Hum. Genet. 43, 333--336 (1978) © by Springer-Verlag 1978
Prenatal Diagnosis of Meckel Syndrome Nico J. Leschot 1. , Jaak J. de Nef 2, Mies J. Becker-Bloemkolk 3, Marianne Verjaal I, and Paul F. Wiesenhaan 4 I Dept. of Human Genetics, University of Amsterdam, Sarphatistraat 217, Amsterdam, The Netherlands z Dept. of Pediatrics, R. K. Maria Stichting, Haarlem, The Netherlands 3Dept. of Pathology, University of Amsterdam, Amsterdam, The Netherlands 4Dept. of Gynecology and Obstetrics, R. K. Maria Stichting, Haarlem, The Netherlands
Summary. The three main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. Prenatal diagnosis of a fetus with Meckel s y n d r o m e was made in the 16th week of gestation by means of amniotic fluid alpha1 fetoprotein estimation. The indication for amniocentesis was a previous child with an occipital meningocele and polycystic kidneys. Interpretation of the alphai-fetoprotein value (240 gg/ml) was difficult due to fetal b l o o d contamination. Prenatal diagnosis is indicated in any pregnancy following the birth of a child with only two major symptoms of Meckel syndrome.
Introduction The main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. At least two of these should be present to establish the diagnosis (Fried et al., 1971). The s y n d r o m e is caused by an autosomal recessive gene. Since open neural tube defects can be detected prenatally by alphal-fetoprotein (AFP) estimation, antenatal diagnosis of Meckel syndrome should be possible in the majority o f cases. We wish to report a family in which, after the birth of the first child with Meckel syndrome, prenatal diagnosis of an affected fetus was made in the 16th week of a subsequent pregnancy.
Case Report A female infant, the first child of nonconsanguineous, healthy parents, was born in 1975 after 32 weeks' gestation. She died after 30 rain, of serious multiple congenital malformations; her birthweight was 2760g. The family history was unremarkable. The malformations included: microcephaly (head circumference 27 cm), epicanthus, dysplastic ears, low-set left ear, saddle nose, median meningocele situated in the upper occipital *
To whom offprint requests should be sent
0340-6717/78/0043/0333/$01.00
334
N.J. Leschot et al.
region while a second smaller meningocele was located in the lower occipital region, and club feet. There was no polydactyly. Physical examination revealed a large mass in the kidney region, minimal development of abdominal wall muscles, and limited extension of elbow and hipjoints. Autopsy (Dr. R. Ingenhoes) revealed: meningocele in the region of the posterior fontanel and a second meningocele in connection with an occipital bone defect, abnormal and enlarged liver with bile duct proliferation, and kidneys showing macro- and microcystic degeneration of the tubuli. Other findings were all within normal limits. Chromosomal analysis revealed a normal female karyotype (46,XX; G banding). The baby was considered to have Meckel syndrome (Dr. Kuijten, Utrecht). The recurrence risk of 25% was discussed with the parents, and the couple were informed of the possibility of prenatal detection of this condition during a subsequent pregnancy. In the 16th week of the uncomplicated second pregnancy amniocentesis was performed after echoscopic examination, and 14ml sanguinolent amniotic fluid was aspirated; AFP estimation revealed a value of 240.0 gg/ml (Behringwerke Reagentia). Unfortunately, however, fetal hemoglobin was also detected in this amniotic fluid sample (0.002mmol/liter). In the routinely observed amniotic fluid cell cultures many macrophages were noted. Chromosomal analysis of the amniotic fluid cells revealed a normal male karyotype (46,XY; Q banding). After our findings had been discussed with the couple, they asked for an interruption of the pregnancy. Extra-amniotic instillation of Fz-alpha prostaglandin in the 17th week of gestation resulted in the stillbirth of a male fetus.
Autopsy Macroscopic Findings S t i l l b o r n male fetus o f 120g. C r o w n - h e e l length 17cm.
