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Clinical heterogeneity in 80 home-reared childrenwith cri du chat syndrome
I
Clinical heterogeneity in 80 home-reared children with cri du chat syndrome A population o f 80 home-reared children with cri du chat syndrome was investigated to document the clinical heterogeneity o f the syndrome and to analyze the factors influencing the severity o f the phenotypic characteristics. When individuals with isolated deletions were compared with those possessing unbalanced translocations involving other chromosomes in addition to number 5, the latter group had a greater incidence o f physical anomalies, more frequent hospitalizations, and a higher mortality. Chronic complaints in both groups included upper respiratory tract infection, otitis media, and a previously unrecognized association with gastrointestinal tract anomalies. In children with terminal deletions, there was a significant negative correlation between the size of the deletion and the individual's intelligence quotient. In addition, patients with larger deletions had more severe growth retardation, particularly with respect to the degree o f microcephaty_ The gradual progression with age of the characteristic facial features remained consistent regardless o f differing racial backgrounds and the size o f the deletion. Our findings delineate the variation in the clinical and karyotypic features o f this syndrome. (J PeolAre 102:528, 1983)
Louise E. Wilkins, Ph.D., Judith A. Brown, Ph.D., Walter E. Nance, M.D., Ph.D., and Barry Wolf, M.D., Ph.D. Richmond,
Va.
CRI DLI CHAT S Y N D R O M E w a s first d e s c r i b e d in 1963 in
three females with dysmorphic facies, mental retardation, and a striking catlike cry during infancy. ~ In all three patients a deletion of the short arm of a B group chromosome was demonstrated and identified subsequently by autoradiography as number 5. 2 Since that time, the incidence of 5p- has been estimated to be approximately one in 50,000 live births, and the phenotype and chromosome findings have been the subject of numerous case reports and institutional surveys. 35 However, most reviews have either been limited in scope or cross-sectional in nature, so the progression of the characteristic facial features with age and the full range and causes of individual clinical
From the Departments o f Human Genetics and Pediatrics, Medical College o f Virginia. Paper 160 from the Department o f Human Genetics o f the Medical College o f Virginia. Supported in part by National Institutes o f Health Predoctoral Training Grant GM 07492 (L,E, W.). Reprint requests: Barry Wolf M.D,, Ph.D. Department o f Human Genetics, Medical College of Virginia, P. O, Box 33, M C V Station, Richmond, VA 23298.
528
TheJournalofPEDIATRICS
variation have not been completely evaluated. The ascertainment of a large population of 80 home-reared children with cri du chat syndrome has permitted a comprehensive compilation of questionnaire and medical record data, which has been validated in almost half of the cases (37 of 80) by personal evaluation and high-resolution chromosome analysis.6 The resulting data base has permitted a further definition of the phenotypic features from infancy to adolescence, documentation of the spectrum of medical complications, and recognition of the relationship between the karyotypic and clinical variation in the syndrome.
SUBJECTS A N D METHODS Eighty individuals with cri du chat syndrome were located through clinic, physician, and parental referrals. Questionnaire responses, medical records, and photographs were collected on the total population, and the resulting data were validated by personal evaluation of 37 children. This subpopulation of affected individuals evaluated personally was representative of the entire population with respect to sex ratio, age, mental development, and distribution of chromosome aberrations. 6 The total study population included 53 females, who ranged in age from 4
V~J/ume 102 /Vumber 4
Clinical heterogeneity in cri du chat syndrome
6mth
9mth
2 yr
4 yr
8 yr
lOyr
52 9
Fig 1. Sequential photographs of a boy with cri du chat syndrome, illustrating phenotypic transition from infancy to late childhood.
months to 27 years (mean age 7 years), and 27 males, who ranged in age from 6 months to 15 years (mean age 6.8 years). Seventy-five children resided with their natural parents, and five were raised in the homes of foster or adoptive parents. Four individuals were placed subsequently in sheltered homes or institutions during their teenage years or in adulthood. In these cases only data on the period prior to placement were included in the analyses. All diagnoses had been confirmed karyotypically by other cytogenetic laboratories. In the 37 individuals personally evaluated, high-resolution prometaphase preparations were examined to localize the breakpoint; the specific karyotype results are described in detail elsewhere. 6 Social quotients were determined for all children, based on parental responses to questions from a modified Vineland Social Maturity Scale Test. In addition, for the 37 children personally examined, intelligence quotients were obtained using a Slosson test administered by the same tester in a standardized sequence. The resulting social maturity estimates showed a significant correlation with developmental scores obtained previously from the medical records (r = 0.65, P < 0.01) and with the intelligence quotient scores obtained for those individuals personally examined (r = 0.83, P < 0 . 0 1 ) . Statistical analyses of the data included both parametric and nonparametric methods. The population of children was classified cytogenetically
into three groups: (1) isolated deletion (n = 48)--parental blood karyotypes did not reveal a demonstrable translocation, and the proband possessed a deletion involving only the short arm of chromosome 5; (2) unbalanced translocation (n = 15)--the proband possessed an unbalanced rearrangement between 5p and another chromosome as a result of either segregation in a parental translocation carrier or de novo rearrangement; (3) unclassified (n = 17)--parental karyotypes were not available. RESULTS Cytogenetie findings. Forty-eight individuals possessed an isolated deletion (group 1). Of these, 27 were examined by high-resolution chromosome analysis, revealing losses of chromosome material ranging in size from 16% to 81% of the short arm of chromosome 5. Two of the individuals reported by other laboratories as having terminal deletions on metaphase preparations were found to possess interstitial deletions when banded prometaphase spreads were examined. The 15 persons in group 2 (eight examined by us) were found to represent structural rearrangements between chromosome 5 and either chromosome 2, 4, 7, 14, 15 (two patients), 19, or 21 (three). In five of those in group 2, the other chromosome involved in the structural rearrangement was not identified with certainty by other laboratories.
