J Med Genet 1992; 29: 733-735

Lethal olivopontoneocerebellar hypoplasia withdysmorphic features in sibs

I D Young, P A McKeever, M V Squier, J Grant

AbstractThis report describes the clinical andneuropathological features in male andfemale sibs who died shortly after birthas a result of frequent convulsions andlack of spontaneous respiratory effect.Both sibs had a prominent occiput withmild contractures and the female alsohad overlapping fingers and rockerbot-tom feet. The genetic and neuropatho-logical findings were consistent with adiagnosis of an autosomal recessive formof olivopontoneocerebellar hypoplasia/atrophy.(J Med Genet 1992;29:733-5)

Department ofClinical Genetics, CityHospital, HucknallRoad, NottinghamNG5 1PB.I D Young

Department ofPathology, LeicesterRoyal Infirmary,Leicester.P A McKeever

Department ofNeuropathology,Radcliffe Infirmary,Oxford.M V Squier

Department of ChildHealth, LeicesterRoyal Infirmary,Leicester.J Grant

Correspondence toDr Young.Received 31 January 1992.Revised version accepted30th March 1992.

Hypoplasia of the cerebellar hemispheres inassociation with undervelopment of the pons('pontoneocerebellar hypoplasia') was de-scribed in 1958 by Norman and Urich' in twounrelated children, both of whom died duringthe first year of life. The parents ofone of thesechildren were second cousins, an observationsuggestive of autosomal recessive inheritance.Recessive inheritance was also proposed as theprobable mode of inheritance in male andfemale sibs who died in early childhood with a

diagnosis of congenital 'olivopontocerebellar'atrophy,2 and in seven cases described in fiveDutch families.' We have recently encoun-tered a further sibship in which two babiesdied shortly after birth with a particularlyfulminant form of familial olivopontoneocere-bellar hypoplasia. One of these infants also hada number of dysmorphic features.

Case reportsThe affected sibs were the products of the first

Figure 1 Case 1 shortly after birth. Note the overlapping 'trisomy 18'fingers and

rockerbottom feet.

two pregnancies of young, healthy, unrelated,Caucasian parents who had no history of rele-vant hereditary disease.

CASE 1Concern first arose at 34 weeks' gestationwhen the mother noticed a reduction in fetalmovements which coincided with the onsetof polyhydramnios. Two weeks later afterspontaneous onset of labour, she delivered afemale infant weighing 1490 g (< 3rd centile).Body length was 39 5 cm (< 3rd centile), andhead circumference 27-2 cm (< 3rd centile).The baby made no attempt to breathe spon-taneously, had frequent convulsions, and diedat the age of 24 hours.

Abnormalities noted during life included aprominent occiput, micrognathia, and contrac-tures of all four limbs with overlappingclenched fingers and bilateral rockerbottomfeet (fig 1). At necropsy the total brain weightwas 140 g (expected weight= approximately350 g), and in particular the hind brain wasdisproportionately small weighing only 2 g(expected weigh= 20 g) (fig 2). The lungs werein proportion to the body size and no visceralabnormalities were present. Chromosomestudies using cultured lymphocytes showed anormal female karyotype.

CASE 2This pregnancy was monitored regularly usingultrasonography from 16 weeks onwards. Noabnormalities were noted until 34 weeks' ges-tation, when, as in the first pregnancy, poly-hydramnios developed in association with areduction in fetal movement. At 36 weeks anintrauterine convulsion was observed. At de-livery three days later the male infant weighed2010 g (3rd centile), length 46 cm (50th cent-ile), and head circumference 295 cm (3rdcentile). Once again the baby made no spon-taneous respiratory effort, showed frequentconvulsive activity, and died at the age of 48hours.Dysmorphic features were less apparent in

this baby than in his affected sister (case 1),and consisted of niild contractures in all limbswith a prominent occiput, receding forehead,and micrognathia (fig 3). A CT scan showedcerebellar hypoplasia with cerebral atrophy.These findings were confirmed at necropsy.Total brain weight was 104 g (expected forgestational age= 366 g) and the hindbrainagain was disproportionately small at 28g(expected weight= 21 g). No other abnormal-ities were detected on internal examination.

