American Journal of Medical Genetics 35310-313 (1990)

Brief Clinical Report

Autosomal Recessive Hydrocephalus With Third Ventricle Obstruction C.W. Chow, P.A. McKelvie, R.McD. Anderson, E.M.D. Phelan, G.L. Klug, and J.G. Rogers Departments of Anatomical Pathology (C.W.C., PA.McK., R.McD.A.1, Radiology (E.M.DP.), and Neurosurgery (G.L.K.), and the Murdoch Institute (J.G.R.), Royal Children’s Hospital, Melbourne, Australia.

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Here we report a brother and sister who pre- sented in the neonatal period with hydro- cephalus. Ultrasonography showed marked dilatation of the lateral ventricles but not the third ventricle. One child with postnatal onset was shunted and had normal development at 3 years. The other child had severe hydro- cephalus at birth and was not treated. Neuro- pathologic studies demonstrated dilatation of the lateral ventricles and marked narrowing of the posterior part of the third ventricle but no other malformations other than those that result directly from hydrocephalus. The po- tential for a good prognosis is emphasized.

KEY WORDS: ventricular obliteration, ultra- sonography, autopsy

INTRODUCTION With the development of shunting procedures in the

1950s, the prognosis of infants with hydrocephalus has improved considerably, with very favourable long-term follow-up results in a substantial proportion of cases [Amacher and Wellington, 1984; Dennis et al., 1981; Raimondi and Soare, 1974; Rennier et al., 19881. In contrast to sporadic cases, the prognosis in genetic hy- drocephalus, mainly the X-linked recessive form, re- mains poor. Many die in the neonatal period. Even with shunting, there is often mental retardation and severe neurological deficit [Halliday et al., 1986; Hecht and Grix, 1982; Rennier et al., 19881. A brother and sister were seen with an unusual form of hydrocephalus; the clinical, radiological, and pathological manifestations are described.

CLINICAL REPORTS Patient 1

This girl was born at term following a normal preg- nancy and delivery. The head circumference (OFC)

Received for publication January 6 , 1989; revision received Au- gust 8, 1989.

Address reprint requests to Dr. C.W. Chow, Department of Ana- tomical Pathology, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia.

Q 1990 Wiley-Liss, Inc.

measured 34 cm at birth. Her head size rapidly in- creased, and when seen at 11 weeks she was markedly macrocephalic. On admission she was an alert, happy baby with an OFC of 47 cm. She was moving all limbs and tone and reflexes were normal. Eyes and digits were normal. No external abnormality was noted over the spine. Ultrasonography showed marked dilatation ofthe lateral ventricles; however, the third ventricle was nar- row and poorly visualized (Fig. 1). The fourth ventricle was normal in size. A ventriculo-peritonea1 shunt was performed. When seen at age 3 years, she seemed devel- opmentally and neurologically normal, although she was still too young for detection of minor degrees of deficit.

Patient 2 The onset of labor was spontaneous at 41 weeks.

Emergency cesarean section was performed because of obstructed labor. Gross hydrocephalus was noticed at birth. He was transferred to the Royal Children’s Hospi- tal. Ultrasonography showed severe dilatation of the lateral ventricles with marked thinning of the cerebral mantle. The third ventricle was narrow and was com- posed of 2 small cavities, one above the other (Fig. 2). The fourth ventricle was normal in size. Because of the thinness of the cerebral mantle, shunting was not un- dertaken. He died at age 10 weeks.

Autopsy showed bronchopneumonia as the cause of death. There was no malformation in the peripheral organs. The OFC was 46.5 cm. There was moderate polygria and marked dilatation of the lateral ventricles with a variable degree of thinning of the cerebral hemi- spheres, the thickness being maximal over the superior frontal region (15 mm) and minimal over the inferior temporal region (3 mm). The corpus callosum was pres- ent but thin, varying from 1 to 2 mm in thickness. The septum pellucidum was absent. The foramina of Monro were patent and normal in size. The fornix was normal. The choroid plexus could not be seen in the third ventri- cle but was preserved, although markedly diminished, in the lateral ventricles. The basal ganglia were normal. The anterior part of the third ventricle was patent, but the posterior part was markedly narrowed, with exten- sive fusion of the thalami and partial fusion of the hypo- thalami. Sections of the aqueduct a t multiple levels showed that the shape varied from diamond to triangu-

