Cockayne Syndrome: Unusual Neuropathological Findings and Review of the Literature Dov Soffer, M D , Harold W. Grotsky, MD, Isabelle Rapin, M D , and Kinuko Suzuki, M D
Two siblings with Cockayne syndrome (CS) are described and the literature on the subject is briefly reviewed. Of particular interest were the unusual neuropathological findings in 1 of the patients. These included microcephaly, white matter atrophy with patchy loss of myelinated fibers, calcifications of the basal ganglia, occasional ferrugination of cerebral and cerebellar neurons, and severe cerebellar degeneration. Findings not previously reported in CS were proliferation of extremely bizarre astrocytes, neurofibrillary tangles, and pigmentation of the globus pallidus. We conclude that brain involvement in CS is a result of primary degeneration in the central nervous system rather than being secondary to angiopathy or normal pressure hydrocephalus, as previously suggested. Soffer D, Grotsky HW, Rapin I, et al: Cockayne syndrome: unusual neuropathological findings and review of
the literature. Ann Neurol 6:340-348, 1979
Cockayne, in 1936 I81 and again in 1946 [91, described a syndrome of “dwarfism with retinal atrophy and deafness” in 2 siblings. The main features of the syndrome were: an onset in late infancy after apparently normal early development; dwarfism; microcephaly; mental retardation; a peculiar facies with sunken eyes, prominent nose, and prognathism; photosensitive dermatitis; pigmentary retinal degeneration; partial deafness; and a progressive neurological disorder characterized mainly by gait disturbance. Additional features included disproportionately long extremities with large hands and feet, limited joint movements, optic atrophy, cataract, carious teeth, and thickened skull bones. More than 50 cases have subsequently been reported [ l , 3, 4 , 6 , 7 , 10, 11, 13, 14, 16, 20, 28, 29,
31-35,37-39,42,43,45-49, 52,53,55-59,6l, 63, 641, many of them in siblings of both sexes [ l , 8, 16, 34,3 5 , 39, 4 3 , 45, 5 2 , 53, 55, 571, suggesting an autosomal recessive inheritance. Almost none of the reported cases have completely fulfilled Cockayne’s criteria. Some have lacked certain features and others have had additional manifestations, including kyphosis and other skeletal anomalies, sexual infantilism, corneal opacities, poor pupillary reflexes, failure of lacrimation, anhidrosis, peripheral neuropathy, seizures, cerebellar signs, pyramidal and extrapyramidal abnormalities. and intracranial calcifications. Labo-
From the I)epartmenr$ o f Pathology. (NeuroDathologv) and I. Neuroscience, ’Ihe Saul R. Korey Deparrment of Neurolom, and the Rose I:. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, N Y , arid Ilepartmenr of Pediatrics, Elizabeth General Hospital, Elizahrrh, NJ. _,
ratory investigations have not revealed any consistent abnormality. Neuropathological findings have likewise varied [12, 3 8 , 4 1 , 4 7 , 55,621. With the considerable range in clinical manifestation, it is difficult to define the syndrome; thus, several “atypical” cases have been reported [15, 17, 2 1 , 29, 44, 541. We describe here a brother and a sister who presented many of the clinical features of CS. Neuropathological findings in 1 of the patients included lesions which, to our knowledge, have not been reported in CS o r any other disorder.
Report of Cases Furnily History The parents came from a small town in Portugal and are distant cousins. They are of normal stature and in good health. Our 2 patients are their only children; t h e mother has had n o miscarriages. The mother’s parents are first cousins. The mother’s first cousin is a dwarf with a large head, short limbs, and normal intelligence. A grandnephew of the mother was stillborn with anomalies. No family member is reported to have had an illness similar to that of our patients. Patient 1 This boy, whom we did not examine in life, was born at home without complications after a full-term, uncomplicated gestation. Birth weight was recalled as 3.2 kg. He was considered normal for the first few months of life, but de-
Accepted for publication AL?r 16, 1979 to Dr Suzuki, Department of Pathology AdCiress reprint college of ~ ~ d i 1300 ~ i ~ ~ , (Neuroparhology),Albert Morris Park Bronx, N Y 10461.
,Fig 1 . (A) Patients 1 (at age 14 years) and 2 (at age 1 1 the striking similarity in their appearance. Their ilyphotic posture is due t o contractures at the hip joints. ( B ) Patient 2,showing scissoring, contractures, and inability t o , o a k without support. Note the tjipical facialfeatures, lack of .rxillarl hair, underdeveloped breasts, and extremelji short staure. ( C I Close-up of Patient 2,demonstrating the character'rticfuries with prominent nose and chin, sunken eyes, and , w g e ears.
. ears). Note
iayed achievement of motor milestones was evident before ;tge 1 year. H e did not pull to standing until 3 years. H e was #,pasticand could cruise with support but never walked ndependently. He was said to have a pigeon chest and minderwent an orthopedic procedure for foot deformities. i4is general health was good, but growth and weight gain were deficient. Eruption of permanent teeth and growth of pubic hair occurred at the expected age. He developed *;evere corneal ulcerations, attributed to incomplete eye closure during sleep, and eventually lost his sight. Hearing was thought to be normal. Speech did not progress be:ond a few words. He attended a special school where his Q was found to be 39. H e did not have seizures and his larents were unaware of any loss of skills. He died of .lneumonia at age 14 years, 9 months. O n examination 6;hortly prior to death his height was 90 cm and weight, 15 kg. Head circumference was 40 cm. His face (Fig 1) was t;imilar in appearance to that of his sister, with a beaked 'lose and prominent, sunken eyes. The teeth were irregular, with numerous caries. There was incurving of several of rhe distal phalanges. T h e third toe overlapped the second.
Patient 2 rhis 12-year, 9-month-old girl is the younger sibling of >atient 1. She was the product of a full-term, uncompli-ated gestation and home delivery. H e r birth weight was -ecalled as 3.0 kg. H e r parents, who were concerned about 2er brother's illness, were reassured at birth that she ap>eared normal. They were not certain until about age 18
months that she, too, was affected. H e r general health has been good despite poor growth and weight gain. H e r permanent teeth erupted at the normal age but were subsequently extracted because of caries and abscesses. She was not unduly sensitive to sunlight. She did not stand with support until about age 2 years and has not achieved independent ambulation. She seems to see and hear adequately. She said her first words at 29" years, but speech has not progressed beyond a few words. Though toilet trained at 4 years, she still has nocturnal incontinence. She began to feed herself at age 6 to 7 years. She developed breast tissue and pubic hair and started regular menstruation at age 12 years, 4 months. She does not dress herself. She attends a school program for multiple-handicapped, retarded children. Examination showed a well-nourished, diminutive child with normal body proportions. Her height could not be measured accurately because of joint contractures but was approximately 88 to 90 cm; her weight was 11 kg, head circumference 40.9 cm, and chest circumference 46 cm (all grossly below the second percentile). The consistency, turgor, smoothness, and pigmentation of the skin were normal. She had deep-set eyes, a very prominent nose, thinlipped mouth, jutting chin, and large pinnas. She had small breasts with large nipples. Pubic hair was well developed and normal in distribution; she had no axillary hair. Skeletal deformities included clinodactyly, hallux valgus with overriding of the second toe, high-arched valgus feet, and fixed joint contractures at the hips, knees, and ankles. She was unable to stand unsupported because of spasticity and scissoring of the legs. She crawled well and took a few steps when supported erect. She had no tremor or other abnormal involuntary movement. Coordination of the hands was limited by spasticity. Tendon stretch reflexes, including the jaw jerk, were hyperactive with spread except for the ankle jerk, which was absent because of previous Achilles tendon surgery. She responded to touch throughout but could not cooperate for more detailed sensory examination. The range of her eye movements was full without nystagmus. Opticokinetic nystagmus could not be evaluated because of poor ocular fixation. There were small
Soffer et al: Neuropathology of Cockayne Syndrome
341
cataracts. The optic discs were pale and atrophic, and there was no retinal degeneration. Vision was present, but acuity could not be assessed because of mental retardation. The pupils were only 2mm in diameter and did not dilate in the dark. The parents did not recall having seen tears in either of their children's eyes. She did not drool and had normally expressive, symmetrical facial mimicking. T h e child was alert, and she smiled and communicated by pointing. She used a few monosyllabic words such as out and go, threw a kiss, and clapped her hands to verbal command. She scribbled with a pencil but did not imitate a straight line or a circle. She seemed to enjoy throwing a ball and retrieving it. She used her right hand for scribbling but threw the ball with her left. Bone age (using the standards ofGreulich and Pyle [ 191) was dysharmonic and varied from 8 to 15 years. There was premature closure of the sutures, a valgus deformity of the femoral neck, and lumbarization of the first sacral vertebra.
