers. The irregular shape of the cartilage bar (see Fig. lb), with a ventral sagittal-plane extension in this vertebra, also produces a partial ventral “sagittal cleft.’’ Figure 4 is an oblique view of a wax plate serial section-reconstruction of a vertebra with coronal cleft, showing the transverse (in the dorsoventral plane)
FIGURE 1. Cuts of undecalcified vertebrae of 25/1z-year-old girl with rhizomelic chondrodysplasia punctata showing, on the left, the transverse cartilage bar of the radiologic vertebral coronal cleft. The small dark spot in the center of the bar presumably indicates the former site of the notochord (the “notochord track”). The cut on the right, in the plane of the posterior portion of the vertebral body shown on the left cut, runs through the posterior vertebral ossification center and shows focal continuity of that center with the ossification centers of the pedicles, as well as excessive caudal extension of the pedicular centers down the sides of the vertebral body. The dorsally directed extension of cartilage from the center of the transverse cartilage bar shows that the dorsal ossification center has, in this plane, a figure-of-8 or figure-of-B shape, analogous to that seen in posteroanterior radiographs of butterfly vertebrae. x 2.1.
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FIGURE 2. Cleared toluidine blue-stained sections of vertebrae of the same patient. (a) A cut in the parasagittal plane, the cartilage band corresponding to the coronal cleft of the vertebral body seen in lateral radiographs. (b) The dorsal portion of the cartilage bar, reflecting the butterfly shape of the dorsal ossification center and, inferiorly in the figure, the ossified bases of the vertebral pedicles. X 2.1.
cartilage bar of the coronal cleft, with a ventral sagittal-plane cartilage projection like that seen also in Fig. 3. In Fig. 5 the anteroposterior view of the ventral face of the cartilage of the coronal cleft shows two loci, one on each side of the sagittal plane, at which bone is continuous, through two “perforations” in the cartilage plate, from ventral to dorsal vertebral ossification centers. The vertebrae in the rhizomelic form of chondrodysplasia punctata thus show not only retarded regression of the cartilage band that normally separates, in earlier embryonic life, the dorsal from the ventral vertebral body ossification centers but also foci of discontinuity of, and of continuity of, loci
FIGURE 3. Specimen of undecalcified vertebral body from which the bony tissue has been dissected to show the cartilage band between the dorsal (above) and ventral vertebral ossification centers. The irregular shape of the cartilage bar, with a ventral sagittal-plane “keel,” produces a partial ventral “sagittal cleft.”
x 2.8.
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FIGURE 4. Wax plate serial section-reconstruction of vertebra with coronal cleft, with the superior face of the vertebral body removed, showing the irregular cartilage bar of the coronal cleft (running from lower left to upper right in the figure) and the sagittal-plane extension of the cartilage into the ventral portion of the vertebral body, as seen also in Fig. 3. X 1.2.
FIGURE 5 . View of the ventral face of the cartilage bar causing the coronal cleft. Of note are the two loci, one on each side of the sagittal plane, at which bone is continuous through two perforations in the cartilage plate between the ventral and dorsal vertebral ossification centers. x 1.5.
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FIGURE 6. (a) Giemsa stain of lumbar vertebra with radiologic coronal cleft, from 1-day-old female with facial dysmorphism suggestive of fetal alcohol syndrome, mild cerebral hypoplasia, right diaphragmatic hernia, and malrotation of intestine. T h e cartilage bar forming the incomplete coronal cleft is less thick than that in the patient with rhizomelic chondrodysplasia punctata. X 2.1. (b) Toluidine blue stain of lumbar vertebra with radiologic coronal cleft, from a 10-month-old female with Apert acrocephalosyndactyly syndrome. T h e cartilage bar of the coronal cleft is more uniform in thickness and relatively more slender than that in the patient with rhizomelic chondrodysplasia punctata. X 1.75.
of vertebral ossification. In this sense, the occurrence of vertebral coronal clefts in the rhizomelic form of chondrodystrophia punctata can be seen as one manifestation of the process of multiple foci of bone formation in the cartilaginous bone templates seen in other loci, particularly around the bones of the pelvis, in the disease.
