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267 THE CRI DU CHAT SYNDROME: NEUROPATHOLOGIC OBSERVATIONS* G. B. SOLITARE Department of Pathology, Yale University School of Medicine New Haven, Connecticut, U.S.A. Developmental retardation both pliysical and mental, a characteristic cat-like cry, microcephaly, epicanthic folds, and hypertelorism, are the major clinical features comprising the "cri du chat" syndrome (Taylor, 1967), which has been associated with a partial deletion of the short arms of one of the B-group (4-5) chromosomes. Some cases may also apparently be associated with an enlargement of the long arms cf one of the B-group {4-5) chromosomes (Atkins and Feingold, 1967) and with a chromosomal mocaicism (Turner, et al., 1966). Detailed post-mortem studies of individuals with this disorder are lacking. The only reported autopsied case (Lejeune, et al., 1964a) to date has been that of a 23 month old girl and the only comment referable to the nervous system was that the child's left cerebellar hemisphere was small. The findings reported here are those of a 19 year old female who displayed the major clinical features of this syndrome and who showed a partial deletion of the short arms of a No. 5 chromosome. CASE REPORT The patient, a girl, was a first child, born in March, 1948 after an unremarkable, full-term, spontaneous delivery, although labour was prolonged. The entire pregnancy had been uneventful; however the mother recalled that during the last trimester she had held an animal which was x-rayed. The father, a physician, and the mother, a nurse, were both 27 years of age at the time of the birth and were not consanguineously related. A second child, a normal boy, was born a year later, and a third child, a girl with the same syndrome, was born 3 years after the patient. This girl is presently 16 years of age. The patient's head circumference was measured at 31.5 cm. at birth. She weighed 2,585 grams and measured 45 cm. in length. When she was 3 days old, a nurse described her cry as cat-like. Development was grossly delayed in all spheres. While she first sat at 1 year, she could stand with assistance only at 4 years and walked akitie at about 10 years. Her anterior fontanclle closed at 5 months. She spoke no words and there was little evidence of any significant personality or intellectual development. There was a history of severe breath-holding spells with cyanosis associated with occasional seizures characterized by tonic-clonic convulsions, for which she was treated with Phenobarbital and Dilantin; however, since the age of 4 years, none of these episodes had been observed. Croup was reported several times and in 1959 she had influenza. In 1963 the patient had an hysterectomy and bilateral salpingo-oopherectomy. She was admitted to the Southbury Training School in August, 1964, at which time she was described as being very, severely retarded. Head circumference was 46 cm. There were hypertelorism and bilateral epicanthal folds. Her forehead was low. The heart, lungs, •Supported, in part, by USPHS research grant No. NB-06882-0I and, in part, by a research grant from the National Association for Retarded Children. (Received June 12th, 1967)

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and abdomen were considered normal. Neurologic examination revealed a generalized, uniform increase in the deep tendon reflexes. While positive Babinski responses were never clearly observed, occasional unsustained ankle clonus could be elicited bilaterally, The patient could see and hear, but because of the severity of her mental retardation, a meaningful sensory examination could not be carried out. Soon after admission studies of her chromosomes showed a partial deletion of the short arms of a No. 5 chromosome (Fig. 1), which was also observed in her sister, and botb were diagnosed as "cri du chat". She had a mental age of 5 months and an IQ of 3 on the basis of her performance on the Catteli Infant Intelligence Scale. Her social age was placed at 13 months on the Vineland Social Maturity Scale with a social quotient of 7. An electroencephalogram in December 1964 was interpreted as being moderately abnormal, but with no specific focal or lateralizing features. Low to medium amplitude 6-8 cycles/sec, slow waves occurred throughout witb superimposed very low voltage fast activity, averaging 30 cycles/sec. Occasionally, there was higher amplitude generalized slow activity of lj-3 cycles/sec. High amplitude sharp activity and suggestive K complex formation were seen from the midline. Except for a short period of fever associated with a cellulitis of the lower lip, there were no serious illnesses while at the Southbury Training School. She ate well, had no seizures, and cyanotic episodes were not noted. One morning, while being prepared for breakfast, the patient had a sudden cyanotic spell, developed a respiratory arrest and died at age 18 11/12. There had been no fever or evidence of any infection prior to her sudden death. Post-mortem examination was begun U hours after death. The patient measured 128 cm. in length and weighed an estimated 60 lbs. Her forehead measured 3 cm. from eyebrows to hairline of the scalp, and head circumference was 46 cm. in greatest dimension. Interpupillary

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21-22 Fijf. 1. Karyotype analysis from peripheral blood culture showing a partial (approximately 1/2) deletion of short arms of a No. 5 chromosome.

