Early onset Cockayne's syndrome: reports with neuropathological … · Revised version accepted for publication 26 August 1988. There was also associated photosensitivity. UV ...

Journal of Medical Genetics 1989, 26, 154-159

Early onset Cockayne's syndrome: case reports withneuropathological and fibroblast studiesM A PATTON*, F GIANNELLIt, A J FRANCISt, M BARAITSERt,B HARDINGt, AND A J WILLIAMS§From *St George's Hospital Medical School, London SW17; tPaediatric Research Unit, Guy's Hospital,London SEI; IJiospitals for Sick Children, Great Ormond Street, London WCI; and §Ysbyty Glan Clwyd,Bodelwyddan, Rhyl, N Wales.

SUMMARY Two patients with early onset Cockayne's syndrome are presented. In each casethere was a striking failure of growth and developmental deterioration around six months of age.It has been suggested that early onset Cockayne's syndrome is a syndrome dinstinct fromCockayne's syndrome, but when the first patient died aged two years 10 months, examination ofthe brain showed a leucodystrophy with 'tigroid' demyelination similar to that reported in lateronset cases of Cockayne's syndrome. Studies of the effects of UV irradiation on culturedfibroblasts from patients showed similar levels of inhibition of RNA synthesis to those seen in acontrol with Cockayne's syndrome.

This evidence suggests it is appropriate to classify early onset Cockayne's syndrome withCockayne's syndrome. Since there is a phenotypic overlap between early onset Cockayne'ssyndrome and COFS syndrome, they may both be classified within the same diagnostic group,but as yet no cellular studies with UV irradiation have been performed in COFS syndrome.

Cockayne's syndrome is an autosomal recessivedisorder with short stature, an atypical retinopathy,deafness, mental deterioration, skin sensitivity toultraviolet light, and a characteristic facies withmarked enophthalmos and a beaked nose. Otherfeatures include cataracts, joint contractures, anda peripheral neuropathy. Since it was first describedin 19361 it has become apparent that it is a pro-gressive disorder with an underlying leucodys-trophy.

In 1971 Lowry et a12 described what they felt to bea new syndrome in a brother and sister withcataracts, microcephaly, kyphosis, and joint con-tractures. The classification of this entity has beencontroversial. Sugarman3 suggested that this syn-drome might be an early form of Cockayne'ssyndrome, while Pena et a14 suggested that thefeatures resembled the cerebro-oculo-facial-skeletal(COFS) syndrome.We present two unrelated patients with clinical

features similar to those described by Lowry et al.2In both, profound growth retardation developedwithin the first year of life and the facial featuresbecame identical to those of Cockayne's syndrome.Received for publication 22 June 1988.Revised version accepted for publication 26 August 1988.

There was also associated photosensitivity. UVirradiation studies on skin fibroblasts were carriedout and showed an inhibition of RNA synthesissimilar to that seen in the control with the later onsetCockayne's syndrome. The first patient died agedtwo years 10 months and necropsy of the brainshowed a 'tigroid' pattern of demyelination similarto that reported in Cockayne's syndrome.5

Case reports

CASE 1This boy was the second child of healthy, unrelatedparents. At his birth his mother was 43 years and hisfather 22 years. His mother had two children by aprevious marriage, the oldest of whom had diedfrom a pulmonary embolus. He was born at termafter a normal pregnancy, with a birthweight of3640 g and head circumference 33-2 cm. At birth anumber of dysmorphic features were noted. He haddeep set eyes with bilateral cataracts, his palate washigh, and his uvula was bifid. There were fixedflexion deformities of the fingers with the thumbadducted across the palm. Hip movement waslimited especially on the left and there were bilateralrocker bottom feet. An initial diagnosis of trisomy

154

on May 21, 2021 by guest. P

rotected by copyright.http://jm

g.bmj.com

/J M

ed Genet: first published as 10.1136/jm

g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/

Early onset Cockayne's syndrome: case reports with neuropathological andfibroblast studies

18 was made, but the karyotype was normal. Otherroutine laboratory investigations were also normal.