F i g 2. Coronal ~ectionof the cerebrum shou'ing markedly dilated lateral ventricle and shrunken corpus calloszrm andfornix. Note peculiar gray mottling of-the albite mutter (arrow) and lack of secondary gyri in the insula. (Centimeter scale.)
Neuropathofogiuf Fznditigs (Patient 1 ) Reportedly, the only notable finding in the general autopsy was bilateral bronchopneumonia. The brain was small, weighing only 450 gm (normal for age, 1,350 gm). The leptomeninges were diffusely thickened and tightly adherent to the brain parenchyma. The cerebral gyri were generally well developed, although formation of secondary gyri was lacking in the insula and in the temporal poles. T h e precentral gyrus was narrow. The cranial nerves were proportionately small. The optic nerves were extremely small, though of normal configuration. T h e blood vessels at the base of the brain were unremarkable. Coronal sections revealed a markedly dilated ventricular system and an extremely thin corpus callosum (Fig 2). The cortical gray mantle was of normal thickness and distribution except for the unusually thick insular cortex. No distinct line of Gennari was seen in the calcarine cortex. The hippocampus consisted of an irregularly arranged mass of gray matter lacking the usual organization. The cerebral white matter mass was greatly reduced and displayed peculiar gray mottling. T h e basal ganglia, thalami, internal capsules, cerebral peduncles, and fornices were attenuated. The brain-
342 Annals o f Neurology
Vol 6 No 4 October 1979
Fig 3 . Altheimer neurojibrillary tangles t n parietal cortex. (Bodzan; ~ 4 6 before 0 309f reduction.) Inset shoz1,s close-up v i e z i ~of a tangle. (H&E: ~ 7 3 before 0 3Ocf reduction.)
F i g 4. Bizarre multinucleated giant astroryte in the cerebral cortex, photographed at two different planes of focus. (H&E; x1,750 before 15% reduction.)
stem structures were small. The substantia nigra and locus ceruleus were well pigmented. The cerebellum was small compared to the cerebrum. The folia were shrunken throughout and widely separated. Microscopic examination revealed a dense, diffuse fibrosis of the leptomeninges without cellular infiltrates. Normal cytoarchitecture of the cerebral cortex was recognized, although it was not as well defined as in normal cortex. Cortical neurons were mature in appearance, and lipofuscin was noted in some neurons. Ferruginated neurons were noted infrequently in the cortex, in particular at the depth of the sulci. Occasional Alzheimer neurofibrillary tangles (Fig 3 ) were encountered in the frontal and parietal cortex. However, we were unable to identify neurofibrillary tangles on electron microscopic sections. Infrequently, typical Hirano bodies were encountered. Senile plaques were not seen. There was a striking diffuse proliferation of bizarre astrocytes throughout the cortex. Some had a single, bizarre, hyperchromatic nucleus resembling Alzheimer type I glia, while others had a large, round o r convoluted, clear nucleus and inconspicuous cytoplasm resembling Alzheimer type I1 glia. Multinucleated astrocytes (Fig 4) containing up to eight nuclei were also found infrequently. Similar astroglial cells were noted in the brainstem and cerebellum. An increased number of microglia (rod cells) was noted as well. The cerebral white matter displayed patchy loss of myelinated fibers throughout in a “tigroid” fashion (Fig 5). The lesions were not related to blood vessels. The affected
areas were hypocellular and displayed diffuse gliosis with marked reduction of oligodendrocytes (Fig 6). Stains for axons and myelin sheaths as well as toluidine blue-stained, plastic-embedded, semi-thin sections showed that axons and myelin sheaths were equally affected. Sudan IV stain revealed only a minimal amount of stainable material free in the center of the lesions. A few foamy macrophages were noted around blood vessels. In the basal ganglia, basophilic calcospherites of varying size were noted (Fig 7A). The smaller basophilic deposits were found mainly in the walls of capillaries and arterioles. The larger deposits were laminated and tended to coalesce and form “brain stones,” which appeared free in the parenchyma. They were located mainly in the putamen and to a lesser extent in the caudate nucleus, globus pallidus, and thalamus. They reacted strongly positively with iron stain and stained weakly or not at all with calcium (von Kossa) stain. In the globus pallidus, basophilic concretions were seen in the vicinity of neurons, astrocytes, and neural and astrocytic processes containing brown-black pigment (Fig 7B) that gave a strong positive reaction for melanin and, occasionally, a weak iron reaction. Similar pigment was present in large axonal spheroids and in the neuropil, adjacent to blood vessels in the globus pallidus. Large axonal spheroids were also noted in the caudate nuclei, internal capsules, and substantia nigra, accompanied by large, bizarre astrocytes. Occasional neurofibrillary tangles of the globose type were found in the hypothalamus. The ependymal lining of the ventricles was denuded in places, with subependymal gliosis. The brainstem showed patchy loss of myelinated axons, diffuse fibrillary gliosis, and bizarre astrocytes; neuronal changes were not apparent. Loss of myelinated fibers, gliosis, and interstitial fibrosis were prominent in the optic nerves and chiasm. The cerebellar cortex presented severe, diffuse deSoffer et al: Neuropathology of Cockayne Syndrome
343
generative changes, more pronounced in the hemispheres than in the vermis. The molecular layer appeared narrowed and hypercellular due to an increased number of astrocytes and microglia. There was a diffuse severe loss of Purkinje and granular cells accompanied by increased Bergmann glia. Many of the remaining Purkinje cells displayed degenerative changes in the form of axonal “torpedoes,” expansion of dendrites with formation of “cactus flowers,’’ and occasional mineralization of soma and dendrites (Fig 8). Binucleated neurons were rarely encountered. The cerebellar white matter showed extensive loss of myelinated fibers, similar to that observed in the cerebral hemispheres. Golgi preparations of the inferior frontal, precentral, and calcarine cortices, the hippocampus, and the cerebellum showed normal general dendritic configurations and a branching pattern of cerebral cortical neurons. Several well-impregnated Purkinje cells revealed unusual dendritic morphology. The most bizarre configuration of the dendritic arbors is shown in Figure 9.
F i g 5 . Sectinti of the fivntal lobe shouliiig loss of ni~~elirrated fibers in the white t n ~ ~ t t in e r LL “tigroid” fashion. (Heidenhairr; X3.5 before 303 redz~cfion.!
Discussion Both of the siblings reported here suffered a disorder characterized by dwarfism, microcephaly, mental retardation, optic atrophy, skeletal deformities, and progressive spasticity with limitation of joint movements. This occurrence in siblings of both sexes, born to consanguinous parents, suggests an autosomal recessive inheritance. These features, as well as the peculiar facies (with sunken eyes, prominent nose, large ears, and jutting chin), the normal birth weight, and normal development in the first months of life are characteristic of CS [ 8 , 9, 20, 24, 391. The normal birth weight and early development also dis-
F i g 6. White matter lesion (right) displayiiig central rarefaction and almost total loss of oligodendrocytes. (HGE: x180 before 35 p’reduction.)
344 Annals of Neurology
Vol 6 No 4
October 1979
F.ig 7.Globus pallidus. (A)Numerous calcospheritesappure r ~ i free ( ~ ~ i n the neuropil and in the wall of a small blood Cnmel (left lower corner). ( B ) Brown-black pigment with J.taining p,,opertieso f melanin i n a neuron and in astrocj1te.r and astiocytic processes i n the vicinity of small blood sessels. ( H & E ; A ~ 3 0B. ~ 6 0 0both , before 2072 redaction.)