530
Wilkins et al.
The Journal of Pediatrics April 1983
i84
84
iii
6 mth
5 yr
6 yr
7 yr
8 yr
9 yr
.......
Fig. 2. Sequential photographs of a girl with cri du chat syndrome, illustrating phenotypic transition from infancy to late childhood.
Phenotype. A comparison of photographs of 40 different children less than one year of age revealed that microcephaly, epicanthal folds, and a flat nasal bridge contributed to a characteristic appearance of hypertelorism. Ocular measurements revealed telecanthus with true hypertelorism (interpupillary distance greater than ninety-fifth percentile) in only four of the 37 personally examined individuals. The face lost much of its infantile fullness during childhood, although the epicanthal folds and oblique palpebral fissures remained. Apparent facial laxity produced a dropped-jaw, open-mouth expression in most children. During late childhood and adolescence, the greater growth of facial structures relative to that of the cranial vault created an impression of crowding and coarseness of the facial features. Prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, and severe malocclusion characterized the adolescent facies. Examination of sequential photographs of individual patients permitted a clear recognition of the stages of transition from the infant to adolescent phenotype (Figs. 1 and 2). The facial features remained subjectively similar despite differences in racial background or deletion size. During the newborn period, the child's cry was recalled as being abnormal by all sets of parents except one. The cry was usually described as weak, high-pitched mewing. The "cat cry" bad been lost by about one third of the
children by 2 years of age. This did not appear to be significantly influenced by the child's sex or chromosome abnormality. Children who had lost the cry did not differ significantly from those who had retained the "cat cry" with respect to level of mental development or verbal abilities. Over half of the children were diagnosed as having cri du chat syndrome before 6 months of age. The presence of subtle dysmorphia in combination with neonatal complications and a high-pitched cry were the features most often cited for initiating a diagnostic evaluation. In at least 10 children the combination of the cry, phenotype, and newborn history were sufficient to make a presumptive clinical diagnosis of cri du chat syndrome prior to chromosome analysis. In four children, the phenotype and characteristic cry prompted repeating of the chromosome analyses despite previous reports of normal karyotypes. Growth patterns. At birth, weights below the tenth percentile in 27% and microcephaly (>2 standard deviations below the mean) in 43% of the children with isolated deletions provided evidence for prenatal growth retardation. Birth length was not a useful indicator of prenatal growth retardation, because only 19% of the population was below the tenth percentile. Physical growth was characterized by decreased height, poor weight gain, and significant microcephaly (Fig. 3). The average 4-year-old
Votume 102 Number 4
Clinical heterogeneity in cri du chat syndrome
Table. Major malformations in cri du chat syndrome
Cardiac abnormalities Strabismus Clubfoot Inguinal hernia Cleft lip/palate Dislocated hips Intestinal malrotation or megacolon *P
% Deletion (n = 65)
% Unbalanced translocation (n = S5)
29 44 21 17 8 5 7
55* 50 21 36 14" 29* 27*
53 1
140 LENGTH
I ZO
I00
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9
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9 9
~
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......
60 !
j
9
9
9I
!
!
|
~
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40 J
< 0.005.
