Humangenetik 27, 63--66 (1975) © by Springer-Verlag 1975
Clinical Case Reports Ring Chromosome 13 in a Polymalformed Anencephalie W. S e h m i d 1, J . P. M i i h l e t h a l e r 2, J . B r i n e r 2, a n d H. K n e c h t l i a Division of Medical Genetics, Department of Pediatrics, University of Zurich 1, Institute of Pathology, Kantonsspital Aarau ~ and Department of gynecology and obstetrics, Stgdtisehes Krankenhaus Baden, AG, Switzerland a I~eceived November 18, 1974
Summary. In the 33rd week of pregnancy an amnioeentesis was performed because of low estriol. X-ray indicated the presence of aneneephaly and a premature delivery was induced. Necropsy, in addition to anencephaly, showed a wide variety of malformations. Tile fetal karyotype determined from cultured amniotie fluid cells revealed a ring chromosome 13. A n e n e e p h a l y n o r m a l l y follows a m u l t i f a e t o r i a l m o d e o f i n h e r i t a n c e (Carter, 1966). This, a n d t h e f a c t t h a t t h e p a t i e n t s u s u a l l y are s t i l l b o r n or die s h o r t l y a f t e r b i r t h , u n d o u b t e d l y is r e s p o n s i b l e for t h e p a u c i t y o f c y t o g e n e t i e studies. T h e r e are, h o w e v e r , a n u m b e r of r e p o r t s on v a r i o u s c y t o g e n e t i e a n o m a l i e s f o u n d in p a t i e n t s w i t h a n e n e e p h a l y or o t h e r n e u r a l - t u b e - c l o s u r e defects (for r e v i e w see W r i g h t et al., 1974). W e wish t o r e p o r t a ease in w h i c h t h e r e is l i t t l e d o u b t t h a t t h e o b s e r v e d a n e n c e p h a l y was t h e l e a d i n g s y m p t o m of a m a l f o r m a t i o n s y n d r o m e c a u s e d b y p a r t i a l m o n o s o m y 13. The mother was a 41-year-old I-gravida. She was hospitalized in the 33rd week of pregnancy because of gastroenteritis, and because 2 days earlier a low estriol value of 2.4 mg~o had been found. Under therapy, gastroenteritis quickly subsisted. A second estriol determination gave a value of 1.2 mg~o. The uterine size was smaller than what corresponded to the duration of amenorrhea; the portio was complete, there was no labor. X-ray showed a small fetus and was suggestive of aneneephaly. Amnioeentesis was performed and, motivated by scientific interest, a sample of the amniotic fluid was sent to the genetics laboratory for determination of the fetal karyotype. 1 day later there was no more doubt as to the diagnosis of aneneephaly; labor was induced and after 2 days a malformed female with aneneephaly was delivered. The fetus measured 32 cm and weighed 900 g. Anencephaly was of the type of encephMoeele of the hemispheres; rudimentary structures of the brainstem and the cerebellum were present. All the bones of the calvarium were hypoplastie and apieally there was a defect measuring 3 by 2 cm (Fig. 1). The posterior lobe of the pituitary gland was absent with resulting accelerated involution of the fetal cortex and severe hypoplasia of the adrenals. The eyes were protruding, with slight hypertelorism (Fig. 2) and the external ears were malformed (Fig. 3). There was a flat nasal bridge with the nares displaced laterally. The neck was broad and short, the thorax cylindrical, the mammitlae low set (Fig. 2). The lower legs were short with pes equinovarus adductus deformity bilaterally. The 5th toe on the right foot was implanted dorsally over the 4th toe. Both thumbs were implanted in a distal position. There were numerous internal malformations: aplasia of the left umbilical artery, horizontal positioning of the braehiocephalie vein, Ieft superior vena cava draining into the coronary sinus, hypoplasia of the distal segments of the azygos vein, a small muscular interventricular septal defect, distal dichotomy of the pulmonary artery (distally to the ductus arteriosus Botalli), distal position of the bifurcation of the trachea with an accessory right apical pul-
64
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Fig. 1. Dorsal view of the defect Fig. 2. Frontal view of the anencephalic female :Fig. 3. Lateral view of the head
monary lobe and incomplete formation of pulmonary fissures, accessory spleen, malrotation of the intestine, anal stenosis, aplasia of the tail of the pancreas, median position of the liver, up]asia of the gall bladder and of the left hepatic duct, severe hypoplasia of both kidneys with hydronephrosis and dilatation of the proximal third of both ureters, hypoplasia of the ovaries, uterus duplex and vagina duplex in the upper third, narrow pelvis, and median fissure of the soft palate.