DISCUSSION Rhizomelic chondrodysplasia punctata is an autosomal recessive genetic disease with abnormality of peroxisomal enzymes or of processes controlled by them, including deficient plasmalogen synthesis, reduced phytanic acid oxidation, and the presence of unprocessed (untrimmed) hepatic peroxisomal 3oxoacyl-coenzyme A thiolase (10). In contrast to the situation in the cerebrohepatorenal (Zellweger) syndrome, peroxisomes are demonstrable ultrastructurally in hepatocytes in rhizomelic chondrodysplasia punctata (10, 11). As mentioned earlier, vertebral coronal clefts can be considered permissible variations of normal vertebral development, especially when limited to the lumbar vertebrae, when not persisting beyond infancy or early childhood, and when due to persistence of the normal cartilage zone between the dorsal and ventral vertebral ossification centers. Of the various reported syndromal associations of coronal cleft, perhaps the best known is that with the rhizomelic form of chondrodysplasia punctata, since coronal clefts are often multiple in this disease, although their presence is not invariant (11). The radiographs
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
VERTEBRA IN CHONDRODYSPLASIA PUNCTATA
599
presented by Sugarman (9) of cuts of the vertebrae of the patient considered in this paper illustrate the possible patterns demonstrable in radiographs or microscopic sections of vertebrae in this condition, depending on the planes of the sections or the radiographs. The material present in this study shows that the cartilage bar forming the basis of the vertebral coronal clefts in this disease varies in thickness, with sagittal plane projections at different levels both dorsally (see Fig. 1) and ventrally (see Figs. 2b, 3 , 4), and is not complete, so that small areas of osseous continuity between the dorsal and ventral vertebral ossification centers can be demonstrated (see Fig. 5 ) . In early embryonic life, the cartilaginous templates of the vertebral bodies are formed by midline fusion of two lateral cartilage anlagen. Bilateral hemivertebra, with right and left vertebral body halves, is thought to result from an abnormality of this fusion process (5), which precedes the appearance of the dorsal and ventral ossification centers of the definitive vertebral bodies. The peroxisomal biochemical defect in the rhizomelic form of chondrodysplasia punctata (McKusick no. 215100) (7) apparently does not seriously derange this earlier stage of vertebral body formation but does retard and disrupt the normal process of fusion of the ventral and dorsal vertebral ossification centers by replacement of the cartilage between the centers, a process comparable to that of epiphyseal closure. Although the cartilage zone that forms the coronal cleft includes the former site of the notochord as it runs through the future locus of the vertebral body (see Fig. 1) and a possible role of defective inductive function of the notochord in the pathogenesis of vertebral coronal cleft has been suggested (4), the microscopic sections of the vertebrae examined in this study showed no residual physaliferous notochord cells. Figure 6 shows sections of decalcified vertebrae with radiologic coronal cleft from a 1-day-old female with anomalies consistent with fetal alcohol syndrome (Fig. 6a) and from a 10-month-old female with Apert acrocephalosyndactyly syndrome (Fig. 6b). By comparison with Fig. 1, representing the patient with rhizomelic chondrodysplasia punctata, these sections show much less massive cartilage bands forming the coronal clefts. These findings suggest that the process most responsible for the vertebral coronal clefts in rhizomelic chondrodysplasia punctata is continued production with deficiency of removal of the cartilage in the “epiphyseal plate” forming the coronal cleft.
REFERENCES 1 . Reichmann S, Lewin T. Coronal cleft vertebrae in growing individuals: A preliminary report. Acta Orthop Scand 1969;40:3-22. 2. Tanaka T, Uhthoff HK. Coronal cleft of vertebrae, a variant of normal enchondral ossification. Acta Orthop Scand 1983;54:389-95. 3. Swischuk LE. Radiology of the Newborn and Young Infant. 2nd ed. Baltimore: Williams & Wilkins, 1980:840.
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1.R. WELLS ET AL.
