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Micrognathia, polydactyly, and cleft palate
Volume 72 Number 6
Brie[ clinical and laboratory observations
8 59
Table I I I . Visible malformations induced in chick embryos by exposure to xylene Exposure
I Ti
HH 3-5 N M
60 min. 120min. 180 rain. 240 rain.
12 22 18 18
3 2 4 2
Total
70
11
%
]
HH 6-10 N M
+
Ti
5 9 3 14
18 39 28 24
6 17 12 8
28 31
109
43
4 11 11 2 40
44
I
HH 11-14 N M
+
Ti
5 12 12 7
7 10 4 9
59 27 26 26
44 23 23 22
36
30
138
112
33
28
] +
4 11 4 __ 3 __ 4 _15
I1
11
8
Ti
HH 8-14 N% M%
89 88 72 68
59.6 47.7 54.2 47.1
1 4 . 6 25.8 30.7 21.6 36.1 9.7 1 9 . 1 33.8
317
52.3
24.9
+%
22.8
H H 3-5, H H 6-10, H H 11-14, and H H 3-14 indicate the developmental stage of the chick embryo.4 Abbreviations: Ti ---- number of chicken embryos; N (N%) = number (or per cent) of normal embryos; M (M%) number (or per cent) of embryos malformed; + (+%) = mortality rate.
4. Nearly half (47.5 per cent) of malformed specimens exhibited rumplessness, which appears to be produced by a similar abnormal developmental mechanism as the syndrome of caudal regression in h u m a n beings. CONCLUSIONS Based upon these results, we believe that xylene is an effective teratogen which interferes with the normal development of chick embryos exposed to its vapor. Further experimental, clinical, and epidemiological studies are in progress. I t is hoped that this preliminary report will stimulate interest in this problem, especially in countries in which m a n y women are employed in industries utilizing organic solvents. SUMMARY I n 5 of the 9 known cases of agenesis of the sacrum reported in Czechoslovakia be-
Micrognathia, polydactyly, and cleft palate R. B. Lowry, M.B., B. Ch., F . R . C . P . ( C ) , *
J. R. Miller, Ph.D., and J. R. MaeLean, M.D. VANCOUVER,
B.
C.,
---
tween 1959 and 1966, a history of close contact during pregnancy with organic solvents (xylene, trichloroethylene, methylchloride, acetone, petrol) was obtained. Experiments with chick embryos exposed to xylene tend to support the hypothesis that fat solvents may have some teratogenic effect and cause the production of sacral agenesis in man.
REFERENCES 1. KuEera, J., Lenz, W., Maler, W.: Missbildungen der Beine und der kaudalen Wirbels~iule bei Kindern diabetischer Miitter, Deutsche reed. Wehnschr. 90: 901, 1965. 2. Rusnak, S. L., Driscoll, S. G.: Congenital spinal anomalies in infants of diabetic mothers, Pediatrics 35: 989, 1965. 3. Lenz, W., and KuEera, J.: L' ~tiologie de la regression caudale, M6d. et Hygiene 25: 241, 1967. 4. Hamburger, V., and Hamilton, H. L.: A series of normal stages in the development of chick embryos, J. Morphol. 88: 49, 1951.
TI~E OCCURRENCE OF micrognathia, polydactyly, and genital anomalies in association has been described extensively in the G e r m a n literature under the titles " D e r T y p u s Rostockiensis ''1 or the "Ullrich-Feichtiger syndrome. ''2, a I n recent years a syndrome was described, first by Smith, Lemli, and Opitz 4 and then by others, which in m a n y respects is similar to the Ullrieh-
CANADA
From The Division of Medical Genetics, Department o[ Paediatrics, University o[ British Columbia, and the Health Centre [or Children, 715 W. 12th Ave., Vancouver, B. C., Canada.
Supported by National Health Grant (Canada) 609-7-155, the Vancouver Foundation and the Children's Hospital, Vancouver. *Address: Department o[ Pacdiatries, 715 W. 12th Ave., Vancouver, B. C., Canada.