30251 WEIGHT
child with cri du chat syndrome was comparable in size to a slender 2-year-old child and had a head circumference equivalent to that of a normal 6-month-old infant; By the age of 10 years, the average child with the syndrome had attained the height of a normal 7-year-old, with head size comparable to that of a normal 1-year-old child. Among children with isolated deletions, there was a nonsignificant correlation between head circumference and deletion size (r = 0.20, P = 0.17). Medical problems. Ninety-two percent of the patients experienced medical complications at the time of delivery or during the newborn period. Neonatal complications, such as poor sucking, need for incubator care, respiratory distress, and jaundice, occurred with approximately equal frequency among individuals with isolated deletion or with unbalanced translocation. The developmental attainment of children with isolated deletions who experienced apnea, jaundice, or heart abnormalities at birth was not significantly lower than that of the rest of the population, as measured by social quotients or age at which they began to walk? Forty-seven percent of those children with isolated deletions and 71% of those with unbalanced translocations required at least one hospitalization for an acute medical condition or for nonelective surgery. Pneumonia and dehydration frequently followed upper respiratory tract and viral infections; 21% of the patients with isolated deletion and 50% of those with unbalanced translocation required at least one hospitalization to stabilize or treat such an illness. Cardiac abnormalities requiring frequent medical intervention during infancy and childhood were present in 29% of the patients with isolated deletion and 55% of those with unbalanced translocation (P < 0.005) (Table). Ten of the 11 cardiac septal defects were found in children with isolated deletions (seven with ventricular septal defects, and three with atrial septal defects), individuals with unbalanced translocations possessed rarer, more complex
20-
tO-
5O2
I
3
4
5
6
55/"3 HEAD CIRCUMFERENCE
d /
50 /
..... ......
................
45H
4o 35
.
.
.
o .
.
t/oi. /
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~ 9
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A G E IN Y E A R S
Fig. 3. Growth parameters in 65 children with cri du chat syndrome caused by isolated deletions (e) and unbalanced translocations (o). Shaded areas represent normal growth development range (third to ninety-seventhpercentiles).
anomalies, including tetralogy of Fallot and endocardial cushion defect. Patent ductus arteriosus was present in four persons with translocations and four with isolated deletions. Of these eight individuals, four required surgical ligation. Seven percent of patients with isolated deletion and 27% of those with unbalanced translocation had gastrointestinal tract anomalies, including four with intestinal malrotation,
532
Wilkins et al.
three with Hirschsprung disease, and two less specific diagnoses of adynamic ileus and intestinal tract obstruction. Among children with isolated deletions, the only deaths after 6 months of age were related to gastrointestinal tract malformations: a 3~A-year-old girl with colitis secondary to megacolon, and a 9tA-year-old boy after colostomy for Hirschsprung disease. Medical problems involving minor malformations that were amenable to surgical correction were present in 45% and 78% of patients with deletion and translocation, respectively (Table). The presence or absence of specific physical malformations was not influenced by the size of the deleted segment in the 37 children studied using prometaphase banding. Thirty-three percent of the children with unbalanced translocations required monthly outpatient medical visits, whereas only 6% of those with isolated deletions required such care. Moreover, one third of the children with isolated deletions required only routine pediatric care. Chronic medical problems requiring attention throughout childhood included upper respiratory tract infections, otitis media, severe constipation, and hyperactivity. Frequent colds and bronchitis were cited by 30% of the parents as the primary reason for doctor visits. Otitis media was a persistent problem in 28% of the children, and necessitated ear tube placement in six children. Constipation represented a chronic problem in 56% of the cases. The mortality among persons with unbalanced translocations was almost six times that of individuals with isolated deletions. Four of the fifteen patients with translocation had died at 5 months, 7 years, 15 years, and 20 years of age, respectively, whereas only three of the remaining children studied were deceased. Development and behavior. The size of the deletion in those individuals with terminal aberrations showed a significant negative correlation with IQ ( r = - 0 . 3 3 , P = 0.02). Hyperactivity and self-stimulatory behavior, which often began as disruptive sleep patterns during infancy, were major problems in both the isolated deletion and translocation subgroups. Among the children with IQ below 40, self-stimulatory behaviors, such as head banging, hand waving, and hand sucking, were common. These children often displayed mannerisms of withdrawal, roving eye movements, and apparently decreased awareness of their surroundings. In the children with IQ above 40, hyperactivity was manifested by restless affect and short attention span. Intensive behavior modification was the most effective method reported for controlling hyperactivity. 7 DISCUSSION Comprehensive data were collected from 80 homereared children with cri du chat syndrome and revealed
The Journal of Pediatrics April 1983