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Fie 2 A typical, non-caseating granuloma as seen in the myocardium with distinct giant cells of the Langhans type. Hematoxylin and i-osiii. (Original magnification X 125).

distance was 7.0 cm. There were bilateral cpicanthal folds. The mouth was not disproportionately small and her teeth were normally arranged and intact except for several carious molars. The tongue appeared normal. Both breasts were immature; however, both axillary and pubic hair were present. A 14 cm. well-healed scar was present over the lower abdomen in the midline. Cyanosis of the fingernail beds wa.s pronounced. Her back was symmetrical. No malformations were noted among the thoracic and abdominal viscera. There was massive, bilateral, haemorrhagic pulmonary edema with petechiae over the pleural surfaces of botb lungs. Diplococcus pneumoniae was cultured on direct smear from tbe lungs, but small foci of acute pneumonitis were relatively inconspicuous. There was evidence of chronic bronchitis and the pulmonary arteries showed moderate intimal thickening. The most striking finding was the presence of numerous, non-caseating granulomata scattered throughout the lungs, but generally in close proximity to the bronchial tree. Similar granulomata were found in the myocardium, where a slight interstitial fibrosis was noted, but were most numerous in the liver, where they were scattered without any recognizable pattern or distribution. A typical granuloma (Fig. 2) was characterized by the presence of lymphocytes, rare plasma cells, mononuclear cells, and giant cells of the Langhans type. Occasional amorphous or granular debris was seen in the giant cells. An occasional granuloma was found adjacent to blood vessels, but tbere was no evidence of any arteritis or phlebitis. Special stains for fungi and acid-fast organisms were unrevealing. Examination under polarized light was also unrevealmg. No similar lesions were encountered in other organs and, in particular, no granulomata were seen in the spleen, lymph nodes, gastrointestinal tract, skeletal muscle, or brain. Tbe thymus

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Fig. 3. Coronal section of ilie rcrebriim tlirough the basal ganglia and temporal poles. The ventricular system is slightly dilated. (Ruler measures 1 cm. in lenglh). Original size. weighed 32 grams, but was intact. The thyroid gland and adrenal glands were small, but otherwise unremarkable. There were no lesions in the pituitary gland. Her kidneys were small, but no lesions were detected. The aorta and its major branches were free of any significant arteriosclernsis. The skull was uniformly small. The brain weighed 750 grams immediately upon removal and it too appeared to be uniformly small. No blood was seen in the subdural or subarathiintd spaces and the leptomeniiiges were thin and delicate. The blood vessels at the base of the brain were normal in their configuration and distribution. The anterior, middle, and posterior fossae bore their usual relationships, but they too appeared diminished in size. The only normal-sized structure was the sella turcica in which an intact pituitary gland sat. The cervical portion of the spinal cord was removed and appeared normal, but small. After fixation in 10 per cent formalin for two weeks the brain was sectioned in a coronal plane at approximately 6 mm. intervals. Randnni samples of brain tissue had been removed at the time of autopsy and were fixed in 4 per cent gluteraldehyde. There was no obvious cortical atrophy. There was a slight degree of dilatation of the ventricular system, particularly in the rostral portions of the lateral ventricles. The corpus callosum measured 2.5 mm. in greatest thickness. No focal lesions were seen in the cortex, white matter, basal ganglia, thalamus, or hypotbalamus (Figs. 3 and 4). The mammillary bodies appeared to be smaller than usual, but were not discoloured. The substantia nigra bilaterally was poorly pigmented, although the locus caeruleus, in contrast, appeared to be well-pigmented. The cerebral peduncles

