Neuropathology and Applied Neurobiology 1991, 17, 163-167
Case report Hurler’s disease with diastematomyelia C. K E O H A N E , J. O’LEARY, M. O’NEILL* A N D P. J. KEARNEYT Departments of Pathology (Neuropathology Laboratory), *Radiology and TPaediatrics, Cork Regional Hospital, Cork, Ireland
KEOHANE C., O’LEARY J., O’NEILLM. & KEARNEY P. J. (199 1) Neuropathology and Applied Neurobiology 17,163-167 Case report. Hurler’s disease with diasternatomyelia
A case of Hurler’s disease is reported in a child with a gibbous deformity of the lumbar vertebrae L1/L2 and a localized diastematomyelia of the spinal cord at L1/L3. The association of an enzyme disorder affecting connective tissue with spinal cord dysraphism has not been reported before, and may be fortuitous. However, as each condition is rare, the occurrence of both gibbous deformity due to Hurler’s and diastematomyelia in the same child, makes it unlikely to be a chance association. We suggest that defective neurulation in this case may be related to mesodermal damage associated with mucopolysaccharidosis. Keywords: Hurler’s disease (MPS 1-H), mucopolysaccharidosis 1, diastematomyelia, CNS malformation
INTRODUCTION
In Hurler’s disease (MPSI-H), a genetic deficiency of alpha-L-iduronidase, results in storage of mucopolysaccharides (also called glycosaminoglycans, GAGS)in connective tissues, especially bone (Lake, 1984;Becker & Yates, 1985),causing deformities. A characteristic bony change is a ‘hook’ shaped lumbar vertebral body which may cause spinal kyphosis and gibbus formation, with secondary cord compression. A partial deficiency of beta-galactosidase is also present, causing ganglioside storage in neurons and Kupffer cells. Congenital malformations with onset in uterine life are not a known feature of Hurler’s disease. We describe a case of Hurler’s disease in which diastematomyelia of the lumbar cord occurred in association with a gibbous deformity and ‘hooked‘ vertebrae, characteristic of mucopolysaccharidosis. CASE H I S T O R Y The patient, a boy aged 2 years 6 months, was the only child of healthy parents, who were second cousins. There was no family history of disease. At 8 months, Hurler’s disease was Correspondence to: Dr Catherine Keohane, Neuropathology Laboratory, Pathology Department, Cork Regional Hospital, Wilton, Cork, Ireland.
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Figure 1. Radiograph showing ‘hooked’ vertebral bodies, maximal at L2 (asterisk). Figure 2. Note hypertelorism, coarse features, hirsutism,enlarged abdomen and umbilical hernia.
diagnosed because of typical facies and skeletal X-ray changes (Figure I), corneal clouding, hepatosplenomegaly and isolation of urinary mucopolysaccharides. The parents did not attend for further management. The patient was mentally retarded and suffered intermittent respiratory difficulties. At age 2 years 6 months he developed acute respiratory distress and died at home. PATHOLOGY At autopsy, there were typical features of mucopolysstccharidosis (Figure 2), with wide forehead, hirsutism, hypertelorism, protruding tongue, enlarged abdomen, hepatosplenomegaly and umbilical hernia. The gibbous deformity affected the lumbar vertebrae L1,L2; the spinal canal at this level appeared narrowed in an anterior-posterior diameter, and widened in transverse diameter. The heart was enlarged (120 g); both the mitral valve and aortic wall were gelatinous due to mucopolysaccharidedeposition. Death was due to mitral valve incompetence. The liver weighed 930 g (normal = < 500 g) and a frozen autopsy sample demonstrated reduction in alpha-L-iduronidase (0.08 nmol/mg protein/h; control = 10.0 nmol/mg protein/h), reduced beta-galactosidase (53.5 nmol/mg protein/h; control = 290 nmol/mg protein/h), and elevated beta-hexosaminidase(71.5 pmol/mg protein/h; control =4.2 pmol/mg protein/h), confirming MPSl-H. Light microscopy showed vacuolated hepatocytes and electronmicroscopy
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Figure 3. a, Lumbar spinal cord divided into two separate structures.The anterior spinal artery is single. b, Lumbar cord distal to a. The cord has partly reunited, with the posterior portions fused.
