■ REVIEW ARTICLE ■

PRENATAL DIAGNOSIS OF INIENCEPHALY

Chih-Ping Chen* Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Department of Biotechnology, Asia University, Taichung, and Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan.

SUMMARY Iniencephaly is characterized by a variable deficit of the occipital bones, resulting in an enlarged foramen magnum; partial or total absence of cervical and thoracic vertebrae with an irregular fusion of those present, accompanied by incomplete closure of the vertebral arches and/or bodies; significant shortening of the spinal column due to marked lordosis and hyperextension of the malformed cervicothoracic spine; and an upward-turned face and mandibular skin directly continuous with that of the chest due to the lack of neck. This article provides a com- prehensive review of the reported cases of prenatally detected iniencephaly, including prenatal diagnosis, associ- ated malformations, associated chromosomal abnormalities, and differential diagnosis. Prenatal diagnosis of a neural tube defect involving a body defect in the occiput and rachischisis of the cervical and thoracic spine with retroflexion of the head should raise the suspicion of iniencephaly. Iniencephaly may be associated with cranio- rachischisis and other structural anomalies. Prenatal diagnosis of non-isolated iniencephaly and craniorachis- chisis should alert one to the possibility of chromosomal abnormalities and prompt a cytogenetic investigation. [Taiwan J Obstet Gynecol 2007;46(3):199–208]

Key Words: aneuploidy, craniorachischisis, iniencephaly, Jarcho–Levin syndrome, Klippel–Feil syndrome, prenatal diagnosis, spondylocostal dysostosis

Introduction mandibular skin directly continuous with that of the chest due to the lack of neck [2]. The incidence of inien- Iniencephaly (the Greek word inion means the nape of cephaly is about 1:1000–1:2000 births [3,4]. Failure the neck) was first reported by Saint-Hilaire [1] to to recognize iniencephaly when it is a part of more describe a neural tube defect involving a bony defect at complex malformations may explain a lower incidence the occiput and rachischisis of the cervical and thoracic in some reports. Lewis [5] classified iniencephaly into spine with retroflexion of the head. Iniencephaly is char- iniencephalus apertus (iniencephaly with encephalo- acterized by a variable deficit of the occipital bones, cele) and iniencephalus clausus (iniencephaly without resulting in an enlarged foramen magnum; partial or encephalocele). Howkins and Lawrie [6] further classi- total absence of cervical and thoracic vertebrae with fied iniencephaly into simple iniencephaly (iniencephalus an irregular fusion of those present, accompanied by apertus and iniencephalus clauses), and iniencephaly incomplete closure of the vertebral arches and/or bodies; with anencephaly (anencephaly with spinal retro- significant shortening of the spinal column due to flexion). There is a female tendency for iniencephaly. marked lordosis and hyperextension of the malformed Iniencephaly may be associated with other anomalies cervicothoracic spine; and an upward-turned face and such as anencephaly, encephalocele, meningomyelocele, hydrocephalus, Dandy-Walker malformation, holopros- encephaly, omphalocele, congenital diaphragmatic her- nia, hydronephrosis, polycystic kidneys, cardiac defects, *Correspondence to: Dr Chih-Ping Chen, Department of Obstetrics caudal regression sequence, arthrogryposis, club foot, and Gynecology, Mackay Memorial Hospital, 92, Section 2, single umbilical artery, and gastrointestinal atresia [7] Chung-Shan North Road, Taipei, Taiwan. E-mail: [email protected] (Figures 1 and 2). Craniorachischisis, an example of Accepted: July 31, 2007 defective neural groove closure combining anencephaly

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Figure 1. Iniencephaly with craniorachischisis.

