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Hereditary hydrocephalus in laboratory animals and humans
Exp. PathoL 1988; 35: 239-246 VEB Gustav Fischer Verlag Jena
Mini-Review
Departments of Anatomy and Surgery (Section of Neurosurgery)2), Faculties of Medicine and Dentistry, The University of Manitoba, Winnipeg, MB, Canada
Hereditary hydrocephalus in laboratory animals and humans!) By J. E. BRUNI, M. R. DEL BIGIO'), E. R. CARDOSO'), and T. V. N. PERSAUD
Address for correspondence: Dr. J. E. BRUNI, Associate Professor, Department of Anatomy, Faculties of Medicine and Dentistry, The University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada, R3E OW3 Key war d s : hydrocephalus, hereditary; hereditary hydrocephalus; congenital hydrocephalus; development, defects; hy·3 mice; mutants, mice; cerebral ventricular dilatation; neuropathology
Summary Cerebral ventricle dilatation secondary to disturbed flow of CSF has been observed as an inheritable trait in a variety oflaboratory animals as well as in humans. In few groups, however, has the neuropathology been adequately elucidated. In most cases, defecti ve development of the cerebral aqueduct or ofthe subarachnoid space has been observed. Further study is needed to understand the developmental mechanisms that fail and give rise to hydrocephalus in such models. Congenital hydrocephalus has been experimentally induced in the offspring oflaboratory animals following maternal treatment with chemicals (16, 39), exposure to viruses (12), by X-irradiation (72, 73), and vitamin deficient diets (15,52,54,55,57). Inherited forms of hydrocephalus, although less common, have also been described in a variety oflaboratory and domestic animals (2,8, 17,25,46) as well as in humans (22). In experimental animals, defects of development such as hereditary hydrocephalus provide useful models to study processes of normal development as well as to help elucidate the pathogenesis of similar conditions in humans (13, 33). Regardless of whether hydrocephalus occurs spontaneously or is induced by environmental agents, however, the cytopathology of the disorder is similar (3, 12).
Hereditary hydrocephalus in the mouse Several distinct hereditary forms of hydrocephalus have been documented in mice including the hy-1 (18), hy-2 (82), hy-3 (6, 30, 50, 51,63,64,80), oh (10), ch (28, 29, 63,65,66), andhpy (13,32) strains. Recessively inherited hydrocephalus has also been reported in inbred mice of the BN and C57BL strains (53,61,74). They all develop a domed-shaped skuIJ during the neonatal period due to dilatation of the ventricular system and usually die prior to maturity. A brief description of the principal mutants follows. hy-1 and hy-2 mutants Hydrocephalus-1 (hy-1) was first described by CLARK (18). It is a recessive mutation, associated with flexed tail, in mice that are no longer available as laboratory stock (27). Some homozygotes 1) This work was supported by grants from the Manitoba Health Research Council and University of Manitoba Faculty Fund.
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showed skull enlargement due to hydrocephalus at birth while others did not until the 2nd week after birth (19). The majority of mice died between 20-40 dofage but some attained sexual maturity and were able to reproduce. Hydrocephalus was shown to be due to occlusion of the cerebral aqueduct but the primary cause was undetermined. A similar mutation, now also extinct, designated hydrocephalus-2 (hy-2) was described by ZIMMERMAN (82) in the offspring of a strain of wild mice. This recessively inherited mutation was more severe than hy-l and associated with inhibition of growth and sterility. hy-3 mutant The recessively inherited hydrocephalus-3 (hy-3) mutation was discovered by GRUNEBERG (30). Although it resembled hy-l and hy-2 it exhibited certain differences suggestive of a new gene locus or allelomorph. The degree of hydrocephalus was more variable in hy-3 mice, the onset of clinical signs was usually later, and a nasal discharge was a peculiar feature of the hydrocephalic young ones (30). The hy-3 mouse develops communicating hydrocephalus that can be identified 3 - 5 d after birth (6). Hydrocephalic animals exhibit growth retardation and usually die by 3 weeks of age. BERRY (6) believed that a defect in the postnatal differentiation of the leptomeninges over the cerebral hemispheres prevented proper development of the subarachnoid space and obstructed CSF flow. The developmental course of hydrocephalus in this strain of mice progresses through 3 stages: 1) dilatation of the lateral ventricles; 2) edema in the periventricular white matter of the lateral ventricles, followed by compression of the quadrigeminal plate and aqueduct and 3) extension of edema into the grey matter, cyst formation, and rupture ofCSF into the subarachnoid space (51,63, 64). Unlike other types of hydrocephalus, aqueductal stenosis is the consequence not the cause of ventricular dilatation in the hy-3 mouse. Ventricular dilatation and edema compress the quadrigeminal plate and proximal aqueduct (50, 64). Displacement and deformity of the cerebral vasculature by the expanding ventricles results in diminished blood flow and cerebral edema and is believed to be the cause of tissue destruction and cyst formation (50, 80). oh mutant An autosomal recessive mutation, called obstructive hydrocephalus (oh), was first described