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Fig. 4. Coronal section of the cerebrum through the thalamus at the level of the mammillary bodies and third ventricle. (Ruler measures 1 cm. in length). X 1. and pyramidal tracts were well-formed and intact. No focal lesions were seen in the mid-brain, pons, medulla, and cervical spinal cord. The cranial nerves all appeared normal. The cerebellar cortex and roof nuclei were intact and no focal lesions were seen in the cerebellar hemispheres and vermis (Fig. 5). Blocks of tissue were removed from the following regions to be embedded in paraffin and sectioned : frontal cortex, parietal cortex, temporal cortex including the Ammon's horn configuration, occipital cortex, basal ganglia, thalamus, hypothalamus including the mammillary bodies, midbrain including the substantia nigra and cerebral peduncles, rostral, mid, and lower pons, rostral, mid, and lower medulla, cervical spinal cord including upper and lower levels as well as cervical enlargement, both cerebellar hemispheres, including the dentate nuclei, and vermi.s. Al! sections were stained with haematoxylin and eosin, Nissl (thinnin), Weil (myelin), Bodian (axons) and Holzer (gHal processes) stains. In addition, selected frozen sections were cut from fixed tissue and stained for myelin (Schroeder) and for senile plaques and neurofibrillary changes (von Braunmiihl). No distinct microscopic lesions were detected. There was no evidence of any infection and no vascular lesions were found. The meninges were not thickened and there were no cellular infiltrates. No abnormalities were seen in the cerebral cortex (Fig. 6). The cytoarchitecture showed no unusual features. The stratification of the neurones was normal and the ganglion cells were fully developed and of normal size. No pigmentary changes or abnormal lipid storage were detected. There were no senile plaques or neurones showing neurofibrillary changes. There was no evidence of any loss of neurones from the Ammon's horn configuration or from

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Fig. 5. Coronal section of the cerebellum through tlie vcrniis and both hemispheres showing the dentate nuclei. (Ruier measures 1 cm. in length). (X 1.3).

Fig.

6. Cerebral cortex, frontal, showing normal cytoarchitecture. Haematoxylin and eosin. (Original magnification X 35).

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Fig. 7. Cerebellar roricx with intact Purkiiijc cell layer and internal granular layer. I-Iaeniatoxylin and eosin. (Original magnification X 35). any other nuclear mass. The astrocytes, oligodendroglia, and microglia appeared in their usual proportions. There was no evidence of demyelinatinn anywhere and no gliosis was demonstrable. The basal ganglia, thalamus, and hypothalamus were without le.sion.s. Approximately one-third of the neurones of the substantia nigra were not pignieiited. 7he remaining neurones contained only a slight to moderate amount of melanin pigment. There was no evidence of loss of pigment in those neurones without pigment; rather it appeared that none had formed. The cranial nerve nuclei, pontine nuclei, inferior olivary nuclei, cerebral peduncles, and pyramidal tracts were without any significant microscopic abnormality. The ependymal lining of the entire ventricular system was intact. There were no discrete lesions in the cervical spinal cord. In the cerebellum, the Purkinje cell layer and internal granular layer were intact (Fig. 7) in both hemispheres and in the vermis. No lesions were found among the neurones of the dentate nuclei. DISCUSSION The overall impression conveyed by the gross and microscopic findings in regard to the nervou.s system is that of a mature, fully-developed brain of uniformly small size. It seems as though we are dealing with a miniature brain complete in all details except for size. The reduction in size, however, does not extend to its parts, as the individual neurones, astrocytes, oligodendroglia, and microglia are of normal size. Since there is no evidence of a loss of niyelin, it is difficult to account for the small size except to imagine that the raw materials, in this case the blastema, was in some way deficient, and that the blastema which was present migrated and differentiated normally.