F i g 9. (A) Purkinje cell exhibiting two long, thin, unbranched priniary dendrites which lack secondary and tertiary brarzches. A massizle tangle of dendritic branches, many with tertiary branchlets and spines, arises from terminal portions o f the pridendrites. (Rapid ~ ~ l ~x400 i , . before20% ( B ) Camera lucida drawing of rapid Golgi preparation to illustrate details of the unusual dendritic morphology of the Purkirije cell shown in A.(Courtesy of Dr D. Purpura.)
F i g 8. (A)Degenerated Purkinje cell with an axonal “torpedo. ’’ (Bodian, ~ 6 0 0 .()B ) Ferruginated Purkinje cell soma and dendrites. (H&E, X600.) (C) Expanded dendrites of a degenerated Purkinje cell (forming a cactuslike expansion) and an axonal “torpedo” in the left lower corner. ( H 6 E ; x400. All before 2076 reduction.) Soffer et al: Neuropathology of Cockayne Syndrome
345
tinguish CS from low-birth-weight dwarfs, particularly Seckel dwarfs, who are microcephalic and have features resembling those of CS but lack the other stigmata of that syndrome [23, 36, 501. O u r patients exhibited additional features commonly noted in CS. These include: poor pupillary response [ 4, 6, 10, 21, 34, 39, 42, 52, GO], impaired lacrimation [ 4, 31, 521, corneal opacities [I, 4 , 10, 16, 38, 49, 521, dental caries [ l , 1 1 , 16, 31, 34, 37, 39, 42, 43, 46, 47, 49, 5 2 , 57, 631, and advanced bone age on roentgenograms [20, 28, 37, 42, 46, 521. Another interesting feature, noted first by Neil1 and Dingwall [39] and supported by others [6, 471, was the surprisingly good social adaptation of‘ the patients despite their severe mental retardatiori. Some other major features of CS, notably photosensitive dermatitis, pigmentary retinal degeneration, deafness, and thickened skull bones, could not be demonstrated in our patients. Lack of pigmentary retinal degeneration, however, has been reported in some cases of CS [ 16, 35, 47, 49, 52, 53, 571 and was not mentioned or could not be examined in others [ l , 111. Grossly unimpaired hearing has also been reported [ 4,3 1,34, 35,37, 53, 57, 591. In other cases, hearing ability was not mentioned [ 4 2 , 4 6 , 6 4 ] The . same is true for skin lesions, which were absent in certain cases [16, 33, 551 or not commented on in others [ l l , 531. It is not surprising that some variability in manifestations exists in a syndrome like CS which involves multiple components [ 121, especially since CS may be a genetically heterogeneous disorder [ 4 8 ] . Although it is difficult to define the syndrome clearly, we believe our patients fit the diagnosis of CS. Until more is known about the cause and pathogenesis of the syndrome, the following diagnostic criteria are suggested as minimal and necessary for its diagnosis: ( 1 ) normal birth weight and normal development in the first months of life; ( 2 ) severe dwarfism; ( 3 ) microcephaly; ( 4 ) typical facial features, including sunken eyes, large nose, jutting chin, and large ears; and ( 5 ) slowly progressive deterioration. Pathologically, the boy’s brain displayed a variety of changes. These included microcephaly; white matter atrophy and patchy loss of myelinated fibers; diffuse proliferation of bizarre astrocytes, predominantly in the cerebral cortex; basal ganglia calcifications and occasional ferrugination of cerebral and cerebellar neurons; pigmentation of the globus pallidus; severe cerebellar cortical degeneration; and ocneurofibrillary tang1es’ most of the features have been described in other conditions 15, 26, 27, 511, the combination has not been reported previously. It differs in some aspects from changes Dreviouslv described in CS. There are only 4 detailed neuropathological reports on CS [ 12, 38,47,55] . In a few additional cases
346 Annals o f Neurology
Vol 6 No 4 October 1979
neuropathological findings were briefly mentioned [12, 4 0 , 41, 621. The most constant findings have been severe microcephaly, white matter atrophy with patchy demyelination, calcification in the basal ganglia with a variable degree of cerebral and cerebellar calcifications, and cerebellar cortical atrophy. Marked variability in intensity and extent of the individual lesions occurred from case to case. This variability has led different authors to stress different aspects of the neuropathological picture. Thus, Crome and Kanjilal [ 121 referred to the changes in their patient as “calcifying vasopathy of the brain” and considered the white matter changes secondary to the angiopathy. Other authors have stressed changes in the white matter and regarded the disease as a form of Ieukodystrophy 121, 34, 3 7 , 4 1 , 4 2 , 511. The fact that patchy (“tigroid” type) demyelination is the hallmark of Pelizaeus-Merzbacher disease led Seitelberger [ 5 11 to include CS as a special type of PMD. This is hardly justified, however, since P M D is a sex-linked disease which has very little in common clinically and pathologically with CS. Likewise, the diagnosis of CS given by some authors [38, 4 7 , 521 to sporadic cases [ 18, 22, 25, 27, 30, 411 characterized by microcephaly, cerebral calcification, and patchy demyelination seems unjustified since it was based only on pathological grounds. The pathogenesis of CS in unknown. Brumback et a1 161 have recently tried to explain some of the neurological abnormalities in CS by the occurrence of normal pressure hydrocephalus. In view of the severe primary changes in the brain, however, it is unlikely that hydrocephalus plays a major pathogenetic role. Recent studies with cultured skin fibroblasts from patients with CS have revealed excessive sensitivity of these cells to ultraviolet light, suggesting a basic cellular defect [ 2 , 481. Schmickel et a1 [481 hypothesized, therefore, that the lesions in CS result from impaired function of a specific endonuclease which recognizes aberrations in deoxyribonucleic acid caused by ultraviolet light. However, because Andrew et a1 [2] have found normal repair in Cockayne cells of deoxyribonucleic acid damaged by ultraviolet light, the significance of the ultraviolet light sensitivity awaits further studies.
Supported in part by National Institutes of Health Grants NS 3356, NS 7098, NS 10803, and HD 01799. Presented in part at the Eighth International Congress of Neuropathology, Washington, DC, September 1978. The authors thank Dr B. K. Der of the Department of Pathology, Elizabeth General Hospital, for t h e autopsy on Patient 1 and Dr F. Spirn for the ophthalmological examination of Patient 2. We also thank Drs D. Purpura and R. D. Terry for their criticism and constructive suggestions on the manuscript.
