314

TABLE Results of analysis ofgene markers

Marker Father Mother Both twins

Sex M F M

Blood groupsABO A 0 AMNSs Ns MNs MNsKidd a+b- a+b+ a+b+

Serum proteinsGm 1,-2,-3, 1,2,-3, 1,2,-3,

-5,16,21 -5,-16,21 -5,-16,21Hp 2-1 2-1 2-1

IsoenzymesPGMI a2-a2 a3-a2 a3-a2GPT 1-1 2-1 1-1EsD 1-1 2-1 2-1

HLAA 26,2 2,W33 26,2B 15,7 W35,- 15,W35C -,W3 W3,WI -,W3

Systems tested but uninformative: Rh, Duffy, Gc, P, ACP, Km, earwax type.

in the thenar areas, bilaterally. Twin 2 showed axialtriradii at t and t' positions, bilaterally, and a proximalloop pattern in the thenar area of the left hand.The probability of the twins being monozygotic was

calculated to be 0 9998, using blood group antigens,serum proteins, isozymes, HLA, and ear wax type(table), and as 0 996 using sequential QandR bandingheteromorphisms. The combined probability was

0 999998.

Discussion

The occurrence of the Rubinstein-Taybi syndromein one of a pair of monozygotic twins is incom-patible with single gene control. It is conceivablethat a minor chromosomal change, beyond thelimits of resolution of existing methods, occurred intwin I after twin development. The chromosomes ofpatients with the syndrome have usually beenreported to be normal. In about 3% of the patientsa structural abnormality of the chromosomes hasbeen seen. However, the nature of the chromosomalabnormality has varied greatly; thus, assignment ofan aetiological role to the chromosome abnormality,even in these cases, would not seem warranted.

It seems that our twins are the first with provenmonozygosity discordant for the syndrome. Alto-gether, eight pairs of monozygotic or like-sexedtwins with the Rubinstein-Taybi syndrome havebeen reported.7 Of these, four pairs were concordantfor the syndrome and the other four pairs were

discordant. Multifactorial inheritance, as suggestedby Roy et al,8 is compatible with the occurrence ofboth concordant and discordant monozygotictwins, but not with the lack of much familialaggregation. No graded severity among cases andclose relatives has been noted.

Case reports

Schinzel et al7 raised the possibility that the syn-drome is the consequence of a single early localisedmalformation giving rise to the malformation com-plex. The malformation complex encompasses theinitial malformation, poor formation of a tissueduring morphogenesis, plus its secondarily deriveddefects. There is a need for further family studies ofpatients with the syndrome.

T KAJII,* K HAGIWARA,* M TSUKAHARA,*H NAKAJIMA,I AND Y FUKUDA"

*Department of Pediatrics, YamaguchiUniversity School of Medicine, Ube; tthe

Department of Forensic Medicine, Tokyo Medicaland Dental University, Tokyo; and "the 2nd

Department of Surgery, Hiroshima UniversitySchool of Medicine, Hiroshima, Japan

References

Rubinstein JH, Taybi H. Broad thumbs and great toesand facial abnormalities: a possible mental retardationsyndrome. AmJ Dis Child 1963:105:588-608.

2 Johnsson CF. Broad thumbs and broad great toes withfacial abnormalities and mental retardation. J Pediatr1966;68:942-51.

3 Takeuchi M. Rubinstein's syndrome in two siblings.Gumma J Med Sci 1966;15:17-22.

4 Simpson NE, Brissenden JE. The Rubinstein-Taybisyndrome: familial and dermatoglyphic data. Am J HamGenet 1973;25:225-9.

5 Der Kaloustian VM, Afifi AK, Sinno AA, Mire J. TheRubinstein-Taybi syndrome: clinical and muscle electronmicroscopic study. Am J Dis Child 1972;124:897-902.

6 Padfield CJ, Partington MW, Simpson NE. TheRubinstein-Taybi syndrome. Arch Dis Child 1968;43:94-101.

7 Schinzel AAGL, Smith DW, Miller JR. Monozygotictwinning and structural defects. JPediatr 1979;95:921-30.

8 Roy FH, Summitt RL, Hiatt RI, Hughes JG. Ocularmanifestations of the Rubinstein-Taybi syndrome. Casereport and review of the literature. Arch Ophthalmol1968 ;79 :272-8.

