Archives of Disease in Childhood, 1986, 61, 545-548

Nephrosis and disturbances of neuronal migration inmale siblings -a new hereditary disorder?L PALM, I HAGERSTRAND, U KRISTOFFERSSON, G BLENNOW, A BRUN,AND C JORGENSEN

Departments of Paediatrics, Pathology, Clinical Genetics, and Obstetrics, University Hospital, Lund, Sweden

SUMMARY Two male siblings (a boy aged 2 years 10 months at death and a male fetus aborted ingestational week 22) showed similar brain and kidney malformations, comprising paraventricularheterotopias, central canal abnormalities (including hydrocephalus in the boy), and glomerularkidney disease with proteinuria. There were no known hereditary diseases in the families of theparents, and there was one healthy sibling of either sex. The malformations thus seem to behereditary in an autosomal or possibly X linked recessive fashion.

Disturbances in the development of the centralnervous system during early gestation occur as theresult of many different noxious factors and events.Infections, intoxications, and acute haemodynamicchanges during early gestation may be the cause ofmigration disturbances such as neuronal heteroto-pias, cortical dyslamination, and other defects.Heterotopias have also been described in connec-tion with several childhood syndromes.' There arehereditary disorders among these, including com-prehensive malformation syndromes where renaldisease also occurs. Congenital nephrosis has beendescribed in cases of microcephaly2 3 and in one caseof migration disturbance.4We report the connection between congenital

nephrosis, migration disturbances, and central canalabnormalities in a boy and an aborted male siblingfetus, possibly constituting a new autosomal or Xlinked recessive syndrome.

Patients

The two cases presented here were the results of thesecond and third pregnancy of healthy, non-consanguinous parents. There were no known her-editary disorders in the family. The first child, ahealthy daughter, was born in 1977, when themother was aged 22. Subsequently, in 1984, after anuneventful fourth pregnancy, during whicha fetoprotein concentrations and ultrasonographyfindings were normal, the mother delivered ahealthy son.

Case 1. This boy was born at term by a normal

delivery in 1979. No attempt at prenatal diagnosiswas made. Birth weight was 3200 g, with Apgarscores of 10-10-10. Because of a radiologicallyverified aqueduct stenosis a ventriculoperitonealshunt operation was performed at the age of 3weeks. Just before operation a urinary tract infec-tion was diagnosed associated with pyuria andmoderate albuminuria. An excretory urogram andvoiding cystourethrogram yielded normal results.The albuminuria disappeared after the urinary tractinfection had been treated.At 5 months the boy had a serous menin-

goencephalitis and a focal epileptic seizure of 30-40minutes' duration. There were no signs of infectionof the shunt. A nephrotic syndrome developed withcontinuing haemoglobinuria and albuminuria and aslight arterial hypertension. The nephrosis was firsttreated with a period of lactose free diet, duringwhich the albuminuria temporarily diminished.Thereafter prednisolone was given without success.A renal biopsy examination was performed. Lightmicroscopy showed very slight glomerular changesofproliferative type, and electron microscopy showedmesangial proliferation and swelling of the epithelialpodocytes. No immunological deposits were foundat electron microscopy or by histochemical examina-tion.Because of further febrile convulsions of long

duration prophylactic treatment with phenobarbi-tone was given. At 10 months there were repeatedsevere general tonic-clonic seizures and at the sametime the arterial hypertension increased. Because ofthe suspicion of nephritis induced by shunt infectionthe shunt was replaced. This operation was compli-

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546 Palm, Hagerstrand, Kristoffersson, Blennow, Brun, and Jorgensen

cated by staphylococcal meningitis and an intra-abdominal abscess. After abdominal surgery andtreatment with antibiotics the new ventriculoperi-toneal shunt had to be exchanged for a ventriculo-atrial shunt. During and after these procedures thenephrosis continued with increasing amounts ofalbuminuria. Arterial blood pressure respondedwell to treatment. The boy was mentally retardedand developed a moderate spastic tetraplegia.Treatment with cloxacillin was started and con-

tinued for about one year. During this time theclinical picture was fairly stable, but at 2-5 years thenephrosis worsened again. Intensive treatment withintravenous high dose, broad range antibiotics wastried without effect. Pulse treatment with methyl-prednisolone followed by long term treatment withoral prednisolone and cyclophosphamide led to

some improvement with rising serum albumin con-centrations for a couple of months. At 2 years and10 months the boy suddenly died during a respira-tory tract infection.