References 1. Alton DJ, McDonald P, Reilly BJ: Cockayne’s syndrome. A report of three cases. Radiology 102:403-406, 1972 2. Andrew AD, Yoder FW, Barrett SF, et al: Cockayne’s syndrome fibroblasts have decreased colony-forming ability but normal rates of unscheduled D N A synthesis after ultraviolet irradiation (abstract). Clin Res 24:624A, 1976 3. Biscatti G , Morganti G: Sindrome di Cockayne in una bambina del centra Italia. Pediatria (Napoli) 74:863-874, 1966 4. Brodrick JD, Dark AJ: Corneal dystrophy in Cockayne’s syndrome. Br J Ophthalmol 57:391-399, 1973 5 . Brucher JM: Neuropathological problems posed by carbon monoxide poisoning and anoxia. Prog Brain Res 24:76-100, 1967 6. Brumback RA, Yoder FW,Andrews AD, et al: Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne’s syndrome. Arch Neurol 35:337-345, 1978 7. Civanto F: Human chromosomal abnormalities. Bull Tulane Med Fac 20:241-253, 1961 8. Cockayne EA: Dwarfism with retinal atrophy and deafness. Arch Dis Child 11:1-8, 1936 9. Cockayne EA: Dwarfism with retinal atrophy and deafness. Arch Dis Child 21:52-54, 1946 10. Coles WH: Ocular manifestations of Cockayne’s syndrome. Am J Ophthalmol 67:762-764, 1969 11. Cotton RB, Keats TE, McCoy EE: Abnormal blood glucose regulation in Cockayne’s syndrome. Pediatrics 46:54-60, 1970 12. Crome L, Kanjilal GC: Cockayne’s syndrome: case report. J Neurol Neurosurg Psychiatry 34: 17 1-178, 1971 13. Cullen M, Mora H : Sindrome de Cockayne. Arch Argent Pediatr 55:16-21, 1961 14. Cunningham M, Godfrey S, Moffat WMV: Cockayne’s syndrome and emphysema. Arch Dis Child 53:722-725, 1978 15. D’Hoore E, Gullotta F: Entmarkungsprozess mit Hirnverkalkungen bei einem microcephaler Saugling-CockayneSyndrom? Acta Neuropathol (Berl) 18:311-3 16, 197 1 16. Fujimoto WY, Greene ML, Seegmiller JE: Cockayne’s syndrome: report of a case with hyperlipoproteinemia, hyperinsulinemia, renal disease, and normal growth hormone. J Pediatr 75:881-884, 1969 17. Gamstrop I: Donohue’s syndrome-leprechaunism-Cockayne’s syndrome. Eur Neurol 7:26-33, 1972 18. Gerstl B, Malamud N, Hayman RB, et al: Morphological and neurochemical study of Pelizaeus-Merzbacher disease. J Neurol Neurosurg Psychiatry 28:540-547, 1965 19. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist. Second edition. Stanford, CA, Stanford University Press, 1959 LO. Guzzetta F: La sindrome di Cockayne discrizione di un caso. Minerva Pediatr 19:891-895, 1967 21. Guzzetta F: Cockayne-Neill-Dingwall syndrome, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1972, vol 13, pp 431-440 2 2 . Hallervorden J: Uber diffuse symmetrische Kalkablagerung bei einem Krankheitsbild mit Mikrocephalie und Meningoencephaliris. Arch Psychiatr Nervenkr 184:579-600, 1950 !3. Harper RG, Orti E, Baker RK. Bird-headed dwarfs (Seckel’s syndrome). J Pediatr 70:799-804, 1967 14. Holmes LB, Moser HW, Halldorsson S, et al: Mental Retardation. An Atlas of Diseases with Associated Physical Abnormalities. New York, Macmillan, 1972 ! 5 . Horanyi-Hechst B, Meyer A: Diffuse sclerosis with preserved myelin island. J Ment Sci 85:22-28, 1939 !6. Iqbal K, Grundke-Iqbal I, Wisniewski HM, et al: Neurofibers in Alzheimer dementia and other condirions, in Katzman R,
Terry RD, Bick BL (eds): Alzheimer’s Disease: Senile Dementia and Related Disorders. New York, Raven, 1978, pp 409-420 27. Jervis GA: Microcephaly with extensive calcium deposits and demyelination. J Neuropathol Exp Neurol 13:3 18-329, 1954 28. Land VJ, Nogrady MB: Cockayne’s syndrome. J Can Assoc Radio1 20:194-203, 1969 29. Lanning M, Simila S: Cockayne’s syndrome. Report of a case with normal intelligence. 2 Kinderheilkd 109:70-75, 1970 30. Laubenthal F, Hallervorden J: Uber ein Geschwesterpaar mit einer eigenartigen friihkindlichen Hirnerkrankung nebst Microcephalie und iiber sein Sippe. Arch Psychiatr Nervenkr 111:7 12-741, 1940 31. Lieberman WJ, Schimek RA, Snyder CH: Cockayne’s disease. A report of a case. Am J Ophthalmol 52:116-118, 1961 32. Lyon G , Robain 0, Philippart M, et al: Leucodystrophie avec calcifications strio-cerebellenses, microcephalie et ranisme. Rev Neurol (Paris) 119:197-210, 1968 33. Marie J, LivDque B, Hesse JC, et al: Nanisme avec retinite pigmentaire et surdite. Syndrome de Cockayne. Sem Hop Paris 34:2808-2812, 1958 34. McDonald WB, Fitch KD, Lewis IC: Cockayne’s syndrome. An heredo-familial disorder of growth and development. Pediatrics 25997-1007, 1960 35. McIntyre CA, Brown HW: Twins with cachectic dwarfism. J Pediatr 67:1204-1206, 1965 36. McKusick VA, Mahloudji M, A b b t t MH, et al: Seckel’s birdheaded dwarfism. N Engl J Med 277:279-286, 1967 37. Moosa A, Dubowitz V: Peripheral neuropathy in Cockayne’s syndrome. Arch Dis Child 45:674-677, 1970 38. Moossy J: The neuropathology of Cockayne’s syndrome. J Neuropathol Exp Neurol 26:654-660, 1967 39. Neil1 CA, Dingwall MM: A syndrome resembling progeria: a review of two cases. Arch Dis Child 25:213-221, 1950 40. Norman RM: Malformations of the nervous system, birth injury and diseases of early life, in Greenfield’s Neuropathology. Second edition. London, Arnold, 1963, p 350 41. Norman RM, Tingey AH: Syndrome of microcephaly, striocerebellar calcifications and leucodystrophy. J Neurol Neurosurg Psychiatry 29157-163, 1966 42. Ohno T, Hirooka M: Renal lesions in Cockayne’s syndrome. Tohoku J Exp Med 89:151-166, 1966 43. Paddison RM, Moossy J, Derbes VJ, et al: Cockayne’s syndrome. Dermatol Trop 2:195-203, 1963 44. Pfeiffer RA, Bachmann KD: An atypical case of Cockayne’s syndrome. Clin Genet 4:28-32, 1973 45. Predescu V, Christodorescu D , Coltoiu A, et al: Syndrome de Cockayne. Arch Fr Pediatr 30:527-532, 1973 46. Riggs W, Seibert J: Cockayne’s syndrome. Roentgen findings. Am J Roentgen01 Radium Ther Nucl Med 116:623-633, 1972 47. Rowlatt U: Cockayne’s syndrome. Report of cise with necropsy findings. Acta Neuropathol (Berl) 14:52-61, 1969 48. Schmickel RD, Chu EHY, Trosko JE, et al: Cockayne syndrome: a cellular sensitivity to ultraviolet light. Pediatrics 60:135-139, 1977 49. Schonenbert H , Frohn K: Das Cockayne-Syndrom. Monatsschr Kinderheilkd 117:103-108, 1969 50. Seckel HPG: Bird-headed Dwarfism. Basel, Krager, 1960 5 1. Seitelberger F: Pelizaeus-Merzbacher disease, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1970, vol 10, pp 150-202 52. Spark H : Cachectic dwarfism resembling the Cockayne-Neil1 type. J Pediatr 66:41-47, 1965 53. Srivastava RN, Gupta PC, Mayekar G , et al: Cockayne’s syndrome in two sisters. Acta Paediatr Scand 63:461-464, 1974 54. Sugarman GI: Syndrome of microcephaly, cataract, kyphosis
Soffer et al: Neuropathology of Cockayne Syndrome
347
55.
56. 57. 58.
59.