Requests for reprints to Professor T Kajii, Depart-ment of Pediatrics, Yamaguchi University School ofMedicine, Ube, Japan 755.

Hydrocephalus, agyria, pseudo-encephalocele, retinal dysplasia,and anterior chamber anomalies

SUMMARY An infant presenting with hydro-cephalus, pseudoencephalocele, agyria, andocular defects, consisting of anterior chamberanomalies and retinal dysplasia, is reported.This is thought to be a further case of anautosomal recessive syndrome of which sixcases have been previously described.Received for publication 28 October 1980

on July 5, 2020 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.18.4.314 on 1 A

ugust 1981. Dow

nloaded from

Case reports

The association of hydrocephalus and ocularabnormalities has been reported many times.1-5Pagon et al5 drew attention to the specific associationbetween Hydrocephalus, Agyria, Retinal Dysplasia,with or without an Encephalocele, and coined themnemonic the HARD ± E syndrome. In additionto reporting two new cases, they found four similarpublished cases4 I and postulated that the inheritanceis autosomal recessive.

Case report

The proband (fig 1), a Caucasian female, was bornat term by normal vaginal delivery. Pregnancy hadbeen uneventful and there was no history of maternalinfection or drug ingestion. Birthweight was 3-6 kg(50th centile), length 51 cm (50th centile), and headcircumference 40 cm (>97th centile). There was asmall skin-covered cystic protrusion at the posteriorfontanelle which was thought to be a small en-cephalocele. The clinical diagnosis of hydro-cephalus was made by transillumination of the skull.There was bilateral microphthalmia with a cornealopacity on the right and a cataract on the left,obscuring visualisation of the fundi. The child diedwithin the first 24 hours of life.Necropsy examination revealed widely patent

cranial sutures with a protrusion of dura materthrough the posterior fontanelle that was notthought to represent a true encephalocele. The brainwas grossly swollen and hydrocephalic. The lateralventricles were widely dilated and the brain wasreduced to a very thin rim of completely structure-less white tissue. The third and fourth ventricles wereboth widely patent. The cerebellum was less severelyaffected and retained some of its normal structuralpattern. The foramen magnum sloped down in a

.- c.@ t - .X:M4 AM

FIG 1 Proband at 4 hours of age.

315

shallow fashion to the cervical canal and it waspostulated that the cause of the hydrocephalus wascompression of the cerebellum or medulla, a formof Arnold-Chiari malformation.

Microscopical examination of the eyes revealedbilateral anomalies involving both anterior andposterior segments. The right eye was small butthe corneoscleral envelope showed no externalabnormality. However, although the cornea ap-peared to have developed normally with a distinctBowman's layer and Descemet's membrane, therewas some vascularisation of the collagenous stroma.Moreover, there was evidence of incompletecleavage of the iridocorneal angle, such that theoutflow system was not open to the anterior chamber,and there were fibrous strands passing between asomewhat hypoplastic iris stroma and the posteriorsurface of the cornea (fig 2). In the region of theiridocorneal attachment there was absence ofDescemet's membrane (fig 3). The neuroretina wasseparated from the pigment epithelium but whetherthis represented congenital detachment, as thepresence of a proteinaceous subretinal exudatemight suggest, or a primary failure of coaptation, asthe concomitance of dysplasia of the inner retinallayers might indicate, could not be determined.Other ocular structures seen in the sections providedseemed to be essentially normal.The left eye was also small and, while the cornea

appeared to be well formed, the iridocorneal anglewas incompletely formed and there was attachmentof the anterior part of the lens capsule to the back

i

FIG 2 Right eye. Histopathology shows an incompletelyseparated anterior chamber angle with connectivetissue (black arrow) linking the periphery of the iristo the posterior surface of the cornea. There is a focusof dysplastic tissue with rosette formation (white arrow)on the surface of the detached retina. (Haematoxylinand eosin. Original magnification x 10.)

on July 5, 2020 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.18.4.314 on 1 A

ugust 1981. Dow

nloaded from

316

FIG 3 Right eye. In this section the mid-zone of the irisis attached to the back ofthe cornea. Although Descenmet'smembrane ispresent centrally (arrow) it is absent over

an areafrom the site ofiridocorneal attachment to theadjacent angle of the anterior chamber. (Haematoxylinand eosin. Original magnification x 110).