by BORIT and SIDMAN (10). The incidence of this mutation was reported to be 17.9 %. Generalized ventricular dilatation is evident within a few days of birth. Incomplete obstruction of the rostral aqueduct and fourth ventricle secondary to compression by the expanding cerebral hemispheres occurs after 2 weeks of age. Affected animals usually die by 1 month of age. The histopathological changes are similar to those reported in other types of hydrocephalus. ch mutant A recessive form of hydrocephalus (ch) that is lethal at birth was described by GRUNEBERG (29). The ch mouse develops obstructive hydrocephalus in association with defects of the musculoskeletal and urogenital systems. Anomalous development of cartilage causes an abnormal shortening of the base of the skull and impeded flow of CSF from the foramen of Magendie in these animals (29). GREEN (28) showed that ventricular dilation began on day 11 of gestation and proposed that the hydrocephalus may develop secondary to retarded development of the subarachnoid space. RAIMONDI et al. (63) further described the development of cellular and extracellular cerebral pathology in this mutant. RICHARDSON et al. (65,66) proposed that abnormal endochondral ossification in the ch mouse was due to a failure of mesenchymal differentiation because of inadequate amounts of the chondroitin-sulfate proteoglycan. Primary failure of mesenchymal differentiation that retards formation of the subarachnoid space of defective development of the basi occiput secondary to failure of chondrification or endochondral ossification may be responsible for the communicating hydrocephalus in these animals (65). hpy mutant Another mutation producing postnatal hydrocephalus associated with polydactyly was originally discovered in descendants of X-irradiated mice (32, 33). Inheritance was recessive and 240
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homo zygotes showed a hopping gait, scoliosis and male sterility although females could breed successfully for a time (33). Hydrocephalus was observed in 20.4 % of offspring by neonatal day 6 and many affected animals died within 14 d (13). Although the overall manifestation of hydrocephalus resembled that in the oh mouse (10), secondary obstruction or stenosis of the aqueduct was not observed in the hpy mutant. The precise factor(s) responsible for the development of this form of non-obstructive hydrocephalus is unknown.
SUMS/NP mutant The pathophysiology of congenital hydrocephalus in a new inbred strain of mouse designated SUMS/NP has been studied recently but not extensively (62, 78). Progressive hydrocephalus which is recessively inherited in this strain, was evident soon after birth in the fornl of an enlarged head, and caused death prior to breeding age 01, 78). Affected animals gradually acquired functional disturbances that included abnormal gait but the syndrome was not associated with skeletal abnormalities (11, 62). eSF pressure in normal and hydrocephalic mice was not significantly different during the first week after birth. After the first week, however, the pressure in normal animals was significantly lower than in hydrocephalic animals (34, 36). In hydrocephalic mice, resistance to eSF absorption from the lateral ventricles was higher than in normal mice at all ages but resistance to absorption from the cisterna magna in hydrocephalic animals was not different from normal at any age (34- 36). JONES (34, 36) concluded from these studies that there was a transient resistance to absorption from the lateral ventricles immediately after birth in normal mice. This was believed to reflect a progressive maturation of the ventricular system which rendered it susceptible to outflow obstruction at this time. In contrast, hydrocephalic animals had a high resistance in the flow pathway between the lateral ventricles and cisterna magna but no defect in absorption from the subarachnoid space. JONES (34, 36) speculated that the site of this resistance was the cerebral aqueduct and was due to an abnormal reduction in its cross-sectional area. In more recent studies it has been confirmed that hydrocephalus develops prenatally in this strain of mice as a result of reduced cross-sectional area or absence of part of the cerebral aqueduct (11, 37). The precise mechanism by which this occurs, however, remains to be determined. In a similar congenitally hydrocephalic mouse (MT/Hokldr) model in which the cerebral aqueduct was narrowed but never completely stenosed TAKEUCHI et al. (71) recently concluded that the primary cause of hydrocephalus was a failure of the subcommissural organ (SeO) and posterior commissure to develop. In this regard similarities between hereditary and various teratogen models are of particular interest. Aqueductal stenosis due to maldevelopment of the seo has also been proposed in X-ray induced congenital hydrocephalus (73) and in hydrocephalus produced by feeding pregnant rats vitamin deficient diets (54,57). OVERHOLSER et al. (57), for example, maintained that the pressure of seo fluid secretion prevented collapse and closure of the cerebral aqueduct during fetal development. Consistent with this hypothesis TAKEUCHI and TAKEUCHI (72) recently concluded that maldevelopment of the seo in X-irradiated fetuses caused a reduction in the amount of its secretions which normally prevented closure of the cerebral aqueduct during embryogenesis, and resulted in stenosis of the aqueduct. NEWBERNE and O'DELL (55) contended that the active mitosis observed in seo cells of vitamin B l2-deficient embryonic rats precluded much functional activity on the part of these cells during fetal development. They concluded, therefore, that a more reasonable explanation for the aqueductal stenosis was the failure of normal mitosis-arresting mechanisms which allowed growth to continue beyond its normal limit. NEWBERNE (54), however, subsequently proposed that an absence of seo secretions resulted in disturbed fluid balance (an excess of fluid) and aqueductal stenosis in vitamin B l2 -deficient hydrocephalic rats. Hereditary hydrocephalus in hamsters