Head. M i c r o c e p h a l y . Occipital encephalocele ( d i a m e t e r 2 cm), r u p t u r e d at the left side; n o r m a l ear i m p l a n t a t i o n ; h y p e r t e l o r i s m , b r o a d m o u t h with h y p o g n a t h i a and micrognathia.
Thorax-Abdomen. N o r m a l h e a r t a n d lungs; n o r m a l liver w i t h o u t cysts; polycystic kidneys; a d r e n a l h y p o p l a s i a ; n o r m a l male testes, n o t descended, which is n o r m a l for the age. Extremities. N o signs o f p o l y d a c t y l y or syndactyly; club feet a n d a r m flexion deformity.
Brain. H y p o p l a s i a o f c e r e b r u m with c o m p l e t e s m o o t h surface; cerebellum a p p a r e n t l y n o r m a l ; cranial nerves were present a n d showed no o b v i o u s a b n o r m alities; an e n c e p h a l o m y e l o c e l e was situated in the r o o f o f the f o u r t h ventricle; the base of the skull s h o w e d a h y p o p l a s t i c a n d s h a l l o w a n t e r i o r a n d lateral cranial fossa; the p o s t e r i o r cranial fossa was b r o a d a n d flat; X - r a y e x a m i n a t i o n revealed cervical arch agenesis.
Placenta. W e i g h t 120g. The u m b i l i c a l cord, which h a d a lateral insertion, c o n t a i n e d three n o r m a l vessels. M i c r o s c o p i c e x a m i n a t i o n s h o w e d an i m m a t u r e aspec t o f the villi with no specific a b n o r m a l i t i e s ,
Microscopic Findings Kidneys. N o r m a l d e v e l o p m e n t , despite i m m a t u r e aspect o f g l o m e r u l a r system a n d p r o x i m a l t u b u l a r system. The distal t u b u l a r system s h o w e d cystic dilatation. N o h e t e r o t o p i c elements were found.
Prenatal Diagnosis of Meckel Syndrome
335
Adrenals. The cortex showed an irregular arrangement with cystic degeneration. The fetal zone was small with regressive changes and many so-called neuroblastoma islands. The other microscopic findings were all within normal limits, except for a generalized immature aspect.
Discussion To the best of our knowledge this is the third prospective case of prenatal detection of Meckel syndrome to be reported. Chemke et al. (1977) reported a case detected prenatally in the 17th week of gestation. Aula et al. (1977) described the prenatal detection of a fetus with Meckel syndrome, with interruption of the pregnancy in the 19th week. Seller et al. (1975) and Milunsky and Alpert (1976) each published a case with elevated A F P values, in which after interruption of the pregnancy the fetus was found to have Meckel syndrome. Since a neural tube defect is not a mandatory symptom of Meckel syndrome (Mecke et al., 1971), prenatal detection of this syndrome by means of A F P determination was thought to be possible only in about 75% of all cases. The observation of Chemke et al. (1977), however, clearly showed that prenatal detection in a case of Meckel syndrome without a neural tube defect is also possible. In the case of Chemke this was probably due to an elevated A F P value of renal origin, though the precise mechanism of A F P kinetics in that observation remains obscure. Polydactyly was not present in our two cases; radiologic examination also failed to reveal any skeletal abnormality of the hands or feet. The other findings correspond well with the clinical description of the two prospectively detected cases reported so far. The A F P value of 240 gg/ml is 36 standard deviations above the mean. We calculated that the fetal blood contamination (0.002 mmol/liter) probably contributed less than 2 gg/ml to this value: fetal serum AFP levels are in the range of 1--4 mg/ml (Adinolfi et al., 1975), while the fetal blood hemoglobin concentration can be estimated as in the range of 6--9 mmol/liter (Altman and Dittmer, 1974). In addition, many macrophages were observed in the amniotic fluid cell cultures, and we concluded that these findings were very suggestive of a fetal neural tube defect. Our case adds further evidence to the view that prenatal diagnosis by means of amniotic fluid A F P estimation is strongly indicated in any pregnancy following the birth of a child with only two symptoms of Meckel syndrome.