*1.

FIG 4 Left eye. Section through the hypoplastic opticnerve showing glial replacement between the fibroussepta. (Haematoxylin and eosin. Originalmagnification x 30.)

of the central cornea where Descemet's membranewas absent. The retina was not attached, and thefinding that the non-attachment reached to theora serrata in the absence of a non-pigmented layerof epithelium in the region of the pars plana of theciliary body was suggestive of defective coaptation.Retinal dysplasia with a suspicion of rosetteformation was also present. The optic nerve was

hypoplastic and showed extensive glial replacement(fig 4).

Discussion

The association of severe brain abnormalities in theform of hydrocephalus, agyria, and, in some

Case reports

instances, encephalocele with retinal dysgenesis hasbeen described before, Walker,' Chemke et al,4 andPagon et al5 having reported a total of six cases.The findings in an infant described by Yanoff et a16possibly represent a further case, although in thatinstance total absence of the optic nerve was theprincipal finding in the orbits. An associationbetween hydrocephalus and either congenital non-attachment or folding of the retina has also beendescribed by Warburg.23 7 In a survey of 14sporadic cases with hydrocephalus she found thatthere was detachment of the retina in all and microph-thalmia in seven. Whether the latter syndrome isthe same as that delineated by Pagon et al5 cannotbe determined for want of necropsy information onthe nature of the central nervous system abnorm-alities. Nevertheless both Drs Pagon and Warburg(personal communications) suspect that this is likely.

Hydrocephalus associated with a thin rim ofstructureless cortex was common to all cases withthe HARD syndrome that came to necropsy and asmall encephalocele, or extrusion of membranesthrough the vault of the skull, was present in threeof six cases. The cause of the hydrocephalus hasbeen variable in the different cases: one case ofPagon et al5 had stenosis of the aqueduct of Sylvius,while the patients of Chemke et a!4 were thought tohave the Dandy-Walker anomaly. The present caseappeared to have a type of Arnold-Chiari mal-formation.The ocular anomalies in the present case compare

closely with those listed by Pagon et a!.5 Congenitaldetachment (or non-attachment) of the retinatogether with retinal dysplasia, as seen in the presentinstance, was a feature of both cases personallyobserved by Pagon and her colleagues,5 of the onecase of Chemke et al4 subjected to detailed histo-pathological examination, and of the case reportedby Walker.' Microphthalmia was a feature of twoof the cases reviewed by Pagon et a!5 and, althoughmeasurements were not made in the present case,the eyes were unusually small. Hypoplasia of theoptic nerve with glial replacement is not unexpectedin a condition manifesting severe brain and retinaldysfunction, but apart from the infant reported byYanoff et al,6 in whom there was total aplasia, othercase reports have not commented on the state of theoptic nerves. Although not identical on the twosides, the anterior segment abnormalities in ourcase can be ascribed to defective separation of theembryonic iris and cornea. Being principallycentral lesions, they compare most closely withPeter's anomaly8 but, since the corneal changes didnot include the defect in Bowman's zone describedin fully-fledged cases, recourse to the less limitingdesignation of anterior cleavage syndrome9 is

on July 5, 2020 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.18.4.314 on 1 A

ugust 1981. Dow

nloaded from

Case reports

preferable. Of the six cases reviewed by Pagon etal,5 three presented anterior chamber abnormalitieswith specific reference to Peter's anomaly in one.As Warburg7 observes, virtually all multisystem

syndromes associated with maldevelopment and non-attachment of the retina are inherited on a recessivebasis. Most are autosomal defects although Norrie'sdisease, in which haemorrhagic detachment is linkedwith deafness and mental retardation, is an X linkedrecessive condition.10 Therefore, especially as con-sanguinity was a feature of the family described byChemke et al,4 it would seem that the association ofhydrocephalus with congenital ocular abnormalitiesaffecting the retina and, in some instances, theanterior chamber has important implications forgenetic counselling.