4. Cohen J, Currarino G , Neuhauser EB. A significant variant in the ossification centers of the vertebral bodies. Am J Roentgenol Radium Ther Nucl Med 1956;76:469-75. 5. Silverman FN, ed. Caffey’s Pediatric X-Ray Diagnosis: An Integrated Imaging Approach. 8th ed. Chicago: Year Book Medical Publishers, 1985;279-301. 6. Gilbert EF, Optiz JM, Spranger JW, Langer LO Jr, Wolfson JJ, Viseskul C . Chondrodysplasia punctata-rhizomelic form. Pathologic and radiologic studies of three infants. Eur J Pediatr 1976;123~89-109. 7. McKusick VA. Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. 9th ed. Baltimore: Johns Hopkins University Press, 1990;1095. 8. Taybi H, Lachman RS. Radiology of syndromes, metabolic disorders, and skeletal dysplasias. 3rd ed. Chicago: Year Book Medical Publishers, 1990;880. 9. Sugarman GI. Chondrodysplasia punctata (rhizomelic type): Case report and pathologic findings. Birth Defects 1974;10:334-40. 10. Heikoop JC, van Roermund CWT, Just WW, et al. Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzymeA thiolase in peroxisomes and impaired processing of the enzyme. J Clin Invest 1990;86:126-30. 11. Wardinsky TD, Pagon RA, Powell BR, et al. Rhizomelic chondrodysplasia punctata and survival beyond one year: A review of the literature and five case reports. Clin Genet 1990;38:84-93. Received October I , I991 Accepted N o v m b n 21, 1991
Theadis R. Wells, HT (ASCP), Benjamin H. Landing, MD, and F. Hines Bostwick, MD 0 Departments of Pathology and
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
Laboratory Medicine, Childrens Hospital Los Angeles and University of Southern California School of Medicine, Los Angeles, California
0 Dissection and serial section-reconstructton preparations from vertebrae with coronal cleft o f a 2%2year-old girl with rhizomelic chondrodysplasia punctata are described. The cartilage plate between the dorsal and ventral vertebral oss$cation centers, abnormal thickness o f which is the explanation of the radiologic coronal cleft, shows differences in thickness, with dorsal and ventral midline extensions and with small foci o f communication ofthe cancellous bone ofthe dorsal and ventral ossification centers ofthe vertebral body bilatmally. Although the process in coronal cleft is in some ways similar to that of radiologic “retarded epiphyseal closure,’’ the explanation o f the coronal clejs in rhizomelic chondrodysp h i a punctata appears to be overproduction o f cartilage in the zone between the dorsal and ventral vertebral body ossification centers, plus reduced removal of cartilage ce1lsJ;om this zone. No evidences of persistence of notochord cells were seen microscopically in sections of the coronal clefts.
KEY WORDS: vertebra, rhizomelic chondrodysplasia punctata.
INTRODUCTION So-called vertebral coronal cleft, seen in lateral spinal radiographs as a radiolucent band running superinferiorly through one or more vertebral bodies, ordinarily results not from a vertebral cleft but from persistence or retarded regression of the cartilage layer between the dorsal and ventral ossification centers of a vertebral body (1-4). Whether an alternative possible explanation for some instances of vertebral coronal cleft, in which the vertebral body would have, in the coronal plane, a figure-of-8 shape, comparable to that which produces in posterior-anterior radiographs the pattern called butterfly vertebra (5), ever occurs is not known. Coronal cleft can be demonstrated in one or more vertebral bodies, more often in the lumbar vertebrae, in up to 5% of newborns, more commonly the lower the gestational age and The authors are indebted to Mrs. Peggy C . Earhart for the preparation of this manuscript. Address reprint requests to: Benjamin H. Landing, M.D., Childrens Hospital of Los Angeles, Anatomic Pathology-Research Division, Box 103, P.O. Box 54700, Los Angeles, California 90054-0700.
Pediatric Patholou, 12:593-600, 1992 CopyrGht 0 1992 by Hemisphere Publishing Corporation
593
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
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T. R. WELLS ET AL.
more often in males. Vertebral coronal clefts have been particularly associated with the peroxisomal disorder rhizomelic chondrodysplasia punctata (4, 6, 7), and the lesion has also been reported with atelosteogenesis, trisomy 13, dyssegmental dysplasia, fibrochondrogenesis, humerospinal dysostosis, Kniest dysplasia, metatropic dysplasia, otospondylomegaepiphyseal dysplasia, and, in patients with imperforate anus, esophageal atresia-tracheoesophageal fistula or myelomeningocele (4-6, 8). This paper describes the anatomic features of vertebral coronal cleft shown by special dissection and serial sectionreconstruction studies in specimens from a 25/12-year-old girl with rhizomelic chondrodysplasia punctata. The clinical history and general pathologic findings of this patient have been reported by Sugarman (9), who also presented radiographs of vertebral sections in different planes. Radiographic, pathologic, and ultrastructural features of the disease have been reviewed by Gilbert et al. (6).