Acknowledgements. The technical assistance of F. Koperdraad and Mrs. M. Stam-Johan is highly appreciated.
References Adinolfi, A., Adinolfi, M., Lessof, M. H.: Alpha-fetoprotein during development and in disease. J. Med. Genet. 12, 138--151 (1975) Altman, P. L., Dittmer, D. S.: Biological Data Book, Vol. III, 2nd ed. Bethesda, Maryland: Federation of American Societies for Experimental Biology 1974
336
N.J. Leschot et al.
Aula, P., Karjalainen, O., Rapola, J., Lindgren, J., Sepp~llg, M.: Prenatal diagnosis of the Meckel syndrome. Am. J. Obstet. Gynecol. 129, 700--702 (1977) Chemke, J., Miskin, A., Rav-Acha, Z., Porath, A., Sagiv, M., Katz, Z.: Prenatal diagnosis of Meckel syndrome: alpha-fetoprotein and beta-trace protein in amniotic fluid. Clin. Genet. 11, 285--289 (1977) Fried, K., Liban, E., Lnrie, M., Friedman, S., Reisner, S. H.: Polycystic kidney associated with malformations of the brain, polydactyly, and other birth defects in newborn sibs. J. Med. Genet. 8, 285--290 (1971) Mecke, S., Passarge, E.: Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders: the Meckel syndrome. Ann. Genet. (Paris) 14, 97--103 (1971) Milunsky, A., Alpert, E.: Prenatal diagnosis of neural tube defects. Obstet. Gynecol. 48, 1--5 (1976) Seller, M. J.: Prenatal diagnosis of a neural tube defect: Meckel syndrome. J. Med. Genet. 12, 109--110 (1975)
Received March 29, 1978
Prenatal Diagnosis of Meckel Syndrome Nico J. Leschot 1. , Jaak J. de Nef 2, Mies J. Becker-Bloemkolk 3, Marianne Verjaal I, and Paul F. Wiesenhaan 4 I Dept. of Human Genetics, University of Amsterdam, Sarphatistraat 217, Amsterdam, The Netherlands z Dept. of Pediatrics, R. K. Maria Stichting, Haarlem, The Netherlands 3Dept. of Pathology, University of Amsterdam, Amsterdam, The Netherlands 4Dept. of Gynecology and Obstetrics, R. K. Maria Stichting, Haarlem, The Netherlands
Summary. The three main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. Prenatal diagnosis of a fetus with Meckel s y n d r o m e was made in the 16th week of gestation by means of amniotic fluid alpha1 fetoprotein estimation. The indication for amniocentesis was a previous child with an occipital meningocele and polycystic kidneys. Interpretation of the alphai-fetoprotein value (240 gg/ml) was difficult due to fetal b l o o d contamination. Prenatal diagnosis is indicated in any pregnancy following the birth of a child with only two major symptoms of Meckel syndrome.
Introduction The main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. At least two of these should be present to establish the diagnosis (Fried et al., 1971). The s y n d r o m e is caused by an autosomal recessive gene. Since open neural tube defects can be detected prenatally by alphal-fetoprotein (AFP) estimation, antenatal diagnosis of Meckel syndrome should be possible in the majority o f cases. We wish to report a family in which, after the birth of the first child with Meckel syndrome, prenatal diagnosis of an affected fetus was made in the 16th week of a subsequent pregnancy.