8 60
Brief clinical and laboratory observations
Feichtiger syndrome. W e describe an i n f a n t whose clinical features resemble the UllrichFeichtiger syndrome, b u t in whom the dermatogtyphic findings a n d some of the clinical features bear resemblance to the SmithLemli-Opitz syndrome. CASE REPORT
S. R., a female infant, was the second child of healthy, unrelated parents, who were 34 and 31 (mother) years of age at the time of delivery. The first child is a normal boy, now two years of age. There have been no miscarriages or stillbirths. The mother had a small amount of vaginal bleeding each day during most of the first trimester, for which she received some "hormone" therapy but was not confined to bed. The maternal weight gain was approximately 9 Kg., and the infant's birth weight was 2,116 grams. Family history revealed nothing of relevance except that both parents had distant ancestors who came from the same part of Ireland. The infant's length was 43 cm. and the head circumference was 30 cm. The outstanding feature was severe micrognathia (Fig. 1). Additional
Fig. 1. Patient at 2 days of age. Note severe micrognathia.
The Journal ol Pediatrics June 1968
abnormalities included a cleft of the soft palate, an extremely broad upper alveolar ridge, bilateral ranulae of the sublingual salivary glands, a very small anterior fontannelle, bilateral ptosis, polydactyly of each hand, and partial syndactyly of the second and third toes of each foot. The ears were large and slanted backwards, but their shape was not grossly abnormal. A loud systolic murmur was heard over the precordium, and there was considerable respiratory distress. Chromosome karyotype from a leukocyte culture was that of a normal female. Chromosomal studies of both parents were carried out and were judged to be normal. The infant failed to thrive despite adequate caloric intake, developed intestinal obstruction, and died at the age of 40 days. At autopsy her weight was 2,490 grams. The principal findings were: a defect of the endocardial cushion type involving the atrial and the ventricular septae, a preductal coarctation of the aorta with a patent ductus arteriosus, focal areas of confluent pneumonia, hypoplastic kidneys (weights 5.6 and 6.1 grams), and dilatation of the colon. No ganglion cells were seen in microscopic sections from the distal portion of the colon. Dermatoglyphics. There were whorls on eight of the ten fingers, and the first finger on each hand had an ulnar loop pattern. The axial triradius was located in the extreme distal position; it was not possible to determine accurate measurements in terms of a "t" position or "atd" angle. There were patterns in both hypothenar areas which were either loops or very small whorls, but no discernible patterns in the thenar or interdigital areas. True simian creases were not present, but bridged or partial simian creases were present bilaterally. On the feet the striking patterns were in the hallucal areas. On the right foot the pattern appeared to be a true arch tibial while on the left foot pattern no true triradius was observed, the ridges were broken, and the ridge fields were observed at right angles to each other. The patient's father had ulnar loops on seven fingers. The second left digit had a whorl pattern, and the second and fourth right digits had radial loops. The occurrence of a radial loop on :the fourth digit is a common feature in mongolism, but occurs very rarely in the general population ( 1.4 per cent). The mother had six whorl patterns and four ulnar loop patterns on the fingers. The hallucal first interdigital patterns were "O/Ld. ''
Volume 72 Number 6
DISCUSSION The multiple anomalies suggested the possibility of a chromosomal aberration. The D1 trisomy syndrome was excluded by the dermal patterns and the normal karyotype. The physical findings, including the dermal patterns of our patient, were similar to those of a syndrome described by Smith, Lemli, and Opitz 4 and subsequently by others. ~-s These children, some of them siblings, were mentally retarded, and had a wide variety of physical anomalies including micrognathia, hypospadias, distinctive facies with a broad nose and anteverted nostrils, a very broad maxillary alveolus, ptosis, and strabismus. The majority of cases have been in boys, but this might be due to easier ascertainment in boys since one of the striking features is severe hypospadias; cleft scrotum and cryporchidism also occur. Three of the patients (including ours) had cleft palates, and two others had bifid uvulas. In those patients whose dermatoglyphics have been recorded it is evident that a high proportion have eight or more whorl patterns