Ring Chromosome 13 in a Polymalibrmed Anencephalie
65
Fig. 4. Partial karyotype, group 13 15 from 4 mitoses; upper 2 rows Orcein-stained, lower 2 rows Giemsa-banded
The k a r y o t y p e was d e t e r m i n e d in c u l t i v a t e d a m n i o t i c fluid cells. 30 mitoses were a n a l y z e d from 12 i n d e p e n d e n t clones s t u d i e d d i r e c t l y on cover glasses; 28 mitoses showed a diploid female k a r y o t y p e w i t h a ring chromosome 13 (Fig. 4). 2 mitoses h a d 45 chromosomes w i t h t h e ring 13 missing. A m n i o t i c fluid alphafetoproteins were n o t y e t s t u d i e d in our l a b o r a t o r y a t t h e t i m e of this observation. The thorough pathological examination of the present case reveals that anencephaly, although the main finding, is just one of many in a polymalformed child. The wide spectrum of anomalies scattered throughout the body is quite typical of the phenotype in autosomal aneuploidies. The main findings in 50 patients with deletions of chromosome 13 recently were reviewed by Niebuhr and Ottosen (1973). It must be pointed out that this selection a priori excluded aneneephaly. In practically all 50 cases microeephaly and other cerebral defects, such as arrhineneephaly, were present hut no neural tube defects are listed. Congenital heart defects were present in the majority of eases. W r i g h t et al. (1974) r e c e n t l y r e p o r t e d a ease of a n e n c e p h a l y born p r e m a t u r e l y in t h e 33rd week of p r e g n a n c y a c c o m p a n i e d b y h y d r a m n i o s . The p a t i e n t h a d an u n b a l a n c e d t r a n s l o c a t i o n i n v o l v i n g a p a r t i a l t r i s o m y 11 and, p r o b a b l y , a t e r m i n a l deletion of chromosome 6. I t is n o t e w o r t h y t h a t in this ease n e c r o p s y revealed a " t y p i c a l l y eranio-rachischisic m a l e " w i t h o u t "gross a n o m a l i e s " of o t h e r organs. The a u t h o r s leave open t h e question w h e t h e r t h e association w i t h a c h r o m o s o m a l a n o m a l y m i g h t h a v e been fortuitous, b u t on t h e basis of t h e observed familial p a t t e r n , a b a l a n c e d reciprocal t r a n s l o e a t i o n in t h e father, c h r o m o s o m a l i n b a l a n e e of t h e m a l f o r m e d i n f a n t a n d a h i s t o r y of consistant r e p r o d u c t i v e casualty, t h e y favor t h e a s s u m p t i o n of a causal relationship. N e u r a l t u b e anomalies or osseous spina bifida are classical s y m p t o m s in surviving p a t i e n t s with t r i s o m y 8 (Longo a n d Maceani, 1965; Caspersson et al., 1972 ; R i i t z l e r et al., in press). I t is, however, n o t y e t k n o w n w h e t h e r this t r i s o m y can lead to aneneephaly. 5
t-Ilxrnangenetik, B d . 27
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W. Schmid et al.
F r o m a prognostic p o i n t of view, a case of a n e n c e p h a l y caused b y a fresh chromosomal m u t a t i o n such as a ring chromosome, a deletion, a d u p l i c a t i o n or a n u m e r i c a l aberration, is quite different from a n o r d i n a r y ease with n o r m a l chromosomes. I n the first ease the recurrence risk is practically nil, in the second ease it is in the order of 5 % (Carter, 1966).
