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Trisomy 18 in a hydrocephalic fetus
T h e Journal o[ P E D I A T R I C S
67
Trisomy 18 in a bydroceploalic fetus Autosoraal trisomies may be responsible [or intrauterine death o[ the [etus. The present report described a [emale hydrocephalic [etus aborted at 25 weeks gestation; leukocyte and skin cultures as well as autoradiography revealed trisomy 18. Further case histories may indicate whether the association of hydrocephalus with trisomy 18 is incidental or significant.
Omar S. EI-Alfi, M. B., M.D.,* John J. Biesele, Ph.D., e* and Priscilla M. Smith, B.A. AUSTIN~ TEXAS
T H E presence of a n extra autosome in the developing fetus results in a d e r a n g e m e n t of its genetic integrity, thus interfering with its development. It is presumed that in the milder derangements, the fetus is born with a set of congenital abnormalities, v a r y i n g in severity, b u t usually clinically recognizable. This category includes the three wellestablished autosomal trisomies, viz: trisomy 13_15,1 17_18,~, a a n d 21, 4 as well as others that are considered possibilities so far, viz: trisomy 6-12, a 19-20, 6 a n d 22. z,s I n the other p r e s u m a b l y severe cases, the fetus dies in utero, a n d autosomal trisomies may, therefore, be considered a cause of i n t r a uterine fetal death. From the Genetics Foundation, The University of Texas, Austin 12, Texas. The research on which this article is based was largely supported by Research Grant GM 06492 [rom the Institute of General Medical Sciences, National Institutes e[ Health, Bethesda 14, Md. "Y'Rosalie B. Hire Postdoctoral Fellow, The University o[ Texas. **Research Career Award 5-K6.CA-18.366 from the National Cancer Institute, National Institutes o[ Health, Bethesda 14, Md.
T h e following is a report t h a t m i g h t help to confirm this statement.
CASE REPORT J. T. was a white female aged 20 years; her husband was 21 years old. Both were University students, were healthy, physically fit, and nonconsanguineous. There is no history of congenital anomalies in their families. She was primigravida, her last menstrual period started May 25, 1962. The pregnancy was uneventful with no history of drug administration, irradiation, or trauma, but the size of uterus was larger than expected. Fetal movements were present, though it was difficult to assess their magnitude. On Nov. 18, 1962, she felt colicky pains, which were associated with vaginal bleeding and dilation of cervix. This was followed by drainage of 2,000 ml. of amniotic fluid and expulsion of the fetus. The total volume of amniotic fluid exceeded 2,500 ml. The fetus was a female, weighing I pound, 3 ounces, and measuring 11 inches from head to heel. The head was hydrocephalic, soft, and its circumference was -+ 11 inches. The left external ear was absent with no sign of an ear canal; both wrists and hands were flexed; the
68
El-Alfi, Biesele, and Smith
right forearm was very short; and the skin showed patchy discoloration. Regrettably an autopsy was not carried out. CHROMOSOMAL
STUDIES
L e u k o c y t e culture. O n e - h a l f milliliter of blood was a s p i r a t e d f r o m the umbilicaI vein
July 1964
a n d directly c u l t u r e d in a 10 ml. centrifuge tube containing 3 ml. Eagle's m e d i u m (with 16 p e r cent calf serum) a n d 0.05 ml. of each of the p h y t o h e m a g g l u t i n i n s M. a n d P. Seventy-two hours later, leukocytes were h a r v e s t e d a n d squashed. O f t h e 13 m e t a phase figures counted, 12 h a d 47 c h r o m o -
Fig. 1. Karyotype of fetus (prepared from a leukocyte culture) showing the supernumerary autosome.
Fig. 2. Karyotype of fetus (prepared from a skin culture) showing the supernumerary autosome.
