Clinicat Genetics 1979: 15: 351-355
Prenatal diagnosis of severe congenital malformations associated with elevated amniotic fluid alpha-feto protein J.
CHEMKEI,
R. NISANI~, R. KASSIF~,M. LANCET^, R. BEISER.~ AND N. HURWITZ~
Clinical Genetics Unit, 2 Department of Obstetrics and Gynecology, 3 Laboratory of Microbiology, and 4 Department of Pathology, Kaplan Hospital, Rehovot, Israel (affiliated to the Hebrew University and Hadassah Medical School)
1
Two cases of severely malformed infants with abnormal fetal images on B-scan sonography and markedly elevated amniotic fluid AFP are presented. There was no evidence of neural tube anomalies. The importance of an amniocentesis and AFP in pregnancies with an abnormal fetal image on B-scan sonography is emphasized, taking into consideration that most pregnancies with elevated fluid AFP have serious fetal anomalies. Received 4 August, revised 29 September, accepted f o r publication 26 October I978 Key words: Alpha-feto-protein; congenital malformations; prenatal diagnosis; trisomy 18;
Turner syndrome; ultrasound.
Amniotic fluid alpha-feto protein (AFP) determination is a well recognized test for the prenatal diagnosis of open neural tube defects. A variety of congenital malformations have also been found to be associated with elevated A F P levels (Seppala 1975, Weiss et al. 1976), even though the mechanism f o r this phenomenon is not always clear. O u r prenatal diagnostic program includes routine B-scan sonographic examination of the uterus in high-risk pregnancies and prior t o every amniocentesis. We have recently encountered two cases of abnormal fetal images on B-scan sonography and markedly elevated amniotic fluid A F P . Both pregnancies were interrupted and the fetuses were severely malformed, without evidence of neural tube anomalies. 0009-9163/79/040351-05
T h e purpose of the present paper is to call attention to the importance of amniocentesis and A F P determination in pregnancies in which mid-trimester B-scan sonography raises the question of abnormal fetal development. Case Reports Case 1. A 19-year-old female, gravida 2,
para 1, a b 0, was admitted to hospital at 20 weeks of gestation, because of imminent abortion. B-scan ultrasonography revealed a n excessive amount of amniotic fluid; the fetal head was not clearly demonstrated and the fetal trunk appeared unusual in shape, resembling a cystic formation. A repeat Bscan at 23 weeks of gestation revealed a
$02.50/0 0 1979 Munksgaard, Copenhagen
352
CHEMKE, NISANI, KASSIF, LANCET, BEISER AND HURWITZ
Fig. 1. Case 1. View of intraabdominal organs. Note displaced and compressed intestinal loops and grossly distended urachus.
fetal head with a biparietal diameter of 5.5 cm, corresponding to 21 weeks of gestation. The fetal chest appeared very small. An abdominal X-ray demonstrated one fetus with a small, abnormally shaped head. The fetal chest appeared compressed. An amniocentesis was performed: AFP levels, assayed by rocket-immunoelectrophoresis (Norgaard-Pedersen 1973), were 450 pg/ml and chromosome analysis of amniotic fluid cell culture revealed a 47, XX, 18 karyotype. In view of the elevated AFP levels and the ultrasonography findings, pregnancy was interrupted by intrauterine instillation of a hypertonic saline solution. The fetus was moderately macerated, weighing 490 g, with a markedly dilated and ruptured abdominal wall. There were no neural tube malformations. The head was dolichocephalic and small,
+
with low-set ears. The chest was very small and compressed upwards by the huge abdomen. Changes secondary t o extreme intraabdominal pressure consisted of posterior displacement and compression of all intraperitoneal organs (Fig. 1). The abdominal wall was replaced by a large cystic formation, a greatly dilated and hypertrophic urachus, connected to the grossly distended urinary bladder, thus forming a vesicoumbilical fistula (Fig. 2). The kidneys and ureters appeared normal, but the urethra and rectum were atretic. The spleen was absent. There was complete agenesis of the uterus, fallopian tubes and vagina. The external genitalia were ambiguous: a small phallus was observed, but no urogenital or anal orifices were present. Histological examination of the gonads revealed normal