confirmed intracytoplasmic faintly granular vacuoles consistent with GAGS. Kupffer cells contained multilamellar cytoplasmic bodies (MCBs) consistent with ganglioside. The brain weighed 1300 g and showed thickened leptomeninges.A portion of the left frontal lobe was snap-frozen and stored at - 70°C. The brain and spinal cord were fixed for 14 days in 20% formol saline. Coronal slices showed distended perivascular spaces causing ‘pitting’of the white matter. Sections were stained by haematoxylin and eosin (H & E), haematoxylin van Gieson (HVG), Lux01 Fast Blue/haematoxylin and eosin (LFB/H & E), periodic acid Schiff (PAS), Alcian Blue (AB), Glees Marsland and Oil Red 0.The leptomeninges, choroid plexuses and perivascular spaces contained vacuolated cells, only faintly stained with AB, even on cryostat sections. Cryostat sections of frozen brain demonstrated PAS positive material in cortical neurons. Some brain stem neurons and anterior horn cells had distended cytoplasm suggestive of the presence of storage material. The spinal cord showed thickened arachnoid and localized diastematomyelia in the lumbar cord (Figure 3a). The cord divided into two structures, separated only by arachnoid and emerging nerve root fibres, before reuniting distally as a single structure partially fused at the
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posterior columns (Figure 3b). The diastematomyelia extended over only a few segments, L1L3. There was no fibrous or bony septum. Each cord had a central canal, and complete sets of anterior and posterior horns, but the nerve roots ar blood vessels did not appear to be duplicated. The medial facing surfaces were hypoplastic. The meninges did not appear more thickened at the level of cord duplication than elsewhere. The central canal was single but dilated just proximal to the duplication, and single and of normal shape distally. The cord did not appear to be shortened. There was no evidence of any other malformation elsewhere in the cord or brain.
DISCUSSION Both Hurler’s disease and diastematomyelia are rare. The possibility of GAG storage-induced vertebral anomaly and cord malformation at the same level in the same patient being due to chance is extremely unlikely. Although the pathology of Hurler’s disease has been described in detail (Lake, 1984; Becker &Yates, 1985), there is no account of spinal cord malformation in the disorder, but it must be acknowledged that the number of cases with autopsy examination of the cord is small. The pathology described to date relates to storage of GAGSor ganglioside, the former resulting in deformities and enlargement of tissues. Mechanical compression by vertebral abnormalities, odontoid subluxation or thickening of the connective tissue may cause cord flattening and tract degeneration (Blaw & Langer, 1969; Brill et al., 1978). These are acquired complications. Diastematomyelia is regarded as an extreme form of spinal dysraphism due to defective neurulation, often associated with neuroectodemal defects, such as spina bifida (Moes & Hendrick, 1963) or other bony abnormalities. A fibrous or bony spur is frequently present, sometimes dividing the two cords or attaching the dura to the overlying bony defect. There was no spina bifida in our case, and the only vertebral anomaly was ‘hooked’ bodies characteristic of mucopolysaccharidosis, thought to be caused by compression atrophy of the ventral edge, due to nucleus pulposus herniation (Caffey, 1978). It is estimated that diastematomyelia occurs during the second or third phases of caudal neural tube formation, which correspond to development of the vertebrae (Lemire et al., 1975; Dryden, 1980). The second (canalization) phase occurs between 30-50 days gestation, and the third (retrogressive differentiation) phase occurs from 50 days and continues into postnatal life (Lemire et al., 1975). Early neural tube forking might also be responsible (Rokos, 1979). To postulate that mucopolysaccharide storage was responsible for the congenital malformation, it would have to be present at a stage of neural tube canalization. We are not aware of any fetal studies showing mucopolysaccharide storage as early as 30 days, but fibroblasts from chorionic villi at 9 weeks gestation show evidence of intracytoplasmic storage of GAGS (Lake, personal communication, 1990).There is increasingsupport for the view that mesoderm plays an important role in the causation of dysraphic conditions (Friede, 1989), and that neural tube defects may result from mesodermal damage underlying the head folds (Morrissey & Mottet, 1980; Takeuchi & Takeuchi, 1985) so that the interaction between mesoderm and ectoderm is responsible for many neuroectodermal defects. This case lends further support for that suggestion. We cannot exclude that diastematomyelia in this child was due to the local high incidence of neural tube defects (Brett & Keohane, 1988)or to genetic or other factors unrelated to Hurler’s disease. However, the concurrence of both gibbous deformity and diastematomyelia at the same level strongly suggests that the disorders may be interrelated in this patient.
