6
UEVLLOI’MI YTAL MtDICINF AND CHI1 D NF UROLOGY. 1976. I8 R ESU MEN A/fesucio‘ri neusokhgicu cpip upsece eri el riifio fi‘iiilc.~tor~liric.o despir6.r tk iritei.ritiqi;i. ti/ tsatciniiento tiiotitic‘o Signos de una diplegia esp6stica ligeramcnte severa aparecieron en un nitio dc 14 aiio~ de edad que habia sido tratado itltiniamente por una fen i Icetonuria. Aparecicron I3 mcws despuis de haber discontin~iado la dieta restrictiva de fenilalamina. La literatura contic‘nc aport ac i o ties de pacicn t es n o t ra t ad os con fen i Ice t on u ria q lie d esar rol I a r o ti con d i c i on e\ d c d es in i e 1 i n izaci 6n c ti 1 a i n 1-a tic i a m8s ad el a n t ad a. Se d i sc LI t e n I its i m pl i c;ic i ones n c u ro Ibg I cns debidas a lu relajacion de la dietu en 10s cases tratados preco/mente y tardiamcnte. REFERENCES Henda. C. E. (I 952) n(,~.~~/o~,/,~~,fittrl L)i.\ovclcv.\ (if’ Mcntciriofi rind Ccrt,hroI Ptrl.\icj.\. New York : Griine R Bickel. H. (1973) In Seakins. J. W. T.. Saunders, R. A,. Toothill, C. (Eds.) Trcwrniciir of’liihoui €rr.o/-\ O/ ,h/(,/t//J(i/iSff/. Edinburgh : Churchill Livingstone. p. 80. (Ilnyton. B. E.. Moncrieff, A. A,. Pampiglione. G., Shepherd. J., (1966) ‘Biochemical and EFG \ludic\ in phenylketonuric children d tiring phenylalanine tolerance tests.’ Archirc,.v oif’Disc~tr.\c, iri C/i~lcl/ioot/. 41, 267. Cowie. V. A. (1971 ) ffi Hickel. H., Hudson, F. P.. Woolf. I-. 1. (Eds.) f/rc,n>,lXc,rorr,tri(r trnd Sovie Oilw. Itihorn Error.\ of Mmiholi.\w. Sttittgart : Georg Thieme. p. 29. Crome. L.. (1971) Iti Bickel. H.. Hiidson. F. P., Woolf. I-. I. (Eds.) f/~c~rij~/~ctoriii,.itr tiid .S(inic, Orlwr /nhovir Error.s of’M~,rciholi.rti,. Stuttgart : Georg Thienie. p. 13 I. -~ Tyinms, V., Woolf. I-. I. (1962) ‘A chemical investigation of the defects of m!clination in phcii>l- kcton uria.’ Joitmcil of’Nci~ro/iigj~, h’rrtro.sirtpyj~ cmd f’.\jdriritrj~, 25, 149. Fuller. K. N., Shuman, J. B. ( 1969) ‘Phenylketoniiria and intelligence. Trimodal response 10 dietary ti’eat- rnent.’ Ntrliw. 221, 639. Hudson, F. P.. Hawcroft, 1. (1973) Iti Seukins. .I. W. T.. Saunders, R. A,, Toothill. C. (Eds.) Troiitm,tcr ,J/ Itihorti Errors of’ .M(,tciholi.cti/. London : Churchill. p. 5 I. Jcrvis. G. A. (1954) ‘Phenylpyxvic oligophrenia (phenylketonuria).’ In Gcvicric.> (im/ //ic Itilic./-ittnrc~~ o/ Inrcyrcirrd Nrrirologic.ol tirid f’.\>xhitifrii, f“rt/(~rn.\. R(w(ir~~/i Pirhlicritioris of’ thr. Associririon of .lic.,-roir \ titid Mmtcil Disiw.w. No. 33. New York: Williams & Wilkins. p. 259. McBean, M. S., Stephenson. J. B. P. (1968) ‘Treatment of classical phenylketonuria.‘ ,4rc/iiws qt’ Di.\tww Mcicl-, C., Lutschg, J., Vasselln, F.. Bibchotf. A. (1975) ‘Progressive neural musculiir iitrophy in :I Pederren. H. E., Birket-Smith, E. (1974) ‘Neurological abnormalities in phenylketonuria.’ .Acrtr iVciirolo,<ricri Stratton. p. 451. if/ (%i/t1/100tl, 43, 1. phenylketonuria.’ D(,l.c.kJlJfiic,frr(i/ Mcdicirrc, ofid Child .‘Vcwro/ogj~, 17, 525. Scr1flrl;nri vie(/, SO, 5 89. Cerebro-hepato-renal Syndrome with Parental Consanguinity S. Variend W. R. Timperley S. Hill L. S. Tuitz Introduction In 1964 Bowen et (11. described two s i bl in gs with si ni i 1 a r ah n o r m al it i es, which later reports confirmed ah a distinct nosological entity. It has been named Zellweger’s syndrome. or cerebro-hepato- renal syndrome. The essential features are h y pot on ia. ni ongo I oi d fa c i es, chond ral calcification, and lesions affecting the brain. liver and kidneys. Most authors ~(irrc,.\ponclc.riei, to Dr. S. Variend, Senior Registrar. Department of t 1 iatopathology, City IHospital, tlticknall Road. Nottingham NG5 I PR. agree that this rare condition i\ trnnsmittccl as an autosonial recessive trait hut el idencc for this has been lacking. The neuropath- ology of this condition is not McII- documented. Case Report This female infant wxs horn after an iine\entFul 39-week pregnancy. The parcnts were hcullh!, tiin1 cousins; the mother was 23 ycsrs old and tlic‘ father 24 years old. There \+;is no family histoip of similarly afected children 01- infant deaths. Thc. hirthweight M’RI 28hOg. Apart from the cord being tight around the neck. delicer? was norm,il. Tlic 660