348
and joint contractures versus Cockayne’s syndrome (letter). J Pediatr 82:351, 1973 Sugarman GI, Landing BH, Reed WB: Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 16:225-232, 1977 Suwa S: Low birth weight dwarfism. Jpn J Pediatr 17:878890, 1964 Tympner KD, Eichin F, Fendel H: Cockayne’s syndrome. 2 Kinderheilkd 104:298-307, 1968 Ueno T, Hatsumo K, Terao K, et al: Case report of Cockayne-Neill’s syndrome and clinical observation. Acta Pediatr Jpn 74:415-422, 1970 Uesugi M, Nakagawa 0, Uesugi T: A case regarded as Cockayne’s syndrome. J Clin Ophthalmol (Tokyo) 4:17771785, 1960
Annals of Neurology
Vol 6 No 4
October 1979
60. Uferman K, Heege-Dohr R, Kosenow W: Augenbeteilungen beim Cockayne-Syndrom. Klin Monatsbl Augenheilkd 162: 655-658, 1973 61. Upjohn C: Familial dwarfism associated with microcephaly, mental retardation and anemia. Proc SOCMed 48:334-335, 1955 62. Urich H: Malformations of the nervous system, perinatal damage and related conditions in early life, in Blackwood W, Corsellis JAN (eds): Greenfield’s Neuropathology. Third edition. London, Arnold, 1976, pp 388-390 63. Wilkins L The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Third edition. Springfield, IL, Thomas, 1965, pp 168, 192 64. Windmiller J, Whalley PJ, Fink CW: Cockayne syndrome with chromosomal analysis. Am J Dis Child 105:204-208, 1963
Two siblings with Cockayne syndrome (CS) are described and the literature on the subject is briefly reviewed. Of particular interest were the unusual neuropathological findings in 1 of the patients. These included microcephaly, white matter atrophy with patchy loss of myelinated fibers, calcifications of the basal ganglia, occasional ferrugination of cerebral and cerebellar neurons, and severe cerebellar degeneration. Findings not previously reported in CS were proliferation of extremely bizarre astrocytes, neurofibrillary tangles, and pigmentation of the globus pallidus. We conclude that brain involvement in CS is a result of primary degeneration in the central nervous system rather than being secondary to angiopathy or normal pressure hydrocephalus, as previously suggested. Soffer D, Grotsky HW, Rapin I, et al: Cockayne syndrome: unusual neuropathological findings and review of
the literature. Ann Neurol 6:340-348, 1979
Cockayne, in 1936 I81 and again in 1946 [91, described a syndrome of “dwarfism with retinal atrophy and deafness” in 2 siblings. The main features of the syndrome were: an onset in late infancy after apparently normal early development; dwarfism; microcephaly; mental retardation; a peculiar facies with sunken eyes, prominent nose, and prognathism; photosensitive dermatitis; pigmentary retinal degeneration; partial deafness; and a progressive neurological disorder characterized mainly by gait disturbance. Additional features included disproportionately long extremities with large hands and feet, limited joint movements, optic atrophy, cataract, carious teeth, and thickened skull bones. More than 50 cases have subsequently been reported [ l , 3, 4 , 6 , 7 , 10, 11, 13, 14, 16, 20, 28, 29,
31-35,37-39,42,43,45-49, 52,53,55-59,6l, 63, 641, many of them in siblings of both sexes [ l , 8, 16, 34,3 5 , 39, 4 3 , 45, 5 2 , 53, 55, 571, suggesting an autosomal recessive inheritance. Almost none of the reported cases have completely fulfilled Cockayne’s criteria. Some have lacked certain features and others have had additional manifestations, including kyphosis and other skeletal anomalies, sexual infantilism, corneal opacities, poor pupillary reflexes, failure of lacrimation, anhidrosis, peripheral neuropathy, seizures, cerebellar signs, pyramidal and extrapyramidal abnormalities. and intracranial calcifications. Labo-
From the I)epartmenr$ o f Pathology. (NeuroDathologv) and I. Neuroscience, ’Ihe Saul R. Korey Deparrment of Neurolom, and the Rose I:. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, N Y , arid Ilepartmenr of Pediatrics, Elizabeth General Hospital, Elizahrrh, NJ. _,
ratory investigations have not revealed any consistent abnormality. Neuropathological findings have likewise varied [12, 3 8 , 4 1 , 4 7 , 55,621. With the considerable range in clinical manifestation, it is difficult to define the syndrome; thus, several “atypical” cases have been reported [15, 17, 2 1 , 29, 44, 541. We describe here a brother and a sister who presented many of the clinical features of CS. Neuropathological findings in 1 of the patients included lesions which, to our knowledge, have not been reported in CS o r any other disorder.
Report of Cases Furnily History The parents came from a small town in Portugal and are distant cousins. They are of normal stature and in good health. Our 2 patients are their only children; t h e mother has had n o miscarriages. The mother’s parents are first cousins. The mother’s first cousin is a dwarf with a large head, short limbs, and normal intelligence. A grandnephew of the mother was stillborn with anomalies. No family member is reported to have had an illness similar to that of our patients. Patient 1 This boy, whom we did not examine in life, was born at home without complications after a full-term, uncomplicated gestation. Birth weight was recalled as 3.2 kg. He was considered normal for the first few months of life, but de-
Accepted for publication AL?r 16, 1979 to Dr Suzuki, Department of Pathology AdCiress reprint college of ~ ~ d i 1300 ~ i ~ ~ , (Neuroparhology),Albert Morris Park Bronx, N Y 10461.
,Fig 1 . (A) Patients 1 (at age 14 years) and 2 (at age 1 1 the striking similarity in their appearance. Their ilyphotic posture is due t o contractures at the hip joints. ( B ) Patient 2,showing scissoring, contractures, and inability t o , o a k without support. Note the tjipical facialfeatures, lack of .rxillarl hair, underdeveloped breasts, and extremelji short staure. ( C I Close-up of Patient 2,demonstrating the character'rticfuries with prominent nose and chin, sunken eyes, and , w g e ears.
. ears). Note
iayed achievement of motor milestones was evident before ;tge 1 year. H e did not pull to standing until 3 years. H e was #,pasticand could cruise with support but never walked ndependently. He was said to have a pigeon chest and minderwent an orthopedic procedure for foot deformities. i4is general health was good, but growth and weight gain were deficient. Eruption of permanent teeth and growth of pubic hair occurred at the expected age. He developed *;evere corneal ulcerations, attributed to incomplete eye closure during sleep, and eventually lost his sight. Hearing was thought to be normal. Speech did not progress be:ond a few words. He attended a special school where his Q was found to be 39. H e did not have seizures and his larents were unaware of any loss of skills. He died of .lneumonia at age 14 years, 9 months. O n examination 6;hortly prior to death his height was 90 cm and weight, 15 kg. Head circumference was 40 cm. His face (Fig 1) was t;imilar in appearance to that of his sister, with a beaked 'lose and prominent, sunken eyes. The teeth were irregular, with numerous caries. There was incurving of several of rhe distal phalanges. T h e third toe overlapped the second.
Patient 2 rhis 12-year, 9-month-old girl is the younger sibling of >atient 1. She was the product of a full-term, uncompli-ated gestation and home delivery. H e r birth weight was -ecalled as 3.0 kg. H e r parents, who were concerned about 2er brother's illness, were reassured at birth that she ap>eared normal. They were not certain until about age 18
months that she, too, was affected. H e r general health has been good despite poor growth and weight gain. H e r permanent teeth erupted at the normal age but were subsequently extracted because of caries and abscesses. She was not unduly sensitive to sunlight. She did not stand with support until about age 2 years and has not achieved independent ambulation. She seems to see and hear adequately. She said her first words at 29" years, but speech has not progressed beyond a few words. Though toilet trained at 4 years, she still has nocturnal incontinence. She began to feed herself at age 6 to 7 years. She developed breast tissue and pubic hair and started regular menstruation at age 12 years, 4 months. She does not dress herself. She attends a school program for multiple-handicapped, retarded children. Examination showed a well-nourished, diminutive child with normal body proportions. Her height could not be measured accurately because of joint contractures but was approximately 88 to 90 cm; her weight was 11 kg, head circumference 40.9 cm, and chest circumference 46 cm (all grossly below the second percentile). The consistency, turgor, smoothness, and pigmentation of the skin were normal. She had deep-set eyes, a very prominent nose, thinlipped mouth, jutting chin, and large pinnas. She had small breasts with large nipples. Pubic hair was well developed and normal in distribution; she had no axillary hair. Skeletal deformities included clinodactyly, hallux valgus with overriding of the second toe, high-arched valgus feet, and fixed joint contractures at the hips, knees, and ankles. She was unable to stand unsupported because of spasticity and scissoring of the legs. She crawled well and took a few steps when supported erect. She had no tremor or other abnormal involuntary movement. Coordination of the hands was limited by spasticity. Tendon stretch reflexes, including the jaw jerk, were hyperactive with spread except for the ankle jerk, which was absent because of previous Achilles tendon surgery. She responded to touch throughout but could not cooperate for more detailed sensory examination. The range of her eye movements was full without nystagmus. Opticokinetic nystagmus could not be evaluated because of poor ocular fixation. There were small
Soffer et al: Neuropathology of Cockayne Syndrome
341
cataracts. The optic discs were pale and atrophic, and there was no retinal degeneration. Vision was present, but acuity could not be assessed because of mental retardation. The pupils were only 2mm in diameter and did not dilate in the dark. The parents did not recall having seen tears in either of their children's eyes. She did not drool and had normally expressive, symmetrical facial mimicking. T h e child was alert, and she smiled and communicated by pointing. She used a few monosyllabic words such as out and go, threw a kiss, and clapped her hands to verbal command. She scribbled with a pencil but did not imitate a straight line or a circle. She seemed to enjoy throwing a ball and retrieving it. She used her right hand for scribbling but threw the ball with her left. Bone age (using the standards ofGreulich and Pyle [ 191) was dysharmonic and varied from 8 to 15 years. There was premature closure of the sutures, a valgus deformity of the femoral neck, and lumbarization of the first sacral vertebra.