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The occurrence of a miniature brain with little or no recognizable pathologic changes in men tally-retarded individuals has been commented upon by Malamud (1964), who refers to such brains hy the term microcephalia vera. Since microcephaly means small head, the term as used by Malamud is confusing—especially since Greenfield and Wolfsohn (193!)) had earlier used this term, microcephalia vera, in its correct context of small or imperfectly developed head. Ostertag (1956), on the other hand, refers to Schob (1930), who in turn cites Giacomini (1890) as the source for the term micrencephaly vera, which refers to a small brain, the smallness of which has presumably resulted from a purely developmental process without recognizable pathologic change. This form of micrencephaly is differentiated by Giacomini from micrencepbaly spuria, a malformation evoked only through pathologic processes (not defined) and micrencepbaly cotiibinata, in wbicb features of both the vera and spuria forms are seen. Ostertag (1956) defines two types of micrencephaly, the barmonious and tbe dysbarmonious. The former is cbaracterized by a uniform diminution of all parts of the brain in contrast to tbe latter or dysbarmonious type in wbich different parts may be affected by different processes. Scbob (1930) also considers two basic types of micrencepbaly, tbe true or pure form witbout recognizable pathologic changes and tbe impure or pseudomicrencephaly, resulting as a consequence of recognizable pathologic processes. More simply, micrenceplialy may be referred to as primary or secondary, tbe primary form being characterized as a miniaturization of tbe brain in all its parts without detectable anatomic lesions or defects except for tbe small size, and a secondary form in wbicb tbe pathogenesis may be understood or implied in terms of vascular or circulatory disturbances, infections, toxins, or other noxious stimuli sucb as radiation. Tbe present case may tben be considered as an example of a primary micrencepbaly or micrencepbalia vera. Of course, tbe act of providing a name or designation does not in itself enhance our understanding of the basic mecbanisms involved, and, furtber, does not clarify the relationship between the smallness of the brain, tbe profound mental retardation, and tbe underlying cbromosomal abnormality. Tbe recent electron miscroscopic observations I)y Gonatas (1967) of altered synapses as tbe only anatomic substrate of disease in tbe brain biopsies of two, severely, mentally-retarded cbildren suggest tbat electron microscopy may provide a new dimension^jotb figuratively and literally—wbicb will permit renewed anatomical study of the mentally-retarded, an effort wbicb has been shunted to tbe background in recent decades. Owing to tbe severe degree of mental retardation, detailed neurological examinations bave been difficult to perform, especially a sens(jry examination. Some patients bave been described as hypotonic (Punnett, et al., 1964) with decreased deep tendon reflexes, others as bypertonic (Hustinx and Wijffels, 1965). There bas been no observation of pyramidal tract disease, although one patient was described

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as having a spastic, shuffling gait (Bergman, et at., 1965). The gait has also been described as waddling (Berg, et al., 1965). The majority of cases reported to date have been infants; however, older children and adolescents have shown a profound delay in the usual developmental milestones. Most have not walked unaided before 10 years and meaningful speech is practically nonexistent. Both abnormal (de Almeida, ct al, 1964; Dumars, et al., 1964; Hustinx and Wijffels, 1965; Milunsky and Chithani, 1966; Punnett, ct al., 1964) and normal (Berg, et al., 1965; Dyggve and Mikkelsen, 1965; Lejeune, t( al, 1964b; Ricci, et al., 1965) electroencephalograms have been reported. No specific or characteristic abnormalities have been described. In the present case, an electroencephalogram at age 16 8/12 years was interpreted as moderately abnormal, but with no specific, focal, or lateralizing features. In the case of Wolf, et al. (1965) in whom a partial deletion of tbe short arm of a B-group chromosome was observed, but without the characteristic findings of the cri du chat syndrome, a non-specifically, abnormal electroencephalogram was also recorded. The one adult (Berg, et al., 1965) to be observed, a male, was said to have normal external genitalia, while the three adolescent females reported (Bergman, et al., 1965; Hijmans and Shearin, 1965; and the present case), were under-developed with no significant breast enlargement, although one girl .was thought to have an enlarged clitoris (Bergman, ct al., 1965). Pubic hair was observed in two of the girls. None of the adolescent females was noted to have menstruated. In the present case, menstruation was not recorded prior to oophorectomy and liysterectomy at age 15 years. The demonstration of a distinct chromosomal aberration in association with a distinct clinical syndrome implies a direct relationship between the two. Clinical and pathological observations aid in delineating the defects, which are presumably a manifestation of this relationship; however, tbe manner in wbicb the abnormal chromosomes effect these changes or defects remains for the present unanswered. Furthermore, the mechanism by which tbe abnormal chromosomes arise is unknown. While the majority of cases (Taylor, 1967) of the cri du chat syndrome have been reported in association with a partial deletion of the short arms of one of the B-group (Denver) or 4-5 chromosomes, and, in particular, the No. 5 chromosome, other cases bave been reported in association with an enlargement of the long arms of one of the B-group chromosomes (Atkins and Feingold, 1967), and a single case has been reported with an associated chromosomal mosaicism (Turner, et al., 1966). In addition, there is a single report (Wolf, et al., 1965) of a deletion of the short arms of a B-group chromosome—in this case No. 4—without the cri du chat syndrome. Berg, et al. (1965) have recorded a partial deletion of the short arms of a Bgroup chromosome in a severely retarded 33 year old male, whose cry supposedly never was described as being cat-like. These authors believe that the variations observed in the syndrome may be a reflection of different degrees of shortening of the involved chromosome. Furthermore, tbey have expressed the opinion that some of the clinical features probably change with increasing age.