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ACKNOWLEDGEMENTS Mrs Elisabeth Young, Institute for Child Health London, UK kindly performed the enzyme analyses. Professor Brian Lake, Pathology Department, The Hospital for Sick Children, Great Ormond Street, gave helpful advice. Ms A. Harrison and Ms J. Barry gave photographic assistance. REFERENCES Becker L.E. & Yates A. (1985) Inherited metabolic disease. In Textbook of Neuropafhology, Eds R.L. Davis & D.M. Robertson, pp. 3 11-315. Williams & Wilkins, Baltimore Blaw M.E. & Langer L.O. (1969) Spinal cord compression in Morquio-Brailsford’s disease. Journal of Pediatrics 74, 593-600 Brett F. & Keohane C. (1988) Neural tube defects in multiple pregnancy. Irish Journal of Medical Science 157, 254 (Abstract) Brill C.B., Rose J.S., Godrnilow L., Sklower S., Wilner J. & Hirschorn K. (1978) Spastic quadriparesis due to C1-C2 subluxation in Hurler syndrome. Journal of Pediarrics 9 2 , 4 4 1 4 3 Caffey J. (1987) Congenital disturbances. In Pediatric X-Ray Diagnosis, Vol. 2, Section 9, 7th edition, p. 1611. Year Book Medical Publishers, Chicago Dryden R.J. (1980) Duplication of the spinal cord: discussion of the possible embryogenesis of diplomyelia. Developmental Medicine and Child Neurology 22,234243 Friede R.L. (1989) In Developmental Neuropathology, 2nd edition, pp. 258-259. Springer-Verlag, Berlin Lake B.D. (1984) Lysosomal enzyme deficiencies. In Greenfield’s Neuropathotogy, 4th edition, pp. 534-539. Eds J.H. Adams, J.A.N. Corsellis & L.W. Duchen. Arnold Press, London Lemire R.J., Loeser J.D., Leech R.W. & Alvord E.C. (1975) Secondary caudal neural tube formation. In Normal and Abnormal Development ofrhe Human Nervous System, pp. 77-80. Harper & Row, Maryland Moes C.A.F. & Hendrick E.B. (1963) Diastematomyelia. Journalof Pediatrics 63,238-248 Morrissey R.E. & Mottet N.K. (1980) Neural tube defects and brain anomalies: a review ofselected teratogens and their possible modes of action. Neurotoxicology 2,125-162 Rokos J. (1979) The pathogenesis of spina bifida and related malformations. In Recent Advances in Neuropafhology I , Eds W.I. Smith & J.B. Cavanagh, pp. 225-245. Churchill Livingstone, Edinburgh Takeuchi I.K. & Takeuchi Y.K. (1985) 5-Azacytidine-induced exencephaly in mice. Journal ofAnatomy 140,403-412
Received 10 July 1990 Accepted 25 September 1990
Case report Hurler’s disease with diastematomyelia C. K E O H A N E , J. O’LEARY, M. O’NEILL* A N D P. J. KEARNEYT Departments of Pathology (Neuropathology Laboratory), *Radiology and TPaediatrics, Cork Regional Hospital, Cork, Ireland
KEOHANE C., O’LEARY J., O’NEILLM. & KEARNEY P. J. (199 1) Neuropathology and Applied Neurobiology 17,163-167 Case report. Hurler’s disease with diasternatomyelia
A case of Hurler’s disease is reported in a child with a gibbous deformity of the lumbar vertebrae L1/L2 and a localized diastematomyelia of the spinal cord at L1/L3. The association of an enzyme disorder affecting connective tissue with spinal cord dysraphism has not been reported before, and may be fortuitous. However, as each condition is rare, the occurrence of both gibbous deformity due to Hurler’s and diastematomyelia in the same child, makes it unlikely to be a chance association. We suggest that defective neurulation in this case may be related to mesodermal damage associated with mucopolysaccharidosis. Keywords: Hurler’s disease (MPS 1-H), mucopolysaccharidosis 1, diastematomyelia, CNS malformation
