- Email: [email protected]
CNS Findings in iniencephaly: case report and literature review
Pathology (2001 ) 33, pp. 112– 115
CNS FINDINGS IN INIENCEPHALY: CASE REPORT AND LITERATURE REVIEW CHRISTINE K.C. LOO , BRIAN FREEM AN
AND
DOROTA STANFORD
Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool NSW
Summary A male iniencephalic foetus of about 25 weeks gestation is described. The baby was born to a 22-year-old mother, who presented with abdominal pain of 1 day duration. An ultrasound scan at that time showed multiple foetal anomalies and the pregnancy was terminated. A stillborn baby was delivered. At autopsy, characteristic findings of iniencephaly were seen in the dysmorphic foetus as well as multiple structural abnormalities. The autopsy results, with emphasis on the neuropathological findings, are described and various hypotheses of the pathogenesis of iniencephaly are discussed with reference to theories of embryological development and other cases in the literature.
pregnancy. The patient was induced at 25 weeks of gestation and a stillborn infant with multiple abnormalities was born by breech delivery.
RESULTS Autopsy The male foetus weighed 946 g ( NR, 581 ± 178 g) with a crown rump length of 185 mm ( NR, 223 ± 40 mm ), crown heel length of 296 mm ( NR, 311 ± 65 mm) and head circumference of 280 mm. Multiple abnormalities were seen ( Fig. 1 and 2). The foetus appeared dysmorphic, with
Key words: Iniencephaly, Klippel-Feil, CNS dysplasia. Accepted 14 September 2000
INTRODUCTION Iniencephaly is a rare congenital malformation consisting of a defect in the occipital bone causing enlargement of the foramen magnum, accompanied by fusion and rachischisis ( spina bifida) of the upper vertebrae and retroflexion of the head on the spine.1 Two forms of iniencephaly, apertus and clausus, were described by Lewis in 1897.2 In iniencephalus apertus, an encephalocoele projects through a substantial defect in the occipital bone. Iniencephalus clausus describes the condition without an encephalocoele. Iniencephaly may be associated with other congenital malformations.1 Iniencephaly varies in severity, and milder forms may be correctable by surgery, while severe cases are not compatible with life.
CASE REPORT A 22-year-old mother presented at 24 weeks of gestation complaining of para-umbilical pain of 1 day duration. Prior to this presentation, she had received no antenatal care since week 12 of gestation. Her previous obstetric history included two miscarriages and one emergency caesarean section for a cord prolapse at 33 weeks. Her medical history included Grave’s disease treated with anti-thyroid medication ( which she stopped taking) and mild asthma. She also had a few episodes of viral upper respiratory tract infections during this pregnancy. She is a smoker and a “social” drinker. Ultrasonography was carried out and multiple foetal abnormalities were detected. The liquor volume was increased. Amniocentesis and fetal blood samples were taken. Chromosomal analysis showed a normal XY phenotype. She was informed of the scan results in a follow-up visit and counselled regarding the bad prognosis. She opted for termination of
Fig. 1 External appearance of foetus at autopsy, anterior view, showing dysmorphic features.
ISSN 0031–3025 printed/ISSN 1465– 3931 online/01/010112 –04 © 2001 Royal College of Pathologists of Australasia DOI: 10.1080/00313020120035000
INIENCEPHALY
113
Neuropathology
Fig. 2 External appearance of foetus at autopsy, lateral view, showing partial absence of neck and marked retroflexion of the head.
low-set ears and bilateral talipes, enlarged head, a disproportionately short trunk and long limbs. Structural abnormalities included a closed iniencephaly ( iniencephalus clausus), marked oedema of the trunk and neck, an enlarged heart with left ventricular hypoplasia and dilated right atrium, hypoplastic lungs, and left diaphragmatic hernia. From a lateral X-ray, it was estimated that only 23 vertebral bodies were present, with the cervical vertebrae appearing fused and twisted ( Fig. 3). The umbilical cord contained two vessels only. Microscopic examination of the lungs showed a pseudoglandular stage of development, corresponding to about 16 weeks of gestation.