MATERIALS AND METHODS Vertebral bodies of the patient, removed at autopsy, were fixed in 10% formalin and processed as follows:
1. Sections of undecalcified vertebra 3-4 mm thick were cut with a jigsaw. Some of these were stained with toluidine blue at pH 2 and then cleared in methyl salicylate to show the distribution of cartilage in relation to the radiologic coronal cleft, and some were not stained. 2. A decalcified vertebra was embedded in paraffin and serial sections 10 mm thick were cut, stained with hematoxylin and eosin, and used for preparation of a wax plate serial section-reconstruction of a vertebra showing coronal cleft. 3. The cancellous bone was dissected from one undecalcified vertebra. The serial section-reconstruction was done by placing the hematoxylin and eosin-stained serial sections in a photographic enlarger and making prints of size calculated to ensure the same magnification in all three dimensions in the reconstruction. Translucent dental wax plates 1 mm thick were placed over the prints, and the outlines of the vertebral body and the cartilage bar of the coronal cleft were cut with a no. 11 surgical blade and stacked to produce the three-dimensional replica of the vertebral structures. The model was sealed with a heated spatula, and segmental cutaways were made to permit visualization of the coronal cleft in the coronal plane. Giemsa and toluidine blue stains of paraffin sections of decalcified lumbar vertebrae showing radiologic coronal clefts, from two patients with other anomaly syndromes, were
VERTEBRA IN CHONDRODYSPLASIA PUNCTATA
595
prepared for comparison with the sections from the 25/i2-year-oldpatient with rhizomelic chondrodysplasia punctata. The various preparations are illustrated in Figures 1-6.
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
RESULTS Figure 1 shows the irregular shape of the cartilage bar of the coronal cleft, as frequently described (e.g., ref 1). Figure 2 , of cleared toluidine bluestained sections of vertebrae of the same patient, shows in (a) a cut in the parasagittal plane, the cartilage band corresponding to the radiologic coronal cleft, and, in (b) a cut in the transverse plane, a dorsal extension of the cartilage bar beneath the superior vertebral surface, indicating a degree of butterfly shape of the dorsal ossification center. The bases of the pedicles are seen on both lower sides of Fig. 2b. Figure 3 shows a specimen in which the bony tissue has been dissected from an undecalcified vertebral body to show the cartilage band of the coronal cleft between the dorsal (above) and ventral (below) embryonic vertebral ossification centers. The irregular shape of the cartilage bar (see Fig. lb), with a ventral sagittal-plane extension in this vertebra, also produces a partial ventral “sagittal cleft.’’ Figure 4 is an oblique view of a wax plate serial section-reconstruction of a vertebra with coronal cleft, showing the transverse (in the dorsoventral plane)
FIGURE 1. Cuts of undecalcified vertebrae of 25/1z-year-old girl with rhizomelic chondrodysplasia punctata showing, on the left, the transverse cartilage bar of the radiologic vertebral coronal cleft. The small dark spot in the center of the bar presumably indicates the former site of the notochord (the “notochord track”). The cut on the right, in the plane of the posterior portion of the vertebral body shown on the left cut, runs through the posterior vertebral ossification center and shows focal continuity of that center with the ossification centers of the pedicles, as well as excessive caudal extension of the pedicular centers down the sides of the vertebral body. The dorsally directed extension of cartilage from the center of the transverse cartilage bar shows that the dorsal ossification center has, in this plane, a figure-of-8 or figure-of-B shape, analogous to that seen in posteroanterior radiographs of butterfly vertebrae. x 2.1.