INTRODUCTION
In Hurler’s disease (MPSI-H), a genetic deficiency of alpha-L-iduronidase, results in storage of mucopolysaccharides (also called glycosaminoglycans, GAGS)in connective tissues, especially bone (Lake, 1984;Becker & Yates, 1985),causing deformities. A characteristic bony change is a ‘hook’ shaped lumbar vertebral body which may cause spinal kyphosis and gibbus formation, with secondary cord compression. A partial deficiency of beta-galactosidase is also present, causing ganglioside storage in neurons and Kupffer cells. Congenital malformations with onset in uterine life are not a known feature of Hurler’s disease. We describe a case of Hurler’s disease in which diastematomyelia of the lumbar cord occurred in association with a gibbous deformity and ‘hooked‘ vertebrae, characteristic of mucopolysaccharidosis. CASE H I S T O R Y The patient, a boy aged 2 years 6 months, was the only child of healthy parents, who were second cousins. There was no family history of disease. At 8 months, Hurler’s disease was Correspondence to: Dr Catherine Keohane, Neuropathology Laboratory, Pathology Department, Cork Regional Hospital, Wilton, Cork, Ireland.
164
C. Keohane et al.
Figure 1. Radiograph showing ‘hooked’ vertebral bodies, maximal at L2 (asterisk). Figure 2. Note hypertelorism, coarse features, hirsutism,enlarged abdomen and umbilical hernia.
diagnosed because of typical facies and skeletal X-ray changes (Figure I), corneal clouding, hepatosplenomegaly and isolation of urinary mucopolysaccharides. The parents did not attend for further management. The patient was mentally retarded and suffered intermittent respiratory difficulties. At age 2 years 6 months he developed acute respiratory distress and died at home. PATHOLOGY At autopsy, there were typical features of mucopolysstccharidosis (Figure 2), with wide forehead, hirsutism, hypertelorism, protruding tongue, enlarged abdomen, hepatosplenomegaly and umbilical hernia. The gibbous deformity affected the lumbar vertebrae L1,L2; the spinal canal at this level appeared narrowed in an anterior-posterior diameter, and widened in transverse diameter. The heart was enlarged (120 g); both the mitral valve and aortic wall were gelatinous due to mucopolysaccharidedeposition. Death was due to mitral valve incompetence. The liver weighed 930 g (normal = < 500 g) and a frozen autopsy sample demonstrated reduction in alpha-L-iduronidase (0.08 nmol/mg protein/h; control = 10.0 nmol/mg protein/h), reduced beta-galactosidase (53.5 nmol/mg protein/h; control = 290 nmol/mg protein/h), and elevated beta-hexosaminidase(71.5 pmol/mg protein/h; control =4.2 pmol/mg protein/h), confirming MPSl-H. Light microscopy showed vacuolated hepatocytes and electronmicroscopy
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Figure 3. a, Lumbar spinal cord divided into two separate structures.The anterior spinal artery is single. b, Lumbar cord distal to a. The cord has partly reunited, with the posterior portions fused.