Case Report A female infant, the first child of nonconsanguineous, healthy parents, was born in 1975 after 32 weeks' gestation. She died after 30 rain, of serious multiple congenital malformations; her birthweight was 2760g. The family history was unremarkable. The malformations included: microcephaly (head circumference 27 cm), epicanthus, dysplastic ears, low-set left ear, saddle nose, median meningocele situated in the upper occipital *
To whom offprint requests should be sent
0340-6717/78/0043/0333/$01.00
334
N.J. Leschot et al.
region while a second smaller meningocele was located in the lower occipital region, and club feet. There was no polydactyly. Physical examination revealed a large mass in the kidney region, minimal development of abdominal wall muscles, and limited extension of elbow and hipjoints. Autopsy (Dr. R. Ingenhoes) revealed: meningocele in the region of the posterior fontanel and a second meningocele in connection with an occipital bone defect, abnormal and enlarged liver with bile duct proliferation, and kidneys showing macro- and microcystic degeneration of the tubuli. Other findings were all within normal limits. Chromosomal analysis revealed a normal female karyotype (46,XX; G banding). The baby was considered to have Meckel syndrome (Dr. Kuijten, Utrecht). The recurrence risk of 25% was discussed with the parents, and the couple were informed of the possibility of prenatal detection of this condition during a subsequent pregnancy. In the 16th week of the uncomplicated second pregnancy amniocentesis was performed after echoscopic examination, and 14ml sanguinolent amniotic fluid was aspirated; AFP estimation revealed a value of 240.0 gg/ml (Behringwerke Reagentia). Unfortunately, however, fetal hemoglobin was also detected in this amniotic fluid sample (0.002mmol/liter). In the routinely observed amniotic fluid cell cultures many macrophages were noted. Chromosomal analysis of the amniotic fluid cells revealed a normal male karyotype (46,XY; Q banding). After our findings had been discussed with the couple, they asked for an interruption of the pregnancy. Extra-amniotic instillation of Fz-alpha prostaglandin in the 17th week of gestation resulted in the stillbirth of a male fetus.
Autopsy Macroscopic Findings S t i l l b o r n male fetus o f 120g. C r o w n - h e e l length 17cm.
Head. M i c r o c e p h a l y . Occipital encephalocele ( d i a m e t e r 2 cm), r u p t u r e d at the left side; n o r m a l ear i m p l a n t a t i o n ; h y p e r t e l o r i s m , b r o a d m o u t h with h y p o g n a t h i a and micrognathia.
Thorax-Abdomen. N o r m a l h e a r t a n d lungs; n o r m a l liver w i t h o u t cysts; polycystic kidneys; a d r e n a l h y p o p l a s i a ; n o r m a l male testes, n o t descended, which is n o r m a l for the age. Extremities. N o signs o f p o l y d a c t y l y or syndactyly; club feet a n d a r m flexion deformity.
Brain. H y p o p l a s i a o f c e r e b r u m with c o m p l e t e s m o o t h surface; cerebellum a p p a r e n t l y n o r m a l ; cranial nerves were present a n d showed no o b v i o u s a b n o r m alities; an e n c e p h a l o m y e l o c e l e was situated in the r o o f o f the f o u r t h ventricle; the base of the skull s h o w e d a h y p o p l a s t i c a n d s h a l l o w a n t e r i o r a n d lateral cranial fossa; the p o s t e r i o r cranial fossa was b r o a d a n d flat; X - r a y e x a m i n a t i o n revealed cervical arch agenesis.
Placenta. W e i g h t 120g. The u m b i l i c a l cord, which h a d a lateral insertion, c o n t a i n e d three n o r m a l vessels. M i c r o s c o p i c e x a m i n a t i o n s h o w e d an i m m a t u r e aspec t o f the villi with no specific a b n o r m a l i t i e s ,
Microscopic Findings Kidneys. N o r m a l d e v e l o p m e n t , despite i m m a t u r e aspect o f g l o m e r u l a r system a n d p r o x i m a l t u b u l a r system. The distal t u b u l a r system s h o w e d cystic dilatation. N o h e t e r o t o p i c elements were found.