In the first few months there were feedingproblems because of oesophageal reflux, but hegained weight satisfactorily up to the age of sevenmonths (fig 1). Thereafter his weight remainedstatic, even with tube feeding, until it declinedfurther in the terminal stages of the illness. After 10months there was no further growth in the headcircumference (37.5 cm).

7 -

Z4 /

Age (months)

FIG 1 Growth charts (with 10th and 90th centile) showinglack of weight gain from around six months.Patient I =-*-. Patient 2=- - 0 - -.

Between three and four months his cataracts wereoperated on and contact lenses provided. Thecontact lenses were poorly tolerated because ofreduced lacrimal secretion. Postoperative examina-tion of the fundus showed hypoplastic optic nervesand there was little evidence of useful vision.

In the second year he became very emaciated withkyphosis (fig 2). There was limitation of jointmovement in the knees and he showed markedphotosensitivity to sunlight. He was grossly retardedwith a developmental age of four to five months. Inthe last months he suffered many chest infections.He died from a chest infection at two years 10months.A neuropathological examination showed a very

small, symmetrical brain (335 g, normal 1120 g) withthe hind brain accounting for only 5% of the total(normal 12%). Coronal slices showed normal corti-cal ribbon and basal ganglia, shrunken thalamus,flattened hippocampus, greatly dilated ventricles,and much reduced white matter with a strikinglystripy or tigroid appearance (fig 3). The optic nerveswere thin and grey.

Histology confirmed the severe though discon-tinuous demyelination and concomitant gliosisthroughout the neuraxis. In addition the cerebral

FIG 2 Case I at 18 months. Cachectic appearance is now very striking. Marked kyphosis and joint contractures alsopresent.

155



g.bmj.com

/J M


g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/

MA Patton, F Giannelli, A J Francis, M Baraitser, B Harding, andA J Williams

cm 55 -

I AI I I

FIG 3 Cutsection ofthe brainfrom case 1 showiventricular enlargement, cerebral atrophy, and rewhite matter.

cortex, basal ganglia, and thalamus contaitudes of mulberry-like calcific concretiofications were also present in the walls of iblood vessels and very commonly in thecortex where Purkinje cell somata andtrees were mineralised, and there werdegenerative changes with axonal torpedendritic asteroid formations.

CASE 2This girl was born by elective caesarian sean uneventful pregnancy. Her parentscousins. She weighed 2700 g at birth and tno neonatal problems. The parents firnworried at about 10 weeks when they ncshe was not following or fixing. Bilaterawere diagnosed and lens extractions carrfour months.Her general development seemed slow

months she was not sitting alone. She seenand apathetic and tended to fall aslfeeding. On examination her weight, lehead circumference were well below the 3She was clearly retarded and microcepmicrophthalmia and a pendular searchiimus. Her liver was moderately enlargedthe hips showed mild bilateral subluxathips and shallow acetabulae. A CT tshowed mild cerebral atrophy, but no c.was seen. An EMG showed some evidencdenervation suggestive of anterior horn cc

ment. Because of the combination of microcephaly,cataract, beakish nose, and small jaw a tentativediagnosis of the COFS syndrome was made.There was persistent vomiting and a Nissen

fundoplication and gastrostomy were carried out.Her weight remained static and she was readmittedat the age of nine months. Further investigationswere performed including chromosome studies,immunoglobulins, T cells subsets, neutrophil mobil-ity, and a bone marrow examination. All of thesewere normal. Liver biopsy showed normalarchitecture.On examination at that stage her weight was 4-96

kg (well below the 7th centile and a slight reductionfrom five months previously). Her length was 78 cmand the head circumference was 38-2 cm. The eyeshad become more sunken (fig 4). She had a narrow

