eyes in arhinencephalic syndromes - british journal of ... · eyes in arhinencephalic syndromes 463...

Brit. J. Ophthal. (1975) 59, 462

Eyes in arhinencephalic syndromes

A. G. KARSERAS* AND K. M. LAURENCEDepartments of Surgery and Child Health, Welsh National School of Medicine, Heath Park, Cardiff

The term arhinencephaly was coined by Geoffrey-Saint-Hilaire in I882 (cited by Morton, I 947)when describing a 'monster' without a properlydeveloped nasal region. He made no reference tothe actual rhinencephalon. Kundrat (I 882) em-braced the rhinencephalon in his study and subse-quently the term has come to refer more to brainabnormalities than the nose alone. Yakovlev (I959)found that the rhinencephalon is never completelyabsent, and De Myer (I97I) suggested that theterm arhinencephaly should be restricted tosimple absence of the olfactory bulbs and tracts,without the often gross associated defects of thebrain (the holoprosencephalies).

In this series absence of the first cranial nervehas been taken as the common denominator in the AF

arhinencephalic syndromes. Although De Myer andZeman (I963) showed that this abnormality maynot be present in the holoprosencephalic spectrumof abnormalities, this is very uncommon and hasnot been found in this study.

Clinical materialNecropsy examinations have been carried out on 22infants with arhinencephaly at this and associatedhospitals over a 15-year period. KML was alerted toarhinencephaly in his first case by the inclusion of thisabnormality in one of severe multiple malformations.Thereafter arhinencephaly, even of the forme frustevariety where there is only hypoplasia of the olfactorybulb and absence of the olfactory tract and trigonewithout other obvious brain abnormality, was activelysought in all necropsy examinations. Therefore selectionof cases with such features has not occurred. However,isolated 'absence' of the first cranial nerve has not beenobserved in the 1735 consecutive autopsies (Laurence,1975) and this is also a rare occurrence in the literature(Stewart, 1939). Furthermore, the incidence of associatedchromosomal abnormalities is not higher in this seriesthan previously reported (Aita, I969).

*Address for reprints: Department of Surgery, Welsh NationalSchool of Medicine, Heath Park, Cardiff

FIG. I Case I. Microcephalic infant with severelyabnormal facies

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Eyes in arhinencephalic syndromes 463

t.

Results

The clinical features, necropsy, ophthalmological,

and cytogenetic findings are given in the Table.Apart from the extreme macrolentis in Case i

F I G. 2 Low power photomicrographof eye of Case I showing micropthalmia,macrolentis, and posterior cyclop.ctendency with deficiency in sclera(arrowed) through which tissuesurrounding choroid protrudes. Opticnerve (N) is included in section.Haematoxylin and eosin. x 5

..o.,

:.:.

I FIG. 3 Case i. Mlacrolentis (L) insitu filling globe. X 5

(Figs i, 2, and 3), the posterior fusion of the eyes(Case 3) and the skin-covered limbal lipoma(Case 8), all the ocular findings have been previouslydescribed in arhinencephalic syndromes. Probablyall the ocular findings that have been described in

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464 British Journal of Ophthalmology

Table Features of arhinencephalic patients

Gestational BirthCase Survival Sex length weighlt Principal external Principal internal Ophthalmological Cytogeneticsnumber (weeks) (g) features findings features findings

I Z weeks F 42 I820 Severe microcephaly Heart malformation Hypertelorism (Fig. I) Normal femaleLow set ears (Fig. I) with atrial septal Severe microphthalmia (46 XX)Incomplete separation defect patent (8-5 mm and 9 5 mmof anus and vulva ductus arteriosus antero-posterior)Low insertion of left superior vena Abnormal and deficientthumbs cava draining into retina

Single palmar crease right atrium Posterior 'cyclopicCongenital Choanal atresia tendency' abnormalitydislocation of hips Bifid uvula (Fig. 2)

Hypoplastic kidneys Gross macrolentisAlobar holoprosence- (Fig. 3)phaly with vestigial Hypoplastic opticolfactory tracts chiasm, optic nerve

