252 JMed Genet 1997;34:252-255 Cebocephaly, alobar holoprosencephaly, spina

bifida, and sirenomelia in a stillbirth J Med Genet: first published as 10.1136/jmg.34.3.252 on 1 March 1997. Downloaded from

Chih-Ping Chen, Shin-Lin Shih, Fen-Fen Liu, Sheau-Wen Jan

Abstract Holoprosencephaly (HPE), a severe form of Cebocephaly and sirenomelia are uncom- cephalic defect with an incidence of 0.63 in mon birth defects. Their association is 10 000 live births with normal chromosomes,23 extremely rare; however, the presence of is characterised by an anomalous craniofacial spina bifida with both conditions is not complex that involves a series of forebrain and unexpected. We report on a female still- midface malformations of graded severity.24 birth with cebocephaly, alobar holopros- HPE is associated with teratogenic and genetic encephaly, cleft palate, lumbar spina factors. Alcohol and maternal diabetes are bifida, sirenomelia, a single umbilical known teratogenic factors. There is a 200-fold artery, and a 46,XX karyotype, but with- increase in the incidence of holoprosencephaly out maternal diabetes mellitus. Our case in infants of diabetic mothers over infants of adds to the examples of overlapping non-diabetic mothers.25 Animal models involv- ing the ingestion of the plant Veratum californi- cephalic and caudal defects, possibly re- cum, which contains steroidal alkaloids, can lated to vulnerability of the midline devel- produce cyclopia in sheep embryos.26 Cytoge- opmental field or axial mesodermal netic abnormalities have been reported in 50% dysplasia spectrum. of all HPE patients and the specific chromo- (JMed Genet 1997;34:252-255) some aberrations include trisomy 13, trisomy 18, triploidy, del(13q), dup(13q), del(18p), del(7) (q36), dup(3) (p24-pter), del(2) (p21), Keywords: holoprosencephaly; cebocephaly; sireno- and del(21)(q22.3).25 At the Human Gene melia; spina bifida. Mapping 11 Conference,27 four putative HPE genes were designated: HPE on chromosome http://jmg.bmj.com/ 21q22.3, HPE2 on 2p2l, HPE3 on 7q36-qter, and HPE4 on 18pter-ql 1. Familial HPE with a Sirenomelia and are well Department of holoprosencephaly normal karyotype has been described with Obstetrics and defined congenital malformations that usually autosomal dominant, recessive, and X linked Gynaecology, Mackay occur independently. Sirenomelia, a severe Memorial Hospital, 92, form of caudal defect with an incidence of 1.5- Table I Summary ofpreviously reported cases ofCNS abnormalities associated with sirenomelia Section 2, Chung-Shan 4.2 per 100 000 births,' is characterised by North Road, Taipei, Taiwan, Republic of complete or incomplete fusion of the lower References CNS abnormalities associated with sirenomelia on September 27, 2021 by guest. Protected copyright. China extremities. Various skeletal and podalic pres- 7 Craniorachischisis totalis (case report) C-P Chen entations of sirenomelia have been described.2 8 Craniorachischisis totalis (case report) There is a 100-150 fold increase in the 9 Anencephaly (case report) Department of incidence of sirenomelia in monozygotic twins 10 Meningomyelocele, hydrocephalus and Radiology, Mackay Arnold-Chiari malformation (1/1 1) over that in and twins.' Memorial Hospital, 92, singletons dizygotic 11 Atelencephaly and cebocephaly (case report) Section 2, Chung-Shan The absence of chromosomal abnormalities 12 Hydrocephalus (2/3) in 2 Hydrocephalus (2/77), hydrocephalus and North Road, Taipei, and familial inheritance has been noted meningomyelocele (1/77), Arnold-Chiari Taiwan, Republic of almost all cases of sirenomelia. Administration malformation, absent corpus callosum, and China of retinoic acid3 and cyclophosphamide' to lumbar meningomyelocele (1/77) S-L Shih 13 Anencephaly and cervicothoracic pregnant mice and hamsters, and destroying meningomyelocele (case report) Department of the axial portion of the caudal mesoderm of 14 Hydrocephalus (1/1 1); spina bifida occulta Medical Research, chicken have been to (1/1 1); spina bifida with meningocele (1/1 1) embryos,5 reported 15 Myelomeningocele, hydrocephalus, and others* Mackay Memorial produce limb defects including sirenomelia. (5/54) Section Hospital, 92, 2, cases are associated 16 Anencephaly (case report) North About 2% of sirenomelia Chung-Shan with maternal diabetes mellitus.6 Common 17 Meningocele (case report) Road, Taipei, Taiwan, 18 Neural tube defects (7/98) (6 low spina bifida, 1 Republic of China associated abnormalities include hemiverte- cervical spina bifida); hydrocephalus (2/98); C-P Chen brae, spina bifida, meningocele, deformed pel- cyclopia (1/98) F-F Liu 19 Craniorachischisis totalis (case report) vis, a single umbilical artery, abnormal internal 20 4/101* S-W Jan and external genitalia, urinary tract anomalies, 6 Meningomyelocele (1/4) 21 Cervicothoracic spina bifida (case report) Correspondence to: imperforate anus, pulmonary hypoplasia, 22 Thoracolumbar meningomyelocele and Dr Chen. tracheo-oesophageal fistula, and cardiovascular Arnold-Chiari malformation (case report) malformation.' Central nervous system (CNS) Present Cebocephaly, alobar holoprosencephaly, and Received 4 July 1996 case lumbar spina bifida (case report) Revised version accepted for anomalies (table 1) present in less than 10% of publication 18 October 1996 patients with sirenomelia. *Nature of CNS abnormalities not reported. Cebocephaly, alobar holoprosencephaly, spina bifida, and sirenomelia in a stillbirth 253

