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Variability of the de Lange syndrome: Report of 3 cases and genetic analysis of 54 families
November, 1969 T h e J o u r n a l o/ P E D I A T R I C S
853
Variability of the de Lange syndrome: Report of 3 casesand genetic analysis of 54 families Three patients are described who have the characteristic clinical and radiologic [eatures o[ the Cornelia de Lange syndrome, except that they do not have severe mental retardation. This suggests that severe mental retardation is not a necessary [eature o[ the syndrome. The syndrome usually occurs sporadically, but there are enough [amilies with well-documented multiple occurrences to suggest that it is familial. The hypothesis o[ simple autosomal recessive inheritance is rejected; the empirical risk o[ recurrence o[ the condition in siblings o[ an affected child is estimated to be between 2 and 5 per cent.
H. Pashayan, M.D., "x"D. Whelan, M.D., F.R.C.P.(C), S. Guttman, M.D., and F. C. Fraser, Ph.D., M.D., F.R.S.C. MONTREAL, QUEBEG~ CANADA
T H E association of several relatively uncommon abnormalities in the same individual may be simply a coincidence or may occur because the abnormalities result from the same cause. When the association occurs more often than can be accounted for by coincidence, the array of abnormalities is called a syndrome. A syndrome so identified is considered to have two or more cardinal features, plus a number of associated features which are less regularly present. If the cause
From the Department o[ Medical Genetics and the Departmen,t o[ Biochemical Genetics of The Montreal Children's Hospital, and the Human Genetics Sector, Department o[ Genetics, McGill University. Supported by Grant-in-Aid No. M T 1584 [rom the Medical Research Council of Canada. Addr e ss; McGilt Un~verslty--Montreal Children's Hospital Research Institute, 2300 Tupper St., Mohtreal 108, Quebec, Canada.
of the syndrome can be identified, it is reasonable to consider within the limits of the syndrome any grouping of the recognized features observed to result from that cause. It may then be recognized that some syndromes may lack one or more of the abnormalities originally described as cardinal features. For example, the gene that causes Marfan's syndrome may cause ectopia lentis in one affected family member but not in another. When the cause of the syndrome has not been identified it may be difficult to decide what the limits of variability are. One may get into a circular argument. Thus, if the syndrome is recognized by the features A, B, and C, and less regularly by D, E, and F, is a patient who lacks C a case of the syndrome? No, because all patients with the syndrome have feature C. But why is feature Vol. 75, No. 5, pp. 853-858
85 4
Pashayan et al.
C considered a constant feature of the syndrome? Because all patients have it. By this kind of fallacious reasoning, the "syndrome by definition" approach, the features of such a syndrome may be forever fixed as those which occurred in the first few patients through whom the syndrome was first identified. By the "syndrome by etiology" approach, on the other hand, if the cause of the syndrome can be identified, it may be recognized that feature C is not always one of those that result from the presence of the etiological factor. Nevertheless, the patient lacking feature C is logically an example of the syndrome. T h e purpose of this report is to point out that this may be the case for the de Lange syndrome1-6 and that severe mental retardation may not be a constant feature of this syndrome. The risk of recurrence of the syndrome in siblings is also evaluated. Three cases are presented, all of whom had the following features of the de Lange syndromer height and weight below the third percentile for age; bushy eyebrows with synophris; long profuse lashes; flat nasal bridge with upturned tip, exposing the nares to front view; increased distance from nose to vermilion of the upper lip; narrow higharched palate (Cases 1 and 3) or cleft palate (Case 2); low-set ears; low hairline; short neck; hirsutism, especially of the shoulders, lower back, and extremities; short arms; short hands with tapering fingers and proximally displaced thumbs; a bridged simian crease on one (Cases 1 and 3) or both (Case 2) hands; microbrachycephaly; radiological signs of chronic pneumonia; narrow ribs; reduced number of sternal ossification centers; abnormal sternal angle. T h e following additional features were present in 2 of the 3 cases: short neck (1, 2); low-set ears (2, 3) ; low hairline (1, 3) ; short arms ( 1, 2) ; incurved fifth fingers (2, 3) ; hepatomegaly (1, 2); delayed bone age (1, 3) ; hypoplastic middle and distal phalanges of the fifth finger (2, 3); flattened iliac crests (2, 3). Features recorded for only 1 of the 3 cases are: delayed closure of the anterioi} fon-
The Journal o[ Pediatrics November 1969
tanelle (1) ; small, wide-spaced teeth (3) ; micrognathia (2) ; short legs (2) ; single crease on the fifth finger (2); ulnar deviation of the wrists (2) ; small feet (1) ; limitation of extension of the elbow (2); overconstriction of the long bones 6 (3); flattening of the distal ossification centers of the radius (3) ; fusion of left first and second ribs (3) ; irregular mottling of the radius and ulna (2) ; short broad first metacarpal (2). Additional details of the case histories are summarized below. CASE REPORTS
Case 1. L. M., a French Canadian girl, was referred at the age of 18 months because of failure to thrive. She was the only child of a 17-year-old mother who was unrelated to her 23-year-old husband. There were no known relatives with retardation or relevant malformations. She was born at term, with a birth weight of 2,728 grams. There were two emotional upsets during the early pregnancy but no history of taking durgs. Shortly after birth, the child became apneic and cyanosed, requiring resuscitation, and then had recurrent perioral cyanosis
Fig. 1. Case 1. Patient L. M. at age 18 months, showing characteristic face and right palm with a bridged simian crease and low-set thumb.