Autosomal Recessive Hydrocephalus 311

Fig. 1. Patient 1, cerebral ultrasound with dilated lateral ventricles and narrow slit-like third ventricle. L, lateral ventricle; arrow, third ventricle; arrowhead, choroid plexus.

lar and measured 1.1 mm high and 0.7 mm wide, with a cross-sectional area of approximately 0.38 mm2, at the narrowest part. The fourth ventricle was normal in size and the foramina ofLuschka and Magendie were patent. Here the choroid plexus was normal. Histology showed that the cortical layering was well preserved with no

Fig. 2. Patient 2, cerebral ultrasound with dilated lateral ventricles and irregular third ventricle. L, lateral ventricle; arrow, third ventri- cle; arrowhead, choroid plexus.

Fig. 3. Patient 2, partial obliteration of the third ventricle at the level of the marnillary bodies. Lux01 fast blue stain. x 14.

microgyria. Scattered ependymal rests and small numbers of reactive astrocytes were seen around the third ventricle, but there was no glial overgrowth inter- nal to the ependymal lining (Fig. 3). There was no gliosis or ependymal irregularity around the aqueduct. Ectopic tissue and neuroglial overgrowth into the meninges were not seen. The brainstem and cerebellum were well preserved, and in transverse sections of the medulla oblongata the pyramids were normal. There were no acute degenerative changes or inflammatory infiltra- tion.

The parents were non-consanguineous and phe- notypically normal. There were no other children. The family history was negative for hydrocephalus as far back as four generations.

DISCUSSION These 2 sibs had an unusual form of hydrocephalus.

Ultrasonography demonstrated marked dilatation of the lateral ventricles in both infants. However, the third ventricle was narrow and irregular, corresponding to focal obliteration demonstrated pathologically in pa- tient 2, unlike the findings in aqueductal stenosis where imaging shows gross dilatation of both the lateral and third ventricles [Harmat et al., 19841. In the absence of an obvious cause, the occurrence in a brother and sister

312 Chow et al.

with normal parents strongly suggests an autosomal recessive disorder.

Hydrocephalus without associated meningomyelocele is a heterogeneous group of disorders. Frequently hydro- cephalus is part of a complex syndrome, either as a minor or an inconsistent manifestation, e.g., Meckel [Salonen, 19841 or Smith-Lemli-Opitz symdrome [Lowry, 19831. Only a small number of entities have been clearly defined where hydrocephalus is a predomi- nant manifestation. The most common is the X-linked recessive form. Considerably less common are autoso- ma1 recessive cases. Some are syndromal, e.g., Walker- Warburg and the hydrolethalus syndromes; others are nonsyndromal LTeebi and Naguib, 19881. Although it is controversial whether aqueduct stenosis is the cause or result of hydrocephalus [Landrieu et al., 19791, usually the lateral, third, and sometimes the fourth ventricles are dilated in both the X-linked and autosomal recessive cases [Bicker and Adams, 1949; Edwards et al., 1961; Teebi and Naguib, 1988; Williams et al., 19841.