and total spina bifida with meningomyelocele, is often (1/63; 1.6%), imperforate anus (1/63; 1.6%), lissence- associated with iniencephaly. phaly (1/63; 1.6%), and sirenomelia (1/63; 1.6%). Poly- hydramnios due to depressed swelling was noted in 36.5% (23/63) of the cases. Of 52 cases with gender Prenatal Diagnosis description, females accounted for 76.9% (40/52) of the cases. Of 16 cases with cytogenetic analysis, five To date, at least 63 cases of prenatally detected inien- cases (31.3%) had chromosomal abnormalities, includ- cephaly with or without craniorachischisis have been ing trisomy 18 (two cases), mosaic trisomy 13 (two reported [2,8–27] (Table). Of these 63 cases, 47 cases cases), and mosaic monosomy X (one case). (75%) had associated abnormalities. The most frequent Iniencephaly has been associated with an elevated single malformations were anencephaly (27/63; 42.9%), maternal serum α-fetoprotein level. With the advent of omphalocele (13/63; 20.6%), club foot (12/63; 19.1%), ultrasonography, iniencephaly can be diagnosed in the encephalocele (9/63; 14.3%), pulmonary defects (9/63; first trimester and in the early second trimester. 14.3%), single umbilical artery (9/63; 14.3%), congenital Marton et al [20] first diagnosed iniencephaly in the diaphragmatic hernia (8/63; 12.7%), facial clefts (6/63; first trimester of pregnancy by the sonographic obser- 9.5%), duodenal atresia (4/63; 6.4%), renal agenesis vation of a short neck, a short crown-rump length, or dysgenesis (4/63; 6.4%), myelomeningocele (4/63; severe fixed retroflexion of the head, and a cervical 6.4%), ventriculomegaly or hydrocephalus (4/63; 6.4%), myelocele mimicking cystic hygroma at 10 weeks’ gesta- abnormal genitalia (2/63; 3.2%), cystic hygroma (2/63; tion. Cuillier et al [24] reported the earliest prenatal diag- 3.2%), heart defects (2/63; 3.2%), holoprosencephaly nosis of iniencephalus apertus and craniorachischisis

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Figure 2. Iniencephaly with encephalocele.

Table. Reported cases of prenatally detected iniencephaly with or without craniorachischisis

Gestational Authors Cytogenetic Prenatal sonographic Associated Gender weeks at [Reference] analysis findings anomalies at birth diagnosis

Mórocz et al [2] Case 1 F NA 33 Anencephaly, Omphalocele containing iniencephaly, the liver and small and large omphalocele intestines, anencephaly Case 2 M NA 33 Iniencephaly, Congenital polyhydramnios diaphragmatic hernia, club foot Case 3 F NA 32 Iniencephaly, Encephalocele, omphalocele microcepehaly, containing the liver, single omphalocele umbilical artery, uterus unicornis, right renal agenesis, agenesis of right ovary and fallopian tube

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Table. (continued)

Gestational Authors Cytogenetic Prenatal sonographic Associated Gender weeks at [Reference] analysis findings anomalies at birth diagnosis