considerable clinical and cytogenetic heterogeneity among affected persons. Although facial features remained con-. sistent despite racial differences and variation in the size of the deletion, the extent of the associated physical malformations and the level of mental development reflected the cytogenetic diversity of this syndrome. The present sample of 80 individuals included patients with simple terminal deletions, interstitial deletions, and a wide variety of structural rearrangements. In a subpopulation of 37 patients in whom prometaphase banding was performed, the size of the deletion was found to vary over such a wide range that the sample included no fewer than 18 distinct deletions and rearrangements. The break points in these 37 individuals were not distributed uniformly along the short arm, and there was evidence for clustering of the deletions at preferential break sites. The application of molecular techniques such as in situ hybridization to the analysis of these deletions will likely reveal further heterogeneity among cases that appear to have the same break points in prometaphase preparations. Ultimately, it may be possible to show that every independent case of cri du chat syndrome is cytogenetically, or at least genetically, distinct. Although the causal mechanisms that result in translocations and sporadic deletions may be different, no differences in parental age, occupation, or radiation exposure could be documented in our small series of patients. 6 When cri du chat syndrome results from the segregation of a familial translocation, the opportunity arises for simultaneous partial trisomy for the other chromosome involved in the rearrangement. It is not surprising, therefore, that these patients were found to exhibit more severe phenotypes. In our series, those with familial and de novo translocations, as a group, did show a greater need for medical care during infancy and childhood, a greater frequency of complex cardiac malformations, a higher mortality, and lower IQ. No two individuals with unbalanced translocations possessed the same rearrangement, so it was not expected that these individuals would exhibit a uniform phenotype, although they were clearly more severely affected than those with isolated deletions. Severe physical anomalies have been suggested for unbalanced translocations involving 9p, 8 and retrospective analysis of mortality among published cases of 5p- supports a higher mortality in individuals with unbalanced translocations. In view of the extreme degree of cytogenetic heterogeneity, it is remarkable that cri du chat syndrome presents such a uniform and recognizable facial phenotype. Among patients with isolated deletions, measured IQ was the only clinical variable that correlated significantly with the size of the missing chromosome segment. Niebuhr 3 has suggested that the phenotypic homogeneity of patients with cri du chat syndrome may imply the existence of a critical site
V~j/urne 102 Number 4
near the tip of the short a r m (5p15.3), the absence of which leads to the characteristic clinical features of the syndrome. However, our observations are inconsistent with the hypothesis, because one of our patients with an interstitial deletion, in which the 5p15.3 band was preserved, showed typical features of cri du chat syndrome. 6 The facial phenotype remains characteristic despite differences in race and deletion size, and a consistent progression of the features with age is recognizable. The clinical heterogeneity documented in this population of children with cri du chat syndrome reflected an underlying diversity of chromosome aberration type and deletion size. Realistic expectations for an affected child's level of physical and mental development should be based on a thorough investigation of parental karyotypes to identify a translocation. The use of high-resolution prometaphase chromosome analysis and reverse banding is needed if the heterogeneity of this syndrome is to be delineated further. Clinical variability in cri du chat syndrome and the identification of the sources of such variation provide the clinician and family additional information on which to base informed decisions concerning the affected child's care. We thank the following persons and organizations for their assistance in locating patients and making clinic facilities available: The Cri du Chat Parent Club, Dr. J. Aase, Dr P. Bader, Dr. A. Bloom, Dr. M. Bocian, Dr. P. Buchanan, Dr. M. Carlin, Dr. D. Cox, D. Delozier, Dr. R. Desnick, Dr. L. Elsas, Dr. E. Engel, D. Eunpu, Dr. R. Fineman, Dr. S. Finley, Dr. U. Francke, Dr. W. Freeman, Dr. P. Gerald, Dr. J. German, L. Godmilow, Dr. J. Hall,
Clinical heterogeneity in cri du chat syndrome
533
Dr. J. Hamerton, P. Hawley, Dr. J. Hermann, Dr. L. Hsu, Dr. L. lmmken, Dr. L. Jackson, Dr. S. Kahler, C. Kasari, Dr. R. Laxova, Dr. J. Opitz, Dr. P. Pallister, Dr. C. Palmer, H. Perkins, Dr. H. Punnett, Dr. J. Rary, Dr. J. Rotter, Dr. L. Russell, R. Schwartz, Dr. C. Scott, Dr. R. Spathes, Dr. R. Summitt, Dr. K~ Taysi, Dr. 1. Uchida, Dr. D. Valle, Dr. D. Warburton, Dr. D. Weaver, Dr. H. Wyandt, Dr. E. Zackai, Dr. E. Zorn. REFERENCES
1. Lejeune J, Lafourcade J, Berger R, Vialette J, Bowswillwald M, Serginge P, Turpin R: Trios cas de deletion partielle du bras court d'un chromosome 5. CR Acad Sci (Paris) 257:3098, 1963. 2. German J, Lejeune J, Mclntyre MN, deGrouchy J: Chromosomal autoradiography in the cri du chat syndrome. Cytogenetics 3:347, 1964. 3. Niebuhr E: The cri du chat syndrome: Epidemiology, cytogenetics and clinical features. Hum Genet 44:227, 1978. 4. Gordon RR, Cooke P: Facial appearance in cri du chat syndrome. Dev Med Child Neurol 10:69, 1968. 5. Breg WR, Steele MW, Miller O J, Warburton D, de Capoa A: The cri du chat syndrome in adolescents and adults: Clinical findings in 13 older patients with partial deletion of the short arm of chromosome no. 5 (5p-). Pediatrics 77:782, 1970. 6. Wilkins LE: Cri du chat syndrome: Population demographics, prometaphase chromosome analysis and phenotype-karyotype correlations. Ph.D. dissertation, May 198t, Medical CoIIege of Virginia. 7. Wilkins LE, Brown JA, Wolf B: Psychomotor development in 65 home-reared children with cri du chat syndrome. J PEDIATR 97:401, 1980. 8. de Grouchy J, Turleau C: Clinical atlas of human chromosomes. New York, 1977, John Wiley, p 75.