The association of holoprosencephaly and sirenomelia is extremely rare. In 1986, Young et

al" first reported a twin infant, born at 33 J Med Genet: first published as 10.1136/jmg.34.3.252 on 1 March 1997. Downloaded from gestational weeks, with cebocephaly, atelen- cephaly, and sirenomelia. Subsequently, only one patient with cyclopia, holoprosencephaly, and sirenomelia has been observed.'8 Here, we report an additional case of holoprosencephaly with sirenomelia. To our knowledge, the com- bination of cebocephaly, alobar holoprosen- cephaly, cleft palate, spina bifida, and sirenom- elia has not been previously reported.

Case report The proband was stillborn at 28 weeks' gestation with a weight of 1500 g and a length of 38 cm. She was the second child of a 25 year old woman. The parents are Chinese, non- .; consanguineous, and healthy. There was no 1 ,f family history of diabetes mellitus, twins, or congenital malformations. Maternal urine I throughout the pregnancy did not contain glu- cose. The mother had one healthy 2 year old child. She denied any exposure to drugs for ovulation before conception, or alcohol, tera- togenic medication, irradiation, or infectious diseases during this pregnancy. Her pregnancy Figure 1 Photograph of the sireniform stillbirth sl owting with this child was uneventful except that cebocephaly with ocular hypotelorism and a single; The lower limbs are fusedfrom the pelvis to the anAkles and oligohydramnios was noted during the second angulated 1800 posteriorly in relation to the trunk. trimester. At 28 weeks' gestation, ultrasonogra- phy indicated intrauterine fetal death. Physical examination of the stillbirth showed d microcephaly, ocular hypotelorism, a single inheritance.28 29 HPE has also been associated nostril, cebocephaly (fig 1), malformed, low set with Martin syndrome, Steinfeld syntdrome, ears, and cleft palate. Detailed evaluation CHARGE association, Meckel-Grubezr syn- showed soft tissue fusion of the lower limbs drome, Kallmann syndrome, Hall-F*allister from the pelvis to the ankles. The feet were http://jmg.bmj.com/ syndrome, and Vasadi syndrome.25 30 CC:mmon normally formed and fused at the heels. The associated abnormalities include microcephaly, fused lower limbs were angulated 1800 posteri- undivided thalamus, agenesis of the corpus orly in relation to the trunk (fig 1). Both knees callosum, arhinencephaly, renal cysts aind dys- and toes pointed backwards. There was imper- plasia, omphalocele, cardiovascular ma]Iforma- forate anus, spina bifida over the lumbar area, tions, club foot, myelomeningocele, ancd intes- and absence of external genitalia (fig 2). The tinal abnormalities.3' umbilical cord contained only a single umbili- on September 27, 2021 by guest. Protected copyright. cal artery and an umbilical vein. Radiographs p showed two femora, two tibiae, two fibulae, incomplete rotation of the legs leading to a medial position of the fibulae, thin ribs, hypoplastic vertebrae, dextroscoliosis of the thoracolumbar spine, sacral agenesis, and poorly formed acetabula. Necropsy showed alobar holoprosencephaly with a single ventri- cle and spina bifida occulta over the lumbar area. Data on the internal organs were not available because of severe calcification and autolysis of the tissue. A cytogenetic study was performed on Giemsa banded chromosomes from cultured chorionic villi cells and showed a normal 46,XX karyotype.