Volume 75 Number 5
whenever she cried. Her weight gain was slow, and she had frequent colds. At 18 months her height and weight were below the third percentile. In addition to the features of the de Lange syndrome listed above there was a chronic nasal d i s c h a r g e and the tongue was large and protruding. A Grade 4 / 6 pansystolic murmur was heard at the fourth left intercostal space. The E C G tracing showed flat T waves over the left ventricular leads. The chest roentgenogram showed an enlarged heart; pulmonary vascular markings were unusually prominent~ suggesting an increased flow to the lungs. T h e tip of the spleen was palpable; the edge of the liver was felt 3 cm. below the right costal margin. Radiologic examination revealed a bone age of 6 months. The child had evidence of retarded physical development. Four upper incisors and 2 lower incisors had appeared. She walked without help and was able to throw toys and eat using her fingers. H e r speech was limited to baby talk using one or two syllable words. A Denver developmental screening test placed her performance at the 17 month level; thus her mental retardation was much less severe than her physical retardation.
Fig. 2. Case 2. Patient A. C. at age 4 months, showing characteristic face.
Variability of de Lange syndrome
B5 5
Case 2. A. C. was a 4-month-old girl admitted for the second time because of a feeding problem and to be fitted with a prosthesis for a cleft palate. The infant was born after a 38 week uneventful pregnancy and weighed 2,381 grams. She was the only child of a 19-year-old French Canadian mother, para 1, gravida 1, unrelated to her 26-year-old Italian husband. There were no near relatives with mental retardation or relevant physical defects. She had first been admitted at 7 hours of age for cyanosis and apneic episodes following birth. She had to be fed by gavage through the first 3 weeks of life and had had one episode of aspiration leading to pneumonia. T h e diagnosis of de Lange syndrome was not suggested at that time. At 4 months the infant's weight, length, and head circumference were all below the third percentile. The diagnosis of the de Lange syndrome was made on the basis of the features listed previously. A Grade 1/6 systolic m u r m u r was present, and the edge of the liver felt 2 cm. below the right costal margin. There was an exostosis on the medial side of the right first metacarpal. The child was able to support her head while in the prone position, to follow a light, and to smile and turn over, indicating that her motor development was normal. Radiologic examination revealed a bone age comparable to that of the new born period. Mental assessment was done at the age of 12 months: She attained a mental age of 9 months, corresponding to an I.Q. of 73. It was felt that her potential was probably higher but that she was too young to be assessed accurately. Case 3. L. T., a Caucasian boy, was admitted at the age of 6 ~ years for removal of nasal polyps and reassessment of mental and physical retardation. T h e mother was 25 years of age when he was born. She was not related to her 28-year-old husband. There was one other child, an apparently normal younger brother; the mother had had a miscarriage prior to the birth of the proband. No relatives had mental retardation or relevant physical stigmata. The patient's birth weight was 2,437 grams. The pregnancy was uneventful except for weak fetal movements. There was a breech presentation and prolonged delivery, requiring the use of forceps; the baby required resuscitation and oxygen. Weight gain was slow and his developmental milestones were delayed. He started talking at 3 years of age at which time there was evidence that speech was markedly impaired. He
85 6
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The Journal o/ Pediatrics November 1969
Cases 1 and 3. I n Case 2 there also was an open field on the left hallucal a r e a - - a patt e r n that is rare in the general population but c o m m o n in mongolism. There was a transitional simian crease on the left h a n d in Gases 1 and 2 and the right h a n d in Case 3. This feature seems characteristic of the de Lange syndrome, having been reported in most of the cases described in the literature. COMMENT
Fig. 3. Case 3. Patient L. T. at age 6 ~ years, showing characteristic face.