Case 4 F NA 36 Anencephaly, Ventricular septal defects, iniencephaly, pulmonary hypoplasia, spina bifida anencephaly Case 5 M NA 28 Iniencephaly, spina bifida, Pulmonary hypoplasia polyhydramnios Case 6 F NA 20 Iniencephaly Case 7 F NA 29 Iniencephaly, spina bifida, polyhydramnios Case 8 F NA 18 Iniencephaly Pulmonary hypoplasia, anencephaly, spina bifida Case 9 F NA 15 Iniencephaly Pulmonary hypoplasia Case 10 F NA 16 Iniencephaly Club foot Case 11 F NA 19 Iniencephaly Foderaro NA NA 22 Polyhydramnios, iniencephaly, Meningomyelocele, et al [8] thoracic spina bifida, hydrocephalus hydrocephalus Meizner & F NA 26 Polyhydramnios, iniencephaly, Omphalocele, anencephaly, Bar-Ziv [9] anencephaly, omphalocele, thoracic rachischisis, club foot, bilateral club feet bilateral cleft lip and palate Shoham F NA 19 Iniencephaly, Cervicothoracic et al [10] meningomyelocele meningomyelocele Hammer et al [11] F 46,XX 33 Polyhydramnios, iniencephaly Meizner F NA 21 Polyhydramnios, Omphalocele, occipital et al [12] iniencephaly, occipital encephalocele encephalocele, omphalocele Sherer et al [13] F 46,XX 13 Acrania, spinal dysraphia, Anencephaly iniencephalus apertus, craniorachischisis Grangé F 47,XX,+18 13 Craniorachischisis, Encephalocele, et al [14] encephalocele, bilateral cystic hygroma cervical hygroma colli Dogan et al [15] Case 1 F NA 31 Polyhydramnios, Congenital diaphragmatic iniencephaly, anencephaly, hernia, anencephaly, cervical spina bifida, duodenal atresia, congenital diaphragmatic club feet hernia, duodenal atresia, bilateral club feet Case 2 F NA 30 Polyhydramnios, iniencephaly, Congenital diaphragmatic anencephaly, cervical spina hernia, anencephaly, bifida, congenital craniorachischisis, single diaphragmatic hernia, umbilical artery single umbilical artery Case 3 F NA 31 Polyhydramnios, Esophageal atresia, absence iniencephaly, anencephaly, of right hemidiaphragm, cervicothoracic spina bifida unilateral cleft lip and palate, anencephaly

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Table. (continued)

Gestational Authors Cytogenetic Prenatal sonographic Associated Gender weeks at [Reference] analysis findings anomalies at birth diagnosis

Case 4 F NA 28 Polyhydramnios, Encephalocele, lissencephaly, iniencephaly, encephalocele, hydrothorax, ascites, ascites, pericardial effusion, pericardial effusion, lissencephaly left congenital diaphragmatic hernia Case 5 M NA 20 Anencephaly Single umbilical artery, cervicothoracic rachischisis, anencephaly Case 6 M NA 21 Polyhydramnios, Omphalocele, iniencephaly, anencephaly, bilateral cleft lip, spina bifida, omphalocele, cervicothoracic rachischisis, bilateral cleft lip anencephaly Case 7 F NA 31 Polyhydramnios, Encephalocele, bilateral iniencephaly, anencephaly, club feet, duodenal atresia, cervicothoracic spina bifida, anencephaly posterior encephalocele, bilateral club feet, duodenal atresia Case 8 F NA 32 Polyhydramnios, Single umbilical artery, iniencephaly, anencephaly, congenital diaphragmatic single umbilical artery, hernia, hypoplastic lungs, hypoplastic lungs, cervicothoracic rachischisis, congenital anencephaly diaphragmatic hernia Case 9 F NA 26 Iniencephaly, anencephaly, Unilateral cleft lip, left club cervicothoracic spina bifida, foot, anencephaly unilateral cleft lip, left club foot Case 10 F NA 30 Polyhydramnios, Congenital diaphragmatic iniencephaly, hernia, hypoplastic lungs, bilateral club feet bilateral club feet Case 11 M NA 26 Polyhydramnios, Omphalocele, iniencephaly, anencephaly, rachischisis, anencephaly omphalocele Case 12 F NA 25 Polyhydramnios, iniencephaly, Omphalocele, left club foot, omphalocele, anencephaly, single umbilical artery, single umbilical artery, anencephaly cervical spina bifida, left club foot Case 13 F NA 24 Iniencephaly, posterior Posterior encephalocele, encephalocele congenital diaphragmatic hernia, hypoplastic lungs, duodenal atresia Case 14 F NA 26 Polyhydramnios, iniencephaly, Bilateral club feet, cleft lip, anencephaly, bilateral club duodenal atresia, feet, cleft lip, spina bifida anencephaly Case 15 F NA 25 Polyhydramnios, Omphalocele, iniencephaly, single umbilical artery, omphalocele, anencephaly, anencephaly single umbilical artery, cervical spina bifida