on the digits, distal axial triradii, and simian creases. Polydactyly, micrognathia, and genital anomalies are the outstanding features of the Ullrich-Feichtiger syndrome? The genital anomaly, consisting of hypospadias, cryptorchidism, and bifid scrotum, is similar to that in the Smith-Lemli-Opitz syndrome and gives an appearance suggestive of pseudohermaphroditism. Some girls have had a bicornuate uterus or septate vagina. Some of the patients in the German literature probably had the D1 syndrome, although, as is evident from our patient, one cannot make definite pronouncements from the clinical description alone. T h e question of whether the UllrlchFeichtiger syndrome and the Smith-LemliOpitz syndrome represent variants of the same syndrome will require further delineation before it can be resolved. Only one of the described patients with the Smith-Lemli-
Brie[ clinical and laboratory observations
86 1
Opitz syndrome had anything resembling polydactyly, and that consisted of an ulnar skin tag? Clinically our patient resembles the Ullrich-Feichtiger syndrome, but the dermatoglyphic similarity (a high frequency of whorls and particularly the arch tibial on one foot) to that of one of Blair and Martin's patients is very striking. Dallaire 9 has studied two further siblings with the Smith-LemliOpitz syndrome, one of whom had similar dermatoglyphic findings in the hallucal area; the other had an arch tibial variant pattern on one hallucal area. Further studies with ~pecial emphasis on the dermatoglyphic patterns will be needed before one can conclude that the syndromes are the same. The authors thank Dr. Alvera Witt for help with the German translations, and Dr. Margaret Corey for the chromosome analysis. REFERENCES 1. Von Weber, J. W., and Schwarz, H.: Der Typus rostockiensis Ullrich-Feichtiger Dyskranio-pygo-phalangie, Helvet. paediat, acta 15: 163, 1960. 2. Ullrlch, O.: Der Status Bonnevie-Ullrlch in Rahmen anderer (Dyskranio-Dysphalangien), Ergebn. inn. Med. Kinderh. neue Folge 2: 456, 1951. 3. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the head and neck, New York, 1964, McGraw-Hill Book Company, Inc., chap. 72, pp. 366-367. 4. Smith, D. W., Lemli, L., and Opitz, J. M.: A newly recognized syndrome of multiple congenital anomalies, J. PEDIAT.64: 210, 1964. 5. Pinsky, L., and DiGeorge, A. M.: A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female, J. PEDIAT. 66: 1049, 1965. 6. Gibson, R.: A case of the Smith-Lemli-Opitz syndrome of multiple congenital anomalies in association with dysplasia epiphysialis punctata, Canad. M. A. J. 92: 574, 1965. 7. Blair, H. R., and Martin, J. K.: A syndrome characterized by mental retardation, short stature, cranlofacial dysplasia and genital anomalies occurring in siblings, J. PEDIAT. 69: 457, 1966. 8. Dallaire, L., and Fraser, F. C.: The syndrome of retardation with urogenital and skeletal anomalies in siblings, J. PEDIAT.69: 459, 1966. 9. Dallaire, L.: Personal communication, 1967.
Brie[ clinical and laboratory observations
8 59
Table I I I . Visible malformations induced in chick embryos by exposure to xylene Exposure
I Ti
HH 3-5 N M
60 min. 120min. 180 rain. 240 rain.
12 22 18 18
3 2 4 2
Total
70
11
%
]
HH 6-10 N M
+
Ti
5 9 3 14
18 39 28 24
6 17 12 8
28 31
109
43
4 11 11 2 40
44
I
HH 11-14 N M
+
Ti
5 12 12 7
7 10 4 9
59 27 26 26
44 23 23 22
36
30
138
112
33
28
] +
4 11 4 __ 3 __ 4 _15
I1
11
8
Ti
HH 8-14 N% M%
89 88 72 68
59.6 47.7 54.2 47.1
1 4 . 6 25.8 30.7 21.6 36.1 9.7 1 9 . 1 33.8
317
52.3
24.9
+%
22.8
H H 3-5, H H 6-10, H H 11-14, and H H 3-14 indicate the developmental stage of the chick embryo.4 Abbreviations: Ti ---- number of chicken embryos; N (N%) = number (or per cent) of normal embryos; M (M%) number (or per cent) of embryos malformed; + (+%) = mortality rate.
4. Nearly half (47.5 per cent) of malformed specimens exhibited rumplessness, which appears to be produced by a similar abnormal developmental mechanism as the syndrome of caudal regression in h u m a n beings. CONCLUSIONS Based upon these results, we believe that xylene is an effective teratogen which interferes with the normal development of chick embryos exposed to its vapor. Further experimental, clinical, and epidemiological studies are in progress. I t is hoped that this preliminary report will stimulate interest in this problem, especially in countries in which m a n y women are employed in industries utilizing organic solvents. SUMMARY I n 5 of the 9 known cases of agenesis of the sacrum reported in Czechoslovakia be-
Micrognathia, polydactyly, and cleft palate R. B. Lowry, M.B., B. Ch., F . R . C . P . ( C ) , *
J. R. Miller, Ph.D., and J. R. MaeLean, M.D. VANCOUVER,
B.