Volume 65 Number 1
Trisomy 18 in hydrocephalic fetus
69
Fig. 3. Chromosome Group E autoradiography before and after film exposure showing 2 No. 17 and 3 No. 18 chromosomes. somes each, and 1 had 45. The extra element was identified as chromosome No. 17 or 18 (Fig. 1). Skin culture. Fetal skin was cultured in 2 ounce bottles, by using Eagle's medium containing 16 per cent calf serum. It was harvested 24 days later, and the chromosomes were spread by squashing. Among the 40 mitotic figures counted, 38 had 47 chromosomes each, and 2 had 45. The extra chromosome was again identified as No. 17 or 18 (Fig. 2). Autoradiography. Tritiated thymidine (5 ~c per milliliter) was added to the skin cultures 6 hours before harvesting, giving a final concentration of 0.2 /~c per milliliter medium. The film strips were exposed for 3 days at 4 ~ C. Among the 5 No. 17 and 18 chromosomes present, 2 No. 17 had minimal labeling, and 2 No. 18 as well as the extra autosome showed a definitely heavier labeling. The supernumerary element was thus identified as No. 18 (Fig. 3). DISCUSSION Trisomy 18, only known since 1960, was first reported by Edwards and colleagues 2 as trisomy 17, and almost simultaneously by Smith and associates s as trisomy 18. Subsequent reports ols showed that this trisomy represents a well-defined syndrome of multiple congenital anomalies. Most of these
anomalies are reproduced in every case, to the extent that a clinical diagnosis is now feasible. These same reports also identified the extra autosome as No. 18. The incidence of this trisomy is a very low one as compared with that of trisomy 21. This sparsity might be due to the difference in length of the two chromosomes 18 and 21; trisomy of a larger autosome is probably more lethal to the developing zygote than trisomy of a shorter one. Therman and co-workers 14 have suggested that trisomies of D or E chromosomes might ordinarily be lethal to the fetus, and that the occasional viable infants might have experienced a specific gene mutation during their development. An alternate suggestion ~ is that trisomy 18 syndrome has a wide spectrum of severity, and that only moderate and mild forms are compatible with extrauterine life. Both suggestions assume that the coexistence of 3 No. 18 chromosomes could be lethal to the developing fetus. The present report supports this assumption. The hydrocephalus manifested by this fetus has not been reported before in the trisomy 18 syndrome. In fact, a skull circumference smaller than normal is mentioned in many of them. It is hard to know whether the hydrocephalus was due to the trisomy per se or to an unrelated event. Further case histories may indicate whether
7 O El-Alfi, Biesele, and Smith
July 1964
this association of h y d r o c e p h a l u s with trisomy 18 is incidental or significant. SUMMARY
A fetus ab o r t ed at 25 weeks of gestation showed trisomy 18 by leukocyte and skin cultures. T h e e x t r a a u t o s o m e was identified by a u t o r a d i o g r a p h y as No. 18. T h e fetus had h y d r o c e p h a l u s in addition to the o t h er anomalies. We wish to thank Dr. J. H. Herrod for his permission to use the clinical data. We are also grateful to Dr. W. K. Long for his invaluable assistance. REFERENCES
1. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P." Multiple congenital anomaly caused by an extra autosome, Lancet 1: 790, 1960. 2. Edwards, J. H., Harnden, D. G., Cameron, A. H., Crosso, V. M., and Wolff, O. H.: A new trisomic syndrome, Lancet 1: 787, 1960. 3. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: A new autosomal trisomy syndrome: Multiple congenital anomalies caused by an extra chromosome, J. PEmAT. 57: 338, 1960. 4. LeJeune, J., Gautier, M., and Turpin, R :
5.
6.
7. 8. 9. 10. 11.
12. 13. 14.
l~tude des chromosomes somatiques de neuf enfants mongoliens, Compt. rend. Acad. Sc. 248: 1721, 1959. E1-Alfi, O. S., Powell, H. C., and Biesele, J. J.: Possible trisomy in chromosome group 6-12 in a mentally retarded patient, Lancet 1: 700, 1963. B66k, J. A., Santesson, B., and Zetterqvist, P.: Association between congenital heart malformations and chromosomal variations, Acta paediat. 50: 217, 1961. Turner, B., and Jennings, A. N.: Trisomy for chromosome 22, Lancet 2: 49, 1961. Hayward, M. D., and Bower, B. D.: Chromosomal trisomy associated with the SturgeWeber syndrome, Lancet 2: 844, 1960. Patau, K., Therman, E., Smith, D. W., and De Mars, R. I.: Trisomy for chromosome No. 18 in man, Chromosoma 12" 280, 1961. Uchida, I. A., Bowman, J. M., and Wang, H. C.: The 18 trisomy syndrome, New England J. Med. 266: 1198, 1962. Holman, G. H., Erkman, B., Zacharias, D. L., and Kock, H. F.: The 18 trisomy syndrome-two new clinical variants. One with associated tracheo-esophageal fistula and the other with probably familial occurrence, New England J. Med. 268: 982, 1963. Heinnichs, E. H., and Allen, S. W.: The 18 trisomy syndrome, a spectrum?, Clin. Pediat. 2: 25, 1963. Gibson, D. A., Uchida, I. A., and Lewis, A. J.: A review of the 18-trisomy syndrome, M. Biol. Illus. 13: 80, 1963. Therman, E., Patau, K., Smith, D. W., and De Mars, R. I.: The D trisomy syndrome and XO gonadal dysgenesis in two sisters, Am. J. Human Genet. 13: 193, 1961.
