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IS VARICELLA VIRUS TERATOGENIC?
362 IS VARICELLA VIRUS TERATOGENIC?
SIR,-We were recently consulted by acquired varicella early in pregnancy.
a
mother who had
Varicella-zoster virus is well known for its neurotropic proIn 1947, Laforet and Lynch’ reported the first pattern of intrauterine varicella during early gestation. Since then there have been further reports23 that maternal varicella early in pregnancy is associated with a definite pattern of structural fetal anomalies-typically encephalomyelitis with cortical atrophy and seizure activity, limb-reduction deformity, and skin scars along the hypoplastic limb. Additional features are radiculitis, cataracts, chorioretinis, and low-birthweight for gestational age. In no case has virus isolation been reported. Despite the paucity of supporting virological and immunological data compared with those that have established the relation between maternal rubella or cytomegalovirus infection and birth defects, the striking clinical similarity of the reported cases strongly suggested varicella intrauterine infection. Does varicella-zoster virus have teratogenic potential? The affinity of the varicella virus for the nervous system provided a logical explanation for the lesions, and the reduction deformity could be ascribed to denervation by peripheral neur-
perties.
opathy. The following case-report draws attention to the need for investigations of the mother before suggesting that a virus has teratogenic potential. The mother was a 24-year-old, healthy gravida 2, para 1. During the third week of pregnancy she was in close contact with
an
active
case
of varicella. 2 weeks later, she became ill
1. Laforet, E. G., Lynch, C. L. J. R. New Engl. J. Med. 1947, 236, 534. 2. Dodion, Fransen, J., Dekegel, D., Thiry, L. Scand. J. infect. Dis. 1973, 149 3. Savage, M. O., Mousa, A., Gordon, R. R. Lancet, 1973, i, 352.
5,
with clinical varicella contracted from her child. 2 weeks later the pregnancy was terminated. Histological examination of the embryo suggested that the developmental stage corresponded not with a 7-week pregnancy but with one of 10 or 11 weeks. The lumbar neural plate was irregularly interrupted, without inflammatory infiltration or necrosis, and an abdominal-wall defect was detected (see
figure). We thought it worth-while to collect additional information on the parental clinical history. X-ray examination of the mother’s spine revealed a defective lower spine with a sacralclosure defect but no skin defect. So we faced two problems. Was the maternal sacral-closure defect related to the neural tube and abdominal-wall defects of the embryo? We discussed a possible monogenic inheritance of defect closure with vanable expressivity, but could find no evidence for this hypothesis. Do the neural-tube and abdominal-wall defects support the suggestion that the varicella virus has teratogenic potential ? Knowledge of the timing of human malformations, the histological data, and the developmental stage of the embryo led to the belief that maternal varicella occurred during 8th or 9th embryonic week and could not be compatible with teratogenic effect. The lack of inflammatory infiltration or necrosis excluded the possibility that the virus may have acted by reopening a normal closure but another possibility is a mutation with severe closure defects. We thought that the mother might be at risk of having a baby with neural-tube or abdominal-wall defect, and ultrasonic examination with alpha-fetoprotein estimation was proposed for a further pregnancy. M. DESSEMOND J. L. LAURENT Department of Medical Genetics, D. CHAPPARD Hotel-Dieu Hospital, 69002 Lyon, France J. M. ROBERT
OVARIAN TERATOMAS AND GENETICS OF
GERM-CELL FORMATION
SIR,-Hecht et aLl argue, on the grounds of relatively early presentation and recorded cases of bilaterality and familial incidence, that benign ovarian teratomas (dermoid cysts) do not arise by a random error in meiosis (as suggested in our theoretical scheme- 1). They propose instead that these tumours result from an inherited gene which influences the fate of the second polar body and may promote fusion with the ovum to initiate the growth of a parthenogenic tumour. While this notion may prove to be correct we would contend that, on the basis of their chromosome analyses,4fusion is indistinguishable from failure of the second meiotic division, as we have proposed. The evidence5-7 relating to an inherited component in the production of ovarian teratomas emphasises that the genetics are unlikely to be simple. Nevertheless, the extreme rarity of multiple ovarian teratomas compared to the number of maturing oocytes, and the variable expression of the predisposition to develop these tumours (as illustrated by the pedigree detailed by Hecht et al.) suggest that a degree of randomness exists in the genesis of teratomas. This is consistent with the acquisition of a final mutation during meiotic prophase in the manner proposed in our simplified scheme for a single locus. The initial normality of such a gene would be preserved by the malignant behaviour of the obligatory homozygote which would result at the first meiotic division of any oocyte with an inherited mutation at this locus.23 We do not concede, therefore, that there is any inconsistency
Histological findings. Drawings of dorsal (upper) and lumbar (lower) sections of embryo showing interrupted lumbar neural plate and abdominal-wall defect.
1. Hecht, F., McCaw, B. K., Paul, S. Lancet, 1976, ii, 1311. 2. Riley, P. A., Sutton, P. M. ibid. 1975, i, 1360. 3. Riley, P A , Sutton, P. M. ibid. 1976, i, 642. 4. Lender, D., McCaw, B. K., Hecht, F. New Engl. J. Med. 1975, 292, 63 5. Abell, M R., Johnson, V. J., Holtz, F. Am. J. Obstet. Gynec. 1965, 92, 6. Plattner, G., Oxorn, H. Can. med. Ass. J. 1973, 108, 892. 7. Feld, D., Labes, J., Nathanson, M. Obstet. Gynec. 1966, 27, 525.