ovaries. Short fifth digits with clinodactyly and a single flexion crease were present on both hands; the dermatoglyphic patterns could not be identified. The umbilical cord had only one artery. Case 2. A 29-year-old female, gravida 2 , para 1, ab 0, had B-scan ultrazonography because of suspected intrauterine growth retardation, at 18 weeks of gestation. A difference of 4 weeks was found between the fetal biparietal diameter and the estimated gestational age. Two translucent formations were observed close to the fetal head (Fig. 3). A tentative diagnosis of bilateral cystic hygroma was established, and a repeat B-scan 2 weeks later revealed the same picture with only a slight increase in the fetal biparietal diameter and with no fetal heart beats. In view of these findings, the pregnancy was terminated by intrauterine instillation of a hypertonic saline solution. Amniotic fluid AFP prior to the termination of pregnancy was 570 pg/ml; attempted culture of amniotic fluid cells was unsuccessful. A macerated female fetus with markedly
AFP A N D PRENATAL D I A G N O S I S
353
Flg. 2. Case 1. Opened thickwalled urachus. Note blindly ending rectum,
edematous limbs was delivered. Large bilateral cystic hygromas of the neck were found. No other congenital malformations were observed. The umbilical cord had two arteries. Discussion
Elevated amniotic fluid AFP has been re-
ported in various types of fetal developmental pathology other than open neural tube defects (Leschot & Treffers 1975, Seppala 1975, Milunsky & Alpert 1976b, Weiss et al. 1976, Clarke et al. 1977, King & Prescott 1978). Recently it was shown that some of these anomalies can also be suspected on Bscan sonography (Valenti et al. 1975, Bartley et al. 1977, Nevin et al. 1978). B-scan
Fig. 3. Case 2. Transverse Bscan sonography at 18 weeks of gestation. a. Fetal head. b. Bilateral cystic areas (cystic hygroma).
354
CHEMKE, NISANI, KASSIF, LANCET, BEISER AND HURWITZ
sonography is routinely performed in many genetic centers prior to amniocentesis, in order to locate the placenta and an amniotic fluid pool; to establish the number of fetuses and their gestational age; and to examine the fetal head and spine in the search for open neural tube defects. The precise cause of the increased amniotic fluid AFP is still a matter for discussion. AFP, being a normal fetal protein, may appear in increased amounts in the amniotic fluid for a variety of reasons, but it appears mainly as a consequence of two groups of fetal conditions: increased production or synthesis by fetal tissues; and transudation or excretion of fetal protein into the amniotic fluid (Weiss et al. 1976). The 200:l concentration gradient between fetal serum and amniotic fluid (Weiss et al. 1976) might explain the transudation of fetal protein through a body defect covered by a thin and highly vascularized membrane. This could be the case in the fetus with trisomy 18 and the persistent urachus in which there may have been transudation of ascitic fluid proteins into the amniotic fluid. Fetuses with Turner syndrome characteristically present with cystic hygroma (Singh 1970, Gellis et al. 1978), and raised amniotic fluid A F P has been reported (Seller et al. 1974, Hunter et al. 1976). Therefore, it can be speculated that our female fetus with bilateral cystic hygroma may also have been a case of Turner syndrome, although the specific chromosomal aberration could not be demonstrated. Another contributing mechanism in this case could be fetal death and maceration, since it has been shown that human fetal skin and muscle are rich sources of this protein before 17.5 weeks of gestation (Lawler & Nash 1977). The importance of alpha-feto protein determinations in every sample of amniotic fluid has been pointed out by several investigators (Wright et al. 1975, Ainbender & Hirschhorn 1976, Milunsky & Alpert 1976a,
Weiss et al. 1978), and is further emphasized by the two present cases of severe fetal malformations, as well as the observation that most pregnancies with elevated amniotic fluid A F P have serious fetal anomalies (Nevin et al. 1978). The present cases illustrate the need for amniocentesis and A F P determinations in pregnancies with an abnormal fetal image on B-scan sonography.