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FIGURE 2. Cleared toluidine blue-stained sections of vertebrae of the same patient. (a) A cut in the parasagittal plane, the cartilage band corresponding to the coronal cleft of the vertebral body seen in lateral radiographs. (b) The dorsal portion of the cartilage bar, reflecting the butterfly shape of the dorsal ossification center and, inferiorly in the figure, the ossified bases of the vertebral pedicles. X 2.1.
cartilage bar of the coronal cleft, with a ventral sagittal-plane cartilage projection like that seen also in Fig. 3. In Fig. 5 the anteroposterior view of the ventral face of the cartilage of the coronal cleft shows two loci, one on each side of the sagittal plane, at which bone is continuous, through two “perforations” in the cartilage plate, from ventral to dorsal vertebral ossification centers. The vertebrae in the rhizomelic form of chondrodysplasia punctata thus show not only retarded regression of the cartilage band that normally separates, in earlier embryonic life, the dorsal from the ventral vertebral body ossification centers but also foci of discontinuity of, and of continuity of, loci
FIGURE 3. Specimen of undecalcified vertebral body from which the bony tissue has been dissected to show the cartilage band between the dorsal (above) and ventral vertebral ossification centers. The irregular shape of the cartilage bar, with a ventral sagittal-plane “keel,” produces a partial ventral “sagittal cleft.”
x 2.8.
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FIGURE 4. Wax plate serial section-reconstruction of vertebra with coronal cleft, with the superior face of the vertebral body removed, showing the irregular cartilage bar of the coronal cleft (running from lower left to upper right in the figure) and the sagittal-plane extension of the cartilage into the ventral portion of the vertebral body, as seen also in Fig. 3. X 1.2.
FIGURE 5 . View of the ventral face of the cartilage bar causing the coronal cleft. Of note are the two loci, one on each side of the sagittal plane, at which bone is continuous through two perforations in the cartilage plate between the ventral and dorsal vertebral ossification centers. x 1.5.
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FIGURE 6. (a) Giemsa stain of lumbar vertebra with radiologic coronal cleft, from 1-day-old female with facial dysmorphism suggestive of fetal alcohol syndrome, mild cerebral hypoplasia, right diaphragmatic hernia, and malrotation of intestine. T h e cartilage bar forming the incomplete coronal cleft is less thick than that in the patient with rhizomelic chondrodysplasia punctata. X 2.1. (b) Toluidine blue stain of lumbar vertebra with radiologic coronal cleft, from a 10-month-old female with Apert acrocephalosyndactyly syndrome. T h e cartilage bar of the coronal cleft is more uniform in thickness and relatively more slender than that in the patient with rhizomelic chondrodysplasia punctata. X 1.75.
of vertebral ossification. In this sense, the occurrence of vertebral coronal clefts in the rhizomelic form of chondrodystrophia punctata can be seen as one manifestation of the process of multiple foci of bone formation in the cartilaginous bone templates seen in other loci, particularly around the bones of the pelvis, in the disease.
DISCUSSION Rhizomelic chondrodysplasia punctata is an autosomal recessive genetic disease with abnormality of peroxisomal enzymes or of processes controlled by them, including deficient plasmalogen synthesis, reduced phytanic acid oxidation, and the presence of unprocessed (untrimmed) hepatic peroxisomal 3oxoacyl-coenzyme A thiolase (10). In contrast to the situation in the cerebrohepatorenal (Zellweger) syndrome, peroxisomes are demonstrable ultrastructurally in hepatocytes in rhizomelic chondrodysplasia punctata (10, 11). As mentioned earlier, vertebral coronal clefts can be considered permissible variations of normal vertebral development, especially when limited to the lumbar vertebrae, when not persisting beyond infancy or early childhood, and when due to persistence of the normal cartilage zone between the dorsal and ventral vertebral ossification centers. Of the various reported syndromal associations of coronal cleft, perhaps the best known is that with the rhizomelic form of chondrodysplasia punctata, since coronal clefts are often multiple in this disease, although their presence is not invariant (11). The radiographs
Fetal Pediatr Pathol Downloaded from informahealthcare.com by University of Sydney on 12/30/14 For personal use only.