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Table. (continued)

Gestational Authors Cytogenetic Prenatal sonographic Associated Gender weeks at [Reference] analysis findings anomalies at birth diagnosis

Case 16 F NA 24 Iniencephaly Case 17 M NA 25 Iniencephaly, posterior Posterior encephalocele encephalocele Case 18 F NA 27 Iniencephaly, single umbilical Single umbilical artery, artery, bilateral club feet, bilateral club feet, posterior encephalocele posterior encephalocele Case 19 F NA 28 Iniencephaly, anencephaly, Single nostril, anencephaly, spina bifida, single nostril, dysplastic kidneys dysplastic kidneys Donaldson M 47,XY,+18 25 Craniorachischisis, Anencephaly, et al [16] thoraco-abdominoschisis thoraco-abdominoschisis Sahid et al [17]* NA Normal 24 (18–28) Iniencephaly (8/8), Single umbilical artery (2/8) chromo- polyhydramnios (6/8), some (7/7) single umbilical artery (2/8)

Balci et al [18] Case 1 M NA 20 Occipital bone defect, Anencephaly retroflexion of the fetal head and neck, anencephaly, craniorachischisis, iniencephaly Case 2 M NA 22 Occipital bone defect, Myelomeningocele, occipital encephalocele, omphalocele containing microcephaly, the heart, liver, spleen, and retroflexion of the fetal head, intestines thoracolumbar spina bifida, meningocele Case 3 F NA 20 Polyhydramnios, occipital Ventriculomegaly bone defect, retroflexion of the fetal head, ventriculomegaly, shortening of the vertebral column, cervical spina bifida Halder et al [19] M FISH: 22 Oligohydramnios, Anencephaly, sirenomelia, one copy X craniorachischisis, renal agenesis, hypoplastic left one copy Y anencephaly, spina bifida, upper limb, imperforate anus, absence of urinary bladder abnormal external genitalia Marton NA NA 10 Iniencephaly, shortened neck Cervical myelocele et al [20] and crown-rump length, severe fixed retroflexion of the head Jeanne-Pasquier et al [21] Case 1 F NA 31 Iniencephaly Pulmonary hypoplasia, ventriculomegaly Case 2 F 46,XX 19 Iniencephaly Anomalous pulmonary lobulation, ventriculomegaly, vermian agenesis, aqueduct atresia

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Table. (continued)

Gestational Authors Cytogenetic Prenatal sonographic Associated Gender weeks at [Reference] analysis findings anomalies at birth diagnosis

Case 3 F NA 16 Anencephaly, Anomalous pulmonary cervical spina bifida lobulation, anencephaly Case 4 F NA 12 Iniencephaly, Omphalocele, congenital omphalocele, congenital diaphragmatic hernia, diaphragmatic hernia anomalous pulmonary lobulation, encephalocele Jeanne-Pasquier F NA 13 Iniencephaly, exencephaly, Omphalocele, anencephaly et al [22] anencephaly, omphalocele Phadke & F Mosaic 19 Iniencephaly, alobar Holoprosencephaly, cyclopia Thakur [23] trisomy 13 holoprosencephaly, cyclopia, cervical spine rachischisis Cuillier NA NA 9 Iniencephalus apertus, Cervical encephalocele et al [24] craniorachischisis, acrania, a cystic structure of cervical encephalocele, a short distorted spine Rousso M NA 21 Iniencephaly, anencephaly Cervicothoracic rachischisis, et al [25] agenesis of left kidney, anencephaly Halder et al [26] Case 1 M Mosaic 21 Iniencephaly, anencephaly Anencephaly, left cleft lip trisomy 13 and palate, club foot, single umbilical artery, dilated right side of the heart Case 2 F Mosaic 24 Iniencephaly, Hydrops fetalis, congenital monosomy X cystic hygroma diaphragmatic hernia, cystic hygroma Polat et al [27] Case 1 F NA 18 Polyhydramnios, Pentalogy of Cantrell, craniorachischisis, anencephaly, omphalocele, omphalocele containing club foot liver, stomach and intestines, ectopia cordis, pentalogy of Cantrell, club foot Case 2 F NA 26 Polyhydramnios, Pentalogy of Cantrell, craniorachischisis, anencephaly, omphalocele, omphalocele containing liver, club hands and feet stomach and intestines, ectopia cordis, pentalogy of Cantrell, bilateral club hands and feet

