British Journal of Ophthalmology, 1986, 70, 742-747

Warburg (HARD±E) syndrome without retinaldysplasia: case report and reviewM F D ATTIA,' J BURN,2 J H McCARTHY,3 D P PUROHIT,4AND D W A MILLIGAN'

From the Departments of 'Ophthalmology, 4Neuropathology, and 'Child Health, Newcastle General Hospital,Newcastle-upon-Tyne; the 2Department ofHuman Genetics, University ofNewcastle-upon-Tyne; and the'Department of Pathology, South Shields General Hospital.

SUMMARY Warburg syndrome is a recently defined autosomal recessive oculocerebral syndrome.It was previously given the acronym HARD±E, indicating what were regarded as thepathognomonic features, namely hydrocephalus, agyria, and retinal dysplasia with or withoutencephalocele. We report the case of a male infant with the typical cerebral features ofhydrocephalus, agyria, and pseudoencephalocele, but without retinal dysplasia. Peters' anomalyand optic nerve hypoplasia were the main ocular defects. We believe that anterior chamber defectsand optic nerve hypoplasia are the ocular defects more directly related developmentally to thecerebral defects. Definition of ocular defects is important, since diagnosis and counselling relyheavily on ocular signs, which help to distinguish this syndrome from neural tube defects in general.

Congenital cerebral abnormalities were reported tobe associated with a variety of eye defects. In theabsence of polydactyly and polycystic kidneys, whichcharacterise the Meckel syndrome,' the associationof hydrocephalus, agyria, and in some casesencephalocele with retinal dysplasia was recognisedas a specific syndrome and was given the mnemonicHARD±E syndrome by Pagon et al.2 More recentreports and reviews"5 have emphasised the vari-ability of expression of this autosomal recessivedisorder. Pagon et al.' suggested that the eponymWarburg syndrome be used instead of HARD±E.We report a case with typical cerebral features of

Warburg syndrome but without retinal dysplasia.

Case report

A full-term white male baby was born to youngCaucasian unrelated parents. The pregnancy wasnormal, with no history of maternal disease or drugintake. Previous obstetric history included a spon-taneous abortion at 10-12 weeks and the birth of anormal female infant. No family history of anycongenital abnormality could be elicited. Birthweight was 2960 g, length 48 cm, and head circumfer-Correspondence to DrM FD Attia, Department of Ophthalmology,Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ.

ence 33-7 cm. External examination (Figs. 1, 2)showed micrognathia, hypertelorism, low-set ears,and a cleft palate extending to the gingival margin.The occipital region showed a reducible, non-pulsatile protrusion, overlying a small bony defect.The overlying skin showed a tuft of hair, covering adermal sinus. A head scan revealed grossly dilatedlateral and third ventricles and absent corpuscallosum. A body scan showed the right kidney to beenlarged, with large cystic spaces. Both eyes wereenlarged and protuberant, with increased cornealdiameter to 13 mm each. There were localised centralcorneal opacities, denser in the left than in the rightcornea (Fig. 1). The pupils were small and fixed, witha transverse diameter of 2-9 mm (right) and 1.7 mm(left). The irides appeared stretched and slightlyatrophic. The intraocular pressure was raised to 26mmHg (right) and 28 mmHg (left), as measured witha Perkins applanation tonometer. A faint red reflexwas evident in both eyes. There was no obviousnystagmus or strabismus. Chromosomal analysisrevealed a normal male karyotype. Serology titres forherpes simplex, rubella, and cytomegalovirus werenot increased. The infant died at the age of 4 days.Post-mortem examination confirmed the facial

anomalies. Other abnormalitities were confined tothe eyes, brain, and urinary system. There was a

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Warburg (HARD±E) syndrome without retinal dysplasia: case report and review

Fig. 3 Theright eye, as seen through the biomicroscope.Note the central cornealstromal opacity, centralposteriorcorneal defect, and very shallow anterior chamber, which isobliterated centrally.

*-- .AN.X .... . M .~~~~~~~~~~~~~~~.. ..........