C.,
---
tween 1959 and 1966, a history of close contact during pregnancy with organic solvents (xylene, trichloroethylene, methylchloride, acetone, petrol) was obtained. Experiments with chick embryos exposed to xylene tend to support the hypothesis that fat solvents may have some teratogenic effect and cause the production of sacral agenesis in man.
REFERENCES 1. KuEera, J., Lenz, W., Maler, W.: Missbildungen der Beine und der kaudalen Wirbels~iule bei Kindern diabetischer Miitter, Deutsche reed. Wehnschr. 90: 901, 1965. 2. Rusnak, S. L., Driscoll, S. G.: Congenital spinal anomalies in infants of diabetic mothers, Pediatrics 35: 989, 1965. 3. Lenz, W., and KuEera, J.: L' ~tiologie de la regression caudale, M6d. et Hygiene 25: 241, 1967. 4. Hamburger, V., and Hamilton, H. L.: A series of normal stages in the development of chick embryos, J. Morphol. 88: 49, 1951.
TI~E OCCURRENCE OF micrognathia, polydactyly, and genital anomalies in association has been described extensively in the G e r m a n literature under the titles " D e r T y p u s Rostockiensis ''1 or the "Ullrich-Feichtiger syndrome. ''2, a I n recent years a syndrome was described, first by Smith, Lemli, and Opitz 4 and then by others, which in m a n y respects is similar to the Ullrieh-
CANADA
From The Division of Medical Genetics, Department o[ Paediatrics, University o[ British Columbia, and the Health Centre [or Children, 715 W. 12th Ave., Vancouver, B. C., Canada.
Supported by National Health Grant (Canada) 609-7-155, the Vancouver Foundation and the Children's Hospital, Vancouver. *Address: Department o[ Pacdiatries, 715 W. 12th Ave., Vancouver, B. C., Canada.
8 60
Brief clinical and laboratory observations
Feichtiger syndrome. W e describe an i n f a n t whose clinical features resemble the UllrichFeichtiger syndrome, b u t in whom the dermatogtyphic findings a n d some of the clinical features bear resemblance to the SmithLemli-Opitz syndrome. CASE REPORT
S. R., a female infant, was the second child of healthy, unrelated parents, who were 34 and 31 (mother) years of age at the time of delivery. The first child is a normal boy, now two years of age. There have been no miscarriages or stillbirths. The mother had a small amount of vaginal bleeding each day during most of the first trimester, for which she received some "hormone" therapy but was not confined to bed. The maternal weight gain was approximately 9 Kg., and the infant's birth weight was 2,116 grams. Family history revealed nothing of relevance except that both parents had distant ancestors who came from the same part of Ireland. The infant's length was 43 cm. and the head circumference was 30 cm. The outstanding feature was severe micrognathia (Fig. 1). Additional
Fig. 1. Patient at 2 days of age. Note severe micrognathia.
The Journal ol Pediatrics June 1968
abnormalities included a cleft of the soft palate, an extremely broad upper alveolar ridge, bilateral ranulae of the sublingual salivary glands, a very small anterior fontannelle, bilateral ptosis, polydactyly of each hand, and partial syndactyly of the second and third toes of each foot. The ears were large and slanted backwards, but their shape was not grossly abnormal. A loud systolic murmur was heard over the precordium, and there was considerable respiratory distress. Chromosome karyotype from a leukocyte culture was that of a normal female. Chromosomal studies of both parents were carried out and were judged to be normal. The infant failed to thrive despite adequate caloric intake, developed intestinal obstruction, and died at the age of 40 days. At autopsy her weight was 2,490 grams. The principal findings were: a defect of the endocardial cushion type involving the atrial and the ventricular septae, a preductal coarctation of the aorta with a patent ductus arteriosus, focal areas of confluent pneumonia, hypoplastic kidneys (weights 5.6 and 6.1 grams), and dilatation of the colon. No ganglion cells were seen in microscopic sections from the distal portion of the colon. Dermatoglyphics. There were whorls on eight of the ten fingers, and the first finger on each hand had an ulnar loop pattern. The axial triradius was located in the extreme distal position; it was not possible to determine accurate measurements in terms of a "t" position or "atd" angle. There were patterns in both hypothenar areas which were either loops or very small whorls, but no discernible patterns in the thenar or interdigital areas. True simian creases were not present, but bridged or partial simian creases were present bilaterally. On the feet the striking patterns were in the hallucal areas. On the right foot the pattern appeared to be a true arch tibial while on the left foot pattern no true triradius was observed, the ridges were broken, and the ridge fields were observed at right angles to each other. The patient's father had ulnar loops on seven fingers. The second left digit had a whorl pattern, and the second and fourth right digits had radial loops. The occurrence of a radial loop on :the fourth digit is a common feature in mongolism, but occurs very rarely in the general population ( 1.4 per cent). The mother had six whorl patterns and four ulnar loop patterns on the fingers. The hallucal first interdigital patterns were "O/Ld. ''