Hydrocephalus inherited as a simple recessive trait in the hamster was reported by YOON and SLANEY (81). This condition of undetermined etiology is evident between 2-6 d after birth. Exp. Pathol. 35 (1988) 4
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Although a few hydrocephalic hamsters survived for several months, most died within 3 weeks of birth. The lateral and third ventricles of affected animals were grossly dilated and the cerebral aqueduct and fourth ventricle were narrowed as a result of compression. Hereditary hydrocephalus in rats
The laboratory rat has a spontaneous incidence of hydrocephalus that has been variously reported to be 0.3% [HAIN 1937, cited in (59)],0.65% [COLTON 1929, cited in (59)], and 1.2% [FRANKLIN and BRENT 1964, cited in (40, 41)]. Congenital hydrocephalus in the rat has not been well characterized. PARK and NOWOSIELSKI-SLEPOWRON (59) reported a high incidence (41 %) of congenital hydrocephalus limited to males in an inbred group of Sprague-Dawley rats. First evident in the form of enlarged heads about 10 d after birth, death occurred during the 4th week. KOHN et al. (40, 41) described a mutant rat strain with a high (44 %) incidence of a communicating type of hydrocephalus. Hydrocephalus could be detected at 1-2 d of age and the rats survived for 4-5 weeks. Dilatation was restricted to the lateral ventricles. The cause has been attributed to underdevelopment of pia-arachnoid cells and veins in the periosteal-dural layers of these animals (40). Descriptions of the morphological characteristics of hydrocephalus in the rat (40, 47) are not unlike those observed in the mouse models. A recessive mutation has been described in the Wistar rat in which hydrocephalus is associated with eye, skeletal, and hair defects (21). Affected animals survived and were capable of reproducing. Disruption of the neuroepithelial basal lamina in the cephalic neural tube and abnormal stratification in the region of the midbrain-thalamic junction evident on embryonic day 11 was believed to be responsible for prenatal stenosis of the cerebral aqueduct in affected animals. Wistar rats of the inbred CPB-WE and Cpb:WU strains also have a high incidence of hydrocephalus associated with (in the former case) abnormal development of the optic tract and other'disorders of the CNS (75). The cause, however, could not be discerned. In another inbred strain of rats, Wistar-Lewis (LEWl1ms), hydrocephalus results from primary occlusion of the third or lateral ventricles during embryological development (67). Hydrocephalic neonates were recognized 2 d after birth and usually died at 10-20 d of age. The pathogenesis of this condition is also not established. Inheritable types of hydrocephalus in humans
In humans, comparatively few forms of hereditary hydrocephalus have been documented (22). The incidence of congenital hydrocephalus has been estimated to be between 0.11 and 3.5 per thousand live births (22, 70). The wide range has been attributed to discrepancies in definitions of hydrocephalus used by various investigators (22). Within families of hydrocephalic children, however, the overall risk of having a second child with hydrocephalus is 1-2%. Hydrocephalus secondary to stenosis of the aqueduct recurs in 5.6-12% of affected families (4, 14). The best known form of hereditary hydrocephaly is the X-chromosome linked aqueductal stenosis that was first reported by WINKEL in 1893 [cited in (7)], the pathology of which was described by BICKERS and ADAMS (7). This form of hydrocephalus is associated to varying degrees with other abnormalities that include mental deficiency, flexion deformity of the thumbs, peculiar facial features, and spasticity (22, 23, 43). It has been identified before the 20th week of gestation (20). X-linked hydrocephalus accounts for approximately 2% of all cases of hydrocephalus (26). New families with this defect continue to be reported (1, 20, 31,42). Although stenosis has been observed throughout the length of the aqueduct, the ependymal lining is usually intact with no surrounding gliosis. The cause of the stenosis is not known but it has been suggested to be secondary to compression by the expanded lateral ventricles (42, 76). Hereditary hydrocephalus in conjunction with neurologic dysfunction, abnormalities of eye, and disturbed cortical architecture (Warburg's or HARD ± E Syndrome) has also been frequently described (9, 58, 60). Although aqueductal stenosis has been reported in this syndrome, it too may be secondary to a posterior fossa abnormality. The disorder is considered to be inherited as 242