Clinical heterogeneity in 80 home-reared children with cri du chat syndrome A population o f 80 home-reared children with cri du chat syndrome was investigated to document the clinical heterogeneity o f the syndrome and to analyze the factors influencing the severity o f the phenotypic characteristics. When individuals with isolated deletions were compared with those possessing unbalanced translocations involving other chromosomes in addition to number 5, the latter group had a greater incidence o f physical anomalies, more frequent hospitalizations, and a higher mortality. Chronic complaints in both groups included upper respiratory tract infection, otitis media, and a previously unrecognized association with gastrointestinal tract anomalies. In children with terminal deletions, there was a significant negative correlation between the size of the deletion and the individual's intelligence quotient. In addition, patients with larger deletions had more severe growth retardation, particularly with respect to the degree o f microcephaty_ The gradual progression with age of the characteristic facial features remained consistent regardless o f differing racial backgrounds and the size o f the deletion. Our findings delineate the variation in the clinical and karyotypic features o f this syndrome. (J PeolAre 102:528, 1983)
Louise E. Wilkins, Ph.D., Judith A. Brown, Ph.D., Walter E. Nance, M.D., Ph.D., and Barry Wolf, M.D., Ph.D. Richmond,
Va.
CRI DLI CHAT S Y N D R O M E w a s first d e s c r i b e d in 1963 in
three females with dysmorphic facies, mental retardation, and a striking catlike cry during infancy. ~ In all three patients a deletion of the short arm of a B group chromosome was demonstrated and identified subsequently by autoradiography as number 5. 2 Since that time, the incidence of 5p- has been estimated to be approximately one in 50,000 live births, and the phenotype and chromosome findings have been the subject of numerous case reports and institutional surveys. 35 However, most reviews have either been limited in scope or cross-sectional in nature, so the progression of the characteristic facial features with age and the full range and causes of individual clinical
From the Departments o f Human Genetics and Pediatrics, Medical College o f Virginia. Paper 160 from the Department o f Human Genetics o f the Medical College o f Virginia. Supported in part by National Institutes o f Health Predoctoral Training Grant GM 07492 (L,E, W.). Reprint requests: Barry Wolf M.D,, Ph.D. Department o f Human Genetics, Medical College of Virginia, P. O, Box 33, M C V Station, Richmond, VA 23298.
528
TheJournalofPEDIATRICS
variation have not been completely evaluated. The ascertainment of a large population of 80 home-reared children with cri du chat syndrome has permitted a comprehensive compilation of questionnaire and medical record data, which has been validated in almost half of the cases (37 of 80) by personal evaluation and high-resolution chromosome analysis.6 The resulting data base has permitted a further definition of the phenotypic features from infancy to adolescence, documentation of the spectrum of medical complications, and recognition of the relationship between the karyotypic and clinical variation in the syndrome.
SUBJECTS A N D METHODS Eighty individuals with cri du chat syndrome were located through clinic, physician, and parental referrals. Questionnaire responses, medical records, and photographs were collected on the total population, and the resulting data were validated by personal evaluation of 37 children. This subpopulation of affected individuals evaluated personally was representative of the entire population with respect to sex ratio, age, mental development, and distribution of chromosome aberrations. 6 The total study population included 53 females, who ranged in age from 4
V~J/ume 102 /Vumber 4
Clinical heterogeneity in cri du chat syndrome
6mth
9mth
2 yr
4 yr
8 yr
lOyr
52 9
Fig 1. Sequential photographs of a boy with cri du chat syndrome, illustrating phenotypic transition from infancy to late childhood.
months to 27 years (mean age 7 years), and 27 males, who ranged in age from 6 months to 15 years (mean age 6.8 years). Seventy-five children resided with their natural parents, and five were raised in the homes of foster or adoptive parents. Four individuals were placed subsequently in sheltered homes or institutions during their teenage years or in adulthood. In these cases only data on the period prior to placement were included in the analyses. All diagnoses had been confirmed karyotypically by other cytogenetic laboratories. In the 37 individuals personally evaluated, high-resolution prometaphase preparations were examined to localize the breakpoint; the specific karyotype results are described in detail elsewhere. 6 Social quotients were determined for all children, based on parental responses to questions from a modified Vineland Social Maturity Scale Test. In addition, for the 37 children personally examined, intelligence quotients were obtained using a Slosson test administered by the same tester in a standardized sequence. The resulting social maturity estimates showed a significant correlation with developmental scores obtained previously from the medical records (r = 0.65, P < 0.01) and with the intelligence quotient scores obtained for those individuals personally examined (r = 0.83, P < 0 . 0 1 ) . Statistical analyses of the data included both parametric and nonparametric methods. The population of children was classified cytogenetically
into three groups: (1) isolated deletion (n = 48)--parental blood karyotypes did not reveal a demonstrable translocation, and the proband possessed a deletion involving only the short arm of chromosome 5; (2) unbalanced translocation (n = 15)--the proband possessed an unbalanced rearrangement between 5p and another chromosome as a result of either segregation in a parental translocation carrier or de novo rearrangement; (3) unclassified (n = 17)--parental karyotypes were not available. RESULTS Cytogenetie findings. Forty-eight individuals possessed an isolated deletion (group 1). Of these, 27 were examined by high-resolution chromosome analysis, revealing losses of chromosome material ranging in size from 16% to 81% of the short arm of chromosome 5. Two of the individuals reported by other laboratories as having terminal deletions on metaphase preparations were found to possess interstitial deletions when banded prometaphase spreads were examined. The 15 persons in group 2 (eight examined by us) were found to represent structural rearrangements between chromosome 5 and either chromosome 2, 4, 7, 14, 15 (two patients), 19, or 21 (three). In five of those in group 2, the other chromosome involved in the structural rearrangement was not identified with certainty by other laboratories.