References
Ainbender, E. & K. Hirschhorn (1976). Routine alpha-fetoprotein studies in amniotic fluid. Lancet i, 597. Bartley, J. A., M. S. Golbus, R. A. Filly & B. D. Hall (1977). Prenatal diagnosis of dysplastic kidney disease. Clin. Genet. 11, 374378. Clarke, P. C., Y. B. Gordon, M. J. Kitau, T. Chard & A. D. McNeal (1977). Alpha-fetoprotein levels in pregnancies complicated by gastrointestinal abnormalities of the fetus. Brit. J . Obstet. Gynaec. 84, 285-289. Gellis, S. S., M. Feingold, G. R. Southerland & J . G. Rogers (1978). Fetal Turner’s syndrome. Amer. J . Dis. Child. 132, 417418. Hunter, A., J. L. Hammerton, T. Baskett & E. Lyons (1976). Raised amniotic fluid alphafetoprotein in Turner syndrome. Lancet i, 598. King, C. R. & G. H. Prescott (1978). Amniotic fluid alpha-fetoprotein elevation with fetal omphalocele and a possible mechanism for its occurrence. Amer. J . Obstet. Gynec. 130, 279-283. Lawler, S. D. & S. G . Nash (1977). Alpha-fetoprotein in fetal skin and muscle. Brit. J . Obstet. Gynaec. 84, 51-54. Leschot, N. J. & P. E. Treffers (1975). Elevated amniotic fluid alpha-fetoprotein without neural-tube defects. Lancet ii, 1141. Milunsky, A. & E. Alpert (1976a). Prenatal diagnosis of neural tube defects. I. Problems and pitfalls: analysis of 2495 cases using the alpha-fetoprotein assay. Obslet. Gynec. 48, 1-5.
Milunsky, A. & E. Alpert (1976b). Prenatal diagnosis of neural tube defects. 11. Analysis of false positive and false negative alphafetoprotein results. Obstet. Gynec. 48, 6-12. Nevin, N. C., A. Ritchie, F. McKeown & G. Roberts (1978). Raised alpha-fetoprotein
AFP AND PRENATAL DIAGNOSIS
levels in amniotic fluid and maternal serum associated with distension of the fetal bladder caused by absence of urethra. J . med. Genet. 15, 61-78. Norgaard-Pedersen, B. (1973). Alpha l-fetoprotein. Scand. J . Immunol. 2, Suppl. 1 . 107-110. Seller, M. J., M. R. Creasy & E. I). Alberman (1974). Alpha-feto protein levels in amniotic fluids from spontaneous abortions. Brit. med. J . 2, 524-525. Seppala, M. (1975). Fetal pathophysiology of human alpha-fetoprotein. Ann. N . Y . Acad. Sci. 259, 59-73. Singh, R. P. (1970). Hygroma of the neck in XO abortuses. Amer. J . clin. Path. 53, 104107. Valenti, C., E. G. Kassner, V. Yermakov & E. Cromb (1975). Antenatal diagnosis of a fetal ovarian cyst. Amer. J . Obstet. Gynec. 123, 216-219.
355
Weiss, R. R., J. N. Macri & K. W. Elligers (1976). Origin of amniotic fluid alpha-fetoprotein in normal and defective pregnancies. Obstet. Gynec. 47, 697-700. Weiss, P. A. M., P. Purstner, W. Lichtenegger & R. Winter (1978). Alpha-fetoprotein content of amniotic fluid in normal and abnormal pregnancies. Obstet. Gynec. 51, 582-585. Wright, E. V., A. S. McIntosh & J. W. Foulds (1975). Importance of routine a-fetoprotein estimations. Lancet i, 769.