86 face with an appearance of sunburnt cheeks. There_J was a generalised increase in tone. Contractures of

the hip adductors had developed bilaterally.!duced

A developmental review showed that there hadwduced been little progress in terms of manipulation, vision,

and speech. It was noted that her hearing seemedacute. At that stage her facial features were verysuggestive of the early onset Cockayne's syndrome.

ned multi- A skin biopsy to look at photosensitivity of thetns. Calci- fibroblasts was performed.meningealcerebellar CELLULAR STUDIESdendritic In Cockayne's syndrome there is marked cellular

e marked sensitivity to UV irradiation manifesting as reduced-does and survival6 and failure of cultured cells to recover a

ction afterwere firstthere werest became)ticed that1 cataractsied out at

and by sixned listlesseep whilength, and5rd centile.ohalic withng nystag-1. X ray of:ion of thebrain scanalcificatione of partialell involve-

FIG 4 Case 2 at nine months. The microcephaly andenophthalmos had initially suggested a diagnosis ofCOFSsyndrome.

156

.-.Ni. "Mm-I:.

:'. nw,&. ;, ..-:..,:': .3-' -4..:..'r.

': it:.;

A

'.",

ak

I.P



g.bmj.com

/J M


g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/


12 4812 4812 4UV dose

4812 4812 48UV dose

calf serum, penicillin, and streptomycin. Thesestrains plus two normal and one Cockayne's syn-drome control strain were irradiated with 0, 4, 8,and 12 J.m of germicidal UV light in order tomeasure their recovery from inhibition of RNAsynthesis 24 and 48 hours after irradiation. This wasdone by the autoradiographic assay previouslydescribed.9 Briefly, cells plated on coverslips andUV irradiated were pulse laballed for one hour with5 iCi/ml 3H-uridine (25 Ci/mmol) and for threehours after irradiation with 10 ,uCi/ml 3H-thymidine(25 Ci/mmol) 3, 6, 24, and 48 hours after irradiation.Then they were fixed and coated with autoradio-graphic film for a 24 hour exposure. After develop-ment, cells undergoing DNA replication were easily

8 12 identified by their dense labelling and excluded fromthe analysis. The remaining cells that were in the Gland G2 phase of the cell cycle undertook only RNAsynthesis, and this was measured by counting theautoradiographic grains overlapping the cells.

This analysis showed a 40 to 60% inhibition ofRNA synthesis in all irradiated strains at three to sixhours after irradiation (data not shown). However,at 24 and 48 hours after irradiation the rate of RNAsynthesis had recovered in normal cells exposed toall but the highest dose (fig 5a). By contrast, theCockayne's syndrome control showed further de-crease of RNA synthesis (fig Sb). The fibroblasts ofpatient 1 failed to recover adequately (fig Sc) andthose of patient 2 behaved in an identical manner tothe Cockayne's syndrome control (fig Sd).

4 8 12

FIG 5 Rate ofRNA synthesis in irradiated GI and G2phase cells expressed as a percentage ofthe rate ofshamirradiated control cells (samples ofat least 25 cells wereanalysedfor each experimental point), 124 hours afterirradiation, and 48 hours after irradiation: (a) =averageoftwo normal control strains, (b)= Cockayne's syndromecontrol, (c) =patient 1, (d) =patient 2. UV dose is in J. m-2.Vertical lines in histograms=SEM.

normal rate of DNA and RNA synthesis severalhours after irradiation.7 x Such a cellular responsehas proved consistent enough to be used in thepostnatal and prenatal diagnosis of the disease.9 Forthis reason, and because of the clinical evidence ofphotosensitivity, it was felt that fibroblast strainsfrom the patients described above should be testedfor their response to UV irradiation. Skin biopsieswere obtained and fibroblast strains were estab-lished in DMEM medium supplemented with 10%