530
Wilkins et al.
The Journal of Pediatrics April 1983
i84
84
iii
6 mth
5 yr
6 yr
7 yr
8 yr
9 yr
.......
Fig. 2. Sequential photographs of a girl with cri du chat syndrome, illustrating phenotypic transition from infancy to late childhood.
Phenotype. A comparison of photographs of 40 different children less than one year of age revealed that microcephaly, epicanthal folds, and a flat nasal bridge contributed to a characteristic appearance of hypertelorism. Ocular measurements revealed telecanthus with true hypertelorism (interpupillary distance greater than ninety-fifth percentile) in only four of the 37 personally examined individuals. The face lost much of its infantile fullness during childhood, although the epicanthal folds and oblique palpebral fissures remained. Apparent facial laxity produced a dropped-jaw, open-mouth expression in most children. During late childhood and adolescence, the greater growth of facial structures relative to that of the cranial vault created an impression of crowding and coarseness of the facial features. Prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, and severe malocclusion characterized the adolescent facies. Examination of sequential photographs of individual patients permitted a clear recognition of the stages of transition from the infant to adolescent phenotype (Figs. 1 and 2). The facial features remained subjectively similar despite differences in racial background or deletion size. During the newborn period, the child's cry was recalled as being abnormal by all sets of parents except one. The cry was usually described as weak, high-pitched mewing. The "cat cry" bad been lost by about one third of the
children by 2 years of age. This did not appear to be significantly influenced by the child's sex or chromosome abnormality. Children who had lost the cry did not differ significantly from those who had retained the "cat cry" with respect to level of mental development or verbal abilities. Over half of the children were diagnosed as having cri du chat syndrome before 6 months of age. The presence of subtle dysmorphia in combination with neonatal complications and a high-pitched cry were the features most often cited for initiating a diagnostic evaluation. In at least 10 children the combination of the cry, phenotype, and newborn history were sufficient to make a presumptive clinical diagnosis of cri du chat syndrome prior to chromosome analysis. In four children, the phenotype and characteristic cry prompted repeating of the chromosome analyses despite previous reports of normal karyotypes. Growth patterns. At birth, weights below the tenth percentile in 27% and microcephaly (>2 standard deviations below the mean) in 43% of the children with isolated deletions provided evidence for prenatal growth retardation. Birth length was not a useful indicator of prenatal growth retardation, because only 19% of the population was below the tenth percentile. Physical growth was characterized by decreased height, poor weight gain, and significant microcephaly (Fig. 3). The average 4-year-old
Votume 102 Number 4
Clinical heterogeneity in cri du chat syndrome
Table. Major malformations in cri du chat syndrome
Cardiac abnormalities Strabismus Clubfoot Inguinal hernia Cleft lip/palate Dislocated hips Intestinal malrotation or megacolon *P
% Deletion (n = 65)
% Unbalanced translocation (n = S5)
29 44 21 17 8 5 7
55* 50 21 36 14" 29* 27*
53 1
140 LENGTH
I ZO
I00
~;iiii~iiiiiiii~:ii!iil :: ~ !iioi~i~i~~:;;~
......
9
--
~z
9 9
~
BO
......
60 !
j
9
9
9I
!
!
|
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W
40 J
< 0.005.