F i g 2. Coronal ~ectionof the cerebrum shou'ing markedly dilated lateral ventricle and shrunken corpus calloszrm andfornix. Note peculiar gray mottling of-the albite mutter (arrow) and lack of secondary gyri in the insula. (Centimeter scale.)
Neuropathofogiuf Fznditigs (Patient 1 ) Reportedly, the only notable finding in the general autopsy was bilateral bronchopneumonia. The brain was small, weighing only 450 gm (normal for age, 1,350 gm). The leptomeninges were diffusely thickened and tightly adherent to the brain parenchyma. The cerebral gyri were generally well developed, although formation of secondary gyri was lacking in the insula and in the temporal poles. T h e precentral gyrus was narrow. The cranial nerves were proportionately small. The optic nerves were extremely small, though of normal configuration. T h e blood vessels at the base of the brain were unremarkable. Coronal sections revealed a markedly dilated ventricular system and an extremely thin corpus callosum (Fig 2). The cortical gray mantle was of normal thickness and distribution except for the unusually thick insular cortex. No distinct line of Gennari was seen in the calcarine cortex. The hippocampus consisted of an irregularly arranged mass of gray matter lacking the usual organization. The cerebral white matter mass was greatly reduced and displayed peculiar gray mottling. T h e basal ganglia, thalami, internal capsules, cerebral peduncles, and fornices were attenuated. The brain-
342 Annals o f Neurology
Vol 6 No 4 October 1979
Fig 3 . Altheimer neurojibrillary tangles t n parietal cortex. (Bodzan; ~ 4 6 before 0 309f reduction.) Inset shoz1,s close-up v i e z i ~of a tangle. (H&E: ~ 7 3 before 0 3Ocf reduction.)
F i g 4. Bizarre multinucleated giant astroryte in the cerebral cortex, photographed at two different planes of focus. (H&E; x1,750 before 15% reduction.)
stem structures were small. The substantia nigra and locus ceruleus were well pigmented. The cerebellum was small compared to the cerebrum. The folia were shrunken throughout and widely separated. Microscopic examination revealed a dense, diffuse fibrosis of the leptomeninges without cellular infiltrates. Normal cytoarchitecture of the cerebral cortex was recognized, although it was not as well defined as in normal cortex. Cortical neurons were mature in appearance, and lipofuscin was noted in some neurons. Ferruginated neurons were noted infrequently in the cortex, in particular at the depth of the sulci. Occasional Alzheimer neurofibrillary tangles (Fig 3 ) were encountered in the frontal and parietal cortex. However, we were unable to identify neurofibrillary tangles on electron microscopic sections. Infrequently, typical Hirano bodies were encountered. Senile plaques were not seen. There was a striking diffuse proliferation of bizarre astrocytes throughout the cortex. Some had a single, bizarre, hyperchromatic nucleus resembling Alzheimer type I glia, while others had a large, round o r convoluted, clear nucleus and inconspicuous cytoplasm resembling Alzheimer type I1 glia. Multinucleated astrocytes (Fig 4) containing up to eight nuclei were also found infrequently. Similar astroglial cells were noted in the brainstem and cerebellum. An increased number of microglia (rod cells) was noted as well. The cerebral white matter displayed patchy loss of myelinated fibers throughout in a “tigroid” fashion (Fig 5). The lesions were not related to blood vessels. The affected
areas were hypocellular and displayed diffuse gliosis with marked reduction of oligodendrocytes (Fig 6). Stains for axons and myelin sheaths as well as toluidine blue-stained, plastic-embedded, semi-thin sections showed that axons and myelin sheaths were equally affected. Sudan IV stain revealed only a minimal amount of stainable material free in the center of the lesions. A few foamy macrophages were noted around blood vessels. In the basal ganglia, basophilic calcospherites of varying size were noted (Fig 7A). The smaller basophilic deposits were found mainly in the walls of capillaries and arterioles. The larger deposits were laminated and tended to coalesce and form “brain stones,” which appeared free in the parenchyma. They were located mainly in the putamen and to a lesser extent in the caudate nucleus, globus pallidus, and thalamus. They reacted strongly positively with iron stain and stained weakly or not at all with calcium (von Kossa) stain. In the globus pallidus, basophilic concretions were seen in the vicinity of neurons, astrocytes, and neural and astrocytic processes containing brown-black pigment (Fig 7B) that gave a strong positive reaction for melanin and, occasionally, a weak iron reaction. Similar pigment was present in large axonal spheroids and in the neuropil, adjacent to blood vessels in the globus pallidus. Large axonal spheroids were also noted in the caudate nuclei, internal capsules, and substantia nigra, accompanied by large, bizarre astrocytes. Occasional neurofibrillary tangles of the globose type were found in the hypothalamus. The ependymal lining of the ventricles was denuded in places, with subependymal gliosis. The brainstem showed patchy loss of myelinated axons, diffuse fibrillary gliosis, and bizarre astrocytes; neuronal changes were not apparent. Loss of myelinated fibers, gliosis, and interstitial fibrosis were prominent in the optic nerves and chiasm. The cerebellar cortex presented severe, diffuse deSoffer et al: Neuropathology of Cockayne Syndrome
343
generative changes, more pronounced in the hemispheres than in the vermis. The molecular layer appeared narrowed and hypercellular due to an increased number of astrocytes and microglia. There was a diffuse severe loss of Purkinje and granular cells accompanied by increased Bergmann glia. Many of the remaining Purkinje cells displayed degenerative changes in the form of axonal “torpedoes,” expansion of dendrites with formation of “cactus flowers,’’ and occasional mineralization of soma and dendrites (Fig 8). Binucleated neurons were rarely encountered. The cerebellar white matter showed extensive loss of myelinated fibers, similar to that observed in the cerebral hemispheres. Golgi preparations of the inferior frontal, precentral, and calcarine cortices, the hippocampus, and the cerebellum showed normal general dendritic configurations and a branching pattern of cerebral cortical neurons. Several well-impregnated Purkinje cells revealed unusual dendritic morphology. The most bizarre configuration of the dendritic arbors is shown in Figure 9.
F i g 5 . Sectinti of the fivntal lobe shouliiig loss of ni~~elirrated fibers in the white t n ~ ~ t t in e r LL “tigroid” fashion. (Heidenhairr; X3.5 before 303 redz~cfion.!
Discussion Both of the siblings reported here suffered a disorder characterized by dwarfism, microcephaly, mental retardation, optic atrophy, skeletal deformities, and progressive spasticity with limitation of joint movements. This occurrence in siblings of both sexes, born to consanguinous parents, suggests an autosomal recessive inheritance. These features, as well as the peculiar facies (with sunken eyes, prominent nose, large ears, and jutting chin), the normal birth weight, and normal development in the first months of life are characteristic of CS [ 8 , 9, 20, 24, 391. The normal birth weight and early development also dis-
F i g 6. White matter lesion (right) displayiiig central rarefaction and almost total loss of oligodendrocytes. (HGE: x180 before 35 p’reduction.)
344 Annals of Neurology
Vol 6 No 4
October 1979
F.ig 7.Globus pallidus. (A)Numerous calcospheritesappure r ~ i free ( ~ ~ i n the neuropil and in the wall of a small blood Cnmel (left lower corner). ( B ) Brown-black pigment with J.taining p,,opertieso f melanin i n a neuron and in astrocj1te.r and astiocytic processes i n the vicinity of small blood sessels. ( H & E ; A ~ 3 0B. ~ 6 0 0both , before 2072 redaction.)
F i g 9. (A) Purkinje cell exhibiting two long, thin, unbranched priniary dendrites which lack secondary and tertiary brarzches. A massizle tangle of dendritic branches, many with tertiary branchlets and spines, arises from terminal portions o f the pridendrites. (Rapid ~ ~ l ~x400 i , . before20% ( B ) Camera lucida drawing of rapid Golgi preparation to illustrate details of the unusual dendritic morphology of the Purkirije cell shown in A.(Courtesy of Dr D. Purpura.)