Cerebro-hepato-renal Syndrome with Parental Consanguinity

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Page 1: Cerebro-hepato-renal Syndrome with Parental Consanguinity

UEVLLOI’MI YTAL MtDICINF AND C H I 1 D NF UROLOGY. 1976. I8

R ESU MEN A/fesucio‘ri neusokhgicu cp ip u p s e c e eri el riifio fi‘iiilc.~tor~liric.o despir6.r t k iritei.ritiqi;i. ti/

tsatciniiento tiiotitic‘o Signos de una diplegia esp6stica ligeramcnte severa aparecieron en un nitio dc 14 a i i o ~

d e edad que habia sido t ra tado itltiniamente por una fen i Icetonuria. Aparecicron I3 mcws despuis de haber discont in~iado la dieta restrictiva de fenilalamina. La literatura contic‘nc apor t ac i o ties de pacicn t es n o t ra t ad o s c o n fen i Ice t on u ria q lie d esar rol I a r o t i con d i c i on e\ d c d es in i e 1 i n izaci 6 n c t i 1 a i n 1-a tic i a m8s ad el a n t ad a. Se d i sc LI t e n I its i m pl i c;ic i ones n c u r o Ibg I cns debidas a lu relajacion de la dietu en 10s cases tratados preco/mente y tardiamcnte.

R E F E R E N C E S Henda. C. E. (I 952) n ( , ~ . ~ ~ / o ~ , / , ~ ~ , f i t t r l L)i.\ovclcv.\ (if’ Mcntciriofi rind Ccrt,hroI Ptrl.\icj.\. New York : Griine R

Bickel. H. (1973) In Seakins. J . W. T.. Saunders, R. A,. Toothill, C . (Eds.) Trcwrniciir of’l i ihoui €rr.o/-\ O /

, h / ( , / t / / J ( i / i S f f / . Edinburgh : Churchill Livingstone. p. 80. (Ilnyton. B. E.. Moncrieff, A. A,. Pampiglione. G., Shepherd. J., (1966) ‘Biochemical and EFG \ludic\ i n

phenylketonuric children d tiring phenylalanine tolerance tests.’ Archirc,.v oif’Disc~tr.\c, i r i C/i~lcl/ioot/. 41, 267. Cowie. V. A. (1971 ) f f i Hickel. H., Hudson, F. P.. Woolf. I-. 1 . (Eds.) f/rc,n>,lXc,rorr,tri(r trnd Sovie Oilw.