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The abnormal chroiiiosoiiie in the case with an enlargement of the long arms (Atkins and Feingold, 1967) was considered to have arisen in several possible ways, including a duplication of a portion of the long arm, breakage with insertion of a chromosomal fragment from another broken chromosome, or a reciprocal translocation following breakage in the long arm and in another chromosotne. In the case associated with chroinosoiiial mosaicism. Turner, et al. (1966) considered the abnormality to reflect either a duplication or translocation B-group chromosome with a partially deleted B-group chroinosc^me and an acentric fragment. An aetiologic agent could not be demonstrated for tlie non-caseating granuloniata found in the myocardium, lungs, and liver. On the basis of histoJogic appearance alone, the lesions are compatihie with those encountered in sarcoidosis. The lack of any significant clinical hi,sU)ry in this regard renders such a diagnosis merely tenable and certainly not definitive. The possible role of Dilantin as an agent in the production of such lesions cannot be excluded (Gori and Pellegrini, 1963), although the patient received this drug for only a short period of time many years before her death. SUMMARY The case report and autopsy finding.s in a 19 year old female with the typical features of the cri du chat syndrome, in whom a partial deletion of the short arms of a No. 5 chromosome was demonstrated, are presented with particular emphasis upon the neuropathologic observations. The findings of a uniformly small brain with no demonstrable lesions is considered as an example of a primary micrencephaly or micrencephatia vera. A discussion of the neuropatliologic findings and of some of the neurologic aspects of the syndrome is presented. ADDENDUM The patient described herein has also been the subject of another study in which she was referred to as Case I in a series of five cases. De Capoa, A., Warburton, D., Breg, W. R., Miller, D. A., and Miller, O. J. (1967) Translocation heterozygosis : A cause of five cases of the Cri du Chat syndrome and two cases with a duplication of chromosome number five in three families. Amer. J. Hum. Genet, 19, 586. ACKNOWLEDGEMENT I wish to thank Dr. W. Roy Breg of the Southbury Training School for the chromosomal analysis and illustration of the patient's karyotype. REFERENCES DE ALMEIDA, J. C. C ,

GONZAGA, M., VIF.IRA, H., BARBOSA, L. T . , ABREU, M . DO G.

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BARCINSKI, M . A. (1964) Partial deletion of the short arm of chromosome 5. "Le cri du chat." Another example. Arch. bras. Endocr., 13, 183. ATKINS, L . and FEINGOLD, M . (1967) Enlarged B-group chromosome (4-5). Association with the cri du chat syndrome. Amer. J. Dis. Child., 113, 277.

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BERG, J. M., DELHANTY, J. D. A., FAUNCH, J. A. and RIDLER, M . A. C. (1965) Partial deletion

of short arm of a chromosome of the 4-5 group (Denver) in an adult male. / . menl. Defic. Res.,9,2\9. BERGMAN, S., FLODSTROM, I. and ANSEHN, S. (1965) "Cri du chat". Lancet, 1, 768.