The skull bones showed a normal configuration except that there was a defect of the occipital bone and in this area, the brain was covered by pachymenix only. The falx cerebri and tentorium cerebelli were intact. The foramen magnum was considerably widened and there was separation of the laminae in the upper vertebral column. The brain weighed 118 g ( unfixed ). The gyral pattern of the cerebrum was consistent with the stated gestational age of 25 weeks, but there appeared to be indentations on the surface where the brain tissue had been compressed by dural strictures ( Figs. 4 and 5). The right occipital lobe had herniated into the posterior cranial fossa. On section, the wall of the cerebral cortex was markedly thinned ( 6–10 mm in thickness) and there was a single, large ventricle. Histological examination of the cortex showed lamination consistent with an age of about 24 weeks of gestation. The corpus callosum and septum pellucidum were absent ( Fig. 6). In the posterior region of the ventricle, there were irregularly shaped nodules of tissue in the floor of the ventricular cavity, possibly representing malformed basal ganglia and/or thalami ( Fig. 7). A cord-like strand of tissue was seen in the frontal cortex, possibly representing a malformed cingulate gyrus. Microscopic examination of this structure revealed white matter covered by a layer of foamy macrophage-like cells. The cerebellum was represented by a rudimentary midline structure of about 20 mm maximum coronal width. Some superficial striations were present, possibly indicating rudimentary folia. Microscopy showed three layers in the
Fig. 3 X-rays of foetus. Left; lateral view; centre, right lateral view; right, AP view, showing unfused laminae.
114
LOO et al.
Pathology ( 2001 ), 33, February
Fig. 4 Dorsal view of brain.
Fig. 6 Frontal half of brain, viewed from posterior, showing single, dilated ventricle and absence of corpus callosum.
cerebellar cortex with scattered small, stellate-shaped Purkinje cells. This was consistent with a developmental age of about 15 weeks. The brainstem was poorly developed with absence of normal medullary structures such as the colliculi, and only a rudimentary pons. The cerebral aqueduct however appeared normal in size and position. The hypophyseal stalk was in the normal position and the oculomotor nerves were present and normally positioned.
central nervous system anomalies that includes anencephaly and spina bifida,6– 8 although this has been doubted by some.4 As with anencephaly, the majority of cases occur in female foetuses, with fewer than 15% of cases being male.4 However, it is possible that from fertilization there may be equal numbers of male and female conceptuses that develop with iniencephaly, but such development is associated with a selective loss of male embryos and foetuses.3,9 Other reported findings in iniencephalic foetuses include polyhydramnios, anencephaly, lissencephaly, encephalocoele, diaphragmatic hernia, duodenal atresia, omphalocoele and clubfoot.10 However there are few reports of the neuropathology of this condition. Central nervous system disorders may include microencephaly, polymicrogyria, heterotopic glial tissue in the leptomeninges, atresia of the ventricular system, marked disorganisation of the brainstem, vermian agenesis, cerebellar cysts, and disorganisation of the spinal cord.11,12 Cerebral anomalies are not considered to be specific for iniencephaly, and although the cerebellum is usually dysplastic in the iniencephalic spectrum, as in our case, an iniencephalic with a normal cerebellum has also been mentioned ( but not described).11
DISCUSSION Iniencephaly was named and first described by SaintHilaire in 1836. It is a rare congenital malformation, although estimates of its incidence vary markedly, ranging from about 1/1,000 to 1/65,000 deliveries.3 The cervical and thoracic vertebrae are often reduced in number, and may have unfused elements anteriorly as well as posteriorly.4 Iniencephaly is probably an extreme form of the Klippel-Feil syndrome,5 and it has also been identified with the Chiari Type III hindbrain hernia.6 It has also been suggested that iniencephaly may belong to a spectrum of
Fig. 5 Ventral view of brain.