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an autosomal recessive trait. Hydrocephalus has also been described as a result of an autosomal dominant gene with partial penetrance (43) and in monozygotic twins (24). Hydrocephalus has been described in association with numerous other inheritable conditions. Communicating hydrocephalus associated with short ribs, thoracic dysplasia, short limbs, and developmental delay may be inherited as an autosomal recessive condition (79). A similar syndrome of communicating hydrocephalus, undescended scapulae, and facial abnormalities is inherited as an autosomal dominant trait with variable expression (77). An autosomal recessive syndrome of communicating hydrocephalus secondary to posterior fossa bleeding and associated with facial, heart, bone, and genital abnormalities has been described (5). Basal cell nevus syndrome, an autosomal dominant disorder that affects mesodermal and ectodermal tissues including meninges, may be associated with hydrocephalus, perhaps secondary to aqueductal stenosis (49). Similarly, von Recklinghausen's disease, an inheritable disorder of neuroectodermal and mesenchymal tissues may be associated with aqueductal stenosis, but no familial cases of hydrocephalus have been described (69). The Dandy-Walker posterior fossa cyst, often inherited recessively, has been observed in siblings repeatedly (22, 44). A similar malformation with basal cistern obstruction to CSF flow, vermal cerebellar agenesis, port wine nevi, and communicating hydrocephalus has been described as an autosomal dominant trait with incomplete expression (56). Hydrocephalus may be associated with known recessive traits such as osteopetrosis, Hurler syndrome, and Tay-Sachs disease. In certain geographical areas, families have increased frequency of hydrocephalus combined with anencephaly, encephalocele, and spina bifida (22). The inheritance of hydrocephalus with neural-tube defects is polygenic and multifactorial; no consistent neuropathology has been observed (44,48). Thus, human hydrocephalus may be inherited as an X-linked, autosomal dominant, or autosomal recessive trait. Although aqueductal stenosis has been documented in several families, many recent reports suggest that the stenosis may be secondary. In general, the mechanism of obstruction to CSF flow in inherited forms of hydrocephalus is not well established, probably because comparatively few cases have been studied in detail. References 1. ALAWAD!, S. A., FARAG, T. I., NAGUIB, K., TEEBI, A. S., ELKHALlFA, M. Y., YASSIN, S.: X-linked hydrocephalus (Bicker-Adams-Edwards-syndrome). J. Kuwait Med. Assoc. 1984; 18: 187-190. 2. BAKER, M. L., PAYNE, L. C., BAKER, G. N.: The inheritance of hydrocephalus in cattle. J. Hered. 1961; 52: 135- \38. 3. BANNISTER, C. M., MUNDY, J. E.: Some scanning electron microscopic observations ofthe ependymal surface of the ventricles of hydrocephalic Hy3 mice and a human infant. Acta Neurochir. 1979; 46: 159-168. 4. BAY, C., KERZIN, L., HALL, B. D.: Recurrence risk in hydrocephalus. Birth Defects: Orig. Art. Ser. 1979; XV (5C): 95- \05. 5. BEEMER, F. A., ERTBRUGGEN, I. Y.: New syndrome: Peculiarfacial appearance, hydrocephalus, double-outlet right ventricle, genital abnormalities, and dense bones with lethal outcome. Am. J. Med. Genet. 1984; 19: 391-398. 6. BERRY, R. J.: The inheritance and pathogenesis ofhydrocephalus-3 in the mouse. J. Pathol. Bacteriol. 1961; 81: 157-167. 7. BICKERS, D. S., ADAMS, R. D.: Hereditary stenosis of the aqueduct of Sylvius as a cause of congenital hydrocephalus. Brain 1949; 72: 246-262. 8. BLACKWELL, R. L., KNOX, J. H., COBB, E. H.: A hydrocephalus lethal in Hereford cattle. J. Hered. 1959; 50: 143-148. 9. BORDARIER, C., AICARD!, J., GOUTIERES, F.: Congenital hydrocephalus and eye abnormalities with severe developmental brain defects: Warburg's syndrome. Ann. Neurol. 1984; 16: 60-65. 10. BORlT, A., SIDMAN, R. L.: New mutant mouse wi.th communicating hydrocephalus and secondary aqueductal stenosis. Acta Neuropathol. 1972; 21: 316-331. 11. BRUNI, J. E., DEL BIGIO, M. R., CARDOSO, E. R., PERSAUD, T. Y. N.: Neuropathology of congenital hydrocephalus in the SUMS/NP mouse. Acta Neurochir. 1988 (in press). 12. - - CLATTENBURG, R. E.: Ependyma: normal and pathological. A review of the literature. Brain Res. Rev. 1985;9: 1-19. Exp. Pathol.
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Psychiat. 1982; 45: 280. 63. RAIMONDI, A. J., BAILEY, O. T., MeLONE, D. G., LAWSON, R. F., EcHEVERRY, A.: The pathophysiology and morphology of murine hydrocephalus in Hy-3 and Ch mutants. Surg. Neurol. 1973; 1: 50-55. 64. - CLARK, S. J., McLoNE, D. G.: Pathogenesis of aqueductal occlusion in congenital murine hydrocephalus. J. Neurosurg. 1976; 45: 66-77. 65. RICHARDSON, R. R.: Congenital genetic murine (ch) hydrocephalus. A structural model of cellular dysplasia and disorganization with the molecular locus of deficient proteoglycan synthesis. Child's Nerv. Syst. 1985; 1: 87-99. 66. - REES, M. G.: Renal dysplasia and chondrodysplasia in the ch hydrocephalic mouse: A cellular model of defective differentiation and organization. Mount Sinai J. Med. 1984; 51: 188-196. 67. SASAKI, S., GOTO, H., NAGANO, H., FURUYA, K., OMATA, Y., KANAZAWA, K., SUZUKI, K., SUDO, K., COLLMANN, H.: Congenital hydrocephalus revealed in the inbred rat, LEW/Jms. Neurosurgery 1983; 13: 548-554. 68. SHANNON, M. W., NADLER, H. L.: X-linked hydrocephalus. J. Med. Genet. 1968; 5: 326-328. 