67
Trisomy 18 in a bydroceploalic fetus Autosoraal trisomies may be responsible [or intrauterine death o[ the [etus. The present report described a [emale hydrocephalic [etus aborted at 25 weeks gestation; leukocyte and skin cultures as well as autoradiography revealed trisomy 18. Further case histories may indicate whether the association of hydrocephalus with trisomy 18 is incidental or significant.
Omar S. EI-Alfi, M. B., M.D.,* John J. Biesele, Ph.D., e* and Priscilla M. Smith, B.A. AUSTIN~ TEXAS
T H E presence of a n extra autosome in the developing fetus results in a d e r a n g e m e n t of its genetic integrity, thus interfering with its development. It is presumed that in the milder derangements, the fetus is born with a set of congenital abnormalities, v a r y i n g in severity, b u t usually clinically recognizable. This category includes the three wellestablished autosomal trisomies, viz: trisomy 13_15,1 17_18,~, a a n d 21, 4 as well as others that are considered possibilities so far, viz: trisomy 6-12, a 19-20, 6 a n d 22. z,s I n the other p r e s u m a b l y severe cases, the fetus dies in utero, a n d autosomal trisomies may, therefore, be considered a cause of i n t r a uterine fetal death. From the Genetics Foundation, The University of Texas, Austin 12, Texas. The research on which this article is based was largely supported by Research Grant GM 06492 [rom the Institute of General Medical Sciences, National Institutes e[ Health, Bethesda 14, Md. "Y'Rosalie B. Hire Postdoctoral Fellow, The University o[ Texas. **Research Career Award 5-K6.CA-18.366 from the National Cancer Institute, National Institutes o[ Health, Bethesda 14, Md.
T h e following is a report t h a t m i g h t help to confirm this statement.
CASE REPORT J. T. was a white female aged 20 years; her husband was 21 years old. Both were University students, were healthy, physically fit, and nonconsanguineous. There is no history of congenital anomalies in their families. She was primigravida, her last menstrual period started May 25, 1962. The pregnancy was uneventful with no history of drug administration, irradiation, or trauma, but the size of uterus was larger than expected. Fetal movements were present, though it was difficult to assess their magnitude. On Nov. 18, 1962, she felt colicky pains, which were associated with vaginal bleeding and dilation of cervix. This was followed by drainage of 2,000 ml. of amniotic fluid and expulsion of the fetus. The total volume of amniotic fluid exceeded 2,500 ml. The fetus was a female, weighing I pound, 3 ounces, and measuring 11 inches from head to heel. The head was hydrocephalic, soft, and its circumference was -+ 11 inches. The left external ear was absent with no sign of an ear canal; both wrists and hands were flexed; the
68
El-Alfi, Biesele, and Smith
right forearm was very short; and the skin showed patchy discoloration. Regrettably an autopsy was not carried out. CHROMOSOMAL
STUDIES
L e u k o c y t e culture. O n e - h a l f milliliter of blood was a s p i r a t e d f r o m the umbilicaI vein
July 1964
a n d directly c u l t u r e d in a 10 ml. centrifuge tube containing 3 ml. Eagle's m e d i u m (with 16 p e r cent calf serum) a n d 0.05 ml. of each of the p h y t o h e m a g g l u t i n i n s M. a n d P. Seventy-two hours later, leukocytes were h a r v e s t e d a n d squashed. O f t h e 13 m e t a phase figures counted, 12 h a d 47 c h r o m o -
Fig. 1. Karyotype of fetus (prepared from a leukocyte culture) showing the supernumerary autosome.
Fig. 2. Karyotype of fetus (prepared from a skin culture) showing the supernumerary autosome.