had frequent colds and a continuous discharge from the nose. At 3y2 years of age he was assessed and classified as being mildly retarded, with the main handicap in the speech area. He was reassessed at 5 years of age and found to be functioning at the level of a 4-year-old child corresponding to an I.Q. of 75. The diagnosis of the de Lange syndrome was made on the basis of the features listed previously. In addition there was syndactyly of the second and third toes on the left foot, and an undescended right testicle. LABORATORY
FINDINGS
A large number of routine laboratory tests on the patients revealed no unusual biochemical or hematologic findings. U r i n a r y chromatography was normal for Cases 1 and 2 and showed hyperglyeinuria in Case 3; plasma chromatography for aminoacids was normal in all cases. Levels of I g M were low in all 3 patients though compatible with age in Case 2. Karyotypes for all 3 cases were normal. T h e dermatoglyphlcs showed a distal trlradius on both hands in Case 2, but n6t in
Each of the 3 patients presented has so m a n y of the features of the de Lange syndrome that it seems reasonable to consider them as examples of the syndrome. Does the fact that they do not manifest the severe degree of mental retardation described in previously reported cases preclude this diagnosis? E a c h of the features of the syndrome can vary in severity. For example, abnormalities of the a r m can vary from phocomelia to a low-placed thumb in an otherwise normal individual. Congenital heart disease (Case 1) is reported in about 12 per cent of cases and cleft palate (Case 2) in about 10 per cent. If variability in degree of involvement is recognized for one organ or system, there is no reason to exclude it for another. T h e mild, rather than severe, mental retardation in the above cases, and limitation to the speech area in Case 3, should not distract us from the diagnosis, but allow us to extend the range of variability recognized as occurring in the syndrome. GENETIC
ASPECTS
T h e first 8 cases reported of the de Lange syndrome were sporadic?, ~, 7-11 T h e first report of a familial occurrence was that of Borghi and associates 12, la in 1954, who described 3 cases and 1 questionable case in the same family. Opitz and associates ~4 in 1964 described a series of families with multiple cases in siblings and suggested that the condition showed autosomal recessive inheritance is, 16 but the diagnosis in a number of the secondary cases was not well established. A r e p o r W of monozygotic twins concordant for the syndrome supports a genetic
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etiology. However, the majority of reported instances of the syndrome are sporadic. M c A r t h u r and Edwards, is on the basis of 20 cases with a negative family history, normal karyotype, and absence of parental consanguinity, rejected the hypothesis of simple autosomal recessive inheritance. A n u m b e r of workers have reported normal karyotypes in patients with the syndrome.14, a9-25 Some reports have described chromosomal variants or abnormalities which, since they are inconsistent, are probably coincidental findingsY G-29 T w o reports have described translocations and suggested that the syndrome might result from an excess of chromosomal material. However, the excess was assumed to involve a segment of chromosome from group A in one case 3~ and group D in the other? a Thus at least one of these is presumably not related to the syndrome. W h e t h e r the sporadic cases with apparently normal karyotypes represent unrecognized chromosomal aberrations, such as unbalanced translocations, remains an open question. Whatever the cause, it may be useful for genetic counseling to estimate the empirical risk of recurrence of the condition once a "sporadic" case has appeared in a family. Because of the uncertainty as to diagnosis in some cases and lack of information about how the cases were ascertained, it did not seem worthwhile to employ the sophisticated mathematical techniques developed by Morton 32 and others to estimate the recurrence risk from the present data. Instead, we have chosen to make assumptions that will provide an upper and lower limit for the estimate. Assuming single ascertainment (i.e., that each family was ascertained through only one affected child), one affected child is excluded from each family and the proportion of affected children is calculated for the remainder. We have excluded the 3 stillborn individuals reported in family 12 of Fig. 1 of the paper by Opitz and associates, ~5 one s i b "purportedly affected" in family 13 and one in family 14, since evidence that they were affected seems inadequate. We also excluded the families of Falek