69. SPADARO, A., AMBROSIO, D., MORACI, A., ALBANESE, V.: Non-tumoral aqueductal stenosis in children affected by von Recklinghausen's disease. Surg. Neurol. 1986; 26: 487-495. 70. STEIN, S. C., FELDMAN, J. G., APFEL, S., KOHL, S. G., GLENN CASEY, A. B.: The epidemiology of congenital hydrocephalus. A study in Brooklyn, NY 1968-1976. Child's Brain 1981; 8: 253-262. 71. TAKEUCHI, 1. K., KIMURA, R., MATSUDA, M., SHOJI, R.: Absence of subcommisural organ in the cerebral aqueduct of congenital hydrocephalus spontaneously occurring in MT/HokIdr mice. Acta Neuropathol. 1987; 73: 320-322. 72. - MURAKAMI, U.: Two types of congenital hydrocephalus induced in rats by X-irradiation in utero: electron microscopic study on the telencephalic wall. J. Anat. 1979; 128: 693-708. 73. - TAKEUCHI, Y. K.: Congenital hydrocephalus following X-irradiation of pregnant rats on an early gestational day. Neurobehav. Toxicol. Teratol. 1986; 8: 143-150. 74. TARASZEWSKY, A., ZALESKA-RuTCZYNSKA, Z.: Congenital hydrocephalus in mice of strains BN and C57BL. Polish Med. J. 1970; 9: 187-195. 75. VAN EDEN, C. G., MULLlNK, J. W. M. A.: Internal hydrocephalus, optic nerve aplasia, and microphthalmia in CPB-WE (Wezob) and Cpb:WU (Wistar) rats. Lab. Animals 1986; 20: 257-265. 17
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76. VARADI, V., CSECSEJ, K., SZEIFERT, G. T., TOTH, Z., PAPP, Z.: Prenatal diagnosis of X-linked hydrocephalus without aqueductal stenosis. J. Med. Genet. 1987; 24: 207-209. 77. WALLER, P. E., AARSKOG, D.: Syndrome of hydrocephalus, costovertebral dysplasia and Sprengel anomaly with autosomal dominant inheritance. Neuropediatrics 1980; 11: 291- 297. 78. WELLER, R. 0., MITCHELL, J., GRIFFIN, R. L.: Cerebral ventriculitis in the hydrocephalic mouse: a histological and scanning electron microscope study. Acta Neuropatho!. 1981; Supp!. VII: 160-161. 79. WINTER, R. M., CAMPBELL, S., WIGGLESWORTH, J. S., NEVRKLA, E. J.: A previously undescribed syndrome of thoracic dysplasia and communicating hydrocephalus in 2 sibs, one diagnosed prenatally by ultrasound. J. Med. Genet. 1987; 24: 204-206. 80. WOZNIAK, M., McLoNE, D. G., RAIMONDI, A. J.: Micro- and macrovascular changes as the direct cause of parenchymal destruction in congenital murine hydrocephalus. J. Neurosurg. 1975; 43: 535-545. 81. YOON, C. H., SLANEY, J.: Hydrocephalus: a new mutation in the Syrian golden hamster. J. Hered. 1972; 36:
344-346. 82. ZIMMERMAN, K.: Eine neue Mutation der Hausmaus: "hydrocephalus". Z. Indukt. Abstamm. Vererb. 1933; 64: 176-180. (Received February 15, 1988)
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Mini-Review
Departments of Anatomy and Surgery (Section of Neurosurgery)2), Faculties of Medicine and Dentistry, The University of Manitoba, Winnipeg, MB, Canada
Hereditary hydrocephalus in laboratory animals and humans!) By J. E. BRUNI, M. R. DEL BIGIO'), E. R. CARDOSO'), and T. V. N. PERSAUD
Address for correspondence: Dr. J. E. BRUNI, Associate Professor, Department of Anatomy, Faculties of Medicine and Dentistry, The University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada, R3E OW3 Key war d s : hydrocephalus, hereditary; hereditary hydrocephalus; congenital hydrocephalus; development, defects; hy·3 mice; mutants, mice; cerebral ventricular dilatation; neuropathology
Summary Cerebral ventricle dilatation secondary to disturbed flow of CSF has been observed as an inheritable trait in a variety oflaboratory animals as well as in humans. In few groups, however, has the neuropathology been adequately elucidated. In most cases, defecti ve development of the cerebral aqueduct or ofthe subarachnoid space has been observed. Further study is needed to understand the developmental mechanisms that fail and give rise to hydrocephalus in such models. Congenital hydrocephalus has been experimentally induced in the offspring oflaboratory animals following maternal treatment with chemicals (16, 39), exposure to viruses (12), by X-irradiation (72, 73), and vitamin deficient diets (15,52,54,55,57). Inherited forms of hydrocephalus, although less common, have also been described in a variety oflaboratory and domestic animals (2,8, 17,25,46) as well as in humans (22). In experimental animals, defects of development such as hereditary hydrocephalus provide useful models to study processes of normal development as well as to help elucidate the pathogenesis of similar conditions in humans (13, 33). Regardless of whether hydrocephalus occurs spontaneously or is induced by environmental agents, however, the cytopathology of the disorder is similar (3, 12).
Hereditary hydrocephalus in the mouse Several distinct hereditary forms of hydrocephalus have been documented in mice including the hy-1 (18), hy-2 (82), hy-3 (6, 30, 50, 51,63,64,80), oh (10), ch (28, 29, 63,65,66), andhpy (13,32) strains. Recessively inherited hydrocephalus has also been reported in inbred mice of the BN and C57BL strains (53,61,74). They all develop a domed-shaped skuIJ during the neonatal period due to dilatation of the ventricular system and usually die prior to maturity. A brief description of the principal mutants follows. hy-1 and hy-2 mutants Hydrocephalus-1 (hy-1) was first described by CLARK (18). It is a recessive mutation, associated with flexed tail, in mice that are no longer available as laboratory stock (27). Some homozygotes 1) This work was supported by grants from the Manitoba Health Research Council and University of Manitoba Faculty Fund.