*Eight cases. NA = not available; F = female; M = male; FISH = fluorescence in situ hybridization. at 9 weeks’ gestation by transvaginal sonographic find- dysraphia, a persistently hyperextended fetal head, and ings of acrania, a cystic structure of cervical encephalo- a close association of the fetal occipital area with the cele, and a short distorted spine. Sherer et al [13] fetal back. Grange et al [14] reported the endovaginal reported the endovaginal sonographic diagnosis of sonographic diagnosis of craniorachischisis at 13 weeks’ iniencephalus apertus and craniorachischisis at 13 gestation with the sonographic findings of a large occip- weeks’ gestation with the findings of acrania, spinal ital defect, a cystic occipital encephalocele, unilateral

Taiwan J Obstet Gynecol • September 2007 • Vol 46 • No 3 205 C.P. Chen ventricular dilation, no cerebellum, and bilateral cervi- 6p may explain the development of craniorachischisis cal cystic hygromas. Jeanne-Pasquier et al [22] reported in the case reported by Wright et al [30]. prenatal diagnosis of iniencephaly, exencephaly, anen- cephaly, and omphalocele at 13 weeks’ gestation. Differential Diagnosis

Reported Chromosomal Abnormalities in Prenatal diagnosis of iniencephaly should include a Association with Iniencephaly and differential diagnosis of cervical hyperextension, nuchal Craniorachischisis tumors such as teratoma, goiter and lymphangioma, cervical myelomeningocele, encephalocele, Klippel–Feil Craniorachischisis has been reported to be associated syndrome, and Jarcho–Levin syndrome [7]. with trisomy 18 [14,16,28,29], and partial monosomy 6p and partial trisomy 11q [30]. The association of Klippel–Feil syndrome trisomy 18 with neural tube defects has been well de- Klippel–Feil syndrome (KFS) is caused by a failure of scribed. Various studies have shown that neural tube segmentation of the cervical vertebrae during early defects occur in 6–11% of trisomy 18 cases [28,31,32]. fetal development. KFS is characterized by a short neck, Seller [33], in a study of mid-trimester human fetuses, a low hairline, and limited movement of the head. KFS found two spina bifidas in 25 fetuses (2/25; 8%) with may be associated with deafness, congenital heart trisomy 13, eight spina bifidas and one anencephaly defects, mental deficiency, cleft palate, rib defects, the in 38 fetuses (9/38; 24%) with trisomy 18, and three Sprengel anomaly, posterior dermoid cysts, scoliosis, spina bifidas in 13 fetuses (3/13; 23%) with triploidy. and renal abnormalities. KFS has been classified into Moore et al [28] reported craniorachischisis, large three types according to the nature, severity, and local- omphalocele, and bilateral cleft lip and palate in a fetus ization of the malformations [36]. Type I comprises with trisomy 18. van Maldergem et al [29] reported extensive fusion of the cervical and upper thoracic verte- craniorachischisis, omphalocele, bilateral radial agene- bral bodies into bony blocks. Type II comprises fusion sis, and distal arthrogryposis in a fetus with trisomy 18. of one or two cervical vertebral bodies. Type III com- Grange et al [14] reported occipital encephalocele, prises both cervical fusion and lower thoracic fusion or craniorachischisis, and cystic hygroma in a fetus with lumbar fusion. Although most cases occur sporadi- trisomy 18. Donaldson et al [16] reported the abdom- cally, both autosomal dominant KFS (OMIM 118100) inal wall defect