Variability of de Lange syndrome
857
and associates 3~ and Broholm and associates, ~1 since both had specific chromosomal abnormalities of the translocation type and m a y be considered high risk families. By this method there are 3 affected siblings out of 138, or 2.2 per cent. Since a n u m b e r of families were ascertained more than once this value will underestimate the frequency of recurrence. Assuming complete ascertainment, the family is counted once for each affected child, excluding one affected each time. This will overestimate the true value. T h e value so obtained is 8 per 156 or 5.1 per cent. T h e true value is assumed to lie between 2.2 and 5.1 per cent. It is recognized that this group of families is probably heterogeneous, containing a few families with a high risk and a majority with a low risk. T h u s the average figure is, in a sense misleading. However, until there is some means to distinguish the high risk families, it is the best estimate available for the counseling of families with normal karyotypes about the risk of recurrence. The authors wish to thank Dr. L. Dallaire for doing the karyotypes and Dr. M. E. Kadish for reviewing the roentgenographs. Gratitude is also expressed to Mrs. M. Forster for secretarial assistance in the preparation of the paper. REFERENCES
1. de Lange, C.: Sur un type nouveau de d~g~n~ration (typus Amstelodamensls), Arch. Med. Enfants 36: 7t3, 1933. 2. de Lange, C.: Nouvelle observation du typus Amstelodamensis et examen anatomopathologique de ce type, Arch. IVied. Enfants 41: 193, 1938. 3. Lee, F. A., and Kenny, F. M.: Skeletal changes in the Cornelia de Lange syndrome, Am. J. Roentgenol. 100: 27, 1967. 4. Gerald, B., and Umansky, R.: The Cornelia de Lange syndrome: Radiographic findings, Radiology 88: 96, 1967. 5. Kuilander, G. J., and deMyer, W.: Roentgenology of the Brachmann-de Lange syndrome, Radiology 88: 101, 1967. 6. Lee, F. A.: Generalized overconstruction of long bones and unilateral Kirner's deformity in a de Lange dwarf, Am. J. Dis. Child. 116: 599, 1968. 7. Vedder, R.: Een "typus degeneratlvus Amstelodamens]s" (de Lange), Nederl. tijdsehr. Geneesk 79: 993, 1935. 8. Pincherle, B.: Premiere observation de typus
85 8
9. 10. 11. 12.
13.
14. 15. ' 16. 17. 18. 19. 20. 21.
Pashayan et al.
Amstelodamensis (de Lange) en Italie, Arch. Med. Enfants 42: 443, 1939. Marie, I., et ah: Typus Amstelodamensis, Nourisson 34: 1, 1946. Keizer, D. P. R.: Typus degenerativus Amstelodamensis (Cornelia de Lange), I.ielvet. paediat, acta 7: 508, 1952. Arnaud, et al.: Un nouveau cas de typus Amstelodamensis (maladie de Cornelia de Lange), Pddiatrie 8: 100, 1953. Borghi, A., Giusti, G., and Bigozzi, U.: Nanismo degenerativo tipo di Amsterdam (typus amstelodamensis--malattia de Cornelia de Lange); Presentazione di un caso e considerazioni di ordine genetico, Acta genet. reed. et gemel. 3: 365, 1954. Borghi, A., CavinG C., Maello, M., et al.: Typus degenerativus amstelodamensis (Cornelia de Lange syndrome). Clinical and radiological considerations in three cases and some remarks on course of the disease at the post pubertal age, Presse M6d. 72: 3373, 1964. Opitz, J. M., Segal, A. T., Lehrke, R., and Nadler, H.: Brachmann/de Lange syndrome, Lancet 2: 1019, 1964. Opitz, J. M.: Editorial comments on the etiology of the Cornelia de Lange syndrome, Year Book of Pediatrics, 1964-65 series. Opitz, J. M.: Birth defect reprint series, Cornelia de Lange syndrome, RE-RS 16, March, 1965. Choo, P. B., and Bianchl, G. N.: Brachmann de Lange syndrome. Report of four cases, Australian Paediat. J. 1: 236~ 1965. McArthur, R. G., and Edwards, J. H.: de Lange syndrome. Report of 20 cases~ Canad. M. A. J. 96: 1185, 1967. Giraud, P.: Clinical conditions with normal chromosome complement, Human Chromosome Newsletter 9: 4, 1963. Laurence, K. M., and Ishmael, J.: Chromosomes in typus degenerativus Amstel0damensis (de Lange's syndrome), Lancet 1: 1426, 1963. Hienz, H. A.: Chromosomes in typus de-
The Journal o~ Pediatrics November 1969
22. 23. 24. 25.