Volume 72 Number 6
DISCUSSION The multiple anomalies suggested the possibility of a chromosomal aberration. The D1 trisomy syndrome was excluded by the dermal patterns and the normal karyotype. The physical findings, including the dermal patterns of our patient, were similar to those of a syndrome described by Smith, Lemli, and Opitz 4 and subsequently by others. ~-s These children, some of them siblings, were mentally retarded, and had a wide variety of physical anomalies including micrognathia, hypospadias, distinctive facies with a broad nose and anteverted nostrils, a very broad maxillary alveolus, ptosis, and strabismus. The majority of cases have been in boys, but this might be due to easier ascertainment in boys since one of the striking features is severe hypospadias; cleft scrotum and cryporchidism also occur. Three of the patients (including ours) had cleft palates, and two others had bifid uvulas. In those patients whose dermatoglyphics have been recorded it is evident that a high proportion have eight or more whorl patterns on the digits, distal axial triradii, and simian creases. Polydactyly, micrognathia, and genital anomalies are the outstanding features of the Ullrich-Feichtiger syndrome? The genital anomaly, consisting of hypospadias, cryptorchidism, and bifid scrotum, is similar to that in the Smith-Lemli-Opitz syndrome and gives an appearance suggestive of pseudohermaphroditism. Some girls have had a bicornuate uterus or septate vagina. Some of the patients in the German literature probably had the D1 syndrome, although, as is evident from our patient, one cannot make definite pronouncements from the clinical description alone. T h e question of whether the UllrlchFeichtiger syndrome and the Smith-LemliOpitz syndrome represent variants of the same syndrome will require further delineation before it can be resolved. Only one of the described patients with the Smith-Lemli-
Brie[ clinical and laboratory observations
86 1
Opitz syndrome had anything resembling polydactyly, and that consisted of an ulnar skin tag? Clinically our patient resembles the Ullrich-Feichtiger syndrome, but the dermatoglyphic similarity (a high frequency of whorls and particularly the arch tibial on one foot) to that of one of Blair and Martin's patients is very striking. Dallaire 9 has studied two further siblings with the Smith-LemliOpitz syndrome, one of whom had similar dermatoglyphic findings in the hallucal area; the other had an arch tibial variant pattern on one hallucal area. Further studies with ~pecial emphasis on the dermatoglyphic patterns will be needed before one can conclude that the syndromes are the same. The authors thank Dr. Alvera Witt for help with the German translations, and Dr. Margaret Corey for the chromosome analysis. REFERENCES 1. Von Weber, J. W., and Schwarz, H.: Der Typus rostockiensis Ullrich-Feichtiger Dyskranio-pygo-phalangie, Helvet. paediat, acta 15: 163, 1960. 2. Ullrlch, O.: Der Status Bonnevie-Ullrlch in Rahmen anderer (Dyskranio-Dysphalangien), Ergebn. inn. Med. Kinderh. neue Folge 2: 456, 1951. 3. Gorlin, R. J., and Pindborg, J. J.: Syndromes of the head and neck, New York, 1964, McGraw-Hill Book Company, Inc., chap. 72, pp. 366-367. 4. Smith, D. W., Lemli, L., and Opitz, J. M.: A newly recognized syndrome of multiple congenital anomalies, J. PEDIAT.64: 210, 1964. 5. Pinsky, L., and DiGeorge, A. M.: A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female, J. PEDIAT. 66: 1049, 1965. 6. Gibson, R.: A case of the Smith-Lemli-Opitz syndrome of multiple congenital anomalies in association with dysplasia epiphysialis punctata, Canad. M. A. J. 92: 574, 1965. 7. Blair, H. R., and Martin, J. K.: A syndrome characterized by mental retardation, short stature, cranlofacial dysplasia and genital anomalies occurring in siblings, J. PEDIAT. 69: 457, 1966. 8. Dallaire, L., and Fraser, F. C.: The syndrome of retardation with urogenital and skeletal anomalies in siblings, J. PEDIAT.69: 459, 1966. 9. Dallaire, L.: Personal communication, 1967.