*.....

~~~~~~~~~~~~~~~~~~~~~~~~... ....

Fig. I Front view oftheface, showing bilateral centralcorneal opacities.

marked right hydronephrosis and hydroureter,caused by a stricture of the distal end of the ureter.The left kidney showed multiple nodules of focalrenal dysplasia in the upper pole.

OCULAR PATHOLOGY

Shortly after death both eyes were examined underthe biomicroscope. The right eye (Fig. 3) showed a

Fig. 2 Lateral view ofthe head, showing buphthalmos,micrognathia, low-set ear, andpseudoencephalocele.

faint central corneal stromal opacity and a posteriorcentral stromal defect, consistent with Peters'anomaly. The anterior chamber was very shallow atthe periphery and absent centrally, with apparentadhesions of the iris-lens diaphragm to the posteriorsurface of the cornea, at the pupillary area. The lefteye showed a denser central corneal stromal opacity.Neither corneal stromal defect nor central adhesionsbetween the cornea and iris-lens diaphragm could bedetected. The anterior chamber was also veryshallow.

Examination of the fixed specimens showed botheyes to be enlarged (diameters right and left: 21 mmtransverse, 19 mm anteroposterior, and 20 mmsuperoinferior). On cross section each eye showed anoptic disc, an optic nerve stump, and retinal bloodvessel of normal appearance. Both retinae wereattached, with no folds or colobomata. A thin,translucent, non-vascular band extended from theoptic disc to the posterior surface of the lens in eacheye.

Microscopic examination of the right eye (Fig. 4)confirmed the central corneal defect involving theposterior stroma, with complete absence of theendothelial cell layer and Descemet's membraneover the defect. The pupillary margin of the irisshowed evidence of adhesion to the margins of thecentral corneal defect, with no inflammatory cellularinfiltrate detected. The left eye (Fig. 5) showed nocentral corneal defect apart from a rather thinDescemet's membrane. The iridocorneal angle was

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%.

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..eFig. 4 Crosssection oftherighteye. Notetheposteriorcentral corneal defect, posterior lenticonus, and normalappearance ofthe retina. (Hand E, x3).

normal and open bilaterally, with a normal trabecu-lar meshwork and canal of Schlemm. The lenscapsule was intact in both eyes. There was a rightposterior lenticonus and central lenticular calcifica-tion (Fig. 4) and a left posterior cortical cataract.Both retinae showed a normal layering with a normalretinal pigment epithelium. Retinal ganglion cellscould be detected in their normal place but werediminished in number. There was no evidence ofrosette formation in either retina when multiplesections were studied. Optic discs were confirmedbilaterally by the absence of overlying retinal tissue.The lamina cribrosa showed no evidence of cupping.Both optic nerve stumps were of normal size. Theywere formed mainly of glial cells and failed to show

Fig. 5 Cross section ofthe lefteye. Note the thick cornea,the thin sclera, and the normal appearance ofthe retina.(HandE, x2-7).

the staining reactions either for nerve fibres (axons)or for myelin.

NEUROPATHOLOGICAL FINDINGSThe skull was large. The dura mater was normal, butthe falx cerebri was very short. The cerebrum showedtotal agyria, with the longitudinal and Sylvian fissuresonly slightly formed. Olfactory bulbs and tracts, opticnerves, chiasma, optic tracts, and lateral geniculatebodies were not identified. Coronal section of thecerebrum (Fig. 6) showed gross hydrocephalus and acontinuous ventricular cavity, due to the absence ofseptum pellucidum and roof of the third ventricle.The basal ganglia, thalamus, and hypothalamic struc-tures were seen only as a bilateral mass of greymatter. In most places the cerebral cortex and whitematter were reduced to a thin strip, which onhistological examination showed a cortex formed byneurons lacking the orderly, layered arrangement,and a very sparsely myelinated white matter contain-ing islands of migrating neuroblasts. The corpuscallosum was severely hypoplastic and visible only asa nodular ridge. In the posterior fossa a Dandy-Walker malformation was identified which hadcaused distortion of the cerebellar hemispheres andbrain stem and widening of the floor of the fourthventricle. The cerebellar vermis showed hypoplasiaand severe cortical dysplasia. The cerebellar hemis-pheres showed a moderate cortical dysplasia. Thecerebellar nuclei and the nuclei of the brain stemwere identified, and the cranial nerves emerging fromthe brain stem and their nuclei were normal.The aqueduct of Sylvius was also normal. The

bulging of the scalp over the small occipital defectwas due to a pseudoencephalocele, since there wasno histological evidence of its continuity with thecranial cavity or the presence of meningeal orneuroglial tissue.

Discussion