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Figure 2 The brain of case I showing marked hypoplasia of both cerebellarhemispheres.

NEUROPATHOLOGYSections of the brains of both sibs showedsimilar changes with most severe involvementof the brainstem and cerebellum. There was

marked loss of neurones with reactive astrocy-tosis in the pontine nuclei. The transversefibres of the pons were depleted. The inferiorolivary nuclei also showed neuronal loss andgliosis. Pyramidal tracts were normal. Thecerebellum showed loss of Purkinje cells anddepletion of the internal granular layer in thehemispheres. The external granular layer was

reduced in thickness but still identifiable. Thevermis, floccules, and nodules (components of

Figure 3 Postmortem view of case 2. Note the pointedocciput.

the archi- and paleocerebellum) were well pre-served. The dentate nuclei retained their nor-mal outline but showed severe neuronal lossand reactive gliosis.

Sections of the cerebral hemispheresshowed no evidence of malformation. Thecortex was normally laminated. Neuronal nec-roses were seen in the hippocampus and subi-culum and there was gliosis and macrophageinfiltration in cerebral white matter, consistentwith recent ischaemia or hypoxia.The spinal cord showed normal anterior

horn cells with normal and symmetrical anter-ior and posterior nerve roots.

DiscussionThe clinical features shared by these sibs in-cluded relative microcephaly, prominent occi-put, micrognathia, and contractures. In addi-tion, case 1 had overlapping fingers androckerbottom feet which initially suggested apossible diagnosis of trisomy 18. Neurologi-cally their disease ran an almost identicalcourse marked by reduction in fetal movementand polyhydramnios, presumably a manifesta-tion of impaired deglutition, from 34 weeksonwards, with subsequent convulsions andfailure to develop spontaneous respiration atbirth. At necropsy both had severe cerebellarhypoplasia and neuropathological studiesshowed olivopontoneocerebellar hypoplasia.The initial diagnosis of trisomy 18 in case 1

was rapidly refuted by the discovery of anormal karyotype. Alternative diagnoseswhich were considered included the Pena-Shokeir and Bowen-Conradi syndromes. ThePena-Shokeir syndrome is generally acceptedas being extremely heterogeneous, represent-ing the phenotype resulting from long stand-ing fetal akinesia.4 Cerebellar hypoplasia hasbeen noted in a small proportion of publishedcases5 although reduction in anterior horn cellsis a more characteristic finding. The absence ofpulmonary hypoplasia in the cases now de-scribed is consistent with the relatively lateonset of reduction in fetal movements (34weeks), and together these observationssuggest that the disease in these infants shouldnot be categorised as falling within the spec-trum of the Pena-Shokeir phenotype.The Bowen-Conradi syndrome is a rare

autosomal recessive disorder described mainlyin the Hutterites.6 The major features areintrauterine growth retardation, microcephaly,micrognathia, contractures, rockerbottom feet,and death in early infancy. The facial profile ofchildren with this condition is very similar tothat in case 2 and cerebellar abnormalitiesconsisting of partial agenesis and 'hypoplasiaor atrophy' have been noted.6 Although thiscondition is regarded as lethal, the degree ofneurological dysfunction is not as severe as inthe cases now reported with the most notice-able differences being the achievement ofspontaneous respiration and rarity of convul-sions in the neonatal period.The neuropathological demonstration of a

small brainstem with hypoplasia of the cere-bellar hemispheres suggests that the disorder

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Lethal olivopontoneocerebellar hypoplasia with dysmorphic features in sibs

in these sibs is best classified as a form ofolivopontoneocerebellar hypoplasia or atro-phy. In 1986, Kawagoe and Jacob7 reportedalmost identical neuropathological findings ina female infant who died at the age of 9 dayshaving had generalised convulsions and 'longterm apnoea attacks'. The child also had bila-teral talipes. These authors proposed that thecerebellar hypoplasia was the primary abnor-mality and that the absence ofnerve cells in thepons and inferior olives was secondary to neur-onal deprivation or inactivity. A further casereport by Pitella and Nogueiral described a 9day old male infant with widely separatednipples, overlapping toes, and hypertrichosisof the gluteal and sacrococcygeal regions withpontoneocerebellar hypoplasia. These authorssuggested that the severe neuronal loss andgliosis in the pontine nuclei may represent theprimary lesion which is followed by neocere-bellar degeneration. Barth et aP reported simi-lar CNS findings in seven children, two boysand five girls, from a Dutch genetic isolate,four of whom died in childhood. Their illnesswas characterised by congenital and occasio-nally progressive microcephaly, myoclonicjerks, generalised convulsions, and profounddevelopmental delay. The neuropathologicalfindings in the case examined by Barth et aPwere similar to those in our own cases.