30251 WEIGHT
child with cri du chat syndrome was comparable in size to a slender 2-year-old child and had a head circumference equivalent to that of a normal 6-month-old infant; By the age of 10 years, the average child with the syndrome had attained the height of a normal 7-year-old, with head size comparable to that of a normal 1-year-old child. Among children with isolated deletions, there was a nonsignificant correlation between head circumference and deletion size (r = 0.20, P = 0.17). Medical problems. Ninety-two percent of the patients experienced medical complications at the time of delivery or during the newborn period. Neonatal complications, such as poor sucking, need for incubator care, respiratory distress, and jaundice, occurred with approximately equal frequency among individuals with isolated deletion or with unbalanced translocation. The developmental attainment of children with isolated deletions who experienced apnea, jaundice, or heart abnormalities at birth was not significantly lower than that of the rest of the population, as measured by social quotients or age at which they began to walk? Forty-seven percent of those children with isolated deletions and 71% of those with unbalanced translocations required at least one hospitalization for an acute medical condition or for nonelective surgery. Pneumonia and dehydration frequently followed upper respiratory tract and viral infections; 21% of the patients with isolated deletion and 50% of those with unbalanced translocation required at least one hospitalization to stabilize or treat such an illness. Cardiac abnormalities requiring frequent medical intervention during infancy and childhood were present in 29% of the patients with isolated deletion and 55% of those with unbalanced translocation (P < 0.005) (Table). Ten of the 11 cardiac septal defects were found in children with isolated deletions (seven with ventricular septal defects, and three with atrial septal defects), individuals with unbalanced translocations possessed rarer, more complex
20-
tO-
5O2
I
3
4
5
6
55/"3 HEAD CIRCUMFERENCE
d /
50 /
..... ......
................
45H
4o 35
.
.
.
o .
.
t/oi. /
I:
~ 9
~"
i
I
i
i
i
2
3
4
A G E IN Y E A R S
Fig. 3. Growth parameters in 65 children with cri du chat syndrome caused by isolated deletions (e) and unbalanced translocations (o). Shaded areas represent normal growth development range (third to ninety-seventhpercentiles).
anomalies, including tetralogy of Fallot and endocardial cushion defect. Patent ductus arteriosus was present in four persons with translocations and four with isolated deletions. Of these eight individuals, four required surgical ligation. Seven percent of patients with isolated deletion and 27% of those with unbalanced translocation had gastrointestinal tract anomalies, including four with intestinal malrotation,
532
Wilkins et al.
three with Hirschsprung disease, and two less specific diagnoses of adynamic ileus and intestinal tract obstruction. Among children with isolated deletions, the only deaths after 6 months of age were related to gastrointestinal tract malformations: a 3~A-year-old girl with colitis secondary to megacolon, and a 9tA-year-old boy after colostomy for Hirschsprung disease. Medical problems involving minor malformations that were amenable to surgical correction were present in 45% and 78% of patients with deletion and translocation, respectively (Table). The presence or absence of specific physical malformations was not influenced by the size of the deleted segment in the 37 children studied using prometaphase banding. Thirty-three percent of the children with unbalanced translocations required monthly outpatient medical visits, whereas only 6% of those with isolated deletions required such care. Moreover, one third of the children with isolated deletions required only routine pediatric care. Chronic medical problems requiring attention throughout childhood included upper respiratory tract infections, otitis media, severe constipation, and hyperactivity. Frequent colds and bronchitis were cited by 30% of the parents as the primary reason for doctor visits. Otitis media was a persistent problem in 28% of the children, and necessitated ear tube placement in six children. Constipation represented a chronic problem in 56% of the cases. The mortality among persons with unbalanced translocations was almost six times that of individuals with isolated deletions. Four of the fifteen patients with translocation had died at 5 months, 7 years, 15 years, and 20 years of age, respectively, whereas only three of the remaining children studied were deceased. Development and behavior. The size of the deletion in those individuals with terminal aberrations showed a significant negative correlation with IQ ( r = - 0 . 3 3 , P = 0.02). Hyperactivity and self-stimulatory behavior, which often began as disruptive sleep patterns during infancy, were major problems in both the isolated deletion and translocation subgroups. Among the children with IQ below 40, self-stimulatory behaviors, such as head banging, hand waving, and hand sucking, were common. These children often displayed mannerisms of withdrawal, roving eye movements, and apparently decreased awareness of their surroundings. In the children with IQ above 40, hyperactivity was manifested by restless affect and short attention span. Intensive behavior modification was the most effective method reported for controlling hyperactivity. 7 DISCUSSION Comprehensive data were collected from 80 homereared children with cri du chat syndrome and revealed
The Journal of Pediatrics April 1983