Prenatal Diagnosis of Meckel Syndrome
335
Adrenals. The cortex showed an irregular arrangement with cystic degeneration. The fetal zone was small with regressive changes and many so-called neuroblastoma islands. The other microscopic findings were all within normal limits, except for a generalized immature aspect.
Discussion To the best of our knowledge this is the third prospective case of prenatal detection of Meckel syndrome to be reported. Chemke et al. (1977) reported a case detected prenatally in the 17th week of gestation. Aula et al. (1977) described the prenatal detection of a fetus with Meckel syndrome, with interruption of the pregnancy in the 19th week. Seller et al. (1975) and Milunsky and Alpert (1976) each published a case with elevated A F P values, in which after interruption of the pregnancy the fetus was found to have Meckel syndrome. Since a neural tube defect is not a mandatory symptom of Meckel syndrome (Mecke et al., 1971), prenatal detection of this syndrome by means of A F P determination was thought to be possible only in about 75% of all cases. The observation of Chemke et al. (1977), however, clearly showed that prenatal detection in a case of Meckel syndrome without a neural tube defect is also possible. In the case of Chemke this was probably due to an elevated A F P value of renal origin, though the precise mechanism of A F P kinetics in that observation remains obscure. Polydactyly was not present in our two cases; radiologic examination also failed to reveal any skeletal abnormality of the hands or feet. The other findings correspond well with the clinical description of the two prospectively detected cases reported so far. The A F P value of 240 gg/ml is 36 standard deviations above the mean. We calculated that the fetal blood contamination (0.002 mmol/liter) probably contributed less than 2 gg/ml to this value: fetal serum AFP levels are in the range of 1--4 mg/ml (Adinolfi et al., 1975), while the fetal blood hemoglobin concentration can be estimated as in the range of 6--9 mmol/liter (Altman and Dittmer, 1974). In addition, many macrophages were observed in the amniotic fluid cell cultures, and we concluded that these findings were very suggestive of a fetal neural tube defect. Our case adds further evidence to the view that prenatal diagnosis by means of amniotic fluid A F P estimation is strongly indicated in any pregnancy following the birth of a child with only two symptoms of Meckel syndrome.
Acknowledgements. The technical assistance of F. Koperdraad and Mrs. M. Stam-Johan is highly appreciated.
References Adinolfi, A., Adinolfi, M., Lessof, M. H.: Alpha-fetoprotein during development and in disease. J. Med. Genet. 12, 138--151 (1975) Altman, P. L., Dittmer, D. S.: Biological Data Book, Vol. III, 2nd ed. Bethesda, Maryland: Federation of American Societies for Experimental Biology 1974
336
N.J. Leschot et al.
Aula, P., Karjalainen, O., Rapola, J., Lindgren, J., Sepp~llg, M.: Prenatal diagnosis of the Meckel syndrome. Am. J. Obstet. Gynecol. 129, 700--702 (1977) Chemke, J., Miskin, A., Rav-Acha, Z., Porath, A., Sagiv, M., Katz, Z.: Prenatal diagnosis of Meckel syndrome: alpha-fetoprotein and beta-trace protein in amniotic fluid. Clin. Genet. 11, 285--289 (1977) Fried, K., Liban, E., Lnrie, M., Friedman, S., Reisner, S. H.: Polycystic kidney associated with malformations of the brain, polydactyly, and other birth defects in newborn sibs. J. Med. Genet. 8, 285--290 (1971) Mecke, S., Passarge, E.: Encephalocele, polycystic kidneys, and polydactyly as an autosomal recessive trait simulating certain other disorders: the Meckel syndrome. Ann. Genet. (Paris) 14, 97--103 (1971) Milunsky, A., Alpert, E.: Prenatal diagnosis of neural tube defects. Obstet. Gynecol. 48, 1--5 (1976) Seller, M. J.: Prenatal diagnosis of a neural tube defect: Meckel syndrome. J. Med. Genet. 12, 109--110 (1975)
Received March 29, 1978