Hydrocephalus due to obstruction of the third ventri- cle is rare, and mainly related to lesions in the anterior portion, near the foramen of Monro [Pribil et al., 19831. Occasionally, obstruction of the third ventricle has been reported as a congenital lesion [Kepes et al., 19691. In that case the atresia of the third ventricle was associ- ated with obliteration of the aqueduct and the anterior part of the fourth ventricle, as well as fusion of the thalami, colliculi of the quadrigeminal plate, and den- tate nuclei. Interestingly, head enlargement was appar- ently not obvious in this patient in the neonatal period even though he had extensive cardiological investiga- tion. Neurological consultation was only sought at age 6 months. Among genetic disorders, the patient with mor- phology closest to our patient is probably case 2 de- scribed by Holmes et al. [ 19731. In that patient there was no narrowing of the anterior part of the third ventricle, but the postero-inferior part was markedly stenotic. However, in contrast t o our patient, the aqueduct was markedly narrowed throughout, the profile of the quad- rigeminal plate was obscured, and the pyramids were hypoplastic. It seems that there is a spectrum of stenosis or atresia in this region, varying from involvement of the aqueduct, as in many cases of X-linked hydro- cephalus, to the third ventricle as in the present case, to the third ventricle and aqueduct as in the case of Holmes et al. [1973], and to the third ventricle, aqueduct, and anterior part of the fourth ventricle as in the case of Kepes et al. [1969]. Common to all these cases is the lack of inflammatory infiltration, or filling of the lumen in- ternal to the ependymal lining by reactive gliosis. The pathogenesis of these lesions is uncertain.

Proposed mechanisms for the obliteration of the lu- men include focal destruction of the ependyma followed by collapse of the lumen as seen in suckling hamsters and mice inoculated with myxovirus [Johnson and Johnson, 19691 and temporary disturbance of fluid se- cretion into the ventricular system as suggested in mice born to dams fed a vitamin BI2 and folic acid-deficient diet [Overholser et al., 19541.

The prognosis in genetic hydrocephalus is generally poor compared with the sporadic form. This is probably

related to the extensive malformations in the central nervous system, often not obviously resulting directly from hydrocephalus. In the X-linked recessive form, ab- sence of the medullary pyramids and corpus callosum and fusion of superior and inferior colliculi, basal gan- glia, and thalami have been reported [Chow et al., 1985; Visekul et al., 19751. In Walker-Warburg syndrome, there is marked neuroglial overgrowth into the men- inges and microgyria and absence of pyramids [Wil- liams et al., 19841. In the hydrolethalus syndrome, mid- line defects and absence of the pituitary gland have been described [Salonen et al., 19811. These abnormalities are not associated with acute degenerative changes, suggesting that damage may have occurred very early during development. It has been noted that the results of shunting are often not closely related to the degree of hydrocephalus. Perhaps of more significance are the associated malformations or other forms of tissue dam- age, e.g., post infective.

In contrast to the above entities, the neuropathology in patient 2 seemed to be mainly third ventricle oblitera- tion. Most of the other features in this patient, e.g., ventricular dilatation, thinning of corpus callosum, de- struction of septum pellicudum, and atrophy of the cho- roid plexus, have been observed in acquired hydro- cephalus. The lack of head enlargement in patient 1 at birth suggests a relatively late onset of obstruction, perhaps at a time when the major structures of the brain are already well formed. In view of the lack of extensive malformations associated with other genetic hydro- cephalus in patient 2 and the encouraging follow-up in patient 1, it is possible that a good result may be poten- tially achievable in this disorder despite the degree of hydrocephalus. If close monitoring by ultrasonography shows that ventricular dilatation is indeed relatively late, it may be possible to undertake early delivery and shunting while the hydrocephalus is still mild, thus further improving the prognosis without resorting to fetal surgery [Clewell et al., 19821.

The presence of morphological hallmarks for various forms of genetic hydrocephalus, e.g., absence of pyra- mids in X-linked reccessive hydrocephalus, marked neuroglial overgrowth into meninges and microgyria in Walker-Warburg syndrome, pre- and postaxial polydac- tyly in the hydrolethalus syndrome, and cystic dyspla- sia of the kidneys in Meckel syndrome [Salonen, 19841, emphasizes the importance of detailed autopsy studies in babies dying with hydrocephalus. Precise classifica- tion with firm prognostication is essential for planning and management of future pregnancies.

ACKNOWLEDGMENTS We thank Mrs. L. Ireland and Mrs. M. Bell for prepar-

ing the manuscript and Mrs. E. McKinnon for technical assistance.