Address: Dr. Juan Chemke Clinical Genetics Unit Kaplan Hospital Rehovot Israel
Prenatal diagnosis of severe congenital malformations associated with elevated amniotic fluid alpha-feto protein J.
CHEMKEI,
R. NISANI~, R. KASSIF~,M. LANCET^, R. BEISER.~ AND N. HURWITZ~
Clinical Genetics Unit, 2 Department of Obstetrics and Gynecology, 3 Laboratory of Microbiology, and 4 Department of Pathology, Kaplan Hospital, Rehovot, Israel (affiliated to the Hebrew University and Hadassah Medical School)
1
Two cases of severely malformed infants with abnormal fetal images on B-scan sonography and markedly elevated amniotic fluid AFP are presented. There was no evidence of neural tube anomalies. The importance of an amniocentesis and AFP in pregnancies with an abnormal fetal image on B-scan sonography is emphasized, taking into consideration that most pregnancies with elevated fluid AFP have serious fetal anomalies. Received 4 August, revised 29 September, accepted f o r publication 26 October I978 Key words: Alpha-feto-protein; congenital malformations; prenatal diagnosis; trisomy 18;
Turner syndrome; ultrasound.
Amniotic fluid alpha-feto protein (AFP) determination is a well recognized test for the prenatal diagnosis of open neural tube defects. A variety of congenital malformations have also been found to be associated with elevated A F P levels (Seppala 1975, Weiss et al. 1976), even though the mechanism f o r this phenomenon is not always clear. O u r prenatal diagnostic program includes routine B-scan sonographic examination of the uterus in high-risk pregnancies and prior t o every amniocentesis. We have recently encountered two cases of abnormal fetal images on B-scan sonography and markedly elevated amniotic fluid A F P . Both pregnancies were interrupted and the fetuses were severely malformed, without evidence of neural tube anomalies. 0009-9163/79/040351-05
T h e purpose of the present paper is to call attention to the importance of amniocentesis and A F P determination in pregnancies in which mid-trimester B-scan sonography raises the question of abnormal fetal development. Case Reports Case 1. A 19-year-old female, gravida 2,
para 1, a b 0, was admitted to hospital at 20 weeks of gestation, because of imminent abortion. B-scan ultrasonography revealed a n excessive amount of amniotic fluid; the fetal head was not clearly demonstrated and the fetal trunk appeared unusual in shape, resembling a cystic formation. A repeat Bscan at 23 weeks of gestation revealed a
$02.50/0 0 1979 Munksgaard, Copenhagen
352
CHEMKE, NISANI, KASSIF, LANCET, BEISER AND HURWITZ
Fig. 1. Case 1. View of intraabdominal organs. Note displaced and compressed intestinal loops and grossly distended urachus.
fetal head with a biparietal diameter of 5.5 cm, corresponding to 21 weeks of gestation. The fetal chest appeared very small. An abdominal X-ray demonstrated one fetus with a small, abnormally shaped head. The fetal chest appeared compressed. An amniocentesis was performed: AFP levels, assayed by rocket-immunoelectrophoresis (Norgaard-Pedersen 1973), were 450 pg/ml and chromosome analysis of amniotic fluid cell culture revealed a 47, XX, 18 karyotype. In view of the elevated AFP levels and the ultrasonography findings, pregnancy was interrupted by intrauterine instillation of a hypertonic saline solution. The fetus was moderately macerated, weighing 490 g, with a markedly dilated and ruptured abdominal wall. There were no neural tube malformations. The head was dolichocephalic and small,
+
with low-set ears. The chest was very small and compressed upwards by the huge abdomen. Changes secondary t o extreme intraabdominal pressure consisted of posterior displacement and compression of all intraperitoneal organs (Fig. 1). The abdominal wall was replaced by a large cystic formation, a greatly dilated and hypertrophic urachus, connected to the grossly distended urinary bladder, thus forming a vesicoumbilical fistula (Fig. 2). The kidneys and ureters appeared normal, but the urethra and rectum were atretic. The spleen was absent. There was complete agenesis of the uterus, fallopian tubes and vagina. The external genitalia were ambiguous: a small phallus was observed, but no urogenital or anal orifices were present. Histological examination of the