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showed skull enlargement due to hydrocephalus at birth while others did not until the 2nd week after birth (19). The majority of mice died between 20-40 dofage but some attained sexual maturity and were able to reproduce. Hydrocephalus was shown to be due to occlusion of the cerebral aqueduct but the primary cause was undetermined. A similar mutation, now also extinct, designated hydrocephalus-2 (hy-2) was described by ZIMMERMAN (82) in the offspring of a strain of wild mice. This recessively inherited mutation was more severe than hy-l and associated with inhibition of growth and sterility. hy-3 mutant The recessively inherited hydrocephalus-3 (hy-3) mutation was discovered by GRUNEBERG (30). Although it resembled hy-l and hy-2 it exhibited certain differences suggestive of a new gene locus or allelomorph. The degree of hydrocephalus was more variable in hy-3 mice, the onset of clinical signs was usually later, and a nasal discharge was a peculiar feature of the hydrocephalic young ones (30). The hy-3 mouse develops communicating hydrocephalus that can be identified 3 - 5 d after birth (6). Hydrocephalic animals exhibit growth retardation and usually die by 3 weeks of age. BERRY (6) believed that a defect in the postnatal differentiation of the leptomeninges over the cerebral hemispheres prevented proper development of the subarachnoid space and obstructed CSF flow. The developmental course of hydrocephalus in this strain of mice progresses through 3 stages: 1) dilatation of the lateral ventricles; 2) edema in the periventricular white matter of the lateral ventricles, followed by compression of the quadrigeminal plate and aqueduct and 3) extension of edema into the grey matter, cyst formation, and rupture ofCSF into the subarachnoid space (51,63, 64). Unlike other types of hydrocephalus, aqueductal stenosis is the consequence not the cause of ventricular dilatation in the hy-3 mouse. Ventricular dilatation and edema compress the quadrigeminal plate and proximal aqueduct (50, 64). Displacement and deformity of the cerebral vasculature by the expanding ventricles results in diminished blood flow and cerebral edema and is believed to be the cause of tissue destruction and cyst formation (50, 80). oh mutant An autosomal recessive mutation, called obstructive hydrocephalus (oh), was first described by BORIT and SIDMAN (10). The incidence of this mutation was reported to be 17.9 %. Generalized ventricular dilatation is evident within a few days of birth. Incomplete obstruction of the rostral aqueduct and fourth ventricle secondary to compression by the expanding cerebral hemispheres occurs after 2 weeks of age. Affected animals usually die by 1 month of age. The histopathological changes are similar to those reported in other types of hydrocephalus. ch mutant A recessive form of hydrocephalus (ch) that is lethal at birth was described by GRUNEBERG (29). The ch mouse develops obstructive hydrocephalus in association with defects of the musculoskeletal and urogenital systems. Anomalous development of cartilage causes an abnormal shortening of the base of the skull and impeded flow of CSF from the foramen of Magendie in these animals (29). GREEN (28) showed that ventricular dilation began on day 11 of gestation and proposed that the hydrocephalus may develop secondary to retarded development of the subarachnoid space. RAIMONDI et al. (63) further described the development of cellular and extracellular cerebral pathology in this mutant. RICHARDSON et al. (65,66) proposed that abnormal endochondral ossification in the ch mouse was due to a failure of mesenchymal differentiation because of inadequate amounts of the chondroitin-sulfate proteoglycan. Primary failure of mesenchymal differentiation that retards formation of the subarachnoid space of defective development of the basi occiput secondary to failure of chondrification or endochondral ossification may be responsible for the communicating hydrocephalus in these animals (65). hpy mutant Another mutation producing postnatal hydrocephalus associated with polydactyly was originally discovered in descendants of X-irradiated mice (32, 33). Inheritance was recessive and 240
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homo zygotes showed a hopping gait, scoliosis and male sterility although females could breed successfully for a time (33). Hydrocephalus was observed in 20.4 % of offspring by neonatal day 6 and many affected animals died within 14 d (13). Although the overall manifestation of hydrocephalus resembled that in the oh mouse (10), secondary obstruction or stenosis of the aqueduct was not observed in the hpy mutant. The precise factor(s) responsible for the development of this form of non-obstructive hydrocephalus is unknown.