Discussion Our case is a rare combination of type I sirenomelia' with sympus dipus, alobar holo- prosencephaly, cebocephaly, and spina bifida, Figure 2 (Left) Anterior view of the lower limbs showing the poplitealfossae and,heels without the association of maternal diabetes pointing forwards. (Right) Posterior view of the lower limbs and the trunk shows lu)mbar spina bifida, and the knees and toes pointing backwards. No external genitalia or a;nus are mellitus, monozygotic twins, abnormal chro- visible. mosomal complements, or familial inheritance. 254 Chen, Shih, Liu, J7an

In 1989, O'Rahilly and Muller32 and in 1992, gene region at 7q36 between D7S396 and the Kallen et al'8 suggested that cyclopia and telomere, and suggested that genes at 7q36

sirenomelia have a similar mode of formation play a critical role in differentiation of midline J Med Genet: first published as 10.1136/jmg.34.3.252 on 1 March 1997. Downloaded from and both may share similar aetiological and mesoderm at both ends of the developing pathogenetic factors affecting the development notochord. Our case, a complex of cebo- of the axial mesoderm. In holoprosencephaly, cephaly, alobar holoprosencephaly, cleft palate, deficiency of prechordal mesoderm occurs at lumbar spina bifida, sirenomelia, a single or before 4 weeks of embryonic age. During the umbilical artery, and a normal chromosomal third week of embryonic life, the prechordal complement, adds examples of overlapping mesoderm migrates forwards into the area holoprosencephaly and caudal dygenesis. anterior to the notochord and evolves into midline facial development. The prechordal mesoderm plays a reciprocal induction role in 1 Escobar LF, Weaver DD, Winn J. Sirenomelia sequence. In: the morphogenesis of the neurectoderm, the Buyse ML, ed. Birth defects enscyclopedia. Cambridge: Black- well Scientific Publications, 1990:1541 -2. forebrain. Deficiencies of prechordal meso- 2 Stocker JT, Heifetz SA. Sirenomelia: a morphological study derm cause midfacial defects as well as incom- of 33 cases and review of the literature. Perspect Pediatr Pathol 1987lO:7-50. plete forebrain development.33 Sirenomelia is 3 Shenefelt RE. Morphogenesis of malformation in hamsters believed to originate before 30 days of embry- caused by retinoic acid: relation to dose and stage at treat- ment. Teratology 1972;5:103-18. onic life and to occur through a failure in later- 4 Manson JM, Smith CC. Influence of cyclophosphamide and alisation secondary to a mesenchymal defi- 4-ketocyclophosphamide on mouse limb development. Teratology, 1977;15:291-9. ciency of the caudal eminence.32 The caudal 5 Duhamel B. From the mermaid to anal imperforation: the eminence contributes to the formation of the syndrome of caudal regression. Arch Dis Child 1961,36: 152-5. notochord, vertebrae, lower limb buds, peri- 6 Twickler D, Budorick N, Pretorius D, et al. Caudal neum, neural plate, neural cord, hindgut, and regression versus sirenomelia: sonographic clues. 7 Ultra- soutnd Med 1993;12:323-30. blood vessels. An extensive disturbance of the 7 Battaglia S, Fraccaro M. Anencefalia in sirenide. Fol Hered axial mesoderm can cause concomitant altera- Pathol 1954;III:197-204. 8 Opitz JM, Gilbert EF. Editorial comment: CNS anomalies tion of neural ectoderm, and consequently and the midline as a "developmental field". An, 7 Med neural tube defects occur." Theories proposed Geniet 1982;12:443-55. 9 Schwaibold H, Oehler U, Helpap R, Bohm N. Sirenomelia for the pathogenesis of sirenomelia can be cat- and anencephaly in one of dizygotic twins. Teratology, 1986; egorised into the vascular disruption hypo- 34:243-7. 10 Stevenson RE, Jones KL, Phelan MC, et al. Vascular steal: thesis and the caudal embryo damage the pathogenetic mechanism producing sirenomelia and hypothesis."' 35 The most likely mechanisms associated defects of the viscera and soft tissues. Pediatrics 1986;78:451-7. are believed to be a deficiency of the caudal 11 Young ID, O'Reilly KM, Kendall CH. Etiological heteroge- mesoderm as well as a decrease of haemoper- neity in sirenomelia. Pediatr Pathol 1986,5:31-43. 12 Harris RD, Nyberg DA, Mack LA, Weinberger E. Anorectal fusion in the caudal region and lower extremi- atresia: prenatal sonographic diagnosis. AYR 1987;149: ties of the embryo.' In 1982, Opitz and Gilbert8 395-400. 