confirmed intracytoplasmic faintly granular vacuoles consistent with GAGS. Kupffer cells contained multilamellar cytoplasmic bodies (MCBs) consistent with ganglioside. The brain weighed 1300 g and showed thickened leptomeninges.A portion of the left frontal lobe was snap-frozen and stored at - 70°C. The brain and spinal cord were fixed for 14 days in 20% formol saline. Coronal slices showed distended perivascular spaces causing ‘pitting’of the white matter. Sections were stained by haematoxylin and eosin (H & E), haematoxylin van Gieson (HVG), Lux01 Fast Blue/haematoxylin and eosin (LFB/H & E), periodic acid Schiff (PAS), Alcian Blue (AB), Glees Marsland and Oil Red 0.The leptomeninges, choroid plexuses and perivascular spaces contained vacuolated cells, only faintly stained with AB, even on cryostat sections. Cryostat sections of frozen brain demonstrated PAS positive material in cortical neurons. Some brain stem neurons and anterior horn cells had distended cytoplasm suggestive of the presence of storage material. The spinal cord showed thickened arachnoid and localized diastematomyelia in the lumbar cord (Figure 3a). The cord divided into two structures, separated only by arachnoid and emerging nerve root fibres, before reuniting distally as a single structure partially fused at the
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posterior columns (Figure 3b). The diastematomyelia extended over only a few segments, L1L3. There was no fibrous or bony septum. Each cord had a central canal, and complete sets of anterior and posterior horns, but the nerve roots ar blood vessels did not appear to be duplicated. The medial facing surfaces were hypoplastic. The meninges did not appear more thickened at the level of cord duplication than elsewhere. The central canal was single but dilated just proximal to the duplication, and single and of normal shape distally. The cord did not appear to be shortened. There was no evidence of any other malformation elsewhere in the cord or brain.
DISCUSSION Both Hurler’s disease and diastematomyelia are rare. The possibility of GAG storage-induced vertebral anomaly and cord malformation at the same level in the same patient being due to chance is extremely unlikely. Although the pathology of Hurler’s disease has been described in detail (Lake, 1984; Becker &Yates, 1985), there is no account of spinal cord malformation in the disorder, but it must be acknowledged that the number of cases with autopsy examination of the cord is small. The pathology described to date relates to storage of GAGSor ganglioside, the former resulting in deformities and enlargement of tissues. Mechanical compression by vertebral abnormalities, odontoid subluxation or thickening of the connective tissue may cause cord flattening and tract degeneration (Blaw & Langer, 1969; Brill et al., 1978). These are acquired complications. Diastematomyelia is regarded as an extreme form of spinal dysraphism due to defective neurulation, often associated with neuroectodemal defects, such as spina bifida (Moes & Hendrick, 1963) or other bony abnormalities. A fibrous or bony spur is frequently present, sometimes dividing the two cords or attaching the dura to the overlying bony defect. There was no spina bifida in our case, and the only vertebral anomaly was ‘hooked’ bodies characteristic of mucopolysaccharidosis, thought to be caused by compression atrophy of the ventral edge, due to nucleus pulposus herniation (Caffey, 1978). It is estimated that diastematomyelia occurs during the second or third phases of caudal neural tube formation, which correspond to development of the vertebrae (Lemire et al., 1975; Dryden, 1980). The second (canalization) phase occurs between 30-50 days gestation, and the third (retrogressive differentiation) phase occurs from 50 days and continues into postnatal life (Lemire et al., 1975). Early neural tube forking might also be responsible (Rokos, 1979). To postulate that mucopolysaccharide storage was responsible for the congenital malformation, it would have to be present at a stage of neural tube canalization. We are not aware of any fetal studies showing mucopolysaccharide storage as early as 30 days, but fibroblasts from chorionic villi at 9 weeks gestation show evidence of intracytoplasmic storage of GAGS (Lake, personal communication, 1990).There is increasingsupport for the view that mesoderm plays an important role in the causation of dysraphic conditions (Friede, 1989), and that neural tube defects may result from mesodermal damage underlying the head folds (Morrissey & Mottet, 1980; Takeuchi & Takeuchi, 1985) so that the interaction between mesoderm and ectoderm is responsible for many neuroectodermal defects. This case lends further support for that suggestion. We cannot exclude that diastematomyelia in this child was due to the local high incidence of neural tube defects (Brett & Keohane, 1988)or to genetic or other factors unrelated to Hurler’s disease. However, the concurrence of both gibbous deformity and diastematomyelia at the same level strongly suggests that the disorders may be interrelated in this patient.