F i g 8. (A)Degenerated Purkinje cell with an axonal “torpedo. ’’ (Bodian, ~ 6 0 0 .()B ) Ferruginated Purkinje cell soma and dendrites. (H&E, X600.) (C) Expanded dendrites of a degenerated Purkinje cell (forming a cactuslike expansion) and an axonal “torpedo” in the left lower corner. ( H 6 E ; x400. All before 2076 reduction.) Soffer et al: Neuropathology of Cockayne Syndrome
345
tinguish CS from low-birth-weight dwarfs, particularly Seckel dwarfs, who are microcephalic and have features resembling those of CS but lack the other stigmata of that syndrome [23, 36, 501. O u r patients exhibited additional features commonly noted in CS. These include: poor pupillary response [ 4, 6, 10, 21, 34, 39, 42, 52, GO], impaired lacrimation [ 4, 31, 521, corneal opacities [I, 4 , 10, 16, 38, 49, 521, dental caries [ l , 1 1 , 16, 31, 34, 37, 39, 42, 43, 46, 47, 49, 5 2 , 57, 631, and advanced bone age on roentgenograms [20, 28, 37, 42, 46, 521. Another interesting feature, noted first by Neil1 and Dingwall [39] and supported by others [6, 471, was the surprisingly good social adaptation of‘ the patients despite their severe mental retardatiori. Some other major features of CS, notably photosensitive dermatitis, pigmentary retinal degeneration, deafness, and thickened skull bones, could not be demonstrated in our patients. Lack of pigmentary retinal degeneration, however, has been reported in some cases of CS [ 16, 35, 47, 49, 52, 53, 571 and was not mentioned or could not be examined in others [ l , 111. Grossly unimpaired hearing has also been reported [ 4,3 1,34, 35,37, 53, 57, 591. In other cases, hearing ability was not mentioned [ 4 2 , 4 6 , 6 4 ] The . same is true for skin lesions, which were absent in certain cases [16, 33, 551 or not commented on in others [ l l , 531. It is not surprising that some variability in manifestations exists in a syndrome like CS which involves multiple components [ 121, especially since CS may be a genetically heterogeneous disorder [ 4 8 ] . Although it is difficult to define the syndrome clearly, we believe our patients fit the diagnosis of CS. Until more is known about the cause and pathogenesis of the syndrome, the following diagnostic criteria are suggested as minimal and necessary for its diagnosis: ( 1 ) normal birth weight and normal development in the first months of life; ( 2 ) severe dwarfism; ( 3 ) microcephaly; ( 4 ) typical facial features, including sunken eyes, large nose, jutting chin, and large ears; and ( 5 ) slowly progressive deterioration. Pathologically, the boy’s brain displayed a variety of changes. These included microcephaly; white matter atrophy and patchy loss of myelinated fibers; diffuse proliferation of bizarre astrocytes, predominantly in the cerebral cortex; basal ganglia calcifications and occasional ferrugination of cerebral and cerebellar neurons; pigmentation of the globus pallidus; severe cerebellar cortical degeneration; and ocneurofibrillary tang1es’ most of the features have been described in other conditions 15, 26, 27, 511, the combination has not been reported previously. It differs in some aspects from changes Dreviouslv described in CS. There are only 4 detailed neuropathological reports on CS [ 12, 38,47,55] . In a few additional cases
346 Annals o f Neurology
Vol 6 No 4 October 1979
neuropathological findings were briefly mentioned [12, 4 0 , 41, 621. The most constant findings have been severe microcephaly, white matter atrophy with patchy demyelination, calcification in the basal ganglia with a variable degree of cerebral and cerebellar calcifications, and cerebellar cortical atrophy. Marked variability in intensity and extent of the individual lesions occurred from case to case. This variability has led different authors to stress different aspects of the neuropathological picture. Thus, Crome and Kanjilal [ 121 referred to the changes in their patient as “calcifying vasopathy of the brain” and considered the white matter changes secondary to the angiopathy. Other authors have stressed changes in the white matter and regarded the disease as a form of Ieukodystrophy 121, 34, 3 7 , 4 1 , 4 2 , 511. The fact that patchy (“tigroid” type) demyelination is the hallmark of Pelizaeus-Merzbacher disease led Seitelberger [ 5 11 to include CS as a special type of PMD. This is hardly justified, however, since P M D is a sex-linked disease which has very little in common clinically and pathologically with CS. Likewise, the diagnosis of CS given by some authors [38, 4 7 , 521 to sporadic cases [ 18, 22, 25, 27, 30, 411 characterized by microcephaly, cerebral calcification, and patchy demyelination seems unjustified since it was based only on pathological grounds. The pathogenesis of CS in unknown. Brumback et a1 161 have recently tried to explain some of the neurological abnormalities in CS by the occurrence of normal pressure hydrocephalus. In view of the severe primary changes in the brain, however, it is unlikely that hydrocephalus plays a major pathogenetic role. Recent studies with cultured skin fibroblasts from patients with CS have revealed excessive sensitivity of these cells to ultraviolet light, suggesting a basic cellular defect [ 2 , 481. Schmickel et a1 [481 hypothesized, therefore, that the lesions in CS result from impaired function of a specific endonuclease which recognizes aberrations in deoxyribonucleic acid caused by ultraviolet light. However, because Andrew et a1 [2] have found normal repair in Cockayne cells of deoxyribonucleic acid damaged by ultraviolet light, the significance of the ultraviolet light sensitivity awaits further studies.
Supported in part by National Institutes of Health Grants NS 3356, NS 7098, NS 10803, and HD 01799. Presented in part at the Eighth International Congress of Neuropathology, Washington, DC, September 1978. The authors thank Dr B. K. Der of the Department of Pathology, Elizabeth General Hospital, for t h e autopsy on Patient 1 and Dr F. Spirn for the ophthalmological examination of Patient 2. We also thank Drs D. Purpura and R. D. Terry for their criticism and constructive suggestions on the manuscript.