26.
27.
28.
29.
30. 31.
32.
generativus Amstelodamensis (de Lange's syndrome), Lancet 2: 585, 1963. Hart, Z. H., Jaslow, R. I., and Gomez, M. R:. The de Lange syndrome, Am. J. Dis. Child. 109: 325, 1965. Silver, K. H.: The de Lange syndrome. Typus Amstelodamensis, Am. J. Dis. Child. 108: 523, 1964. Vischer, D.: Typus degenerativus (Amstelodamensis Cornelia de Lange syndrome), Helvet. paediat, acta 20: 415, 1965. Huang, C.-C., Emanuel, I., Huang, S.-W., and Chen, T.-Y.: Two cases of the de Lange syndrome in Chinese infants, J. PEDIAT. 71: 251, 1967. Schlesinger, B., Calyton, B., Bodion, M., and Jones, K. V.: Typus degenerativus Amstelodamensis, Arch. Dis. Childhood 38: 349, 1963. Jervis, G. A., and Stimson, C. W.: de Lange syndrome. The "Amsterdam type" of mental defect with congenital malformations, J. PEDIAT. 63: 635, 1963. Geudeke, M., Bijlsma, J. B., Bruijne, J. I., et al.: Chromosomen onderzoek bij typus degeneratlvus Amstelodamensis (syndroom van de Lange), Maandschr. kindergeneesk. 31: 248, 1963. Massimo, L., arid Vianello, M. G.: Syndrome of multiple malformations with supplementary chromosome in female child, Ann. Paediat. 204: 244, 1965. Falek, A., Schmidt, R., and Jervis, G. A.: Familial de Lange syndrome with chromosome abnormalities, Pediatrics 37: 92, 1966. Broholm, K. A., Eeg-Olofsson, O., and Hall, B.: An inherited chromosome aberration in a girl with signs of de Lange syndrome. Case report, Acta paediat, scandinav. 57: 547, 1968. Morton, N. E.: Segregation and linkage, in Burdette, W. J., editor: Methodology in human genetics, San Francisco, 1962, HoldenDay.
853
Variability of the de Lange syndrome: Report of 3 casesand genetic analysis of 54 families Three patients are described who have the characteristic clinical and radiologic [eatures o[ the Cornelia de Lange syndrome, except that they do not have severe mental retardation. This suggests that severe mental retardation is not a necessary [eature o[ the syndrome. The syndrome usually occurs sporadically, but there are enough [amilies with well-documented multiple occurrences to suggest that it is familial. The hypothesis o[ simple autosomal recessive inheritance is rejected; the empirical risk o[ recurrence o[ the condition in siblings o[ an affected child is estimated to be between 2 and 5 per cent.
H. Pashayan, M.D., "x"D. Whelan, M.D., F.R.C.P.(C), S. Guttman, M.D., and F. C. Fraser, Ph.D., M.D., F.R.S.C. MONTREAL, QUEBEG~ CANADA
T H E association of several relatively uncommon abnormalities in the same individual may be simply a coincidence or may occur because the abnormalities result from the same cause. When the association occurs more often than can be accounted for by coincidence, the array of abnormalities is called a syndrome. A syndrome so identified is considered to have two or more cardinal features, plus a number of associated features which are less regularly present. If the cause
From the Department o[ Medical Genetics and the Departmen,t o[ Biochemical Genetics of The Montreal Children's Hospital, and the Human Genetics Sector, Department o[ Genetics, McGill University. Supported by Grant-in-Aid No. M T 1584 [rom the Medical Research Council of Canada. Addr e ss; McGilt Un~verslty--Montreal Children's Hospital Research Institute, 2300 Tupper St., Mohtreal 108, Quebec, Canada.