Discussion

In 1971 Lowry et a12 described a brother and sisterwith bilateral congenital cataracts, microcephaly,progressive joint contractures, and kyphosis. Inboth cases the facial features were similar with largeears, enophthalmos, and a prominent nasal bridge.In both patients there was very marked growthdelay. Their first patient weighed 4-8 kg at five yearsand their second patient weighed 7-6 kg at sevenyears of age. Both children were severely retarded.A necropsy with a full neuropathological examina-tion was available from the second patient.'0 Thisshowed a very small brain with atrophy of the whitematter. There was extensive calcification in both thecerebrum and cerebellum. The retina showed pig-mentary changes. Although many of the clinical andpathological features were similar to those seen inCockayne's syndrome, the authors felt that the earlyonset distinguished this disorder from the typicalCockayne's syndrome.

Since then two further reports of early onsetCockayne's syndrome have been published. Moyeret all reported monozygous twins with similar

100-

." 80-.nCD

-c(A 60-z

o 40-a)

a:20-

0-

100-

80'

60-

40

20

.C

CA

zcr:0a)

a:

0j

157

84

Ki



g.bmj.com

/J M


g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/

MA Patton, F Giannelli, A J Francis, M Baraitser, B Harding, and A J Williams

growth failure. The maximum recorded weight was4 kg at 12 months and thereafter there was nofurther weight gain. Cataracts were not present atbirth, but had developed at two and a half years inone of the twins. The other report by Houston et al'2was of monozygous twins and an affected brother.Once again the growth failure started in the firstyear of life and very little growth took place afterthis. Skin photosensitivity was reported as a promin-ent feature in one of the twins. The neuropatholo-gical findings reported in these two papers aresimilar to those reported by Dolman et al'0 and arecomparable with the findings in Cockayne'ssyndrome.5There are many similarities between COFS syn-

drome and early onset Cockayne's syndrome. WhenCOFS syndrome was first described by Pena andShokeir 3 in 1974, they reported the features ofmicrocephaly, microphthalmia, cataracts, blepharo-phimosis, flexion contractures, skeletal abnormali-ties, and failure to thrive in infants between the agesof one month and 27 months. Most of the patients intheir series died in infancy with a mean age of deathof 13-7 months. However, in 1978 Pena et al4reviewed two of the surviving patients and found athird member of the family had become affected.One had lived until five years by which time she wasprofoundly cachectic and had not increased herweight from five months of age (3-3 kg). Atnecropsy there were small foci of calcific deposits inboth the grey and white matter and there was also adepletion of white matter compatible with aleucodystrophy. Their second patient was institu-tionalised when examined at three and a half yearsof age, and had not gained weight despite adequatecaloric intake. His weight was 4-3 kg. Clinically hewas microcephalic with deep set eyes, cataracts, aprominent nasal bridge, and flexion contractures atthe elbows and knees. Their third patient was seenat four years of age and weighed 3-6 kg. He had hadsimilar problems and facially resembled the appear-ance seen in Cockayne's syndrome.The growth pattern of the two patients in this

report has been striking. Both had normal birthweights and appeared to grow normally for the firstfew months of life, but from around six months ofage showed virtually no further weight gain. In-crease in length also virtually ceased at this stage,but this was more difficult to quantify because of thejoint contractures. There were considerable feedingproblems but these were unlikely to be the mostsignificant factor in the growth failure. The firstpatient was the subject of a local newspaper articledescribing him as "the boy who wouldn't grow". Thestriking failure to thrive with subsequent emaciationis similar to that seen in the reported cases of both

early onset Cockayne's syndrome and COFS syn-drome.Both patients in this report showed severe de-

velopmental delay. In the neonatal period there washypotonia and later spastic quadriplegia developed.Neither children acquired speech or sat indepen-dently. The CT brain scans in the second patientshowed generalised cerebral atrophy but no evi-dence of calcification. The neuropathological ex-amination in patient 1 showed reduction in whitematter with demyelination in a pattern consistentwith the leucodystrophy seen in Cockayne's syn-drome.The patients reported here had various degrees of