(i-o mm diameter),*and optic disc

2 Still-biith F 35

3 5 min F 36

4 I itr M 33

2I00 Large abnormal head Bifid epiglottis Anophthalmia Normal female(Fig. 4) Hypoplastic lungs Absent optic nerves (46 XX)

I cm long proboscis Malrotation of Absent optic foraminaShort arms with an intestines and Absent sella turcicaulnar supernumerary universal mesentery (Fig. 5)digit on each side Absent pituitaryShort legs Absent fetal zoneBilateral congenital in adrenalsdislocation of hip Brain with alobar

holoprosencephalyAbsent olfactorytract and second andthird nerves

HydrocephalusHypoplasia ofcerebellum

2000 2 cm long proboscis Multi-lobulated Severe hypotelorism Trisomic female(Fig. 6) kidneys (Fig. 6) (47 XX, D +)Low set ears Alobar holoprosence- Severe microphthalmiaRocker bottom feet phaly with absent (antero-posterior I I mm)

olfactory tracts with posterior fusionEthmocephaly of eyeballs (Figs 7 and 8)

Optic nerve hypoplasia(I'7 mm diameter)*

Hypoplastic chiasm

1480 Microcephaly Cleft palate Hypotelorism Trisomic maleDeficiency of scalp Malrotated intestine Mongoloid slant of (47 XY, D +I)Midline hare lip and and universal palpebral apertureshypoplasia of nose mesentery Microphthalmia (I3 mmLow set ears Large dysgenetic antero-posterior)Micrognathos kidneys with micro- Colobomata of irides,Poorly developed cysts ciliary bodies, and lensespenis Brain with alobar Abnormal retinal folds

Single palmar holoprosencephaly Optic nerve diametercreases and semi-vestigial 2-9 mm*

Rocker bottom feet olfactory tractwith six toes each Large suprarenals

with cytomegaly

20mnin Mi 38 2100 Bilateral hare lipwith floatingpremaxilla

MicrognathosLow set earsWebbing of neckSingle palmarcreases

Hypoplastic penis

Cleft palate Eyes normal sizePatent ductus (I6-5 mm antero-arteriosus posterior)

Tracheo-oesophageal Hypoplasia optic nervefistula and (I-6 mm diameter)*oesophageal atresia colobomata and

Meckel's diverticulum hypoplasia of opticPolycystic kidneys discsBrain with absentolfactory tracts andvestigial olfactorybulbs

Trisomic male(47 XY, D +)



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Principal externalfeatures

Micrognathos(Fig. 9)Low set earsExtra ulnar digit(right) (Fig. Io)

Single palmarcrease

Hypoplastic penisSacrococcygeal pitRocker bottom feet

Principal internal Ophthalmologicalfindings features

Patent ductus Prominent epicanthicarteriosus folds

Cleft of soft palate Antimongoloid slope ofMeckel's diverti- palpebral fissuresculum and Eyeballs 14 and I6 mmmalformation of gut (antero-posterior)Polycystic kidneys Colobomata of irideswith hydronephrosis and ciliary bodies

Double ureter right Mass of retrolentalside white tissues (Fig. I I)

Vestigial olfactory Abnormal retinal foldstracts in the other- (Fig. 12)wise normal brain Absence of retinal

vesselsAplasia of optic discOptic nerve I-8 mm x0o9 rmn*Chiasm normal

7 45 min M 37 2500 Bilateral hare lipwith hypoplasticpremaxilla

MicrognathosLow set abnormalearsSmall exomphalosHypoplastic penisFlexion deformityof wrists

Rocker bottom feet

Cleft palateMalformed heartwith ventricularseptal defect andpatent ductusarteriosus

Absent left umbilicialartery

Polycystic kidneysDouble ureterLarge suprarenalgland

Brain with absentolfactory tracts andvestigial olfactorybulbs

Mongoloid slant to Trisomic malepalpebral fissures (47 XY, D +)

Microphthalmia (s I mmantero-posterior)

Colobomata of iridesand ciliary bodiesMass of white tissuebehind lens continuouswith infolding of scleraover ciliary colobomatousarea (Fig. 13)