Itihorn Error.\ of Mmiholi . \w. Sttittgart : Georg Thieme. p. 29. Crome. L.. (1971) Iti Bickel. H.. Hiidson. F. P., Woolf. I-. I . (Eds.) f / ~ c ~ r i j ~ / ~ c t o r i i i , . i t r t i i d .S(inic, Orlwr /nhovir

Error.s of’M~,rciholi.rti,. Stuttgart : Georg Thienie. p. 13 I . -~ Tyinms, V . , Woolf. I-. I . (1962) ‘A chemical investigation of the defects o f m!clination i n phcii>l-

kcton uria.’ Joitmcil of’Nci~ro/i igj~, h’rrtro.sirtpyj~ c m d f ’ . \ jdrir i tr j~, 25, 149. Fuller. K. N., Shuman, J . B. ( 1969) ‘Phenylketoniiria and intelligence. Trimodal response 10 dietary t i ’eat-

rnent.’ N t r l i w . 221, 639. Hudson, F. P.. Hawcroft, 1. (1973) I t i Seukins. . I . W. T.. Saunders, R . A,, Toothill. C . (Eds.) Troiitm,tcr , J /

Itihorti Errors of’ .M(,tciholi.cti/. London : Churchill. p. 5 I . Jcrvis. G . A. (1954) ‘Phenylpyxvic oligophrenia (phenylketonuria).’ I n Gcvicric.> (im/ / / i c Itilic./-ittnrc~~ o/

Inrcyrcirrd Nrrirologic.ol tirid f’.\>xhitifrii, f“rt/(~rn.\. R ( w ( i r ~ ~ / i Pirhlicritioris of’ thr. Associririon of .lic.,-roir \ t i t i d

M m t c i l Disiw.w. No. 33. New York: Williams & Wilkins. p. 259. McBean, M. S., Stephenson. J . B. P. (1968) ‘Treatment of classical phenylketonuria.‘ ,4rc/iiws qt’ Di.\tww

Mcicl-, C., Lutschg, J . , Vasselln, F.. Bibchotf. A. (1975) ‘Progressive neural musculiir iitrophy in :I

Pederren. H. E., Birket-Smith, E. (1974) ‘Neurological abnormalities in phenylketonuria.’ .Acrtr iVciirolo,<ricri

Stratton. p. 451.

i f / (%i/t1/100tl, 43, 1.

phenylketonuria.’ D(, l .c .kJlJf i ic , f rr ( i / Mcdicirrc, ofid Child .‘Vcwro/ogj~, 17, 525.

Scr1flrl;nri vie(/, SO, 5 89.

Cerebro-hepato-renal Syndrome with Parental Consanguinity S. Variend W. R. Timperley S . Hi l l L . S. Tuitz

Introduction In 1964 Bowen et (11. described two

s i bl in gs with si ni i 1 a r a h n o r m al it i es, which later reports confirmed a h a distinct nosological entity. I t h a s been named Zellweger’s syndrome. or cerebro-hepato- renal syndrome. T h e essential features a re h y pot on ia. ni ongo I oi d fa c i es, chond ral calcification, and lesions affecting the brain. liver and kidneys. M o s t authors

~(irrc,.\ponclc.riei, to Dr. S. Variend, Senior Registrar. Department of t 1 iatopathology, City IHospital, tlticknall Road. Nottingham N G 5 I PR.

agree that this rare condition i \ trnnsmittccl as a n autosonial recessive trait hut e l idencc for this has been lacking. The neuropath- ology o f this condition is not M c I I - documented.

Case Report This female infant wxs horn after an iine\entFul

39-week pregnancy. The parcnts were hcullh!, t i i n1

cousins; the mother was 2 3 ycsrs o l d and t l ic‘

father 24 years old. There \+;is no family histoip of similarly afected children 01- infant deaths. Thc. hirthweight M’RI 28hOg. Apart f r o m the cord being tight around the neck. delicer? was norm,il. Tl ic

660

Page 2: Cerebro-hepato-renal Syndrome with Parental Consanguinity

CASE REPORTS

placenta weighed 520g; the umbilical cord was normal. There was marked hypotonia, which persisted. The forehead was unusually high, the nasal bridge was flat and there was marked brachycephaly. Her length was 49cm and the skull circumference was 33cm. The sutures were widely separated with soft adjacent skull bones and the fontanelles were unusually large. The joints were hyperextensible, with dislocation of the right hip and a metatarsus adduction deformity of the feet. The skin felt redundant. The patellae were large, and passive movements of the knee joints produced a palpable click. There was a harsh systolic cardiac murmur.

On the second day there was a brief generalised clonic convulsion. At this stage the skin showed scattered focal haemorrhages, mainly involving the trunk. The infant required tube-feeding and on the fifth day developed a left-sided pneumonia and died two days later.