Fig. 7 Posterior half of brain, viewed from anterior, showing disorganised neural tissue in floor of ventricle.
INIENCEPHALY
The pathogenesis of the axial dysraphic disorders, including iniencephaly, is unknown. One theory can be traced back to Morgagni ( ca. 1760) who proposed that fluid pressure from a hydrocephalic brain could cause hydromyelia in the spinal cord and push the adjacent bones apart.6 Gardner has argued that the primary defect in dysraphia lies in altered growth and altered fluid dynamics of the central nervous system after the neuropores have closed.6,7 Iniencephaly, in particular, results from an internal hydrocephalus pushing the hindbrain into the cervical region, thereby preventing normal formation of the occiput and adjacent vertebrae. Iniencephalus apertus is frequently associated with polyhydramnios.12,13 If the iniencephaly remains closed then polyhydramnios may not ensue. An alternative view has placed the primary defect of iniencephaly not in the neural tissue, but in the adjacent mesoderm, i.e., in the paraxial or chordoaxial mesoderm.14 This theory appears to be based on the incorrect premise that mesodermal growth is the agency responsible for elevation of the neural folds, whereas it would appear, from a large body of embryological studies in the human, that the growth of the neurectoderm itself is the main cause or “engine” that drives the development and segmentation of the mesoderm.15,16 The laminae of the cervical vertebrae normally start to fuse when the fetus is about 40 mm long, and at this time the occipital dural girdle ( which constituted the boundary for the guidance framework for the squamous part of the occipital bone) is well-developed.15 Clearly, the iniencephalic defect in the occipital bone must arise before this time. The youngest iniencephalic embryo described to date, was estimated to be about 50 days post gestation.17 The general consensus is that iniencephaly would have to arise soon after closure of the cranial neuropore at Carnegie Stage XI ( ca. 24 days, 2.5–4.5 mm).4 The failure in the fusion of the cervical neural arches may be caused by a failure of the foramen of Magendie to open, thereby causing local hydrocephalus and distension in the region of the fourth ventricle.3 This would lead to marked changes in the cerebellum, as seen in the present case and reported by others. 11,12 Iniencephaly is usually fatal but five rare cases with longterm survival have been reported and surgical correction of this deformity has also been described.18 – 20 Whether or not iniencephaly is compatible with life seems to depend on the severity of the associated anomalies and the degree of retroflexion.
115
Address for correspondence: C.K.C. L., Department of Anatomical Pathology, South Western Area Pathology Service, Locked Bag 7090, Liverpool BC, NSW 1871, Australia. E-mail: [email protected].
References 1. Papp, Z. Atlas of Fetal Diagnosis. Amsterdam: Elsevier, 1992; 118. 2. Lewis, HF. Iniencephalus. Am J Obstet 1897; 35: 11– 53. 3. Nishimura H, Okamoto N. Iniencephal y. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology, vol. 30. Amsterdam: NorthHolland, 1976; 257–68. 4. Lemire RJ, Loeser JD, Leech RW, Alvord EC. Normal and abnormal development of the human nervous system. Hagerstown: Harper & Row, 1975: 306–7. 5. Gilmour JR. The essential identity of the Klippel-Feil syndrome and iniencephaly. J Pathol Bacteriol 1941; 53: 117– 31. 6. Gardner WJ. Myelocele: rupture of the neural tube? Clin Neurosurg 1967; 15: 57–79. 7. Gardner WJ. The dysraphic states. From syringomyelia to anencephaly. Amsterdam: Excerpta Medica, 1973; 167– 81. 8. Lemire RJ, Beckwith JB, Shepard TH. Iniencephaly and anencephal y with spinal retroflexion. A comparative study of eight human specimens. Teratology 1972; 6: 27–36. 