ri

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 unevent-
ful; 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)

268 CRI DU CHAT SYNDROME

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

K 4—5

; X
n 6 12

16 17-18 V 19-20

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.
 G. B. SOLITARE 269

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 dispropor-
tionately 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
270 CRI DU CHAT SYNDROME

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 other-
wise 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
 G. B. SOLITARE 271

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 neuro-
fibrillary 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
272 CRI DU CHAT SYNDROME

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).
 G. B. SOLITARE 273

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.
274 CRI DU CHAT SYN

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
 0, B. SOLITARE 275

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 B-
group 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.
276 CRI DU CHAT SYNDROME

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 transloca-
tion 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 granu-
loniata 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.

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 G. B. SOLITARE 277

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