13 Pfeiffer RA, Becker V. Comments on Schwaibold's "si- proposed the concept of midline developmen- renomelia and anencephaly in one of dizygotic twins". tal field. They suggested that in early embryo- Teratology 1988;38:497-8. http://jmg.bmj.com/ 14 Sirtori M, Ghidini A, Romero R, Hobbins JC. Prenatal genesis the midline is a weakly buffered field. diagnosis of sirenomelia. Y Ultrasounnd Med 1989;8:83-8. Difficulties in the early process of determina- 15 Duncan PA, Shapiro LR, Klein RM. Sacrococcygeal dysgenesis association. Ant .7Med Geniet 1991;41:153-61. tion because of midline vulnerability may cause 16 Rodriguez JI, Palacios J, Razquin S. Sirenomelia and anen- both duplication and deficiencies.36 Holopros- cephaly. Ani Y Med Genet 1991;39:25-7. 17 Gupta R, Gupta M, Gupta S. Sirenomelia bipus (mermaid) encephaly, spina bifida, cleft palate, and with meningocele. Indian .7 Pediatr 1992;59:387-8. sirenomelia in this case all belong to the 18 Kallen B, Castilla EE, Lancaster PAL, et al. The cyclops and the mermaid: an epidemiological study of two types of rare midline anomalies. In 1981, Russsel et al37 sug- malformation. 7 Med Geniet 1992;29:30-5. on September 27, 2021 by guest. Protected copyright. gested the term "axial mesodermal dysplasia" 19 Rodriguez JI, Palacios J. Craniorachischisis totalis and sirenomelia. Ani Y Med Genet 1992;43:732-6. to describe a disturbance during early embryo- 20 Duncan PA, Shapiro LR. Interrelationships of the hemifa- genesis which affects the mesodermal cell cial microsomia-VATER, VATER, and sirenomelia pheno- types. Ant Y Med Genet 1993;47:75-84. migration during the primitive streak period. 21 Kulkarni ML, Sureshkumar C, Sindhur PS. Sirenomelia Combined anomalies in both the cranial and with spina bifida. Indian J Pediatr 1994;31:51-5. 22 McCoy MC, Chescheir NC, Kuller JA, et al. A fetus with caudal regions have been suggested as exam- sirenomelia, omphalocele, and meningomyelocele, but nor- ples of axial mesodermal dysplasia."' Our case mal kidneys. Teratology 1994;50:168-71. 23 Roach E, DeMeyer W, Conneally PM, et al. shows the combination of the most extreme Holoprosencephaly: birth data, genetic and demographic anomalies of the cephalic and caudal regions of analyses of 30 families. Birth Defects 1977,11:294-313. 24 DeMyer W, Zeman W, Palmer CG. The face predicts the the embryo, cebocephaly and sirenomelia. It is brain: diagnostic significance of median facial anomalies related to deficiencies of or damage to both for holoprosencephaly (arhinencephaly). Pediatrics 1963; 34:256-63. prechordal mesoderm and caudal mesoderm 25 Muenke M. Holoprosencephaly as a genetic model to study during early embryonic life and can be consid- normal craniofacial development. Senmin Dev Bi'ol 1994;5: 293-301. ered an example of axial mesodermal dysplasia. 26 Cohen MM Jr, Sulik KK. Perspectives on holoprosencephaly. The prevalence of cases with a combination Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach and experimen- of some form of holoprosencephaly with any tal studies. YCraniofac Genet Dev Biol 1992;12:196-244. degree of caudal dysgenesis has been estimated 27 Frezal J, Schinzel A. Report of the committee on clinical disorders, chromosome aberration, and uniparental dis- at about 7.9 per million livebirths3" which is omy. Cytogeniet Cell Genet 199 1;58:986-1052. significantly higher than would be expected by 28 Muenke M. Clinical, cytogenetic and molecular approaches to the genetic heterogeneity of holoprosencephaly. Ant .7 chance. Morichon-Delvallez et al39 concluded Med Genet 1989;34:237-45. that the terminal region of 7q contains genes 29 Cohen MM Jr. Perspectives on holoprosencephaly. Part I. Epidemiology, genetics, and syndromology. Teratology implicated in the development of the central 1989;40:21 1-35. nervous system and the caudal region. Lynch et 30 Cohen MM Jr. An update on the holoprosencephalic disor- ders. .7 Pediatr 1982;101:865-9. al40 further concluded that a sacral agenesis 31 Nyberg DA, Pretorius DH. Cerebral malformations. In: gene maps to the HPE3 holoprosencephaly Nyberg DA, Mahony BS, Pretorius DH, eds. Diagnostic Cebocephaly, alobar holoprosencephaly, spina bifida, and sirenomelia in1 a stillbirth 255