References 1. Alton DJ, McDonald P, Reilly BJ: Cockayne’s syndrome. A report of three cases. Radiology 102:403-406, 1972 2. Andrew AD, Yoder FW, Barrett SF, et al: Cockayne’s syndrome fibroblasts have decreased colony-forming ability but normal rates of unscheduled D N A synthesis after ultraviolet irradiation (abstract). Clin Res 24:624A, 1976 3. Biscatti G , Morganti G: Sindrome di Cockayne in una bambina del centra Italia. Pediatria (Napoli) 74:863-874, 1966 4. Brodrick JD, Dark AJ: Corneal dystrophy in Cockayne’s syndrome. Br J Ophthalmol 57:391-399, 1973 5 . Brucher JM: Neuropathological problems posed by carbon monoxide poisoning and anoxia. Prog Brain Res 24:76-100, 1967 6. Brumback RA, Yoder FW,Andrews AD, et al: Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne’s syndrome. Arch Neurol 35:337-345, 1978 7. Civanto F: Human chromosomal abnormalities. Bull Tulane Med Fac 20:241-253, 1961 8. Cockayne EA: Dwarfism with retinal atrophy and deafness. Arch Dis Child 11:1-8, 1936 9. Cockayne EA: Dwarfism with retinal atrophy and deafness. Arch Dis Child 21:52-54, 1946 10. Coles WH: Ocular manifestations of Cockayne’s syndrome. Am J Ophthalmol 67:762-764, 1969 11. Cotton RB, Keats TE, McCoy EE: Abnormal blood glucose regulation in Cockayne’s syndrome. Pediatrics 46:54-60, 1970 12. Crome L, Kanjilal GC: Cockayne’s syndrome: case report. J Neurol Neurosurg Psychiatry 34: 17 1-178, 1971 13. Cullen M, Mora H : Sindrome de Cockayne. Arch Argent Pediatr 55:16-21, 1961 14. Cunningham M, Godfrey S, Moffat WMV: Cockayne’s syndrome and emphysema. Arch Dis Child 53:722-725, 1978 15. D’Hoore E, Gullotta F: Entmarkungsprozess mit Hirnverkalkungen bei einem microcephaler Saugling-CockayneSyndrom? Acta Neuropathol (Berl) 18:311-3 16, 197 1 16. Fujimoto WY, Greene ML, Seegmiller JE: Cockayne’s syndrome: report of a case with hyperlipoproteinemia, hyperinsulinemia, renal disease, and normal growth hormone. J Pediatr 75:881-884, 1969 17. Gamstrop I: Donohue’s syndrome-leprechaunism-Cockayne’s syndrome. Eur Neurol 7:26-33, 1972 18. Gerstl B, Malamud N, Hayman RB, et al: Morphological and neurochemical study of Pelizaeus-Merzbacher disease. J Neurol Neurosurg Psychiatry 28:540-547, 1965 19. Greulich WW, Pyle SI: Radiographic Atlas of Skeletal Development of the Hand and Wrist. Second edition. Stanford, CA, Stanford University Press, 1959 LO. Guzzetta F: La sindrome di Cockayne discrizione di un caso. Minerva Pediatr 19:891-895, 1967 21. Guzzetta F: Cockayne-Neill-Dingwall syndrome, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1972, vol 13, pp 431-440 2 2 . Hallervorden J: Uber diffuse symmetrische Kalkablagerung bei einem Krankheitsbild mit Mikrocephalie und Meningoencephaliris. Arch Psychiatr Nervenkr 184:579-600, 1950 !3. Harper RG, Orti E, Baker RK. Bird-headed dwarfs (Seckel’s syndrome). J Pediatr 70:799-804, 1967 14. Holmes LB, Moser HW, Halldorsson S, et al: Mental Retardation. An Atlas of Diseases with Associated Physical Abnormalities. New York, Macmillan, 1972 ! 5 . Horanyi-Hechst B, Meyer A: Diffuse sclerosis with preserved myelin island. J Ment Sci 85:22-28, 1939 !6. Iqbal K, Grundke-Iqbal I, Wisniewski HM, et al: Neurofibers in Alzheimer dementia and other condirions, in Katzman R,
Terry RD, Bick BL (eds): Alzheimer’s Disease: Senile Dementia and Related Disorders. New York, Raven, 1978, pp 409-420 27. Jervis GA: Microcephaly with extensive calcium deposits and demyelination. J Neuropathol Exp Neurol 13:3 18-329, 1954 28. Land VJ, Nogrady MB: Cockayne’s syndrome. J Can Assoc Radio1 20:194-203, 1969 29. Lanning M, Simila S: Cockayne’s syndrome. Report of a case with normal intelligence. 2 Kinderheilkd 109:70-75, 1970 30. Laubenthal F, Hallervorden J: Uber ein Geschwesterpaar mit einer eigenartigen friihkindlichen Hirnerkrankung nebst Microcephalie und iiber sein Sippe. Arch Psychiatr Nervenkr 111:7 12-741, 1940 31. Lieberman WJ, Schimek RA, Snyder CH: Cockayne’s disease. A report of a case. Am J Ophthalmol 52:116-118, 1961 32. Lyon G , Robain 0, Philippart M, et al: Leucodystrophie avec calcifications strio-cerebellenses, microcephalie et ranisme. Rev Neurol (Paris) 119:197-210, 1968 33. Marie J, LivDque B, Hesse JC, et al: Nanisme avec retinite pigmentaire et surdite. Syndrome de Cockayne. Sem Hop Paris 34:2808-2812, 1958 34. McDonald WB, Fitch KD, Lewis IC: Cockayne’s syndrome. An heredo-familial disorder of growth and development. Pediatrics 25997-1007, 1960 35. McIntyre CA, Brown HW: Twins with cachectic dwarfism. J Pediatr 67:1204-1206, 1965 36. McKusick VA, Mahloudji M, A b b t t MH, et al: Seckel’s birdheaded dwarfism. N Engl J Med 277:279-286, 1967 37. Moosa A, Dubowitz V: Peripheral neuropathy in Cockayne’s syndrome. Arch Dis Child 45:674-677, 1970 38. Moossy J: The neuropathology of Cockayne’s syndrome. J Neuropathol Exp Neurol 26:654-660, 1967 39. Neil1 CA, Dingwall MM: A syndrome resembling progeria: a review of two cases. Arch Dis Child 25:213-221, 1950 40. Norman RM: Malformations of the nervous system, birth injury and diseases of early life, in Greenfield’s Neuropathology. Second edition. London, Arnold, 1963, p 350 41. Norman RM, Tingey AH: Syndrome of microcephaly, striocerebellar calcifications and leucodystrophy. J Neurol Neurosurg Psychiatry 29157-163, 1966 42. Ohno T, Hirooka M: Renal lesions in Cockayne’s syndrome. Tohoku J Exp Med 89:151-166, 1966 43. Paddison RM, Moossy J, Derbes VJ, et al: Cockayne’s syndrome. Dermatol Trop 2:195-203, 1963 44. Pfeiffer RA, Bachmann KD: An atypical case of Cockayne’s syndrome. Clin Genet 4:28-32, 1973 45. Predescu V, Christodorescu D , Coltoiu A, et al: Syndrome de Cockayne. Arch Fr Pediatr 30:527-532, 1973 46. Riggs W, Seibert J: Cockayne’s syndrome. Roentgen findings. Am J Roentgen01 Radium Ther Nucl Med 116:623-633, 1972 47. Rowlatt U: Cockayne’s syndrome. Report of cise with necropsy findings. Acta Neuropathol (Berl) 14:52-61, 1969 48. Schmickel RD, Chu EHY, Trosko JE, et al: Cockayne syndrome: a cellular sensitivity to ultraviolet light. Pediatrics 60:135-139, 1977 49. Schonenbert H , Frohn K: Das Cockayne-Syndrom. Monatsschr Kinderheilkd 117:103-108, 1969 50. Seckel HPG: Bird-headed Dwarfism. Basel, Krager, 1960 5 1. Seitelberger F: Pelizaeus-Merzbacher disease, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North-Holland, 1970, vol 10, pp 150-202 52. Spark H : Cachectic dwarfism resembling the Cockayne-Neil1 type. J Pediatr 66:41-47, 1965 53. Srivastava RN, Gupta PC, Mayekar G , et al: Cockayne’s syndrome in two sisters. Acta Paediatr Scand 63:461-464, 1974 54. Sugarman GI: Syndrome of microcephaly, cataract, kyphosis
Soffer et al: Neuropathology of Cockayne Syndrome
347
55.
56. 57. 58.
59.
348
and joint contractures versus Cockayne’s syndrome (letter). J Pediatr 82:351, 1973 Sugarman GI, Landing BH, Reed WB: Cockayne syndrome: clinical study of two patients and neuropathologic findings in one. Clin Pediatr 16:225-232, 1977 Suwa S: Low birth weight dwarfism. Jpn J Pediatr 17:878890, 1964 Tympner KD, Eichin F, Fendel H: Cockayne’s syndrome. 2 Kinderheilkd 104:298-307, 1968 Ueno T, Hatsumo K, Terao K, et al: Case report of Cockayne-Neill’s syndrome and clinical observation. Acta Pediatr Jpn 74:415-422, 1970 Uesugi M, Nakagawa 0, Uesugi T: A case regarded as Cockayne’s syndrome. J Clin Ophthalmol (Tokyo) 4:17771785, 1960
Annals of Neurology
Vol 6 No 4
October 1979
60. Uferman K, Heege-Dohr R, Kosenow W: Augenbeteilungen beim Cockayne-Syndrom. Klin Monatsbl Augenheilkd 162: 655-658, 1973 61. Upjohn C: Familial dwarfism associated with microcephaly, mental retardation and anemia. Proc SOCMed 48:334-335, 1955 62. Urich H: Malformations of the nervous system, perinatal damage and related conditions in early life, in Blackwood W, Corsellis JAN (eds): Greenfield’s Neuropathology. Third edition. London, Arnold, 1976, pp 388-390 63. Wilkins L The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence. Third edition. Springfield, IL, Thomas, 1965, pp 168, 192 64. Windmiller J, Whalley PJ, Fink CW: Cockayne syndrome with chromosomal analysis. Am J Dis Child 105:204-208, 1963