9. Bell JE, Gosden CM. Central nervous system abnormalities– contrasting patterns in early and late pregnancy. Clin Genet 1978; 13: 387– 96. 10. Dogan MM, Ekici E, Yapar EG, Soysal ME, Soysal SK, Gokmen J. Iniencephaly: sonographic-pathologic correlation of 19 cases. J Perinat Med 1996; 24: 510–1. 11. Aleksic S, Budzilovich G, Greco MA, Feigin I, Epstein F, Pearson J. Iniencephaly: a neuropathologic study. Clin Neuropatho l 1983; 2: 55– 61. 12. Aleksic S, Budzilovich GN. Iniencephaly. In: Myrianthopoulos NC, editor. Handbook of clinical neurology, vol. 50. Amsterdam: Elsevier, 1987; 129– 36. 13. Morocz I, Szeifert GT, Molnar P, Toth Z, Csecsei K, Papp Z. Prenatal diagnosis and pathoanatomy of iniencephaly. Clin Genet 1986; 30: 81– 6. 14. Jones MC, Jones KL, Chernoff GF. Possible mesodermal origin for axial dysraphic disorders. J Pediatr 1982; 101: 845– 9. 15. Blechschmidt E. The stages of human development before birth. Basel: Karger, 1960. 16. Blechschmidt E, Gasser RF. Biokinetics and biodynamics of human differentiation. Principles and applications. Springfield: Thomas, 1978; 30–67. 17. Lockwood CB. Retroflexion of an early human embryo associated with absence of the spinal medulla and imperfections of the vertebral column. Trans Obstet Soc London 1887; 29: 234– 3. 18. Sherk HH, Shut L, Chung S. Iniencephalic deformity of the cervical spine with Klippel-Feil anomalies and congenital elevation of the scapula. J Bone Joint Surg 1974; 56A: 1254– 9. 19. Gartman JJ, Melin TE, Lawrence WT, Powers SK. Deformity correction and long-term survival in an infant with iniencephaly. Case Report. J Neurosurg 1991; 75: 126–30. 20. Erdincler P, Kaynar MY, Canbaz B, Kocer N, Kuday C, Ciplak, N. Iniencephaly: neuroradiological and surgical features. Case report and review of the literature. J Neurosurg 1998; 98: 317–20.
CNS FINDINGS IN INIENCEPHALY: CASE REPORT AND LITERATURE REVIEW CHRISTINE K.C. LOO , BRIAN FREEM AN
AND
DOROTA STANFORD
Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool NSW
Summary A male iniencephalic foetus of about 25 weeks gestation is described. The baby was born to a 22-year-old mother, who presented with abdominal pain of 1 day duration. An ultrasound scan at that time showed multiple foetal anomalies and the pregnancy was terminated. A stillborn baby was delivered. At autopsy, characteristic findings of iniencephaly were seen in the dysmorphic foetus as well as multiple structural abnormalities. The autopsy results, with emphasis on the neuropathological findings, are described and various hypotheses of the pathogenesis of iniencephaly are discussed with reference to theories of embryological development and other cases in the literature.
pregnancy. The patient was induced at 25 weeks of gestation and a stillborn infant with multiple abnormalities was born by breech delivery.
RESULTS Autopsy The male foetus weighed 946 g ( NR, 581 ± 178 g) with a crown rump length of 185 mm ( NR, 223 ± 40 mm ), crown heel length of 296 mm ( NR, 311 ± 65 mm) and head circumference of 280 mm. Multiple abnormalities were seen ( Fig. 1 and 2). The foetus appeared dysmorphic, with
Key words: Iniencephaly, Klippel-Feil, CNS dysplasia. Accepted 14 September 2000
INTRODUCTION Iniencephaly is a rare congenital malformation consisting of a defect in the occipital bone causing enlargement of the foramen magnum, accompanied by fusion and rachischisis ( spina bifida) of the upper vertebrae and retroflexion of the head on the spine.1 Two forms of iniencephaly, apertus and clausus, were described by Lewis in 1897.2 In iniencephalus apertus, an encephalocoele projects through a substantial defect in the occipital bone. Iniencephalus clausus describes the condition without an encephalocoele. Iniencephaly may be associated with other congenital malformations.1 Iniencephaly varies in severity, and milder forms may be correctable by surgery, while severe cases are not compatible with life.