gonads revealed normal ovaries. Short fifth digits with clinodactyly and a single flexion crease were present on both hands; the dermatoglyphic patterns could not be identified. The umbilical cord had only one artery. Case 2. A 29-year-old female, gravida 2 , para 1, ab 0, had B-scan ultrazonography because of suspected intrauterine growth retardation, at 18 weeks of gestation. A difference of 4 weeks was found between the fetal biparietal diameter and the estimated gestational age. Two translucent formations were observed close to the fetal head (Fig. 3). A tentative diagnosis of bilateral cystic hygroma was established, and a repeat B-scan 2 weeks later revealed the same picture with only a slight increase in the fetal biparietal diameter and with no fetal heart beats. In view of these findings, the pregnancy was terminated by intrauterine instillation of a hypertonic saline solution. Amniotic fluid AFP prior to the termination of pregnancy was 570 pg/ml; attempted culture of amniotic fluid cells was unsuccessful. A macerated female fetus with markedly
AFP A N D PRENATAL D I A G N O S I S
353
Flg. 2. Case 1. Opened thickwalled urachus. Note blindly ending rectum,
edematous limbs was delivered. Large bilateral cystic hygromas of the neck were found. No other congenital malformations were observed. The umbilical cord had two arteries. Discussion
Elevated amniotic fluid AFP has been re-
ported in various types of fetal developmental pathology other than open neural tube defects (Leschot & Treffers 1975, Seppala 1975, Milunsky & Alpert 1976b, Weiss et al. 1976, Clarke et al. 1977, King & Prescott 1978). Recently it was shown that some of these anomalies can also be suspected on Bscan sonography (Valenti et al. 1975, Bartley et al. 1977, Nevin et al. 1978). B-scan
Fig. 3. Case 2. Transverse Bscan sonography at 18 weeks of gestation. a. Fetal head. b. Bilateral cystic areas (cystic hygroma).
354
CHEMKE, NISANI, KASSIF, LANCET, BEISER AND HURWITZ
sonography is routinely performed in many genetic centers prior to amniocentesis, in order to locate the placenta and an amniotic fluid pool; to establish the number of fetuses and their gestational age; and to examine the fetal head and spine in the search for open neural tube defects. The precise cause of the increased amniotic fluid AFP is still a matter for discussion. AFP, being a normal fetal protein, may appear in increased amounts in the amniotic fluid for a variety of reasons, but it appears mainly as a consequence of two groups of fetal conditions: increased production or synthesis by fetal tissues; and transudation or excretion of fetal protein into the amniotic fluid (Weiss et al. 1976). The 200:l concentration gradient between fetal serum and amniotic fluid (Weiss et al. 1976) might explain the transudation of fetal protein through a body defect covered by a thin and highly vascularized membrane. This could be the case in the fetus with trisomy 18 and the persistent urachus in which there may have been transudation of ascitic fluid proteins into the amniotic fluid. Fetuses with Turner syndrome characteristically present with cystic hygroma (Singh 1970, Gellis et al. 1978), and raised amniotic fluid A F P has been reported (Seller et al. 1974, Hunter et al. 1976). Therefore, it can be speculated that our female fetus with bilateral cystic hygroma may also have been a case of Turner syndrome, although the specific chromosomal aberration could not be demonstrated. Another contributing mechanism in this case could be fetal death and maceration, since it has been shown that human fetal skin and muscle are rich sources of this protein before 17.5 weeks of gestation (Lawler & Nash 1977). The importance of alpha-feto protein determinations in every sample of amniotic fluid has been pointed out by several investigators (Wright et al. 1975, Ainbender & Hirschhorn 1976, Milunsky & Alpert 1976a,
Weiss et al. 1978), and is further emphasized by the two present cases of severe fetal malformations, as well as the observation that most pregnancies with elevated amniotic fluid A F P have serious fetal anomalies (Nevin et al. 1978). The present cases illustrate the need for amniocentesis and A F P determinations in pregnancies with an abnormal fetal image on B-scan sonography.