Optic nerve diameter2mm X 1-3 mm

72 hr F 40 3400 MicrocephalyMedian hare lipFlat nose

MicrognathosGrossly abnormallow set ears withaccessory auricles

Rocker bottom feet

Cleft palateMalformed heartwith atrial septaldefect, large intra-ventricular septaldefect, transpositionof great vessels andstenosis of mitralvalveSemi-lobularholoprosencephalywith vestigialolfactory tracts andabsent cerebellum

Mongoloid slant to Cultures failedpalpebral fissuresEyes normal size(20 mm antero-posterior)

I cm diameter skin-covered lipoma in rightpalpebral fissure (FigsI5 and s6)Colobomata of opticnerve heads (Fig. 17)Optic nerve diameter2-I X o-8 mm*

* (i) mean cross-sectional dimensions of the optic nerve near the chiasma in 24 normal neonates of over 32 weeks' gestation was i-8 X 2-7 mm(range 1-25 - 2-0 X 1-9 - 3-5 mm)

(ii) mean diameter of the optic nerve just before entrv into the eyeball in six normal neonates of over 32 weeks' gestation was 2-6 mm(range 2-2 - 3-1 mm)

the trisomy D syndrome can occur in the arhine-cephalic cases with trisomy D.

In all eight cases clinically ascertainable ocularphysical signs were present. These varied fromanophthalmia (Case 2, Figs 4 and 5) to normal-sizedeyes with isolated colobomata of optic discs (Case 8)or hyoplasia of the discs (Case 5). Ethmocephaly(absence of the ethmoid bones) was present inCase 3 (Figs 6 and 7) and this allowed posteriorfusion of the globes. This represents a forme frusteof the cyclopean process. Extreme hypotelorismmay represent the clinical counterpart, but Case i

shows that hypertelorism can occur with thecyclopic tendency.

Discussion

Cyclopia was not present in this series. It is themost dramatic ocular abnormality in arhinencephalyand has received the most attention in ophthalmicliterature. It is, however, a rare condition invariablyassociated with the gross brain abnormality ofalobar holoprosencephaly, and incompatible withlife. Many of the cyclopean eyes reported are fused

Casenumber

6

Survival

72 hr

GestationalSex length

(weeks)

M 38

Birthweight(g)

--(70

Cytogenseticsfindings

Fibroblastcultures failed



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466 British Jouirnal of Ophthalmology

FIG. 4 Facies of Ceanophthalmia and pr(

FIG. 6 Facies of Case 3 showing proboscis andhypotelorism. Microphthalmic eyes showing posteriorfusion were found inside the orbits

ase 2 showing large head with NO

oboscis

0X0 S10FII 7 Dissection of eyes, Case 3, showing posteriorfusion (arrowed)

MM.,-V . FIG. 5 (left) Base of skull of Case z showing the absence0 1 2 of optic foramina and pituitary fossa. Site normally

cm occupied by fossa is arrowed



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FIG. 8 Low power photo-micrograph of communicationbetween two eyes showing bothabnormal choroidal and retinalelements. Communication (C)and abnormal eyeballs (E) arelabelled. Haematoxylin andeosin. x 5

eyes with duplication of various ocular components-for example, Case 2 (Gartner, I947).

In many cases the facial abnormalities predict thestate of the brain (De Myer, I97I), but this is notinvariable (Fischer, 1905, cited by Morton, 1947;Snodgrass, Butler, France, Crome, and Russell,I966; Bligh and Laurence, I967; Hintz, Menking,and Sotos, I968; Robain and Gorce, 1972).The severity of eye involvement in this series is

parallel to the severity of brain involvement inCases I to 5 but not in Cases 6 to 8 (Figs 9-I7).Prediction of the brain from the eyes is notpossible, therefore, but the changes found in theeyes in this series should arouse the ophthalmolo-gists' interest in the brain and the endocrine system(see below). This is especially so when such ocularabnormalities are associated with hypotelorism(suggesting a tendency to cyclopia), and externalnasal abnormality (suggesting arhinencephaly),or cleft lip/palate (Kundrat, i 882; De Myer,Zeman, and Palmer, I964).