The acronym HARD±E was applied to cases show-ing hydrocephalus, agyria, and retinal dysplasia withor without encephalocele, based on early reports."The cases reported by Warburg9 were also suspectedof being related but were not included owing toinsufficient evidence. Pagon et al. , Bordarier et al. ,and Whitley et al.S have redefined the syndrome inthe light of recent reports. They considered that a lessrestrictive name than HARD±E was necessary. Thesuggestion 6f Pagon et al.3 to call it Warburg syn-drome was accepted in recognition of the pioneerwork of this researcher."'

Retinal dysplasia and non-attachment were foundin almost all of the eyes studied histologically. In thepresent case, however, both retinae were normally

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Fig. 6 Coronal sectionsofthe cerebrum, showingagyria, hydrocephaluswith a large singleventricular cavity, andabsence ofoptic nerves andchiasma.

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attached. No rosette formation could be detected toindicate retinal dysplasia. Lahav and Albert" postu-lated that retinal dysplasia is caused by cellularproliferation of the inner layer of the optic cup, whichmay be accompanied by folding of the retina. Thiscan occur as an abortive response of a retina,damaged by a number of factors, such as viralinfection. They also suggested that orderly retinaldevelopment may depend on the organising influenceof an adjacent retinal pigment epithelium. Hencenon-inflammatory retinal dysplasia usually develops

over areas devoid of pigment epithelium and incongenitally non-attached areas. This indicates thatretinal dysplasia is secondary to retinal non-attachment during a faulty development of the opticvesicle. As it is a common, non-specific, and non-pathognomonic abnormality," it is not appropriate toconsider retinal dysplasia a primary major compo-nent of the Warburg syndrome.The ocular signs of Warburg syndrome have been

listed in recent reviews.35 They included differentdegrees of Peters' anomaly, unilateral and bilateral.

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There were also cases with a combination of centraland peripheral anterior chamber defects3' and caseswith peripheral defects only.3 In the cases withPeters' anomaly central corneal opacity was thecommonest sign. Other opacities in the media werealso common, namely, congenital cataract and per-sistent hyperplastic primary vitreous. A degree ofboth was found in the case reported here. Theposterior lenticonus seen in this case has also beenpreviously reported.'2 When a clear view of thefundus could be achieved, a pale non-attached retina,together with retinal folds, would be the commonestsign expected. Optic disc hypoplasia and colobomatamay also be seen. Abnormalities of the size of theglobe were frequent, including microphthalmia and,less commonly, buphthalmos, as in the present case.

Bilateral optic nerve hypoplasia was prominent inthe case reported here. It is believed to result from afailure of the retinal ganglion cells to form nervefibres while the mesodermal component of the opticnerve develops, forming an optic disc and retinalblood vessels. 315

Yanoff et al. 13 reported a case with striking similari-ties to our case, including agyria, hydrocephalus,cerebellar hypoplasia, clouded corneas, micro-gnathia, low-set ears, and unilateral hydronephrosis.Retinal dysplasia was also not detected. The mainocular feature in that case was bilateral optic nerveaplasia, the pathogenesis of which is believed to besimilar to that of optic nerve hypoplasia. 4 Theabsence of the mesodermal component recognised bythe absence of optic discs and retinal blood vessels isprobably due to lack of induction caused by theabsence of nerve fibres. 13 14

In the case reported here the possibility of opticnerve atrophy secondary to glaucoma rather thanprimary hypoplasia could be excluded, as the intra-ocular pressure was only slightly raised, and that wasmainly compensated for by enlargement of theglobes, with no definite cupping of the optic discs.'6The posterior corneal defect in Peters' anomaly

could be explained by an incomplete migration of theinitial two waves of mesenchymal cells, which formthe corneal endothelium with its Descemet's mem-brane and then the corneal stroma. 17 "X

Johnston 9 concluded that the cephalic neural crestprovides the origin for most facial and ocular struc-tures apart from the retina and lens, epithelialtissues, vascular endothelia, and skeletal musclecells. He suggested that the neural crest cells, form-ing the mesenchyme of the frontonasal processes, arederived from the forebrain neural folds and that theformation of the neural tube and crest may depend onthe same inductor. Inadequate induction could resultin simultaneous deficiencies of both structures. Thefrontonasal crest must form a relatively large mass of

cells in a limited time to achieve normal primarypalate formation. Experimentally, reducing thenumber of these crest cells in the chick and mouseembryos resulted in cleft palate with associated brainand eye defects.Bahn et al.'0 introduced a classification of corneal