References Carter, C. O. : The genetics of spina bifida. In: Spina bifida~Proceedings of a Symposium held at the Apothecaries Hall, London, E.C. 4, 11 June 1965. London: National Fund for Research into Poliomyelitis and Other Crippling Diseases 1966 Caspersson, T., Lindsten, J., Zech, L., Buckton, K. E., Price, W. H. : Four patients with trisomy 8 identified by the fluorescence and Giemsa banding techniques. J. reed. Genet. 9, 1--7 (1972) Longo, A., Maccani, U.: I1 corredo cromosomico nell'encefMocele. Aggiorn. pediat. 16, 311-318 (1965) Niebuhr, E., Ottosen, J. : Ring chromosome D (13) associated with multiple congenital raMformations. Ann. G4n@t. 16, 157--166 (1973) Rfitzler, L., Briner, J., Saur, F., Schmid, W. : Mosaik-Trisomie-8. Helv. paediat. Aeta (in press) Wright, Y. ~., Clark, W. E., Breg, W. R. : Craniorachisehisis in a partially trisomic 11 fetus in a family with reproductive failure and a reciprocal translocation t(6p~ ; l l q - - ) . J. med. Genet. 11, 69--75 (1974) Prof. Dr. W. Sehmid Abteilung fiir Medizinische Genetik UniversitEts-Kinderklinik CH-8032 Ziirich, Switzerland
Clinical Case Reports Ring Chromosome 13 in a Polymalformed Anencephalie W. S e h m i d 1, J . P. M i i h l e t h a l e r 2, J . B r i n e r 2, a n d H. K n e c h t l i a Division of Medical Genetics, Department of Pediatrics, University of Zurich 1, Institute of Pathology, Kantonsspital Aarau ~ and Department of gynecology and obstetrics, Stgdtisehes Krankenhaus Baden, AG, Switzerland a I~eceived November 18, 1974
Summary. In the 33rd week of pregnancy an amnioeentesis was performed because of low estriol. X-ray indicated the presence of aneneephaly and a premature delivery was induced. Necropsy, in addition to anencephaly, showed a wide variety of malformations. Tile fetal karyotype determined from cultured amniotie fluid cells revealed a ring chromosome 13. A n e n e e p h a l y n o r m a l l y follows a m u l t i f a e t o r i a l m o d e o f i n h e r i t a n c e (Carter, 1966). This, a n d t h e f a c t t h a t t h e p a t i e n t s u s u a l l y are s t i l l b o r n or die s h o r t l y a f t e r b i r t h , u n d o u b t e d l y is r e s p o n s i b l e for t h e p a u c i t y o f c y t o g e n e t i e studies. T h e r e are, h o w e v e r , a n u m b e r of r e p o r t s on v a r i o u s c y t o g e n e t i e a n o m a l i e s f o u n d in p a t i e n t s w i t h a n e n e e p h a l y or o t h e r n e u r a l - t u b e - c l o s u r e defects (for r e v i e w see W r i g h t et al., 1974). W e wish t o r e p o r t a ease in w h i c h t h e r e is l i t t l e d o u b t t h a t t h e o b s e r v e d a n e n c e p h a l y was t h e l e a d i n g s y m p t o m of a m a l f o r m a t i o n s y n d r o m e c a u s e d b y p a r t i a l m o n o s o m y 13. The mother was a 41-year-old I-gravida. She was hospitalized in the 33rd week of pregnancy because of gastroenteritis, and because 2 days earlier a low estriol value of 2.4 mg~o had been found. Under therapy, gastroenteritis quickly subsisted. A second estriol determination gave a value of 1.2 mg~o. The uterine size was smaller than what corresponded to the duration of amenorrhea; the portio was complete, there was no labor. X-ray showed a small fetus and was suggestive of aneneephaly. Amnioeentesis was performed and, motivated by scientific interest, a sample of the amniotic fluid was sent to the genetics laboratory for determination of the fetal karyotype. 1 day later there was no more doubt as to the diagnosis of aneneephaly; labor was induced and after 2 days a malformed female with aneneephaly was delivered. The fetus measured 32 cm and weighed 900 g. Anencephaly was of the type of encephMoeele of the hemispheres; rudimentary structures of the brainstem and the cerebellum were present. All the bones of the calvarium were hypoplastie and apieally there was a defect measuring 3 by 2 cm (Fig. 1). The posterior lobe of the pituitary gland was absent with resulting accelerated involution of the fetal cortex and severe hypoplasia of the adrenals. The eyes were protruding, with slight hypertelorism (Fig. 2) and the external ears were malformed (Fig. 3). There was a flat nasal bridge with the nares displaced laterally. The neck was broad and short, the thorax cylindrical, the mammitlae low set (Fig. 2). The lower legs were short with pes equinovarus adductus deformity bilaterally. The 5th toe on the right foot was implanted dorsally over the 4th toe. Both thumbs were implanted in a distal position. There were numerous internal malformations: aplasia of the left umbilical artery, horizontal positioning of the braehiocephalie vein, Ieft superior vena cava draining into the coronary sinus, hypoplasia of the distal segments of the azygos vein, a small muscular interventricular septal defect, distal dichotomy of the pulmonary artery (distally to the ductus arteriosus Botalli), distal position of the bifurcation of the trachea with an accessory right apical pul-
64
W. Schmid et al.
Fig. 1. Dorsal view of the defect Fig. 2. Frontal view of the anencephalic female :Fig. 3. Lateral view of the head
monary lobe and incomplete formation of pulmonary fissures, accessory spleen, malrotation of the intestine, anal stenosis, aplasia of the tail of the pancreas, median position of the liver, up]asia of the gall bladder and of the left hepatic duct, severe hypoplasia of both kidneys with hydronephrosis and dilatation of the proximal third of both ureters, hypoplasia of the ovaries, uterus duplex and vagina duplex in the upper third, narrow pelvis, and median fissure of the soft palate.