of the syndrome can be identified, it is reasonable to consider within the limits of the syndrome any grouping of the recognized features observed to result from that cause. It may then be recognized that some syndromes may lack one or more of the abnormalities originally described as cardinal features. For example, the gene that causes Marfan's syndrome may cause ectopia lentis in one affected family member but not in another. When the cause of the syndrome has not been identified it may be difficult to decide what the limits of variability are. One may get into a circular argument. Thus, if the syndrome is recognized by the features A, B, and C, and less regularly by D, E, and F, is a patient who lacks C a case of the syndrome? No, because all patients with the syndrome have feature C. But why is feature Vol. 75, No. 5, pp. 853-858
85 4
Pashayan et al.
C considered a constant feature of the syndrome? Because all patients have it. By this kind of fallacious reasoning, the "syndrome by definition" approach, the features of such a syndrome may be forever fixed as those which occurred in the first few patients through whom the syndrome was first identified. By the "syndrome by etiology" approach, on the other hand, if the cause of the syndrome can be identified, it may be recognized that feature C is not always one of those that result from the presence of the etiological factor. Nevertheless, the patient lacking feature C is logically an example of the syndrome. T h e purpose of this report is to point out that this may be the case for the de Lange syndrome1-6 and that severe mental retardation may not be a constant feature of this syndrome. The risk of recurrence of the syndrome in siblings is also evaluated. Three cases are presented, all of whom had the following features of the de Lange syndromer height and weight below the third percentile for age; bushy eyebrows with synophris; long profuse lashes; flat nasal bridge with upturned tip, exposing the nares to front view; increased distance from nose to vermilion of the upper lip; narrow higharched palate (Cases 1 and 3) or cleft palate (Case 2); low-set ears; low hairline; short neck; hirsutism, especially of the shoulders, lower back, and extremities; short arms; short hands with tapering fingers and proximally displaced thumbs; a bridged simian crease on one (Cases 1 and 3) or both (Case 2) hands; microbrachycephaly; radiological signs of chronic pneumonia; narrow ribs; reduced number of sternal ossification centers; abnormal sternal angle. T h e following additional features were present in 2 of the 3 cases: short neck (1, 2); low-set ears (2, 3) ; low hairline (1, 3) ; short arms ( 1, 2) ; incurved fifth fingers (2, 3) ; hepatomegaly (1, 2); delayed bone age (1, 3) ; hypoplastic middle and distal phalanges of the fifth finger (2, 3); flattened iliac crests (2, 3). Features recorded for only 1 of the 3 cases are: delayed closure of the anterioi} fon-
The Journal o[ Pediatrics November 1969
tanelle (1) ; small, wide-spaced teeth (3) ; micrognathia (2) ; short legs (2) ; single crease on the fifth finger (2); ulnar deviation of the wrists (2) ; small feet (1) ; limitation of extension of the elbow (2); overconstriction of the long bones 6 (3); flattening of the distal ossification centers of the radius (3) ; fusion of left first and second ribs (3) ; irregular mottling of the radius and ulna (2) ; short broad first metacarpal (2). Additional details of the case histories are summarized below. CASE REPORTS
Case 1. L. M., a French Canadian girl, was referred at the age of 18 months because of failure to thrive. She was the only child of a 17-year-old mother who was unrelated to her 23-year-old husband. There were no known relatives with retardation or relevant malformations. She was born at term, with a birth weight of 2,728 grams. There were two emotional upsets during the early pregnancy but no history of taking durgs. Shortly after birth, the child became apneic and cyanosed, requiring resuscitation, and then had recurrent perioral cyanosis
Fig. 1. Case 1. Patient L. M. at age 18 months, showing characteristic face and right palm with a bridged simian crease and low-set thumb.