The full blood-count, serum calcium, magnesium, cerebrospinal fluid, urinary aminoacids, urinary organic acids, urinary electrolytes, prothombin time, thrombin time, partial thromboplastin time, chromosomal analysis and the ECG were all normal. Radiological examination (Dr. R. K. Levick) confirmed the presence of pneumonia with widening of the upper part of the thoracic cavity at the level of the 8th rib. Pin-point foci of calcification involving the upper femoral, acetab- ular and patellar cartilages were present. The IVP revealed no abnormality.

Autopsy Findings Macroscopic Findings

No abnormality was found in the heart, liver, spleen, gastro-intestinal tract, adrenals kidneys, thymus or female genital tract. The lungs were consolidated.

The brain showed marked hypoplasia of the olfactory bulbs and irregularity of the convolu- tional pattern, with pachygyria and microgyria (Fig. 1). The corpus callosuni was thin and there was a large cavuni septum pellucidum. Demarca- tion between grey and white matter was poor in all areas and the deep nuclear groups were barely recognisable. The white matter was hypoplastic. Most of the white matter in the periventricular region had a pale yellow appearance. Myelination within the cerebellum and cerebellar peduncles was poor, The lateral ventricles were slightly dilated, with several small cysts in their walls. The cerebellum showed hypoplasia of the verniis and tonsils. The spinal cord appeared normal.

Microscopic Findings The epiphyseal, arytenoid and thyroid cartilages

contained small foci of amorphous calcium deposit. This calcification did not appear t o be related to any abnormality of the cartilage or to ossification centres, which appeared normal.

Confluent pneumonia was confirmed in both lungs. In the liver, the small bile ducts in the portal tracts were more numerous than normal and many contained bile plugs (Fig. 2) . There was a moderate

Fig. 1 ( b e h ) . Lateral view of brain showing ab- normal convolutional pattern ( )i 1.1 /3) . Fig. 2 (righi). Liver showing a portal tract with increase in small bile ducts, many of which con- tain bile olugs. (HE stain x 100.)

66 I

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1976, 18

amount of iron pigment in Kupffer cells but this was probably within normal limits for the age of the child.

The renal architecture was essentially normal, but there were a few small cortical cysts, the largest Imm in diameter (Fig. 3). These were probably dilated Bowman capsules and appeared to be similar to the cortical cysts commonly seen in the neonate, but were more numerous than normal. The ovaries showed normal follicles containing ova, but there were also immature areas containing primitive tubular structures as seen in early gonadal development.

Marked disorganisation o f neurones in all areas of the cerebral hemispheres was noted, particularly in the frontal, parietal and occipital areas. The molecular layer was increased in width and the usual cortical layering of neurones was absent. Many of the microgyri were located beneath the cortical surface and were joined along their molecular layers. Most neurones were poorly developed and the large pyramidal types, such as the Betz cells, were few in number. Many neurones were developed little further than the 'blast cell' stage and islands and strands of these cells could be seen scattered in the subcortical area (Fig. 4), the centrumovale and in the subependymal area. Some neurones of the pyramidal type could be seen in these areas, but most cells were of an undifferentiared type. The deep neuronal nuclei were poorly defined and again the majority of the neurones were of an undifferentiated type.

The cerebellar cortex was well differentiated. Purkinje cells were reduced in number and many

heterotopic Purkinje cells were found in the granular cell layer and the underlying white matter. Heterotopic islands of grey matter containing both pyramidal neurones and undifferentiated cells were seen in the subcortical zone. The dentate nucleus was divided into several distinct islands of neurones and the normal serrations were absent. Within the medulla, the olivary nuclei showed similar changes (Fig. 5). The pons contained large numbers of well-differentiated neurones but the distribution was abnormal, with isolated patches containing no neuronal cells. The distribution of neurones within the grey matter of the spinal cord appeared to be normal.

Myelination was virtually absent in the cerebral hemispheres and only a few isolated myelinated fibres were found within the centrum ovale. Poorly defined bundles of well-myelinated fibres could also be seen running through the midbrain and pons. Myelination of fibres within the cerebellum and cerebrellar peduncles was moderately well developed. Within the medulla, myelination was well developed apart from in the pyramidal tracts. The vast majority of fibres within the spinal cord were myelinated, but there was poor myelination cf both the lateral and anterior cortico-spinal tracts.

There were large numbers of astrocytes within the poorly myelinated areas of the brain, many of which were of the gemistocytic and fibrous type (Fig. 6) . The gemistocytic forms, found mainly in the hemispheres, contained large amounts of granular material which stained strongly with sudanophilic dyes (Fig. 7) and weakly with the

Fig. 3 ([eft). Renal cortex containing small cysts. (HE stain x 40.) Fig. 4 (right). Islands of undifferentiated cells in subcortical white matter. (Haematoxylin and eosin (HE) stain x 100.)