Pontoneocerebellar hypoplasia is a term ap-plied to a group of conditions with a variety ofclinical presentations and of heterogeneousneuropathology. In our cases, severe neuronalloss and gliosis in the pontine nuclei, dentatenuclei, inferior olivary nuclei, and neocerebel-lum suggest a degenerative process occurringafter these structures had developed, that is,atrophy rather than primary hypoplasia. Theclinical history of reduced fetal movements at34 weeks of gestation is consistent with rela-tively late onset of the disorder. The aetiologyis diverse and the condition has been associ-ated with both metabolic disease2 and anticon-vulsant ingestion during pregnancy.910 These

cases confirm that this appearance may also bethe consequence of an autosomal recessiveneurodegenerative process.

Note added in proofA third pregnancy was complicated by poly-hydramnios at 32 weeks. A fetal scan showedgrowth retardation and fixed flexion of onewrist and hand. A male infant was delivered at38 weeks, birth weight 2760 g, with micro-cephaly and fixed flexion contractures of thelimbs. The heart rate was 40/minute and therewere no spontaneous respirations. Resusci-tation was not attempted and the infant diedaged 10 minutes.

The authors are grateful to Dr U M Mac-Fadyen for referring the family.

1 Norman RM, Urich H. Cerebellar hypoplasia associatedwith systemic degeneration in early life. J Neurol Neuro-surg Psychiatry 1958;21:159-66.

2 Harding BN, Dunger DB, Grant DB, Erdohazi M. Familialolivopontocerebellar atrophy with neonatal onset: a reces-sively inherited syndrome with systemic and biochemicalabnormalities. J Neurol Neurosurg Psychiatry1988;51:385-90.

3 Barth PG, Vrensen GFJM, Uylings HBM, Oorthuys JWE,Stam FC. Inherited syndrome of microcephaly, dyskine-sia and pontocerebellar hypoplasia: a systemic atrophywith early onset. J Neurol Sci 1990;97:25-42.

4 Hall JG. Invited editorial comment: analysis of Pena Shok-eir phenotype. Am J Med Genet 1986;25:99-117.

5 Lindhout D, Hageman G, Beemer FA, Ippel PF, Breslau-Siderius L, Willemse J. The Pena-Shokeir syndrome:report ofnine Dutch cases. AmJ7 Med Genet 1985;21:655-68.

6 Hunter AGW, Woerner SJ, Montalvo-Hicks LDC, et al.The Bowen-Conradi syndrome - a highly lethal autoso-mal recessive syndrome of microcephaly, micrognathia,low birth weight and joint deformities. Am J Med Genet1979;3:269-79.

7 Kawagoe T, Jacob H. Neocerebellar hypoplasia with sys-temic combined olivo-ponto-dentatal degeneration in a 9-day-old baby: contribution to the problem of relationsbetween malformation and systemic degeneration in earlylife. Clin Neuropathol 1986;5:203-8.

8 Pitella JEH, Nogueira AMMF. Pontoneocerebellar hypo-plasia: report of a case in a newborn and review of theliterature. Clin Neuropathol 1990;9:33-8.

9 Gadisseaux JF, Rodriguez J, Lyon J. Pontoneocerebellarhypoplasia - a probable consequence of prenatal destruc-tion of the pontine nuclei and a possible role of phenytoinintoxication. Clin Neuropathol 1984;3:160-7.

10 Squier W, Hope PL, Lindenbaum RH. Neocerebellarhypoplasia in a neonate following intra-uterine exposureto anticonvulsants. Dev Med Child Neurol 1990;32:725-42.

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