SUMS/NP mutant The pathophysiology of congenital hydrocephalus in a new inbred strain of mouse designated SUMS/NP has been studied recently but not extensively (62, 78). Progressive hydrocephalus which is recessively inherited in this strain, was evident soon after birth in the fornl of an enlarged head, and caused death prior to breeding age 01, 78). Affected animals gradually acquired functional disturbances that included abnormal gait but the syndrome was not associated with skeletal abnormalities (11, 62). eSF pressure in normal and hydrocephalic mice was not significantly different during the first week after birth. After the first week, however, the pressure in normal animals was significantly lower than in hydrocephalic animals (34, 36). In hydrocephalic mice, resistance to eSF absorption from the lateral ventricles was higher than in normal mice at all ages but resistance to absorption from the cisterna magna in hydrocephalic animals was not different from normal at any age (34- 36). JONES (34, 36) concluded from these studies that there was a transient resistance to absorption from the lateral ventricles immediately after birth in normal mice. This was believed to reflect a progressive maturation of the ventricular system which rendered it susceptible to outflow obstruction at this time. In contrast, hydrocephalic animals had a high resistance in the flow pathway between the lateral ventricles and cisterna magna but no defect in absorption from the subarachnoid space. JONES (34, 36) speculated that the site of this resistance was the cerebral aqueduct and was due to an abnormal reduction in its cross-sectional area. In more recent studies it has been confirmed that hydrocephalus develops prenatally in this strain of mice as a result of reduced cross-sectional area or absence of part of the cerebral aqueduct (11, 37). The precise mechanism by which this occurs, however, remains to be determined. In a similar congenitally hydrocephalic mouse (MT/Hokldr) model in which the cerebral aqueduct was narrowed but never completely stenosed TAKEUCHI et al. (71) recently concluded that the primary cause of hydrocephalus was a failure of the subcommissural organ (SeO) and posterior commissure to develop. In this regard similarities between hereditary and various teratogen models are of particular interest. Aqueductal stenosis due to maldevelopment of the seo has also been proposed in X-ray induced congenital hydrocephalus (73) and in hydrocephalus produced by feeding pregnant rats vitamin deficient diets (54,57). OVERHOLSER et al. (57), for example, maintained that the pressure of seo fluid secretion prevented collapse and closure of the cerebral aqueduct during fetal development. Consistent with this hypothesis TAKEUCHI and TAKEUCHI (72) recently concluded that maldevelopment of the seo in X-irradiated fetuses caused a reduction in the amount of its secretions which normally prevented closure of the cerebral aqueduct during embryogenesis, and resulted in stenosis of the aqueduct. NEWBERNE and O'DELL (55) contended that the active mitosis observed in seo cells of vitamin B l2-deficient embryonic rats precluded much functional activity on the part of these cells during fetal development. They concluded, therefore, that a more reasonable explanation for the aqueductal stenosis was the failure of normal mitosis-arresting mechanisms which allowed growth to continue beyond its normal limit. NEWBERNE (54), however, subsequently proposed that an absence of seo secretions resulted in disturbed fluid balance (an excess of fluid) and aqueductal stenosis in vitamin B l2 -deficient hydrocephalic rats. Hereditary hydrocephalus in hamsters
Hydrocephalus inherited as a simple recessive trait in the hamster was reported by YOON and SLANEY (81). This condition of undetermined etiology is evident between 2-6 d after birth. Exp. Pathol. 35 (1988) 4
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Although a few hydrocephalic hamsters survived for several months, most died within 3 weeks of birth. The lateral and third ventricles of affected animals were grossly dilated and the cerebral aqueduct and fourth ventricle were narrowed as a result of compression. Hereditary hydrocephalus in rats
The laboratory rat has a spontaneous incidence of hydrocephalus that has been variously reported to be 0.3% [HAIN 1937, cited in (59)],0.65% [COLTON 1929, cited in (59)], and 1.2% [FRANKLIN and BRENT 1964, cited in (40, 41)]. Congenital hydrocephalus in the rat has not been well characterized. PARK and NOWOSIELSKI-SLEPOWRON (59) reported a high incidence (41 %) of congenital hydrocephalus limited to males in an inbred group of Sprague-Dawley rats. First evident in the form of enlarged heads about 10 d after birth, death occurred during the 4th week. KOHN et al. (40, 41) described a mutant rat strain with a high (44 %) incidence of a communicating type of hydrocephalus. Hydrocephalus could be detected at 1-2 d of age and the rats survived for 4-5 weeks. Dilatation was restricted to the lateral ventricles. The cause has been attributed to underdevelopment of pia-arachnoid cells and veins in the periosteal-dural layers of these animals (40). Descriptions of the morphological characteristics of hydrocephalus in the rat (40, 47) are not unlike those observed in the mouse models. A recessive mutation has been described in the Wistar rat in which hydrocephalus is associated with eye, skeletal, and hair defects (21). Affected animals survived and were capable of reproducing. Disruption of the neuroepithelial basal lamina in the cephalic neural tube and abnormal stratification in the region of the midbrain-thalamic junction evident on embryonic day 11 was believed to be responsible for prenatal stenosis of the cerebral aqueduct in affected animals. Wistar rats of the inbred CPB-WE and Cpb:WU strains also have a high incidence of hydrocephalus associated with (in the former case) abnormal development of the optic tract and other'disorders of the CNS (75). The cause, however, could not be discerned. In another inbred strain of rats, Wistar-Lewis (LEWl1ms), hydrocephalus results from primary occlusion of the third or lateral ventricles during embryological development (67). Hydrocephalic neonates were recognized 2 d after birth and usually died at 10-20 d of age. The pathogenesis of this condition is also not established. Inheritable types of hydrocephalus in humans