662

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CASE REPORTS

Fig. 5 ( lef t ) . Olivary nuclei showing abnormal patterns of neurones. ( H E stain x 60.) Fig. 6 (right). Cerebral white-matter containing numerous gemistocytic astrocytes. (HE stain x 650.)

Fig. 7 ( k f r ) . White matter astrocytes distended with sudanophilic particles. (Sudan 1V Fig. 8 (right). Electronmicrograph of sudanophilic granules in astrocytes. The granules have a laminated appearance. ( x 12,600.)

650.)

PAS stain. No metachromatic substance could be detected. Oligodendrocytes in the cerebral hemi-

Discussion The features of this case correspond

spheres were considerably reduced in poorly myelinated areas.

Fragments of tissue were fixed in 2 per cent

with previous descriptions of the condition known as Zellweger syndrome (cerebra- -

phosphate buffered gluteraldehyde, post-osmi- hepato-renal syndrome) (Bowen et a/. cated, embedded in araldite and stained with 1964, Passarge and McAdams 1967, uranyl acetate and lead citrate. Electronmicro- scopical examination showed that the granules in the astrocytes were composed of laminated osmiophilic material (Fig. 8).

punnet and Kirkpatrick 1968, opitz et 1969, Poznanski et al. 1970).

The chondral calcification in this con-

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1976, 18

dition may lead to an erroneous diagnosis of chondrodystrophia calcificans congenita (Conradi’s syndrome); in the latter con- dition the calcification tends to be wide- spread, hypotonia is usually absent and there is usually no major organ involve- ment.

The sparse, small renal cortical cysts described here appear to be similar to the renal cysts in the case described by Punnet and Kirkpatrick (1968) and certainly con- trast with the numerous prominent cysts reported by others (Passargeand McAdams 1967, Opitz et al. 1969). Periportal fibrosis and cirrhosis of the liver are commonly described. The changes in the liver in this patient were unimpressive and consisted of a slight increase in the number of bile ducts, many of which contained bile plugs. However, this could reflect an early stage in the development of the hepatic lesion.

The central nervous system is almost always affected and shows a multitude of gross and microscopic abnormalities. There have been few detailed reports on the neuropathology of this condition, and the gross features most commonly described are an irregular convolutional pattern, prominent pachygyria and microgyria (Passarge and McAdams 1967, Opitz et al. 1969, Volpe and Adams 1972). Other features include hypoplastic olfactory bulbs, a thinc orpus callosum and a re- duction in the volume of white matter.

On microscopic examination, myelin is always deficient but varies in degree and location. Thus myelin deficiency has been reported as slight by Volpe and Adams (1972), but a marked reduction has also been described by Passarge and McAdams (1967). Characteristically, the demyelinated areas contain astrocytes laden with sudanophilic material, which on electron- microscopy in our case was shown to be composed of multiple layers of laminated osmiophilic membrane. The significance of this finding is not known, but it is possible

that these structures are abnormal mito- chondria.

It has been suggested that the sub- cortical islands of grey matter represent a failure of neuronal migration (Volpe and Adams 1972), but fundamentally the aetiology remains unknown. Increased iron deposition in certain tissues led Opitz et 01. (1969) to suggest a congenital defect of iron metabolism as an underlying cause. However, this finding is not always present (Poznanski et al. 1970) and increased deposits of iron were not found in the liver and kidneys in our case. It has also recently been suggested that the cause might involve a defect in pipecolic acid metabolism (Danks et al. 1975).

The neuropathological findings in our case are essentially the same as those reported by previous authors (Passarge and McAdams 1967, Volpe and Adams 1972) and the brain defect would therefore appear to be specific. However, lesser degrees of the cerebral anomaly have also been reported (Opitz et al. 1969) and in two cases the brains were said to be normal (Smith et al. 1965). These findings imply that a spectrum of defect might exist with regard to this part of the syndrome.

Familial incidence of this condition is well-documented and it has always been suggested that it is inherited as an auto- soma1 recessive trait. Parental consan- guinity has recently been reported in one case (Danks et al. 1975). The parents of the patient described here were first cousins and this would further support an autosomal recessive mode of inheri- tance.