Volume 65 Number 1
Trisomy 18 in hydrocephalic fetus
69
Fig. 3. Chromosome Group E autoradiography before and after film exposure showing 2 No. 17 and 3 No. 18 chromosomes. somes each, and 1 had 45. The extra element was identified as chromosome No. 17 or 18 (Fig. 1). Skin culture. Fetal skin was cultured in 2 ounce bottles, by using Eagle's medium containing 16 per cent calf serum. It was harvested 24 days later, and the chromosomes were spread by squashing. Among the 40 mitotic figures counted, 38 had 47 chromosomes each, and 2 had 45. The extra chromosome was again identified as No. 17 or 18 (Fig. 2). Autoradiography. Tritiated thymidine (5 ~c per milliliter) was added to the skin cultures 6 hours before harvesting, giving a final concentration of 0.2 /~c per milliliter medium. The film strips were exposed for 3 days at 4 ~ C. Among the 5 No. 17 and 18 chromosomes present, 2 No. 17 had minimal labeling, and 2 No. 18 as well as the extra autosome showed a definitely heavier labeling. The supernumerary element was thus identified as No. 18 (Fig. 3). DISCUSSION Trisomy 18, only known since 1960, was first reported by Edwards and colleagues 2 as trisomy 17, and almost simultaneously by Smith and associates s as trisomy 18. Subsequent reports ols showed that this trisomy represents a well-defined syndrome of multiple congenital anomalies. Most of these
anomalies are reproduced in every case, to the extent that a clinical diagnosis is now feasible. These same reports also identified the extra autosome as No. 18. The incidence of this trisomy is a very low one as compared with that of trisomy 21. This sparsity might be due to the difference in length of the two chromosomes 18 and 21; trisomy of a larger autosome is probably more lethal to the developing zygote than trisomy of a shorter one. Therman and co-workers 14 have suggested that trisomies of D or E chromosomes might ordinarily be lethal to the fetus, and that the occasional viable infants might have experienced a specific gene mutation during their development. An alternate suggestion ~ is that trisomy 18 syndrome has a wide spectrum of severity, and that only moderate and mild forms are compatible with extrauterine life. Both suggestions assume that the coexistence of 3 No. 18 chromosomes could be lethal to the developing fetus. The present report supports this assumption. The hydrocephalus manifested by this fetus has not been reported before in the trisomy 18 syndrome. In fact, a skull circumference smaller than normal is mentioned in many of them. It is hard to know whether the hydrocephalus was due to the trisomy per se or to an unrelated event. Further case histories may indicate whether
7 O El-Alfi, Biesele, and Smith
July 1964
this association of h y d r o c e p h a l u s with trisomy 18 is incidental or significant. SUMMARY
A fetus ab o r t ed at 25 weeks of gestation showed trisomy 18 by leukocyte and skin cultures. T h e e x t r a a u t o s o m e was identified by a u t o r a d i o g r a p h y as No. 18. T h e fetus had h y d r o c e p h a l u s in addition to the o t h er anomalies. We wish to thank Dr. J. H. Herrod for his permission to use the clinical data. We are also grateful to Dr. W. K. Long for his invaluable assistance. REFERENCES
1. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P." Multiple congenital anomaly caused by an extra autosome, Lancet 1: 790, 1960. 2. Edwards, J. H., Harnden, D. G., Cameron, A. H., Crosso, V. M., and Wolff, O. H.: A new trisomic syndrome, Lancet 1: 787, 1960. 3. Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: A new autosomal trisomy syndrome: Multiple congenital anomalies caused by an extra chromosome, J. PEmAT. 57: 338, 1960. 4. LeJeune, J., Gautier, M., and Turpin, R :
5.
6.
7. 8. 9. 10. 11.
12. 13. 14.
l~tude des chromosomes somatiques de neuf enfants mongoliens, Compt. rend. Acad. Sc. 248: 1721, 1959. E1-Alfi, O. S., Powell, H. C., and Biesele, J. J.: Possible trisomy in chromosome group 6-12 in a mentally retarded patient, Lancet 1: 700, 1963. B66k, J. A., Santesson, B., and Zetterqvist, P.: Association between congenital heart malformations and chromosomal variations, Acta paediat. 50: 217, 1961. Turner, B., and Jennings, A. N.: Trisomy for chromosome 22, Lancet 2: 49, 1961. Hayward, M. D., and Bower, B. D.: Chromosomal trisomy associated with the SturgeWeber syndrome, Lancet 2: 844, 1960. Patau, K., Therman, E., Smith, D. W., and De Mars, R. I.: Trisomy for chromosome No. 18 in man, Chromosoma 12" 280, 1961. Uchida, I. A., Bowman, J. M., and Wang, H. C.: The 18 trisomy syndrome, New England J. Med. 266: 1198, 1962. Holman, G. H., Erkman, B., Zacharias, D. L., and Kock, H. F.: The 18 trisomy syndrome-two new clinical variants. One with associated tracheo-esophageal fistula and the other with probably familial occurrence, New England J. Med. 268: 982, 1963. Heinnichs, E. H., and Allen, S. W.: The 18 trisomy syndrome, a spectrum?, Clin. Pediat. 2: 25, 1963. Gibson, D. A., Uchida, I. A., and Lewis, A. J.: A review of the 18-trisomy syndrome, M. Biol. Illus. 13: 80, 1963. Therman, E., Patau, K., Smith, D. W., and De Mars, R. I.: The D trisomy syndrome and XO gonadal dysgenesis in two sisters, Am. J. Human Genet. 13: 193, 1961.