In humans, comparatively few forms of hereditary hydrocephalus have been documented (22). The incidence of congenital hydrocephalus has been estimated to be between 0.11 and 3.5 per thousand live births (22, 70). The wide range has been attributed to discrepancies in definitions of hydrocephalus used by various investigators (22). Within families of hydrocephalic children, however, the overall risk of having a second child with hydrocephalus is 1-2%. Hydrocephalus secondary to stenosis of the aqueduct recurs in 5.6-12% of affected families (4, 14). The best known form of hereditary hydrocephaly is the X-chromosome linked aqueductal stenosis that was first reported by WINKEL in 1893 [cited in (7)], the pathology of which was described by BICKERS and ADAMS (7). This form of hydrocephalus is associated to varying degrees with other abnormalities that include mental deficiency, flexion deformity of the thumbs, peculiar facial features, and spasticity (22, 23, 43). It has been identified before the 20th week of gestation (20). X-linked hydrocephalus accounts for approximately 2% of all cases of hydrocephalus (26). New families with this defect continue to be reported (1, 20, 31,42). Although stenosis has been observed throughout the length of the aqueduct, the ependymal lining is usually intact with no surrounding gliosis. The cause of the stenosis is not known but it has been suggested to be secondary to compression by the expanded lateral ventricles (42, 76). Hereditary hydrocephalus in conjunction with neurologic dysfunction, abnormalities of eye, and disturbed cortical architecture (Warburg's or HARD ± E Syndrome) has also been frequently described (9, 58, 60). Although aqueductal stenosis has been reported in this syndrome, it too may be secondary to a posterior fossa abnormality. The disorder is considered to be inherited as 242
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an autosomal recessive trait. Hydrocephalus has also been described as a result of an autosomal dominant gene with partial penetrance (43) and in monozygotic twins (24). Hydrocephalus has been described in association with numerous other inheritable conditions. Communicating hydrocephalus associated with short ribs, thoracic dysplasia, short limbs, and developmental delay may be inherited as an autosomal recessive condition (79). A similar syndrome of communicating hydrocephalus, undescended scapulae, and facial abnormalities is inherited as an autosomal dominant trait with variable expression (77). An autosomal recessive syndrome of communicating hydrocephalus secondary to posterior fossa bleeding and associated with facial, heart, bone, and genital abnormalities has been described (5). Basal cell nevus syndrome, an autosomal dominant disorder that affects mesodermal and ectodermal tissues including meninges, may be associated with hydrocephalus, perhaps secondary to aqueductal stenosis (49). Similarly, von Recklinghausen's disease, an inheritable disorder of neuroectodermal and mesenchymal tissues may be associated with aqueductal stenosis, but no familial cases of hydrocephalus have been described (69). The Dandy-Walker posterior fossa cyst, often inherited recessively, has been observed in siblings repeatedly (22, 44). A similar malformation with basal cistern obstruction to CSF flow, vermal cerebellar agenesis, port wine nevi, and communicating hydrocephalus has been described as an autosomal dominant trait with incomplete expression (56). Hydrocephalus may be associated with known recessive traits such as osteopetrosis, Hurler syndrome, and Tay-Sachs disease. In certain geographical areas, families have increased frequency of hydrocephalus combined with anencephaly, encephalocele, and spina bifida (22). The inheritance of hydrocephalus with neural-tube defects is polygenic and multifactorial; no consistent neuropathology has been observed (44,48). Thus, human hydrocephalus may be inherited as an X-linked, autosomal dominant, or autosomal recessive trait. Although aqueductal stenosis has been documented in several families, many recent reports suggest that the stenosis may be secondary. In general, the mechanism of obstruction to CSF flow in inherited forms of hydrocephalus is not well established, probably because comparatively few cases have been studied in detail. References 1. ALAWAD!, S. A., FARAG, T. I., NAGUIB, K., TEEBI, A. S., ELKHALlFA, M. Y., YASSIN, S.: X-linked hydrocephalus (Bicker-Adams-Edwards-syndrome). J. Kuwait Med. Assoc. 1984; 18: 187-190. 2. BAKER, M. L., PAYNE, L. C., BAKER, G. N.: The inheritance of hydrocephalus in cattle. J. Hered. 1961; 52: 135- \38. 3. BANNISTER, C. M., MUNDY, J. E.: Some scanning electron microscopic observations ofthe ependymal surface of the ventricles of hydrocephalic Hy3 mice and a human infant. Acta Neurochir. 1979; 46: 159-168. 4. BAY, C., KERZIN, L., HALL, B. D.: Recurrence risk in hydrocephalus. Birth Defects: Orig. Art. Ser. 1979; XV (5C): 95- \05. 5. BEEMER, F. A., ERTBRUGGEN, I. Y.: New syndrome: Peculiarfacial appearance, hydrocephalus, double-outlet right ventricle, genital abnormalities, and dense bones with lethal outcome. Am. J. Med. Genet. 1984; 19: 391-398. 6. BERRY, R. J.: The inheritance and pathogenesis ofhydrocephalus-3 in the mouse. J. Pathol. Bacteriol. 1961; 81: 157-167. 7. BICKERS, D. S., ADAMS, R. D.: Hereditary stenosis of the aqueduct of Sylvius as a cause of congenital hydrocephalus. Brain 1949; 72: 246-262. 8. BLACKWELL, R. L., KNOX, J. H., COBB, E. H.: A hydrocephalus lethal in Hereford cattle. J. Hered. 1959; 50: 143-148. 9. BORDARIER, C., AICARD!, J., GOUTIERES, F.: Congenital hydrocephalus and eye abnormalities with severe developmental brain defects: Warburg's syndrome. Ann. Neurol. 1984; 16: 60-65. 10. BORlT, A., SIDMAN, R. L.: New mutant mouse wi.th communicating hydrocephalus and secondary aqueductal stenosis. Acta Neuropathol. 1972; 21: 316-331. 11. BRUNI, J. E., DEL BIGIO, M. R., CARDOSO, E. R., PERSAUD, T. Y. N.: Neuropathology of congenital hydrocephalus in the SUMS/NP mouse. Acta Neurochir. 1988 (in press). 12. - - CLATTENBURG, R. E.: Ependyma: normal and pathological. A review of the literature. Brain Res. Rev. 1985;9: 1-19. Exp. Pathol.
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