Recognition of treatable endocrine abnormalitiesin the more extreme cases of arhinencephaly is notimportant. Such endocrine abnormalities are

consequent to maldevelopment of the pituitary-hypothalamic axis and have been found at necropsy

for many years. Klopfstock (I921) claimed absentadrenal glands in a cyclopic patient, and Haworth,Medovy, and Lewis (I96I) in two out of threearhinencephalic cases, failed to find the pituitarygland and the adrenals were hypoplasic. Case 2

(see Fig. 5) shows an absent pituitary gland.Badtke (1948) found an enlarged adrenal gland

in an arhinencephalic infant and Cases 4 and 7

also showed this.Pituitary malfunction has also been recognized

clinically. Pitressin responsive diabetes insipidus,adrenal insufficiency (Hintz and others, I968), and

diabetes insipidus (Robain and Gorce, 1972) havebeen described. Ladurner, Summer, and Reinisch(1972) describe the clinical and pathological featuresof a two-year-old anophthalmic arhinencephalic withpituitary dysfunction. The similarity of this reportto Case 2 in this series is striking.

Recognition of such endocrine dysgenesisbecomes important in the less severe cases ofarhinencephaly which may survive to adult life,especially in view of the report of isolated endocrinedysgenesis (growth hormone deficiency) in a siblingof two familial cases of holoprosencephaly (Romsheand Sotos, I973). This finding shows that in thefamilial cases of arhinencephaly the severity ofclinical involvement can vary from neonatal deathto isolated, treatable pituitary dysfunction.The possibility also exists that arhinencephaly

can occur with hypothyroidism as McDermott,Insley, Barton, Rowe, Edward, and Cameron (I968)described both conditions occurring in syndromescaused by deficiency of the short arm of chromo-some i8.The familial nature of some cases of arhinence-

phaly has been noted for many years (Klopfstock,1921; Grebe, I944). These familial cases showedgreat phenotypic variability, involving many sys-

tems. That a prezygote, preuterine origin ofarhinencephaly can occur is suggested by the rare

occurrence of twin cyclopean or cebocephalicmonsters (Ellis, i 865; Duyse, 1905). Morton (I947),on the basis of detailed anatomical dissection andcorrelation with embryology, favoured a geneticorigin of his case of arhinencephaly. Gruber (1948)also argues for a genetic origin because of theassociation of typically hereditary malformationswith cyclopia and the high incidence of abortionsin the families involved.

Cyclopia has been produced experimentally in

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FIG. IO Left hand of Case 6 showing transverse palmarcrease and ulnar polydactyly

FIG. 9 Head of Case 6 showing low set ears andmicrognathos

fish (Stockard, I909; Majina and Ingalls, I966),and induced in sheep by ingestion of the plantVeratrum californicum (Babbott, Binns, and Ingalls,I962). Rarely, in man has a relationship betweenarhinencephaly and maternal diabetes been des-cribed (Dekaban and Magee, 1958; Robain andGorce, 1972, Case 9), or simulation of arhinencephalyby toxoplasmosis (Liebaldt, I972).

Despite these findings, it is becoming increasinglyrecognized that chromosomal abnormalities may

underly cyclopia and other arhinencephalic syn-

dromes in man. Arhinencephaly has recently come

into prominence because of its common occurrence

in the trisomy D syndromes (McKusick, I96I;Miller, Piccard, Alkan, Warner, and Gerald, I963;Laurence, I966). Conversely, about 40 per cent ofarhinencephalics have trisomy D (Laurence, I966;Aita, I969). It has been suggested that when thereare few other congenital abnormalities, arhinence-phalics have normal chromosomes (McDermott andothers, I968; De Myer, Zeman, and Palmer, I963).Normal chromosomes with multiple congenitalabnormalities have been found in Cases i and z

and these have also been found by others (Millerand Seldon, I967; Landau, Barry, and Koch, I963;

:

T

FIG. II Section of eyeball of Case 6 showing uvealcoloboma (Co) which is continuous with mass of retrolentaltissue (T). Abnormal retinal folds are seen radiating tothis. Cornea (C) and iris (I) are also labelled. x 4

Robain and Gorce, 1972). As Miller and Seldonstated, however, 'it is important to acknowledgethat in these apparently non-trisomic patients suchchromosomal material may still be present attachedto another chromosome in an amount too small tobe detected by current methods of study'. Moreover,other cryptogenic chromosomal defects cannot beexcluded, especially as deletion of the short arm of




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FIG. I2 Abnormal retinal folds, Case 6 Haematoxylin and eosin. x 6o

I/

CHFIG. I3 Dissection of eye of Case 7 to show iris (I),coloboma (Co), ingrowth of sclera (IS) at colobomatoussite. Cut edge of sclera (S) is indicated and alsounderlying ciliary body and choroid (CH). x 6

chromosome i 8 has been missed in cebocephaly(Haworth and others, I96I, Case i), and diagnosedretrospectively (Uchida, McRae, Wang, and Ray,I965, Case 3). Gorlin, Yunis, and Anderson (I968)found deletion of the short arm of chromosomes I8in cebocephaly with little other congenital abnor-mality. Other arhinencephalic syndromes withdeficiency of the short arm of chromosome i 8 havebeen described by Faint and Lewis (I964-cyclops);Nitowsky, Sundhvananda, Konigsberg, and Weinber(I966-cyclops); Pfeiffer (I966); McDermott andothers (I968). Arhinencephaly has also been des-cribed with trisomy E (I7-I8 group) by Robain andGorce (I 972, Case I 3) and France (quoted byMcDermott and others, I968).The mosaicism of an extra piece of chromosome

material in a cyclops (Pfitzer and Miuntefering,I968) is similar to the cytogenetic finding in theoculo-anal syndrome (Schachenmann, Schmid,Fraccaro, Mannini, Tiepolo, Perona, and Sartori,I 965).France (see McDermott and others, I968) found

a deletion of chromosome 5 and Cohen (I966)described cyclopia occurring with a normal

Bi



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FIG. 14 Photomicrograph of Case 7. Retrolental mass, consisting largely of abnormal retinal elements.Haematoxylin and eosin. x 100

monosomy G mosaicism. These seem to be the _ aonly reports in which the chromosome abnor-malities were definitely not involving the D (13-15)or E (17-18) groups of chromosomes. Trisomies ofthese groups are now well recognized causes ofocular abnormalities and it would seem deletions, _partial trisomies, and mosaicisms cause similar _developmental defects, as seen in thearhinence-Kphalicsyndromes._

In familial cases of arhinencephaly with normal _ > t>chromosomes De Myer and others (1963) suggested _?_a recessive inheritance, but familial cryptogenicchromosomal abnormality has to be considered also. _ °-'...Thus Hintz and others(Ig68) described familial holo-prosencephaly with normal chromosomes, but the _lefacial cleft, single transverse palmar creases, familialpolydactyly, and recurrent abortions suggest thatsu c ha cryptogenicchromosomal defect is present.tOvert familial chromosomal defects in familial

arhinencephalic syndromes have been described (\by Uchida and others (I965), McDermott and(1.15others (1I968 short arm deficiency of chromosomeT ofI8). Conen, Erkman, and Metaxotou (1966)founddepresumptivefamilial trisomy D in holoprosencephaly

(Case i), whilst Pfitzer andM.ntefering (1968)described a carrier state of chromosomal abnor-mality in four related mothers, where in additionto I I congenitally defective births and abortionsFaIG. 1 Facies of Case 8 shozvinggrossly abnormal earrfour cyclops were born. dermal lipoma, and grossly abnormal nose



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Eyes in arhinencephalic syndromes 47I.: .: :.SyP...x

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FIG. I6 Low-power photomicrograph through eyeball and lipoma, Case 8. Haematoxylin and eosin. x 7

It is probable that many of the reported twinand familial arhinencephalics previously reportedhad abnormal chromosomes. It is important torecognize these syndromes clinically and ophthal-mologically, and to determine their relationship tosuch chromosomal abnormalities. The recognitionof carrier states, and the in utero cytogenetic studiesof amniotic cells may spare the unfortunate parentsof such monstrosities from similar traumaticexperiences.