endothelial disorders based on neural crest origin.They postulated that Peters' anomaly, together withother anterior chamber cleavage syndrome variantsand congenital glaucoma, is caused by an abnormalneural crest cell migration.The present case shows a combination of cleft

palate, Peters' anomaly, and a deficiency of forebraintissue including the cerebral cortex, diencephalonand sensory retina, which shows a deficiency ofretinal ganglion cells causing optic nerve hypoplasia.All these defects could be caused by a developmentalfailure of the forebrain and its associated neuralcrest. Optic nerve hypoplasia, together with Peters'anomaly and other anterior chamber defects, couldbe considered the ocular abnormalities more directlyrelated developmentally to the brain defects inWarburg syndrome.Three associated anomalies in the case reported

here are worthy of comment. Micrognathia wasreported in three other cases4 '3 and unilateral hydro-nephrosis in one case.'3 Cleft palate was not reportedin the literature but has been noted in another case (PFarndon, unpublished observation).Warburg syndrome is regarded as being an auto-

somal recessive trait. This is supported by its frequentoccurrence in sibs,347 2 21 the consanguinity of parentsin one family,' the good health of all the parentsinvolved, and the lack of evidence of any otheraetiology, such as maternal infection or drug intake.The diagnosis of Warburg syndrome is important sothat the parents can be advised of its 25% recurrencerisk and of the possibility of prenatal diagnosis bydetailed ultrasound study. The ocular signs are themajor clues to the clinical diagnosis of Warburgsyndrome in a neonate with a major neurologicaldeficit and a demonstrable hydrocephalus with orwithout a posterior encephalocele.

References

1 Fried K, Liban E, Lurie M, Friedman S, Reisner SH. Polycystickidneys associated with malformations of the brain, polydactylyand other birth defects in newborn sibs. J Med Genet 1971; 8:285-90.

2 Pagon RA, Chandler JW, Collie WR et al. Hydrocephalus,agyria, retinal dysplasia, encephalocele (HARD±E) syndrome:an autosomal recessive condition. Birth Defects 1978; 14:233-41.

3 Pagon RA, Clarren SK, Milam DF Jr, Hendrickson AE.Autosomal recessive eye and brain anomalies: Warburgsyndrome. J Pediatr 1983; 102: 542-6.

4 Bordarier C, Aicardi J, Goutieres F. Congenital hydrocephalus

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and eye abnormalities with severe developmental brain defects:Warburg syndrome. Ann Neurol 1984; 16: 60-5.

5 Whitley CB, Thompson TR, Mastri AR, Gorlin RJ. Warburgsyndrome: lethal neurodysplasia with autosomal recessiveinheritance. J Pediatr 1983; 102: 547-51.

6 Walker AE. Lissencephaly. Arch Neurol Psychiatr 1942: 48:13-29.

7 Chemke J, Czernobilsky B, Mundel G, Barishak YR. A familialsyndrome of central nervous system and ocular malformations.Clin Genet 1975; 7: 1-7.

8 Winter RM, Garner A. Hydrocephalus, agyria, pseudo-encephalocele, retinal dysplasia and anterior chamberanomalies. J Med Genet 1981; 18: 314-7.

9 Warburg M. Hydrocephaly, congenital retinal non-attachmentand congenital falciform fold. AmJ Ophthalmol 1978; 85: 88-94.

10 Warburg M. The heterogeneity of microphthalmia in thementally retarded. Birth Defects 1971; 7: 136-54.

11 Lahav M, Albert DM. Clinical and histopathologic classificationof retinal dysplasia. Am J Ophthalmol 1973; 75: 648-67.

12 Levine RA, Gray DL, Gould N, Pergament E, Stillerman ML.Warburg syndrome. Ophthalmology (Rochester) 1983; 91:1600-3.

13 Yanoff M, Rorke LB, Allman MI. Bilateral optic system aplasiawith relatively normal eyes. Arch Ophthalmol 1978; 96: 97-101.

14 Weiter JJ, McLean IW, Zimmerman LE. Aplasia of the opticnerve and disk. Am J Ophthalmol 1977; 83: 569-76.

15 Whinery RD, Blodi FC. Hypoplasia of the optic nerve: a clinicaland histopathologic correlation. Ophthalmology (Rochester)1963; 67: 733-8.

16 Quigley HA, Addicks EM, Green WR, Maumenee AE. Opticnerve damage in human glaucoma. II. The site of injury andsusceptibility to damage. Arch Ophthalmol 1981; 99: 635-49.

17 Waring GO III, Rodriguez MM, Laibson PR. Anterior chambercleavage syndrome. A step ladder classification. SurvOphthalmol 1975; 20: 3-27.

18 Reese AB, Ellsworth RM. The anterior chamber cleavagesyndrome. Arch Ophthalmol 1966; 75: 307-18.

19 Johnston MC. The neural crest in abnormalities of the face andbrain. Birth Defects 1975; 11: 1- 18.

20 Bahn CF, Falls HF, Varley GA, Meyer RF, Edelhauser HF,Bourne WM. Classification of corneal endothelial disordersbased on neural crest origin. Ophthalmology (Rochester) 1984;91: 558-63.

21 Ayme S, Mattei JF. HARD (±E) syndrome: report of a sixthfamily with support for autosomal recessive inheritance. Am JMed Genet 1983; 14: 759-66.

Acceptedfor publication 24 January 1986.

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