DuMARS, K. W., Jr., GASKILL, C . and KITZMILLER, N . (1964) Le cri du chat (crying cat) syndrome. Amer. J. Dis. Child., 108, 533. DYGGVE, H . V. and MIKKELSEN, M . (1965) Partial deletion of the short arms of a chromosome of the 4-5 group (Denver). Arch. Dis. Childh., 40, 82. GiACOMiNi, C. (1890) I cervelli dei microcefali. G. Accad. Med. Torino, 33, 343. GoNATAs, N. K. (1967) Synaptic abnormalities in neuropsychiatric diseases. Proc. Amer. Assoc. Path. Bacter.. 64, 13a. GoRi, A. and PELLEGRINI, G. F . (1963) Analisi sperimentale di quadri patologici alia terapia con 3 metiI-5, 5 fenil-etil idantoina. Riv. Anat. pat., 23, 635. GREENFIELD, J. G. and WOLFSOHN, J. M. (1935) Microcephalia vera: a study of two brains illustrating the agyric form and the complex microgyric form. Arch. Neurol. Psychiat. {Chic). 33, 1296. HijMANS, J. C. and SHEARIN, D . B. (1965) Partial deletion of shnrt arms of chromosome No. 5. Report of a case in a fraternal twin. Amer. J. Dis. Child., 109, 85. HusTiNx, T, W. J. and WIJFFELS, J. C. H. M. (1965) "Gri du chat" syndrome. Lancet, 2, 135. LEJEUNE, J . , GAUTIER, M . , LAFOURCADE, J., BEROER, R . and TURPIN, R . (1964a) Deletion

partieile du bras court du chromosome 5 cinquiinne cas de syndrome du cri du chat. .^nn. Genet., 7, 7. LEJEUNE, J., LAFOURCADE, J., DE GROUCHY, J., BERGER, R . , GAUTIER, M . , SALMON, G . and

TURPIN, R . (1964b) Deletion partieile du bras court du chromosome 5. Individualisation d'un nouvel etat morbide. Sem. Hop. Paris, 40, 1069. MALAMtJD, N. (1964) Neuropathology, in Mental Retardation, edited by H, A. Stevens and R. Heber. Ghicago and London : Univ. Chicago Press, p. 429. MiLUNSKY, A. and GHITHAM, R. G. (1966) The cri du chat syndrome. / . ment. Defic. Res., 10, 153. OsTERTAO, B. (1956) Die Einzelformen der Verbildungen (einschliesslich Syringomyelie), in Handbuch der Speziellen Pathologischen Anatomie und Histologie. edited by F. Henke and O. Lubarsch. Vol. XIII, PI. 4. Erkrankungen des Zentralen Nervensystems IV. edited by W. Scholz. Berlin : Springer, p. 363. PuNNF.TT, H. H., CARPENTER, G. G . and DIGEORGE, A. M. (1964) Deletion of short arm of chromosome 5. Lancet, 2, 588. Riccr, N., VENTIMIGLIA, B., DALLAPICCOLA, B., FRANCESCHINI, F . and PRETO, G . (1965) "Gri

du chat" syndrome. Lancet, 1, 1278. ScHOB, F. (1930) Pathologische Anatomie der Idiotie, in Handbuch der Ceisteskrankheiten. edited by O. Bumke. Vol. XI. Pt. 7. Die Anatomie der Psychosen. edited by W. Spielmeyer. Berlin: Springer, p. 779. TAYLOR, A. I. (1967) Patau's, Edwards' and cri du chat syndromes: a tabulated summary of current findings. Develop. Med. Child Neurol., 9, 78. TURNER, J. H., BASS, L . N . and KAPLAN, S. (1966) Ghromosome mosaicism in a child with features characteristic of the "cat cry" syndrome. / . med. Genet., 3, 66. WOLF, U . , PORSCH, R . , BAITSCH, H . and REINWEIN, H . (1965) Deletion on short arms of a

B-chromosome without "cri du chat" syndrome. Lancet, 1, 769.