We are indebted to Dr D A S Lawrence of theLuton and Dunstable Hospital, Bedfordshire, forcarrying out the necropsy examination on the patient,and to Dr Roberta Pagon of the Children's Ortho-pedic Hospital and Medical Center, Seattle, DrMette Warburg of the Children's Hospital, Vangede,Copenhagen, and Professor S Ry Andersen of theEye Pathology Institute, Copenhagen for theirinstructive comments. We also thank Dr M J Chapplefor bringing the patient to our attention.

R M WINTER* AND A GARNERt

*The Kennedy-Galton Centre,Harperbury Hospital, Harper Lane, Radlett,

Hertfordshire WD7 9HQ;*the Division of Inherited Metabolic Diseases,

Clinical Research Centre,Watford Road, Harrow, Middlesex HAI 3UJ; and

tthe Department ofPathology,Institute of Ophthalmology,

Judd Street, London WCIH 9QS.References

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

2 Warburg M. The heterogeneity of microphthalmia in thementally retarded. In: Bergsma D, ed. The eye. part VIII.Huntington, New York: Krieger for The NationalFoundation-March of Dimes, 1971: 136-54.Warburg M. Hydrocephaly, congenital retinal non-attachment, and congenital falciform fold. Am JOphthalmol 1978 ;85 :88-94.Chemke J, Czernobilsky B, Mundel G, et al. A familialsyndrome of central nervous system and ocular mal-formations. Clin Genet 1975 ;7:1-7.

5 Pagon RA, Chandler JW, Collie WR, et al. Hydro-cephalus, agyria, retinal dysplasia, encephalocele(HARD ±E) syndrome: an autosomal recessive con-dition. Birth Defects 1978; XIV, No 6B: 233-41.

6 Yanoff M, Rorke LB, Allman MI. Bilateral optic systemaplasia with relatively normal eyes. Arch Ophthalmol 1978;96:97-101.

317

Warburg M. Retinal malformations: aetiological hetero-geneity and morphological similarity in congenitalretinal non-attachment and falciform folds. TransOphthalmol Soc UK 1979 ;99:272-83.

8 Peters A. Ueber angeborene Defektbildungier Descemet-schenmembranen. Klin Monatsbl Augenheilkd 1906;44:27-40.

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

10 Warburg M. Norrie's disease (atrofia bulborum here-ditaria). Acta Ophthalmol 1963 ;41 :134-46.

Requests for reprints to Dr R M Winter, Divisionof Inherited Metabolic Diseases, Clinical ResearchCentre, Watford Road, Harrow, Middlesex HAl3UJ.

Poland-Mobius syndromeSUMMARY A patient with stigmata of both theMobius syndrome and the Poland syndrome ispresented. This is now the twelfth well-docu-mented patient with a combination of the twosyndromes. The association of the Polandsyndrome and the Mobius syndrome occurswith sufficient frequency that the combinationprobably represents a formal genesis mal-formation syndrome of unknown aetiologythat should be designated the Poland-Mobiussyndrome.

Both the Mobius syndrome and the Poland syn-drome are well reported congenital anomalies. ThePoland syndrome consists of absence of the pectoralismajor muscle and, in the majority of patients, synd-actyly, brachydactyly, and hypoplasia of the hand.1 2The Mobius syndrome consists of a variable degree offacial paralysis with inability to abduct the eyesbeyond the midpoint.3 Both syndromes have beenassociated with a large number of other anomalies.Recently there have been numerous reports de-scribing a combination of the two syndromes inindividual patients. It is the purpose of this paperto report a patient who had characteristics of bothsyndromes and to review briefly the other casesreported.

Case report

This 14-year-old male was admitted to NewingtonChildren's Hospital for bilateral resection of themedial rectus muscles for correction of esotropia.The patient was the 2821 g product of a normalterm pregnancy, labour, and delivery. At birth hewas noted to have numerous anomalies includingReceived fir publication 4 November 1980

on July 5, 2020 by guest. Protected by copyright.

http://jmg.bm

j.com/

J Med G

enet: first published as 10.1136/jmg.18.4.314 on 1 A

ugust 1981. Dow

nloaded from