Volume 75 Number 5
whenever she cried. Her weight gain was slow, and she had frequent colds. At 18 months her height and weight were below the third percentile. In addition to the features of the de Lange syndrome listed above there was a chronic nasal d i s c h a r g e and the tongue was large and protruding. A Grade 4 / 6 pansystolic murmur was heard at the fourth left intercostal space. The E C G tracing showed flat T waves over the left ventricular leads. The chest roentgenogram showed an enlarged heart; pulmonary vascular markings were unusually prominent~ suggesting an increased flow to the lungs. T h e tip of the spleen was palpable; the edge of the liver was felt 3 cm. below the right costal margin. Radiologic examination revealed a bone age of 6 months. The child had evidence of retarded physical development. Four upper incisors and 2 lower incisors had appeared. She walked without help and was able to throw toys and eat using her fingers. H e r speech was limited to baby talk using one or two syllable words. A Denver developmental screening test placed her performance at the 17 month level; thus her mental retardation was much less severe than her physical retardation.
Fig. 2. Case 2. Patient A. C. at age 4 months, showing characteristic face.
Variability of de Lange syndrome
B5 5
Case 2. A. C. was a 4-month-old girl admitted for the second time because of a feeding problem and to be fitted with a prosthesis for a cleft palate. The infant was born after a 38 week uneventful pregnancy and weighed 2,381 grams. She was the only child of a 19-year-old French Canadian mother, para 1, gravida 1, unrelated to her 26-year-old Italian husband. There were no near relatives with mental retardation or relevant physical defects. She had first been admitted at 7 hours of age for cyanosis and apneic episodes following birth. She had to be fed by gavage through the first 3 weeks of life and had had one episode of aspiration leading to pneumonia. T h e diagnosis of de Lange syndrome was not suggested at that time. At 4 months the infant's weight, length, and head circumference were all below the third percentile. The diagnosis of the de Lange syndrome was made on the basis of the features listed previously. A Grade 1/6 systolic m u r m u r was present, and the edge of the liver felt 2 cm. below the right costal margin. There was an exostosis on the medial side of the right first metacarpal. The child was able to support her head while in the prone position, to follow a light, and to smile and turn over, indicating that her motor development was normal. Radiologic examination revealed a bone age comparable to that of the new born period. Mental assessment was done at the age of 12 months: She attained a mental age of 9 months, corresponding to an I.Q. of 73. It was felt that her potential was probably higher but that she was too young to be assessed accurately. Case 3. L. T., a Caucasian boy, was admitted at the age of 6 ~ years for removal of nasal polyps and reassessment of mental and physical retardation. T h e mother was 25 years of age when he was born. She was not related to her 28-year-old husband. There was one other child, an apparently normal younger brother; the mother had had a miscarriage prior to the birth of the proband. No relatives had mental retardation or relevant physical stigmata. The patient's birth weight was 2,437 grams. The pregnancy was uneventful except for weak fetal movements. There was a breech presentation and prolonged delivery, requiring the use of forceps; the baby required resuscitation and oxygen. Weight gain was slow and his developmental milestones were delayed. He started talking at 3 years of age at which time there was evidence that speech was markedly impaired. He
85 6
Pashayan et al.
The Journal o/ Pediatrics November 1969
Cases 1 and 3. I n Case 2 there also was an open field on the left hallucal a r e a - - a patt e r n that is rare in the general population but c o m m o n in mongolism. There was a transitional simian crease on the left h a n d in Gases 1 and 2 and the right h a n d in Case 3. This feature seems characteristic of the de Lange syndrome, having been reported in most of the cases described in the literature. COMMENT
Fig. 3. Case 3. Patient L. T. at age 6 ~ years, showing characteristic face.