Gastro-intestinal haemorrhage is com- monly described, usually associated with hypoprothrombinaemia (Bowen et al. 1965, Passarge and McAdams 1967, Punnet and Kirkpatrick 1968). Bleeding into the skin is unusual, especially as all the clotting tests were normal. This could imply an intrinsic capillary defect.

664

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CASE REPORTS

AUTHORS’ APPOINTMENTS S. Variend, Registrar in Paediatrics, Department of Paediatrics, Jessop Hospital for Women, Sheffield. (Present address: Department of Histopathology, City Hospital, Hucknall Road, Nottingham NGS 1PB.) W. R. Timperley, Consultant Neuropathologist, Department of Neuropathology, The Royal Infirmary, Sheffield. S . Hill, Consultant Pathologist, Department of Pathology, Jessop Hospital for Women, Sheffield L. S . Taitz, Consultant Paediatrician, Department of Child Health, Children’s Hospital, Western Bank, S heffiel d.

SUMMARY A case of cerebro-hepato-renal syndrome with some unusual features is reported. The

neuropathological findings are described in detail. Electronmicroscopy showed astrocytes in the demyelinated areas of the brain to contain granules composed of laminated osmio- philic material. These structures could be abnormal mitochondria. The parental con- sanguinity in this case would further support an autosomal recessive mode of inheritance.

RESUME Syndrome cPrPbro-hkpato-rPnal avec consanguinitg parentale

Les auteurs rapportent un cas de syndrome cirtbro-hipato-rinal avec manifestations inhabituelles. Les donntes neuropathologiques sont dicrites en ditail. Au microscope electronique, les astrocytes des zones dtmyilinisees du cerveau contenaient des granules faites d’un inattriel osmiophile laminaire. Ces structures pourraient Stre des mitochondries anormales. La consanguinitk parentale serait en faveur d’une transmission hirtditaire ricessive autosomale.

ZUSAMMENFASSUNG Cerebro-hepato-renales Syndroni bei Konsanguinitat der Eltern

Es wird uber einen Fall mit cerebro-hepato-renalem Syndrom mit einigen auffalligen Faktoren berichtet. Die neuropathologischen Befunde werden im Detail beschrieben. Durch die Elektronenmikroskopie konnten in den Astrocyten, die in den demyelinisierten Arealen des Gehirns gefunden wurden, Granula nachgewiesen werden, die aus Schichten osmiophilen Materials zusammengesetzt sind. Diese Strukturen konnen abnorme Mito- chondrien sein. Die Konsanguinitat der Eltcrn in diesem Fall wurde erneut die Annahme eines autosomal recessiven Erbganges stiitzen.

REFERENCES Bowen, P., Lee, C. S. N., Zellweger, H.. Lindenberg, R. (1964) ‘A familial syndrome of multiple congenital

defects.’ Bulletin of the Johns Hopkins Hospital, 114, 402. Danks, D . M., Tippet, P., Adams, C., Campbell, P. (1975) ‘Cerebro-hepato-renal syndrome of Zellweger.’

Journal of Pediatrics, 86, 382. Opitz, J. M., ZuRhein, G. M., Vitale, L., Shahidi, N., Howe, J. J., Chou, S. M., Shanklin, D. R., Sybers,

H. D., Dood, A. R., Gerritsen, T. (1969) ‘The Zellweger cerebro-hepato-renal syndrome.’ Birth Defects: Original Article Series, 5 , (2), 144.

Passarge, E., McAdams, A. J. (1967) ‘Cerebro-hepato-renal syndrome.’ Journal of Pedinlrics, 71, 691. Poznanski, A. K., Nosanchuk, J. S . , Baublis, J . , Holt, J. F. (1970) ‘The cerebro-hepato-renal syndrome

(CHRS) (Zellweger’s syndrome).’ Anrerican Journal of Roentgenology, 109, 31 3 . Punnett, H. H., Kirkpatrick, J. A. (1968) ‘A syndrome of ocular abnormalities, calcification of the cartilage,

and failure to thrive.’ Journal of Pediatrics, 73, 602. Smith, D. W., Opitz, J . M., Inhorn, S. L. (1965) ‘A syndrome of multiple congenital defects including

polycystic kidneys and intrahepatic biliary dysgenesis in two siblings.’ Journal qf Pediatrics, 67, 617. Volpe, J. J . , Adams, R. D. (1972) ‘Cerebro-hepato-renal syndrome of Zellweger: an inherited disorder of

neuronal migration.’ Acta Neuroputhologira, 20, 175.

665