considerable clinical and cytogenetic heterogeneity among affected persons. Although facial features remained con-. sistent despite racial differences and variation in the size of the deletion, the extent of the associated physical malformations and the level of mental development reflected the cytogenetic diversity of this syndrome. The present sample of 80 individuals included patients with simple terminal deletions, interstitial deletions, and a wide variety of structural rearrangements. In a subpopulation of 37 patients in whom prometaphase banding was performed, the size of the deletion was found to vary over such a wide range that the sample included no fewer than 18 distinct deletions and rearrangements. The break points in these 37 individuals were not distributed uniformly along the short arm, and there was evidence for clustering of the deletions at preferential break sites. The application of molecular techniques such as in situ hybridization to the analysis of these deletions will likely reveal further heterogeneity among cases that appear to have the same break points in prometaphase preparations. Ultimately, it may be possible to show that every independent case of cri du chat syndrome is cytogenetically, or at least genetically, distinct. Although the causal mechanisms that result in translocations and sporadic deletions may be different, no differences in parental age, occupation, or radiation exposure could be documented in our small series of patients. 6 When cri du chat syndrome results from the segregation of a familial translocation, the opportunity arises for simultaneous partial trisomy for the other chromosome involved in the rearrangement. It is not surprising, therefore, that these patients were found to exhibit more severe phenotypes. In our series, those with familial and de novo translocations, as a group, did show a greater need for medical care during infancy and childhood, a greater frequency of complex cardiac malformations, a higher mortality, and lower IQ. No two individuals with unbalanced translocations possessed the same rearrangement, so it was not expected that these individuals would exhibit a uniform phenotype, although they were clearly more severely affected than those with isolated deletions. Severe physical anomalies have been suggested for unbalanced translocations involving 9p, 8 and retrospective analysis of mortality among published cases of 5p- supports a higher mortality in individuals with unbalanced translocations. In view of the extreme degree of cytogenetic heterogeneity, it is remarkable that cri du chat syndrome presents such a uniform and recognizable facial phenotype. Among patients with isolated deletions, measured IQ was the only clinical variable that correlated significantly with the size of the missing chromosome segment. Niebuhr 3 has suggested that the phenotypic homogeneity of patients with cri du chat syndrome may imply the existence of a critical site
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near the tip of the short a r m (5p15.3), the absence of which leads to the characteristic clinical features of the syndrome. However, our observations are inconsistent with the hypothesis, because one of our patients with an interstitial deletion, in which the 5p15.3 band was preserved, showed typical features of cri du chat syndrome. 6 The facial phenotype remains characteristic despite differences in race and deletion size, and a consistent progression of the features with age is recognizable. The clinical heterogeneity documented in this population of children with cri du chat syndrome reflected an underlying diversity of chromosome aberration type and deletion size. Realistic expectations for an affected child's level of physical and mental development should be based on a thorough investigation of parental karyotypes to identify a translocation. The use of high-resolution prometaphase chromosome analysis and reverse banding is needed if the heterogeneity of this syndrome is to be delineated further. Clinical variability in cri du chat syndrome and the identification of the sources of such variation provide the clinician and family additional information on which to base informed decisions concerning the affected child's care. We thank the following persons and organizations for their assistance in locating patients and making clinic facilities available: The Cri du Chat Parent Club, Dr. J. Aase, Dr P. Bader, Dr. A. Bloom, Dr. M. Bocian, Dr. P. Buchanan, Dr. M. Carlin, Dr. D. Cox, D. Delozier, Dr. R. Desnick, Dr. L. Elsas, Dr. E. Engel, D. Eunpu, Dr. R. Fineman, Dr. S. Finley, Dr. U. Francke, Dr. W. Freeman, Dr. P. Gerald, Dr. J. German, L. Godmilow, Dr. J. Hall,
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Dr. J. Hamerton, P. Hawley, Dr. J. Hermann, Dr. L. Hsu, Dr. L. lmmken, Dr. L. Jackson, Dr. S. Kahler, C. Kasari, Dr. R. Laxova, Dr. J. Opitz, Dr. P. Pallister, Dr. C. Palmer, H. Perkins, Dr. H. Punnett, Dr. J. Rary, Dr. J. Rotter, Dr. L. Russell, R. Schwartz, Dr. C. Scott, Dr. R. Spathes, Dr. R. Summitt, Dr. K~ Taysi, Dr. 1. Uchida, Dr. D. Valle, Dr. D. Warburton, Dr. D. Weaver, Dr. H. Wyandt, Dr. E. Zackai, Dr. E. Zorn. REFERENCES
1. Lejeune J, Lafourcade J, Berger R, Vialette J, Bowswillwald M, Serginge P, Turpin R: Trios cas de deletion partielle du bras court d'un chromosome 5. CR Acad Sci (Paris) 257:3098, 1963. 2. German J, Lejeune J, Mclntyre MN, deGrouchy J: Chromosomal autoradiography in the cri du chat syndrome. Cytogenetics 3:347, 1964. 3. Niebuhr E: The cri du chat syndrome: Epidemiology, cytogenetics and clinical features. Hum Genet 44:227, 1978. 4. Gordon RR, Cooke P: Facial appearance in cri du chat syndrome. Dev Med Child Neurol 10:69, 1968. 5. Breg WR, Steele MW, Miller O J, Warburton D, de Capoa A: The cri du chat syndrome in adolescents and adults: Clinical findings in 13 older patients with partial deletion of the short arm of chromosome no. 5 (5p-). Pediatrics 77:782, 1970. 6. Wilkins LE: Cri du chat syndrome: Population demographics, prometaphase chromosome analysis and phenotype-karyotype correlations. Ph.D. dissertation, May 198t, Medical CoIIege of Virginia. 7. Wilkins LE, Brown JA, Wolf B: Psychomotor development in 65 home-reared children with cri du chat syndrome. J PEDIATR 97:401, 1980. 8. de Grouchy J, Turleau C: Clinical atlas of human chromosomes. New York, 1977, John Wiley, p 75.