had frequent colds and a continuous discharge from the nose. At 3y2 years of age he was assessed and classified as being mildly retarded, with the main handicap in the speech area. He was reassessed at 5 years of age and found to be functioning at the level of a 4-year-old child corresponding to an I.Q. of 75. The diagnosis of the de Lange syndrome was made on the basis of the features listed previously. In addition there was syndactyly of the second and third toes on the left foot, and an undescended right testicle. LABORATORY
FINDINGS
A large number of routine laboratory tests on the patients revealed no unusual biochemical or hematologic findings. U r i n a r y chromatography was normal for Cases 1 and 2 and showed hyperglyeinuria in Case 3; plasma chromatography for aminoacids was normal in all cases. Levels of I g M were low in all 3 patients though compatible with age in Case 2. Karyotypes for all 3 cases were normal. T h e dermatoglyphlcs showed a distal trlradius on both hands in Case 2, but n6t in
Each of the 3 patients presented has so m a n y of the features of the de Lange syndrome that it seems reasonable to consider them as examples of the syndrome. Does the fact that they do not manifest the severe degree of mental retardation described in previously reported cases preclude this diagnosis? E a c h of the features of the syndrome can vary in severity. For example, abnormalities of the a r m can vary from phocomelia to a low-placed thumb in an otherwise normal individual. Congenital heart disease (Case 1) is reported in about 12 per cent of cases and cleft palate (Case 2) in about 10 per cent. If variability in degree of involvement is recognized for one organ or system, there is no reason to exclude it for another. T h e mild, rather than severe, mental retardation in the above cases, and limitation to the speech area in Case 3, should not distract us from the diagnosis, but allow us to extend the range of variability recognized as occurring in the syndrome. GENETIC
ASPECTS
T h e first 8 cases reported of the de Lange syndrome were sporadic?, ~, 7-11 T h e first report of a familial occurrence was that of Borghi and associates 12, la in 1954, who described 3 cases and 1 questionable case in the same family. Opitz and associates ~4 in 1964 described a series of families with multiple cases in siblings and suggested that the condition showed autosomal recessive inheritance is, 16 but the diagnosis in a number of the secondary cases was not well established. A r e p o r W of monozygotic twins concordant for the syndrome supports a genetic
Volume 75 Number 5
etiology. However, the majority of reported instances of the syndrome are sporadic. M c A r t h u r and Edwards, is on the basis of 20 cases with a negative family history, normal karyotype, and absence of parental consanguinity, rejected the hypothesis of simple autosomal recessive inheritance. A n u m b e r of workers have reported normal karyotypes in patients with the syndrome.14, a9-25 Some reports have described chromosomal variants or abnormalities which, since they are inconsistent, are probably coincidental findingsY G-29 T w o reports have described translocations and suggested that the syndrome might result from an excess of chromosomal material. However, the excess was assumed to involve a segment of chromosome from group A in one case 3~ and group D in the other? a Thus at least one of these is presumably not related to the syndrome. W h e t h e r the sporadic cases with apparently normal karyotypes represent unrecognized chromosomal aberrations, such as unbalanced translocations, remains an open question. Whatever the cause, it may be useful for genetic counseling to estimate the empirical risk of recurrence of the condition once a "sporadic" case has appeared in a family. Because of the uncertainty as to diagnosis in some cases and lack of information about how the cases were ascertained, it did not seem worthwhile to employ the sophisticated mathematical techniques developed by Morton 32 and others to estimate the recurrence risk from the present data. Instead, we have chosen to make assumptions that will provide an upper and lower limit for the estimate. Assuming single ascertainment (i.e., that each family was ascertained through only one affected child), one affected child is excluded from each family and the proportion of affected children is calculated for the remainder. We have excluded the 3 stillborn individuals reported in family 12 of Fig. 1 of the paper by Opitz and associates, ~5 one s i b "purportedly affected" in family 13 and one in family 14, since evidence that they were affected seems inadequate. We also excluded the families of Falek
Variability of de Lange syndrome
857
and associates 3~ and Broholm and associates, ~1 since both had specific chromosomal abnormalities of the translocation type and m a y be considered high risk families. By this method there are 3 affected siblings out of 138, or 2.2 per cent. Since a n u m b e r of families were ascertained more than once this value will underestimate the frequency of recurrence. Assuming complete ascertainment, the family is counted once for each affected child, excluding one affected each time. This will overestimate the true value. T h e value so obtained is 8 per 156 or 5.1 per cent. T h e true value is assumed to lie between 2.2 and 5.1 per cent. It is recognized that this group of families is probably heterogeneous, containing a few families with a high risk and a majority with a low risk. T h u s the average figure is, in a sense misleading. However, until there is some means to distinguish the high risk families, it is the best estimate available for the counseling of families with normal karyotypes about the risk of recurrence. The authors wish to thank Dr. L. Dallaire for doing the karyotypes and Dr. M. E. Kadish for reviewing the roentgenographs. Gratitude is also expressed to Mrs. M. Forster for secretarial assistance in the preparation of the paper. REFERENCES
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The Journal o~ Pediatrics November 1969
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