AutopsyThe immediate cause of death was bronchitis. Thebrain weighed 1015 g. The ventricular system abovethe sylvian aqueduct was dilatated. There wereatrophic, thin gyri in the parieto-occipital region ofone hemisphere, histologically with the occurrenceof an old, large, incomplete cortical infarct. Therewere solid periventricular neuronal heterotopiasbilaterally (Fig. 1).The kidneys were of normal size and appearance.

Together they weighed 136 g. Many small pale dotswere observed, both in the cortex and the medulla.They corresponded histologically to heaps of foamcells lying between tubular structures. The glomerulishowed no or very slight proliferative changes, andno progress of the glomerular lesions had occurred.

Case 2. This pregnancy was carefully followed.a Fetoprotein values of amniotic fluid in gestationalweek 17 were increased 20-fold in two independentsamples. The cytogenetic analysis was normal.Ultrasonography showed an oligohydramniosis, abroadening of the uppermost part of the vertebralcolumn, and an increased ecogenicity from thekidney regions. Intrauterine growth was slowing

Fig. 1 A nodular heterotopia in one of the lateral ventriclesfrom the child (haematoxylin-eosin stain).

Fig. 2 Nodular heterotopias (H) in one of the lateralventricles from the fetus, with plexus choroideus (P) in theupper part (haematoxylin-eosin stain).

.: .i .: :6,; 5. ,'.; Ii .. v.:. --'T

Fig. 3 The kidney from the fetus, showing many smallcysts (S) mainly on the border between cortex (C) andmedulla (M) (haematoxylin-eosin stain).

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Nephrosis and disturbances of neuronal migration in male siblings-a new hereditary disorder? 547

Fig. 4 Electron microscopy from the kidney ofthe fetus,showing normal podocytes (P), but somewhat irregularbasal membrane (B) with varying density, and capillarylumen superior, epithelium inferior.

Fig. 5 Electron microscopy form the kidney ofthefetus,showing abnormal, fused podocytes (P), abnormal basalmembrane (B), and capillary lumen superior, epitheliuminferior.

down. Legal abortion was made in gestational week22.

AutopsyThe male fetus showed no gross malformations atautopsy. There was no hydrocephalus, and thekidneys were of normal appearance. Histologically,multiple neuronal, solid heterotopias were found inboth lateral ventricles (Fig. 2). In sections fromdifferent parts of the spinal cord the central canalwas found to be split into two or three tubes lyingnear each other or sometimes at considerabledistance.The kidneys showed histologically several small

cysts lying mainly at the cortical-medullary junction.The cysts were lined by a rather high epithelium and

contained eosinophilic fluid. Otherwise, the imma-ture structures were judged to be normal. Electronmicroscopy disclosed slight glomerular changes,occasionally consisting of fused podocytes and ir-regularities of the basal membranes (Figs. 3-5).

Discussion

The main features of interest in this boy and hissibling fetus are the migration disturbance, thecentral canal malformation and the renal diseaseand the relation between them, as well as thepossible hereditary nature of the disease.

If there is a common cause, genetic or environ-mental, for the renal and central nervous systemmalformation this must be searched for very early ingestation. The development of new kidney nephronscontinues until gestational week 36, and the earliestchanges in congenital nephrosis might date back asfar as the eighth to 10th week. In the fetal brainmigration of neurons from the ventricular zone intothe developing cortical plate takes place from thesixth to eighth gestational weeks onwards. The firstcortical plate is formed in the eighth to 10th week.In the telencephalon the main process of migrationis completed at about six months of gestation.5 Inour study the fetus, 22 weeks old at abortion, waswell past the most active migration period. Theforking of the central canal in the fetus suggests alesion about the time for closure of the neural tubeearly in neurogenesis.6 The development of theaqueductal stenosis shown on x ray film in the elderbrother is less clearly defined in time.