Ring Chromosome 13 in a Polymalibrmed Anencephalie
65
Fig. 4. Partial karyotype, group 13 15 from 4 mitoses; upper 2 rows Orcein-stained, lower 2 rows Giemsa-banded
The k a r y o t y p e was d e t e r m i n e d in c u l t i v a t e d a m n i o t i c fluid cells. 30 mitoses were a n a l y z e d from 12 i n d e p e n d e n t clones s t u d i e d d i r e c t l y on cover glasses; 28 mitoses showed a diploid female k a r y o t y p e w i t h a ring chromosome 13 (Fig. 4). 2 mitoses h a d 45 chromosomes w i t h t h e ring 13 missing. A m n i o t i c fluid alphafetoproteins were n o t y e t s t u d i e d in our l a b o r a t o r y a t t h e t i m e of this observation. The thorough pathological examination of the present case reveals that anencephaly, although the main finding, is just one of many in a polymalformed child. The wide spectrum of anomalies scattered throughout the body is quite typical of the phenotype in autosomal aneuploidies. The main findings in 50 patients with deletions of chromosome 13 recently were reviewed by Niebuhr and Ottosen (1973). It must be pointed out that this selection a priori excluded aneneephaly. In practically all 50 cases microeephaly and other cerebral defects, such as arrhineneephaly, were present hut no neural tube defects are listed. Congenital heart defects were present in the majority of eases. W r i g h t et al. (1974) r e c e n t l y r e p o r t e d a ease of a n e n c e p h a l y born p r e m a t u r e l y in t h e 33rd week of p r e g n a n c y a c c o m p a n i e d b y h y d r a m n i o s . The p a t i e n t h a d an u n b a l a n c e d t r a n s l o c a t i o n i n v o l v i n g a p a r t i a l t r i s o m y 11 and, p r o b a b l y , a t e r m i n a l deletion of chromosome 6. I t is n o t e w o r t h y t h a t in this ease n e c r o p s y revealed a " t y p i c a l l y eranio-rachischisic m a l e " w i t h o u t "gross a n o m a l i e s " of o t h e r organs. The a u t h o r s leave open t h e question w h e t h e r t h e association w i t h a c h r o m o s o m a l a n o m a l y m i g h t h a v e been fortuitous, b u t on t h e basis of t h e observed familial p a t t e r n , a b a l a n c e d reciprocal t r a n s l o e a t i o n in t h e father, c h r o m o s o m a l i n b a l a n e e of t h e m a l f o r m e d i n f a n t a n d a h i s t o r y of consistant r e p r o d u c t i v e casualty, t h e y favor t h e a s s u m p t i o n of a causal relationship. N e u r a l t u b e anomalies or osseous spina bifida are classical s y m p t o m s in surviving p a t i e n t s with t r i s o m y 8 (Longo a n d Maceani, 1965; Caspersson et al., 1972 ; R i i t z l e r et al., in press). I t is, however, n o t y e t k n o w n w h e t h e r this t r i s o m y can lead to aneneephaly. 5
t-Ilxrnangenetik, B d . 27
66
W. Schmid et al.
F r o m a prognostic p o i n t of view, a case of a n e n c e p h a l y caused b y a fresh chromosomal m u t a t i o n such as a ring chromosome, a deletion, a d u p l i c a t i o n or a n u m e r i c a l aberration, is quite different from a n o r d i n a r y ease with n o r m a l chromosomes. I n the first ease the recurrence risk is practically nil, in the second ease it is in the order of 5 % (Carter, 1966).
References Carter, C. O. : The genetics of spina bifida. In: Spina bifida~Proceedings of a Symposium held at the Apothecaries Hall, London, E.C. 4, 11 June 1965. London: National Fund for Research into Poliomyelitis and Other Crippling Diseases 1966 Caspersson, T., Lindsten, J., Zech, L., Buckton, K. E., Price, W. H. : Four patients with trisomy 8 identified by the fluorescence and Giemsa banding techniques. J. reed. Genet. 9, 1--7 (1972) Longo, A., Maccani, U.: I1 corredo cromosomico nell'encefMocele. Aggiorn. pediat. 16, 311-318 (1965) Niebuhr, E., Ottosen, J. : Ring chromosome D (13) associated with multiple congenital raMformations. Ann. G4n@t. 16, 157--166 (1973) Rfitzler, L., Briner, J., Saur, F., Schmid, W. : Mosaik-Trisomie-8. Helv. paediat. Aeta (in press) Wright, Y. ~., Clark, W. E., Breg, W. R. : Craniorachisehisis in a partially trisomic 11 fetus in a family with reproductive failure and a reciprocal translocation t(6p~ ; l l q - - ) . J. med. Genet. 11, 69--75 (1974) Prof. Dr. W. Sehmid Abteilung fiir Medizinische Genetik UniversitEts-Kinderklinik CH-8032 Ziirich, Switzerland