Hurler’s disease with diastematomyelia
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ACKNOWLEDGEMENTS Mrs Elisabeth Young, Institute for Child Health London, UK kindly performed the enzyme analyses. Professor Brian Lake, Pathology Department, The Hospital for Sick Children, Great Ormond Street, gave helpful advice. Ms A. Harrison and Ms J. Barry gave photographic assistance. REFERENCES Becker L.E. & Yates A. (1985) Inherited metabolic disease. In Textbook of Neuropafhology, Eds R.L. Davis & D.M. Robertson, pp. 3 11-315. Williams & Wilkins, Baltimore Blaw M.E. & Langer L.O. (1969) Spinal cord compression in Morquio-Brailsford’s disease. Journal of Pediatrics 74, 593-600 Brett F. & Keohane C. (1988) Neural tube defects in multiple pregnancy. Irish Journal of Medical Science 157, 254 (Abstract) Brill C.B., Rose J.S., Godrnilow L., Sklower S., Wilner J. & Hirschorn K. (1978) Spastic quadriparesis due to C1-C2 subluxation in Hurler syndrome. Journal of Pediarrics 9 2 , 4 4 1 4 3 Caffey J. (1987) Congenital disturbances. In Pediatric X-Ray Diagnosis, Vol. 2, Section 9, 7th edition, p. 1611. Year Book Medical Publishers, Chicago Dryden R.J. (1980) Duplication of the spinal cord: discussion of the possible embryogenesis of diplomyelia. Developmental Medicine and Child Neurology 22,234243 Friede R.L. (1989) In Developmental Neuropathology, 2nd edition, pp. 258-259. Springer-Verlag, Berlin Lake B.D. (1984) Lysosomal enzyme deficiencies. In Greenfield’s Neuropathotogy, 4th edition, pp. 534-539. Eds J.H. Adams, J.A.N. Corsellis & L.W. Duchen. Arnold Press, London Lemire R.J., Loeser J.D., Leech R.W. & Alvord E.C. (1975) Secondary caudal neural tube formation. In Normal and Abnormal Development ofrhe Human Nervous System, pp. 77-80. Harper & Row, Maryland Moes C.A.F. & Hendrick E.B. (1963) Diastematomyelia. Journalof Pediatrics 63,238-248 Morrissey R.E. & Mottet N.K. (1980) Neural tube defects and brain anomalies: a review ofselected teratogens and their possible modes of action. Neurotoxicology 2,125-162 Rokos J. (1979) The pathogenesis of spina bifida and related malformations. In Recent Advances in Neuropafhology I , Eds W.I. Smith & J.B. Cavanagh, pp. 225-245. Churchill Livingstone, Edinburgh Takeuchi I.K. & Takeuchi Y.K. (1985) 5-Azacytidine-induced exencephaly in mice. Journal ofAnatomy 140,403-412
Received 10 July 1990 Accepted 25 September 1990