of thoraco-abdominoschisis extending and autosomal recessive KFS (OMIM 214300) have from the neck to the pelvis and craniorachischisis in a been reported. Clarke et al [37] reported a paracentric fetus with trisomy 18. Phadke and Thakur [23] re- inversion of inv(8)(q22.2q22.3) in a family with KFS. ported prenatal diagnosis of iniencephaly, alobar holo- Fukushima [38] reported a de novo balanced reciprocal prosencephaly, and cyclopia in a fetus with mosaic translocation t(5;17)(q11.2;q23) in a patient with KFS. trisomy 13. Halder et al [26] reported mosaic trisomy Papagrigorakis et al [39] reported a de novo inv(2) 13 in a fetus with iniencephaly, anencephaly, facial (p12q34) in a patient with KFS. Goto et al [40] reported clefts, single umbilical artery, dilatation of the right a t(5;8)(q35.1;p21.1) translocation in a family with side of the heart, and club foot. They also reported KFS. The gene(s) responsible for KFS has yet to be mosaic monosomy X in a fetus with iniencephaly, determined. It is possibly located on 5q11.2, 5q35.1, cystic hygroma, congenital diaphragmatic hernia and 8p21.1, or 17q23. hydrops fetalis [26]. Wright et al [30] reported cranio- rachischisis in a fetus with partial trisomy 11q and Spondylocostal dysostosis partial monosomy 6p due to an unbalanced translo- Spondylocostal dysostosis or Jarcho–Levin syndrome cation inherited from a carrier father with a reciprocal is an autosomal recessive disorder. Spondylocostal translocation, t(6p;11q). Interestingly, the human dysostosis is characterized by a shortened trunk, an TFAP2A (transcription factor AP-2α) gene maps at opisthotonus position of the head, a short neck, a 6p24, and the AP-2 knockout mice have been shown barrel-shaped thorax, multiple wedge-shaped and block to exhibit anencephaly, craniofacial abnormalities, vertebrae, spina bifida, and rib anomalies. Mutations thoraco-abdominoschisis, and skeletal defects [34]. The in the genes that are important components of the human homologue (JMJ) of the mouse jumonji gene, Notch signaling pathway are responsible for the devel- which is required for the closure of the neural tube, opment of spondylocostal dysostosis. Autosomal reces- also maps at 6p23–6p24 [35]. The haploinsufficiency sive spondylocostal dysostosis type 1 (SCDO1; OMIM of genes involving in craniofacial formation at distal 277300) is caused by mutations in the DLL3 gene

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(OMIM 602768) at 19q13; autosomal recessive spondy- 13. Sherer DM, Hearn-Stebbins B, Harvey W, Metlay LA, locostal dysostosis type 2 (SCDO2; OMIM 608681) is Abramowicz JS. Endovaginal sonographic diagnosis of inien- caused by mutations in the MESP2 gene (OMIM 605195) cephaly apertus and craniorachischisis at 13 weeks, men- strual age. J Clin Ultrasound 1993;21:124–7. at 15q26.1; and autosomal recessive spondylocostal 14. Grange G, Favre R, Gasser B. Endovaginal sonographic dysostosis type 3 (SCDO3; OMIM 609813) is caused by diagnosis of craniorachischisis at 13 weeks of gestation. mutations in the LFNG gene (OMIM 602576) at 7p22. Fetal Diagn Ther 1994;9:391–4. 15. Dogan MM, Ekici E, Yapar EG, Soysal ME, Soysal SK, Gokmen O. Iniencephaly: sonographic-pathologic correlation Conclusion of 19 cases. J Perinat Med 1996;24:501–11. 16. Donaldson SJF, Wright CA, de Ravel TJL. Trisomy 18 with total craniorachischisis and thoraco-abdominoschisis. 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