CASE REPORT A 22-year-old mother presented at 24 weeks of gestation complaining of para-umbilical pain of 1 day duration. Prior to this presentation, she had received no antenatal care since week 12 of gestation. Her previous obstetric history included two miscarriages and one emergency caesarean section for a cord prolapse at 33 weeks. Her medical history included Grave’s disease treated with anti-thyroid medication ( which she stopped taking) and mild asthma. She also had a few episodes of viral upper respiratory tract infections during this pregnancy. She is a smoker and a “social” drinker. Ultrasonography was carried out and multiple foetal abnormalities were detected. The liquor volume was increased. Amniocentesis and fetal blood samples were taken. Chromosomal analysis showed a normal XY phenotype. She was informed of the scan results in a follow-up visit and counselled regarding the bad prognosis. She opted for termination of
Fig. 1 External appearance of foetus at autopsy, anterior view, showing dysmorphic features.
ISSN 0031–3025 printed/ISSN 1465– 3931 online/01/010112 –04 © 2001 Royal College of Pathologists of Australasia DOI: 10.1080/00313020120035000
INIENCEPHALY
113
Neuropathology
Fig. 2 External appearance of foetus at autopsy, lateral view, showing partial absence of neck and marked retroflexion of the head.
low-set ears and bilateral talipes, enlarged head, a disproportionately short trunk and long limbs. Structural abnormalities included a closed iniencephaly ( iniencephalus clausus), marked oedema of the trunk and neck, an enlarged heart with left ventricular hypoplasia and dilated right atrium, hypoplastic lungs, and left diaphragmatic hernia. From a lateral X-ray, it was estimated that only 23 vertebral bodies were present, with the cervical vertebrae appearing fused and twisted ( Fig. 3). The umbilical cord contained two vessels only. Microscopic examination of the lungs showed a pseudoglandular stage of development, corresponding to about 16 weeks of gestation.
The skull bones showed a normal configuration except that there was a defect of the occipital bone and in this area, the brain was covered by pachymenix only. The falx cerebri and tentorium cerebelli were intact. The foramen magnum was considerably widened and there was separation of the laminae in the upper vertebral column. The brain weighed 118 g ( unfixed ). The gyral pattern of the cerebrum was consistent with the stated gestational age of 25 weeks, but there appeared to be indentations on the surface where the brain tissue had been compressed by dural strictures ( Figs. 4 and 5). The right occipital lobe had herniated into the posterior cranial fossa. On section, the wall of the cerebral cortex was markedly thinned ( 6–10 mm in thickness) and there was a single, large ventricle. Histological examination of the cortex showed lamination consistent with an age of about 24 weeks of gestation. The corpus callosum and septum pellucidum were absent ( Fig. 6). In the posterior region of the ventricle, there were irregularly shaped nodules of tissue in the floor of the ventricular cavity, possibly representing malformed basal ganglia and/or thalami ( Fig. 7). A cord-like strand of tissue was seen in the frontal cortex, possibly representing a malformed cingulate gyrus. Microscopic examination of this structure revealed white matter covered by a layer of foamy macrophage-like cells. The cerebellum was represented by a rudimentary midline structure of about 20 mm maximum coronal width. Some superficial striations were present, possibly indicating rudimentary folia. Microscopy showed three layers in the
Fig. 3 X-rays of foetus. Left; lateral view; centre, right lateral view; right, AP view, showing unfused laminae.
114
LOO et al.
Pathology ( 2001 ), 33, February
Fig. 4 Dorsal view of brain.