skin photosensitivity, which led us to investigate theeffects of germicidal UV light on the fibroblasts.The level of RNA synthesis after UV light wasinhibited at 24 and 48 hours in both patients. In thesecond patient the response was almost identical tothat seen in the Cockayne's syndrome control.The combination of clinical features, neuro-

pathology, and fibroblast studies indicates that theearly onset Cockayne's syndrome is correctly classi-fied with Cockayne's syndrome. The underlyingbiochemical abnormality in Cockayne's syndromehas not been identified, and there may still bebiochemical differences between the early onsetCockayne's syndrome and that with a later onset.Fibroblast complementation studies have indicatedthat three complementation groups exist. 14 Comple-mentation studies have not as yet been undertakenin the patients in this report.

It would also seem appropriate to consider COFSsyndrome within the same classification. The naturalhistory and neuropathology reported by Pena et aP'has considerable similarity with the cases reportedhere. No studies on the effects of UV irradiation onfibroblasts from patients with COFS syndrome havebeen reported.

The cellular studies were supported by a grant fromthe Cancer Research Campaign. Secretarial assist-ance was provided by Mrs Sheena Willoughby.

ReferencesCockayne EA. Dwarfism with retinal atrophy and deafness.Arch Dis Child 1936;11:1-8.

2 Lowry RB, MacLean R, McLean DM, Tischler B. Cataracts,microcephaly, kyphosis and limited joint movement in twosiblings: a new syndromc. J Pediatr 1971;79:282-4.

3 Sugarman GI. Syndrome of microccphaly, cataracts, kyphosis,and joint contractures vcrsus Cockayne syndrome. J Pediatr1973;82:351.

4 Pena SDJ, Evans J, Hunter AGW. COFS syndrome revisited.Birth Defects 1978;XIV(6B):205-13.Moosy J. The neuropathology of Cockayne's syndrome.J Neuropathol Exp Neurol 1967;26:654-60.

6 Wade MH, Chu EHY. Effects of DNA damaging agents on

158



g.bmj.com

/J M


g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/


cultured fibroblasts derived from patients with Cockaynesyndrome. Mutat Res 1979;59:49-60.

7 Lehmann AR, Kirk-Bell S, Mayne L. Abnormal kinetics ofDNA synthesis in ultraviolet-irradiated cells from patients withCockayne's syndrome. Cancer Res 1979;39:4237-41.

8 Mayne LV, Lehmann AR. Failure of RNA synthesis to recover

after UV-irradiation: an early defect in cells from individualswith Cockayne's syndrome and xeroderma pigmentosum.Cancer Res 1979;42:1473-8.

9 Lehmann AR, Francis AJ, Giannelli F. Prenatal diagnosis ofCockayne's syndrome. Lancet 1985;i:486-8.

10 Dolman CL, Wright VJ. Necropsy of original case of Lowry'ssyndrome. J Med Genet 1978;15:227-45.Moyer DB, Marquis P, Shertzer ME, Burton BK. Cockayne

syndrome with early onset of manifestations. Am J Med Genet1982;13:225-30.

12 Houston CS, Zaleski WA, Rozdilsky B. Identical male twinsand brother with Cockayne syndrome. Am J Med Genet1982;13:21 1-23.

13 Pena SDJ, Shokeir MHK. Autosomal recessive cerebro-oculo-facial-skeletal (COFS) syndrome. Clin Genet 1974;5:285-93.

14 Lehmann AR. Three complementation groups in Cockaynesyndrome. Mutat Res 1982;106:347-56.

Correspondence to Dr M A Patton, Department ofClinical Genetics, St George's Hospital MedicalSchool, Cranmer Terrace, London SW17 ORE.

159



g.bmj.com

/J M


g.26.3.154 on 1 March 1989. D

ownloaded from

http://jmg.bmj.com/

Early onset Cockayne's syndrome: reports with neuropathological … · Revised version accepted for publication 26 August 1988. There was also associated photosensitivity. UV ...

Documents