Several types of congenital hereditary nephrosishave been described, all with a suggested autosomalrecessive inheritance.7 Congenital nephrosis of theFinnish type is well characterised as an autosomalrecessive disorder. The kidney morphology in ourboy, who died aged 2 years 10 months, however,does not agree with congenital nephrosis of theFinnish type, and children with this type of nephro-sis do not usually survive infancy. In the fetus thepresence of tubular cysts may fit in with thediagnosis of Finnish type nephrosis, although theglomerular findings are very discrete.8 Heterotopiashave been described as the sole finding in monozy-gotic twins.9 No heredity was found in a seriesof five children with infantile spasms and hetero-topias.' Renal malformations and neuronal hetero-topias have been described in syndromes withrecessive heredity such as Zellweger's syndrome10 11and Potter's syndrome.12 The combination of con-genital nephrosis and migration disturbances hasearlier been reported and considered important inone isolated case.4 Cases of congenital nephrosistogether with microcephaly and hiatus hernia have

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548 Palm, Hagerstrand, Kristoffersson, Blennow, Brun, and Jorgensen

been reported in siblings but without description ofdisturbed neuronal migration.2 3A distinct hereditary disorder may be considered

in our cases. No other cases of nephrosis wereknown in this family, and there was no connectionwith Finland. Although the finding of two affectedboys in the same family suggests an X linkedinheritance of this new syndrome, an autosomalmode of inheritance cannot be excluded, especiallyas all previous reports of hereditary nephrosessuggest an autosomal recessive mode of in-heritance.7 In this context it should be mentionedthat prenatal diagnosis in this disorder may bepossible by a fetoprotein monitoring.

We are indebted to Dr Juhani Rapola, Univcrsity Hospital,Helsinki, and Dr J R Pincott, the Hospital for Sick Children, GreatOrmond Street, London, for their judgment on the kidneymorphology.

References

Palm L, Blennow G, Brun A. Infantile spasms and neuronalheterotopias. Acta Paediatr Scand 1986. (In press).

2 Galloway WH, Mowat AP. Congenital microcephaly withhiatus hernia and nephrotic syndrome in two sibs. J Med Genet1968;5:319-21.Shapiro LR, Duncan PA, Farnsworth PB, Lefkowitz M.Congenital microcephaly, hiatus hernia and nephrotic syn-

drome: an autosomal recessive syndrome. Birth Defects1976;12(5):275-8.

4Robain 0, Deonna T. Pachygyria and congenital nephrosisdisorder of migration and neuronal orientation. Acta Neuro-pathol (Berl) 1983;60:137-41.

5Rakic P. Neuronal migration and contact guidance in theprimate telencephalon. Postgrad Med J 1978;54:25-40.

6 Kallen B. Errors in the differentiation of the central nervoussystem. Birth Defects 1979;15(3):43-53.McKusick VA, ed. Mendelian inheritance in man. Catalogs ofautosomal dominant, autosomal recessive and X-linkedphenotypes. 6th ed. Baltimore, United States: The JohnHopkins University Press, 1983.

8 Autio-Harmainen H, Rapola J. Renal pathology of fetuses withcongenital nephrosis of the finnish type. Nephron 1981;29:158-63.

9 Pavone L, Mollica F, Incorpora G, Pampiglione G. Infantilespasm syndrome in two monozygotic twins. Arch Dis Child1980;55:870-2.

10 Della Giustina E, Goffinet AM, Landrieu P, Lyon G. A golgistudy of the brain malformation in Zellweger's cerebro-hepato-renal disease. Acta Neuropathol (Berl) 1981;55:23-8.

l 'Brun A, Gilboa M, Meuwisse GW, Nordgren H. The Zellwegersyndrome: subcellular pathology, neuropathology and thedemonstration of pneumocystis carinii pneumonitis in twosiblings. Eur J Pediatr 1978;127:229-45.

12 Grunnet ML, Bale JF. Brain abnormalities in isifants with Pottersyndrome (oligohydramnios tetrad). Neurology (NY) 1981;31:15714.

Correspondence to Dr L Palm, Department of Paediatrics,Jniversity Hospital, S-221 85 Lund, Sweden.

Received 28 February 1986

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