Fig. 6 Frontal half of brain, viewed from posterior, showing single, dilated ventricle and absence of corpus callosum.
cerebellar cortex with scattered small, stellate-shaped Purkinje cells. This was consistent with a developmental age of about 15 weeks. The brainstem was poorly developed with absence of normal medullary structures such as the colliculi, and only a rudimentary pons. The cerebral aqueduct however appeared normal in size and position. The hypophyseal stalk was in the normal position and the oculomotor nerves were present and normally positioned.
central nervous system anomalies that includes anencephaly and spina bifida,6– 8 although this has been doubted by some.4 As with anencephaly, the majority of cases occur in female foetuses, with fewer than 15% of cases being male.4 However, it is possible that from fertilization there may be equal numbers of male and female conceptuses that develop with iniencephaly, but such development is associated with a selective loss of male embryos and foetuses.3,9 Other reported findings in iniencephalic foetuses include polyhydramnios, anencephaly, lissencephaly, encephalocoele, diaphragmatic hernia, duodenal atresia, omphalocoele and clubfoot.10 However there are few reports of the neuropathology of this condition. Central nervous system disorders may include microencephaly, polymicrogyria, heterotopic glial tissue in the leptomeninges, atresia of the ventricular system, marked disorganisation of the brainstem, vermian agenesis, cerebellar cysts, and disorganisation of the spinal cord.11,12 Cerebral anomalies are not considered to be specific for iniencephaly, and although the cerebellum is usually dysplastic in the iniencephalic spectrum, as in our case, an iniencephalic with a normal cerebellum has also been mentioned ( but not described).11
DISCUSSION Iniencephaly was named and first described by SaintHilaire in 1836. It is a rare congenital malformation, although estimates of its incidence vary markedly, ranging from about 1/1,000 to 1/65,000 deliveries.3 The cervical and thoracic vertebrae are often reduced in number, and may have unfused elements anteriorly as well as posteriorly.4 Iniencephaly is probably an extreme form of the Klippel-Feil syndrome,5 and it has also been identified with the Chiari Type III hindbrain hernia.6 It has also been suggested that iniencephaly may belong to a spectrum of
Fig. 5 Ventral view of brain.
Fig. 7 Posterior half of brain, viewed from anterior, showing disorganised neural tissue in floor of ventricle.
INIENCEPHALY
The pathogenesis of the axial dysraphic disorders, including iniencephaly, is unknown. One theory can be traced back to Morgagni ( ca. 1760) who proposed that fluid pressure from a hydrocephalic brain could cause hydromyelia in the spinal cord and push the adjacent bones apart.6 Gardner has argued that the primary defect in dysraphia lies in altered growth and altered fluid dynamics of the central nervous system after the neuropores have closed.6,7 Iniencephaly, in particular, results from an internal hydrocephalus pushing the hindbrain into the cervical region, thereby preventing normal formation of the occiput and adjacent vertebrae. Iniencephalus apertus is frequently associated with polyhydramnios.12,13 If the iniencephaly remains closed then polyhydramnios may not ensue. An alternative view has placed the primary defect of iniencephaly not in the neural tissue, but in the adjacent mesoderm, i.e., in the paraxial or chordoaxial mesoderm.14 This theory appears to be based on the incorrect premise that mesodermal growth is the agency responsible for elevation of the neural folds, whereas it would appear, from a large body of embryological studies in the human, that the growth of the neurectoderm itself is the main cause or “engine” that drives the development and segmentation of the mesoderm.15,16 The laminae of the cervical vertebrae normally start to fuse when the fetus is about 40 mm long, and at this time the occipital dural girdle ( which constituted the boundary for the guidance framework for the squamous part of the occipital bone) is well-developed.15 Clearly, the iniencephalic defect in the occipital bone must arise before this time. The youngest iniencephalic embryo described to date, was estimated to be about 50 days post gestation.17 The general consensus is that iniencephaly would have to arise soon after closure of the cranial neuropore at Carnegie Stage XI ( ca. 24 days, 2.5–4.5 mm).4 The failure in the fusion of the cervical neural arches may be caused by a failure of the foramen of Magendie to open, thereby causing local hydrocephalus and distension in the region of the fourth ventricle.3 This would lead to marked changes in the cerebellum, as seen in the present case and reported by others. 11,12 Iniencephaly is usually fatal but five rare cases with longterm survival have been reported and surgical correction of this deformity has also been described.18 – 20 Whether or not iniencephaly is compatible with life seems to depend on the severity of the associated anomalies and the degree of retroflexion.