ultrasound offetal anonmalies. Chicago: Year Book Medical 36 Lubinsky MS. Midline developmental "weakness" as a con- Publishers, 1990:83-145. sequence of determinative field properties. Am Med Getnet 32 O'Rahilly R, Muller F. Interpretation of some median Suippl 1987;3:23-8.

anomalies as illustrated by cyclopia and symmelia. Teratol- 37 Russel LJ, Weaver DD, Bull MJ. The axial mesodermal dys- J Med Genet: first published as 10.1136/jmg.34.3.252 on 1 March 1997. Downloaded from ogy 1989;40:409-2 1. plasia. Pediatrics 1981 ;67: 176-82. 33 Norman MG. Central nervous system. In: Dimmick JE, 38 Martinez-Frias ML, Bermejo E, Garcia A, et al. Holopros- Kalousek DK, eds. Developmental pathology of the embryo encephalv associated with caudal dysgenesis: a clinical- anidfetuis. Philadelphia: J B Lippincott, 1992:341-82. epidemiological analysis. Amn _7 Med Getnet 1994;53:46-51. 34 Jones KL. Holoprosencephaly sequence. In: Jones KL, ed. 39 Morichon-Delvallez N, Delezoide AL, Vekemans M. Holo- Smith's recognizable patterns of hunman mnalfornmation. 4th ed. prosencephaly and sacral agenesis in a fetus with a terminal Philadelphia: W B Saunders, 1988:546-7. deletion 7q36-*7qter. _7 Med Gentet 1993;30:521-4. 35 Langer B, Stoll C, Nicolau R, et al. Sirenomelia and situs 40 Lynch SA, Bond PM, Copp AJ, et al. A gene for autosomal inversus: case report and review of the literature. Fetal dominant sacral agenesis maps to the holoprosencephaly Diagn Ther 1996;11:79-84. region at 7q36. Nat Genet 1995;11:93-5. http://jmg.bmj.com/ on September 27, 2021 by guest. Protected copyright.