REFERENCES Amacher AL, Wellington J (1984): Infantile hydrocephalus: Long-term

results of surgical therapy. Child8 Brain 11217-229. Bicker DS, Adams RD (1949): Hereditary stenosis of the aqueduct of

Sylvius as a cause of congenital hydrocephalus. Brain 72:246-260. Chow CW, Halliday JL, Anderson RMcD, Danks DM. Fortune DW

Autosomal Recessive Hydrocephalus 313

(1985): Congenital absence of pyramids and its significance in ge- netic diseases. Acta Neuropathol (Berl) 65313-317.

Clewell WH, Johnson ML, Meier PR, Newkirk JB, Sheldon LZ, Hendee RW, Bowes WA Jr, Hecht F, O’Keefe D, Henry GP, Shikes RH 11982): A surgical approach to the treatment of fetal hydrocephalus. N Engl J Med 306:1320-1325.

Dennis M, Fitz CR, Netley CT, Sugar J, Harwood-Nash DCF, Hendrick EB, Hoffman HJ, Humphreys RP (1981): The intelligence ofhydro- cephalic children. Arch Neurol 38:607-615.

Edwards JH, Norman RM, Roberts JM (1961): Sex-linked hydro- cephalus, report of a family with 15 affected members. Arch Dis Child 36:481-485.

Halliday J , Chow CW, Wallace D, Danks DM (1986): X linked hydro- cephalus: A survey of a 20 year period in Victoria, Australia. J Med Genet 23:23-31.

Harmat G, Paraicz E, Szenasy J (1984): Ultrasound control of progres- sive hydrocephalus in infancy. Childs Brain 11:230-241.

Hecht F, Grix A (1982): Treatment of fetal hydrocephalus. N Engl J Med 307:1211.

Holmes LB, Nash A, Zurhein GM, Levin M, Opitz JM (1973): X-linked aqueductal stenosis: Clinical and neuropathological findings in two families. Pediatrics 51:697-704.

Johnson RT, Johnson KP (1969): Hydrocephalus as a sequela of experi- mental myxovirus infections. Exp Mol Path01 1058-80.

Kepes JJ, Clough C, Villanueva A (1969): Congenital fusion of the thalami (atresia of the third ventricle) and associated anomalies in a 6 months old infant. Acta Neuropathol (Berl) 13:97-104.

Landrieu I: Ninane J, Feriere G. Lyon G (1979): Aqueductal stenosis in

X-linked hydrocephalus: A secondary phenonemon? Dev Med Child Neurol 21:637-642.

Lowry RB (1983): Variability in the Smith-Lemli-Opitz syndrome: Overlap with the Meckel syndrome. Am J Med Genet 14:429-433.

Overholser MD, Whitley JR, O’Dell BL, Hogan AG (1954): The ven- tricular system in hydrocephalic rat brains produced by a deficiency of vitamin BE or of folic acid in the maternal diet. Anat Rec

Pribil S, Boone SC, Waley R (1983): Obstructive hydrocephalus a t the anterior third ventricle caused by dilated veins from an arte- riovenous malformation. Surg Neurol 20:487-492.

Raimondi AJ, Soare P (1974): Intellectual development in shunted hydrocephalic children. Am J Dis Child 127:664-671.

Rennier D, Saint-Rose C, Pierre-Katin A, Hirsch JF (1988): Prenatal hydrocephalus: Outcome and prognosis. Childs Nerv Syst

Salonen R (1984): The Meckel syndrome: Clinicopathological findings in 67 patients. Am J Med Genet 18571-689.

Salonen R, Herva R, Norio R (1981): The hydrolethalus syndrome: Delineation of a “new”, lethal malformation syndrome based on 28 patients. Clin Genet 19:321-330.

Teebi AS, Naguib RK (1988): Autosomal recessive non-syndromal hy- drocephalus. Am J Med Genet 31:467-470.

VisekuI C, Gilbert EF, Opitz JM (1975): X-linked hydrocephalus, fur- ther observations. Z Kinderheilkd 119:lll-121.

Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS Jr (1984): Cerebro-ocular dysgenesis (Walker-Warburg syndrome): Neuropathologic and etiologic analysis. Neurology: 34:1531-1541.

120:917-933.

4:213-222.