115
Address for correspondence: C.K.C. L., Department of Anatomical Pathology, South Western Area Pathology Service, Locked Bag 7090, Liverpool BC, NSW 1871, Australia. E-mail: [email protected].
References 1. Papp, Z. Atlas of Fetal Diagnosis. Amsterdam: Elsevier, 1992; 118. 2. Lewis, HF. Iniencephalus. Am J Obstet 1897; 35: 11– 53. 3. Nishimura H, Okamoto N. Iniencephal y. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology, vol. 30. Amsterdam: NorthHolland, 1976; 257–68. 4. Lemire RJ, Loeser JD, Leech RW, Alvord EC. Normal and abnormal development of the human nervous system. Hagerstown: Harper & Row, 1975: 306–7. 5. Gilmour JR. The essential identity of the Klippel-Feil syndrome and iniencephaly. J Pathol Bacteriol 1941; 53: 117– 31. 6. Gardner WJ. Myelocele: rupture of the neural tube? Clin Neurosurg 1967; 15: 57–79. 7. Gardner WJ. The dysraphic states. From syringomyelia to anencephaly. Amsterdam: Excerpta Medica, 1973; 167– 81. 8. Lemire RJ, Beckwith JB, Shepard TH. Iniencephaly and anencephal y with spinal retroflexion. A comparative study of eight human specimens. Teratology 1972; 6: 27–36. 9. Bell JE, Gosden CM. Central nervous system abnormalities– contrasting patterns in early and late pregnancy. Clin Genet 1978; 13: 387– 96. 10. Dogan MM, Ekici E, Yapar EG, Soysal ME, Soysal SK, Gokmen J. Iniencephaly: sonographic-pathologic correlation of 19 cases. J Perinat Med 1996; 24: 510–1. 11. Aleksic S, Budzilovich G, Greco MA, Feigin I, Epstein F, Pearson J. Iniencephaly: a neuropathologic study. Clin Neuropatho l 1983; 2: 55– 61. 12. Aleksic S, Budzilovich GN. Iniencephaly. In: Myrianthopoulos NC, editor. Handbook of clinical neurology, vol. 50. Amsterdam: Elsevier, 1987; 129– 36. 13. Morocz I, Szeifert GT, Molnar P, Toth Z, Csecsei K, Papp Z. Prenatal diagnosis and pathoanatomy of iniencephaly. Clin Genet 1986; 30: 81– 6. 14. Jones MC, Jones KL, Chernoff GF. Possible mesodermal origin for axial dysraphic disorders. J Pediatr 1982; 101: 845– 9. 15. Blechschmidt E. The stages of human development before birth. Basel: Karger, 1960. 16. Blechschmidt E, Gasser RF. Biokinetics and biodynamics of human differentiation. Principles and applications. Springfield: Thomas, 1978; 30–67. 17. Lockwood CB. Retroflexion of an early human embryo associated with absence of the spinal medulla and imperfections of the vertebral column. Trans Obstet Soc London 1887; 29: 234– 3. 18. Sherk HH, Shut L, Chung S. Iniencephalic deformity of the cervical spine with Klippel-Feil anomalies and congenital elevation of the scapula. J Bone Joint Surg 1974; 56A: 1254– 9. 19. Gartman JJ, Melin TE, Lawrence WT, Powers SK. Deformity correction and long-term survival in an infant with iniencephaly. Case Report. J Neurosurg 1991; 75: 126–30. 20. Erdincler P, Kaynar MY, Canbaz B, Kocer N, Kuday C, Ciplak, N. Iniencephaly: neuroradiological and surgical features. Case report and review of the literature. J Neurosurg 1998; 98: 317–20.