References
Ainbender, E. & K. Hirschhorn (1976). Routine alpha-fetoprotein studies in amniotic fluid. Lancet i, 597. Bartley, J. A., M. S. Golbus, R. A. Filly & B. D. Hall (1977). Prenatal diagnosis of dysplastic kidney disease. Clin. Genet. 11, 374378. Clarke, P. C., Y. B. Gordon, M. J. Kitau, T. Chard & A. D. McNeal (1977). Alpha-fetoprotein levels in pregnancies complicated by gastrointestinal abnormalities of the fetus. Brit. J . Obstet. Gynaec. 84, 285-289. Gellis, S. S., M. Feingold, G. R. Southerland & J . G. Rogers (1978). Fetal Turner’s syndrome. Amer. J . Dis. Child. 132, 417418. Hunter, A., J. L. Hammerton, T. Baskett & E. Lyons (1976). Raised amniotic fluid alphafetoprotein in Turner syndrome. Lancet i, 598. King, C. R. & G. H. Prescott (1978). Amniotic fluid alpha-fetoprotein elevation with fetal omphalocele and a possible mechanism for its occurrence. Amer. J . Obstet. Gynec. 130, 279-283. Lawler, S. D. & S. G . Nash (1977). Alpha-fetoprotein in fetal skin and muscle. Brit. J . Obstet. Gynaec. 84, 51-54. Leschot, N. J. & P. E. Treffers (1975). Elevated amniotic fluid alpha-fetoprotein without neural-tube defects. Lancet ii, 1141. Milunsky, A. & E. Alpert (1976a). Prenatal diagnosis of neural tube defects. I. Problems and pitfalls: analysis of 2495 cases using the alpha-fetoprotein assay. Obslet. Gynec. 48, 1-5.
Milunsky, A. & E. Alpert (1976b). Prenatal diagnosis of neural tube defects. 11. Analysis of false positive and false negative alphafetoprotein results. Obstet. Gynec. 48, 6-12. Nevin, N. C., A. Ritchie, F. McKeown & G. Roberts (1978). Raised alpha-fetoprotein
AFP AND PRENATAL DIAGNOSIS
levels in amniotic fluid and maternal serum associated with distension of the fetal bladder caused by absence of urethra. J . med. Genet. 15, 61-78. Norgaard-Pedersen, B. (1973). Alpha l-fetoprotein. Scand. J . Immunol. 2, Suppl. 1 . 107-110. Seller, M. J., M. R. Creasy & E. I). Alberman (1974). Alpha-feto protein levels in amniotic fluids from spontaneous abortions. Brit. med. J . 2, 524-525. Seppala, M. (1975). Fetal pathophysiology of human alpha-fetoprotein. Ann. N . Y . Acad. Sci. 259, 59-73. Singh, R. P. (1970). Hygroma of the neck in XO abortuses. Amer. J . clin. Path. 53, 104107. Valenti, C., E. G. Kassner, V. Yermakov & E. Cromb (1975). Antenatal diagnosis of a fetal ovarian cyst. Amer. J . Obstet. Gynec. 123, 216-219.
355
Weiss, R. R., J. N. Macri & K. W. Elligers (1976). Origin of amniotic fluid alpha-fetoprotein in normal and defective pregnancies. Obstet. Gynec. 47, 697-700. Weiss, P. A. M., P. Purstner, W. Lichtenegger & R. Winter (1978). Alpha-fetoprotein content of amniotic fluid in normal and abnormal pregnancies. Obstet. Gynec. 51, 582-585. Wright, E. V., A. S. McIntosh & J. W. Foulds (1975). Importance of routine a-fetoprotein estimations. Lancet i, 769.
Address: Dr. Juan Chemke Clinical Genetics Unit Kaplan Hospital Rehovot Israel