VERTEBRA IN CHONDRODYSPLASIA PUNCTATA
599
presented by Sugarman (9) of cuts of the vertebrae of the patient considered in this paper illustrate the possible patterns demonstrable in radiographs or microscopic sections of vertebrae in this condition, depending on the planes of the sections or the radiographs. The material present in this study shows that the cartilage bar forming the basis of the vertebral coronal clefts in this disease varies in thickness, with sagittal plane projections at different levels both dorsally (see Fig. 1) and ventrally (see Figs. 2b, 3 , 4), and is not complete, so that small areas of osseous continuity between the dorsal and ventral vertebral ossification centers can be demonstrated (see Fig. 5 ) . In early embryonic life, the cartilaginous templates of the vertebral bodies are formed by midline fusion of two lateral cartilage anlagen. Bilateral hemivertebra, with right and left vertebral body halves, is thought to result from an abnormality of this fusion process (5), which precedes the appearance of the dorsal and ventral ossification centers of the definitive vertebral bodies. The peroxisomal biochemical defect in the rhizomelic form of chondrodysplasia punctata (McKusick no. 215100) (7) apparently does not seriously derange this earlier stage of vertebral body formation but does retard and disrupt the normal process of fusion of the ventral and dorsal vertebral ossification centers by replacement of the cartilage between the centers, a process comparable to that of epiphyseal closure. Although the cartilage zone that forms the coronal cleft includes the former site of the notochord as it runs through the future locus of the vertebral body (see Fig. 1) and a possible role of defective inductive function of the notochord in the pathogenesis of vertebral coronal cleft has been suggested (4), the microscopic sections of the vertebrae examined in this study showed no residual physaliferous notochord cells. Figure 6 shows sections of decalcified vertebrae with radiologic coronal cleft from a 1-day-old female with anomalies consistent with fetal alcohol syndrome (Fig. 6a) and from a 10-month-old female with Apert acrocephalosyndactyly syndrome (Fig. 6b). By comparison with Fig. 1, representing the patient with rhizomelic chondrodysplasia punctata, these sections show much less massive cartilage bands forming the coronal clefts. These findings suggest that the process most responsible for the vertebral coronal clefts in rhizomelic chondrodysplasia punctata is continued production with deficiency of removal of the cartilage in the “epiphyseal plate” forming the coronal cleft.
REFERENCES 1 . Reichmann S, Lewin T. Coronal cleft vertebrae in growing individuals: A preliminary report. Acta Orthop Scand 1969;40:3-22. 2. Tanaka T, Uhthoff HK. Coronal cleft of vertebrae, a variant of normal enchondral ossification. Acta Orthop Scand 1983;54:389-95. 3. Swischuk LE. Radiology of the Newborn and Young Infant. 2nd ed. Baltimore: Williams & Wilkins, 1980:840.
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000
1.R. WELLS ET AL.
4. Cohen J, Currarino G , Neuhauser EB. A significant variant in the ossification centers of the vertebral bodies. Am J Roentgenol Radium Ther Nucl Med 1956;76:469-75. 5. Silverman FN, ed. Caffey’s Pediatric X-Ray Diagnosis: An Integrated Imaging Approach. 8th ed. Chicago: Year Book Medical Publishers, 1985;279-301. 6. Gilbert EF, Optiz JM, Spranger JW, Langer LO Jr, Wolfson JJ, Viseskul C . Chondrodysplasia punctata-rhizomelic form. Pathologic and radiologic studies of three infants. Eur J Pediatr 1976;123~89-109. 7. McKusick VA. Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. 9th ed. Baltimore: Johns Hopkins University Press, 1990;1095. 8. Taybi H, Lachman RS. Radiology of syndromes, metabolic disorders, and skeletal dysplasias. 3rd ed. Chicago: Year Book Medical Publishers, 1990;880. 9. Sugarman GI. Chondrodysplasia punctata (rhizomelic type): Case report and pathologic findings. Birth Defects 1974;10:334-40. 10. Heikoop JC, van Roermund CWT, Just WW, et al. Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzymeA thiolase in peroxisomes and impaired processing of the enzyme. J Clin Invest 1990;86:126-30. 11. Wardinsky TD, Pagon RA, Powell BR, et al. Rhizomelic chondrodysplasia punctata and survival beyond one year: A review of the literature and five case reports. Clin Genet 1990;38:84-93. Received October I , I991 Accepted N o v m b n 21, 1991