105
SIR,-We were recently consulted by acquired varicella early in pregnancy.
a
mother who had
Varicella-zoster virus is well known for its neurotropic proIn 1947, Laforet and Lynch’ reported the first pattern of intrauterine varicella during early gestation. Since then there have been further reports23 that maternal varicella early in pregnancy is associated with a definite pattern of structural fetal anomalies-typically encephalomyelitis with cortical atrophy and seizure activity, limb-reduction deformity, and skin scars along the hypoplastic limb. Additional features are radiculitis, cataracts, chorioretinis, and low-birthweight for gestational age. In no case has virus isolation been reported. Despite the paucity of supporting virological and immunological data compared with those that have established the relation between maternal rubella or cytomegalovirus infection and birth defects, the striking clinical similarity of the reported cases strongly suggested varicella intrauterine infection. Does varicella-zoster virus have teratogenic potential? The affinity of the varicella virus for the nervous system provided a logical explanation for the lesions, and the reduction deformity could be ascribed to denervation by peripheral neur-
perties.
opathy. The following case-report draws attention to the need for investigations of the mother before suggesting that a virus has teratogenic potential. The mother was a 24-year-old, healthy gravida 2, para 1. During the third week of pregnancy she was in close contact with
an
active
case
of varicella. 2 weeks later, she became ill
1. Laforet, E. G., Lynch, C. L. J. R. New Engl. J. Med. 1947, 236, 534. 2. Dodion, Fransen, J., Dekegel, D., Thiry, L. Scand. J. infect. Dis. 1973, 149 3. Savage, M. O., Mousa, A., Gordon, R. R. Lancet, 1973, i, 352.
5,
with clinical varicella contracted from her child. 2 weeks later the pregnancy was terminated. Histological examination of the embryo suggested that the developmental stage corresponded not with a 7-week pregnancy but with one of 10 or 11 weeks. The lumbar neural plate was irregularly interrupted, without inflammatory infiltration or necrosis, and an abdominal-wall defect was detected (see
figure). We thought it worth-while to collect additional information on the parental clinical history. X-ray examination of the mother’s spine revealed a defective lower spine with a sacralclosure defect but no skin defect. So we faced two problems. Was the maternal sacral-closure defect related to the neural tube and abdominal-wall defects of the embryo? We discussed a possible monogenic inheritance of defect closure with vanable expressivity, but could find no evidence for this hypothesis. Do the neural-tube and abdominal-wall defects support the suggestion that the varicella virus has teratogenic potential ? Knowledge of the timing of human malformations, the histological data, and the developmental stage of the embryo led to the belief that maternal varicella occurred during 8th or 9th embryonic week and could not be compatible with teratogenic effect. The lack of inflammatory infiltration or necrosis excluded the possibility that the virus may have acted by reopening a normal closure but another possibility is a mutation with severe closure defects. We thought that the mother might be at risk of having a baby with neural-tube or abdominal-wall defect, and ultrasonic examination with alpha-fetoprotein estimation was proposed for a further pregnancy. M. DESSEMOND J. L. LAURENT Department of Medical Genetics, D. CHAPPARD Hotel-Dieu Hospital, 69002 Lyon, France J. M. ROBERT
OVARIAN TERATOMAS AND GENETICS OF
GERM-CELL FORMATION
SIR,-Hecht et aLl argue, on the grounds of relatively early presentation and recorded cases of bilaterality and familial incidence, that benign ovarian teratomas (dermoid cysts) do not arise by a random error in meiosis (as suggested in our theoretical scheme- 1). They propose instead that these tumours result from an inherited gene which influences the fate of the second polar body and may promote fusion with the ovum to initiate the growth of a parthenogenic tumour. While this notion may prove to be correct we would contend that, on the basis of their chromosome analyses,4fusion is indistinguishable from failure of the second meiotic division, as we have proposed. The evidence5-7 relating to an inherited component in the production of ovarian teratomas emphasises that the genetics are unlikely to be simple. Nevertheless, the extreme rarity of multiple ovarian teratomas compared to the number of maturing oocytes, and the variable expression of the predisposition to develop these tumours (as illustrated by the pedigree detailed by Hecht et al.) suggest that a degree of randomness exists in the genesis of teratomas. This is consistent with the acquisition of a final mutation during meiotic prophase in the manner proposed in our simplified scheme for a single locus. The initial normality of such a gene would be preserved by the malignant behaviour of the obligatory homozygote which would result at the first meiotic division of any oocyte with an inherited mutation at this locus.23 We do not concede, therefore, that there is any inconsistency
Histological findings. Drawings of dorsal (upper) and lumbar (lower) sections of embryo showing interrupted lumbar neural plate and abdominal-wall defect.
1. Hecht, F., McCaw, B. K., Paul, S. Lancet, 1976, ii, 1311. 2. Riley, P. A., Sutton, P. M. ibid. 1975, i, 1360. 3. Riley, P A , Sutton, P. M. ibid. 1976, i, 642. 4. Lender, D., McCaw, B. K., Hecht, F. New Engl. J. Med. 1975, 292, 63 5. Abell, M R., Johnson, V. J., Holtz, F. Am. J. Obstet. Gynec. 1965, 92, 6. Plattner, G., Oxorn, H. Can. med. Ass. J. 1973, 108, 892. 7. Feld, D., Labes, J., Nathanson, M. Obstet. Gynec. 1966, 27, 525.
105