SummaryThe ocular features of eight cases of arhinencephaly

have been described. Prediction of the degree ofbrain involvement from the eye defects could notbe made, but eye abnormalities were present in allcases. The relationship of these syndromes tochromosomal abnormalities is emphasized. In theless severe cases treatable endocrine dysgenesismust be excluded.

We wish to thank Mr Ralph Marshall of the Departmentof Medical Illustration, and Mr T. J. Cooke of theDepartment of Child Health, for the photographs andphotomicrographs, and Mr J. 0. Dew also of theDepartment of Child Health, for the histological prepara-tions.

References

AITA, J. A. (I969) 'Congenital Facial Anomalies with Neurologic Defects'. Thomas, Springfield, Ill.BABBOTT, F. L. JR., BINNS, w., and INGALLS, T. H. (I962) Arch. Environm. Hlth, 5, IO9BADTKE, G. (1948) V. Graefes Arch. Ophthal., 148, 490BLIGH, A. S., and LAURENCE, K. M. (I967) Clin. Radiol., I8, 383



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FIG. 17 Coloboma of optic nerve head, Case 8. X 20

COHEN, M. M. (I966) J. Pediat., 69, 793CONEN, P. E., ERKMAN, B., and METAXOTOU, C. (I966) Amer. Y. Dis. Child., III, 236DEKABAN, A. S., and MAGEE, K. R. (1958) Neurology (Minneap.), 8, 193DE MYER, W. (I97i) Birth Defects, 7, 85

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DUYSE, G. M. (I905) Teratologie Encyclop. franj. d'Ophtal., II, 483ELLIS, R. (I865) Trans. obstet. Soc. Lond., 7, i6oFAINT, S., and LEWIS, F. J. w. (I964) Hum. Chromos. Newsl., 14, 5GARTNER, S. (I947) Arch. Ophthal. (Chicago), 37, 220GORLIN, R. J., YUNIS, j., and ANDERSON, V. E. (i968) Amer. Y. Dis. Child., 115, 473GREBE, H. (1944) Erbarzt., 12, 138GRUBER, J. v. (1948) Arch. Klaus-Stift Vererb.-Forsch., 23, 233HAWORTH, J. C., MEDOVY, H., and LEWIS, A. J. (I96I) J. Pediat., 59, 726HINTZ, R. L., MENKING, M., and SOTOS, J. F. (I968) Ibid., 72, 8iKLOPFSTOCK, A. (192I) Mschr. Geburtsh. Gyndk., 56, 59KUNDRAT, H. (i882) Wien. med. Bl., 5, 1395LADURNER, G. SUMMER, K., and REINISCH, H. (1972) Wien. Z. Nervenheilk., 30, 93LANDAU, J. W., BARRY, J. M., and KOCH, R. (I963) Y. Pediat., 62, 895LAURENCE, K. M. (I966) Proc. 5th Int. Congress Neuropath., Zurich, p. 722

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, and SELDON, R. F. (I967) Neurology (Minneap.), 17, I087MORTON, W. R. M. (1947) Anat. Rec., 98, 45NITOWSKY, H. M., SUNDHVANANDA, N., KONIGSBERG, U. R., and WEINBER, G. T. (I966) Pediatrics, 37, 260PFEIFFER, R. A. (I966) Hum. Genet., 2, I78



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PFITZER, P., and MUNTEFERING, H. (I968) Nature (Lond.), 217, I07IROBAIN, o., and GORCE, F. (I972) Arch. franjc. Pediat., 29, 86iROMSHE, C. A., and SOTOS, J. F. (1973) J7. Pediat., 83, io88SCHACHENMANN, G., SCHMID, W., FRACCARO, M., MANNINI, A., TIEPOLO, L., PERONA, G. P., and SARTORI, E. (I965) Lancet,

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