■ REVIEW ARTICLE ■ SYNDROMES, DISORDERS AND MATERNAL RISK FACTORS ASSOCIATED WITH NEURAL TUBE DEFECTS (VII) Chih-Ping Chen1,2,3,4,5* 1Department of Obstetrics and Gynecology, and 2Medical Research, Mackay Memorial Hospital, Taipei, 3Department of Biotechnology, Asia University, 4School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, and 5Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan. SUMMARY Neural tube defects (NTDs) may be associated with syndromes, disorders and maternal risk factors. This article provides a comprehensive review of the syndromes, disorders and maternal risk factors associated with NTDs, including DK phocomelia syndrome (von Voss-Cherstvoy syndrome), Siegel-Bartlet syndrome, fetal warfarin syndrome, craniotelencephalic dysplasia, Czeizel-Losonci syndrome, maternal cocaine abuse, Weissenbacher- Zweymüller syndrome, parietal foramina (cranium bifidum), Apert syndrome, craniomicromelic syndrome, XX- agonadism with multiple dysraphic lesions including omphalocele and NTDs, Fryns microphthalmia syndrome, Gershoni-Baruch syndrome, PHAVER syndrome, periconceptional vitamin B6 deficiency, and autosomal dominant Dandy-Walker malformation with occipital cephalocele. NTDs associated with these syndromes, disorders and maternal risk factors are a rare but important cause of NTDs. The recurrence risk and the preventive effect of mater- nal folic acid intake in NTDs associated with syndromes, disorders and maternal risk factors may be different from those of nonsyndromic multifactorial NTDs. Perinatal diagnosis of NTDs should alert doctors to the syndromes, disorders and maternal risk factors associated with NTDs, and prompt thorough etiologic investigation and genetic counseling. [Taiwan J Obstet Gynecol 2008;47(3):276–282] Key Words: congenital malformations, disorders, maternal risk factors, neural tube defects, syndromes Introduction NTDs varies with race, geographic location, socioeco- nomic class, nutritional status, and multiple predisposing Neural tube defects (NTDs) have an incidence of 1–2 per factors such as single gene disorders, chromosomal 1,000 births and are considered to be a heterogeneous abnormalities, teratogens, maternal diabetes, family condition resulting from failure of normal neural tube history of NTDs, and polymorphisms in the genes con- closure between the third and fourth week of embryonic trolling folate metabolism. There is considerable evidence development. The three common types of NTDs are to suggest that genetic and environmental factors con- anencephaly, spina bifida and encephalocele, while less tribute to the etiology of NTDs. NTDs may be associated common types include amniotic band syndrome, limb– with maternal and fetal risk factors. body wall complex, cloacal exstrophy or omphalocele- exstrophy-imperforate anus-spinal defects complex, and other types of spinal abnormalities. The incidence of DK Phocomelia Syndrome (von Voss-Cherstvoy Syndrome) *Correspondence to: Dr Chih-Ping Chen, Department DK phocomelia syndrome (OMIM 223340) or von Voss- of Obstetrics and Gynecology, Mackay Memorial Cherstvoy syndrome is characterized by phocomelia, Hospital, 92, Section 2, Chung-Shan North Road, thrombocytopenia, encephalocele, and urogenital mal- Taipei, Taiwan. E-mail: [email protected] formations. Phocomelia usually involves only the upper Accepted: June 26, 2008 limbs and is limited to radial anomalies. All reported 276 Taiwan J Obstet Gynecol • September 2008 • Vol 47 • No 3 Syndromes, Disorders and Maternal Risk Factors with NTDs cases of DK phocomelia syndrome have been sporadic, [13] reported a 6-month-old child with frontal with both sexes affected by this syndrome and having encephalocele, craniosynostosis and developmental normal chromosomes, except for a case described by retardation. Hughes et al [12] reported two affected Bamforth and Lin [1] with mosaicism for a deletion of sisters with hydrocephalus, frontal encephalocele, cran- 13q12 in the fibroblasts but with normal lymphocyte iosynostosis, developmental delay, microcephaly, and chromosomes. Lubinsky et al [2] reported consanguinity hypoplastic optic nerves. Frontal encephalocele associ- in DK phocomelia syndrome and suggested an autoso- ated with craniotelencephalic dysplasia may be caused mal recessive pattern of inheritance. Meningoence- by craniosynostosis and hydrocephalus. Gupta et al phalocele is the most characteristic central nervous [14] reported a 2-year-old boy with bilateral microph- system malformation associated with DK phocomelia thalmia with cyst, facial clefts, limb anomalies and eth- syndrome [1–7]. A defect of the corpus callosum is moidal encephalocele, and suggested a new syndrome another common brain anomaly [2,4,6]. with features of Waardenburg syndrome, cerebro-oculo- nasal syndrome and craniotelencephalic dysplasia. Siegel-Bartlet Syndrome Czeizel-Losonci Syndrome Siegel-Bartlet syndrome, or craniofacial anomalies, cataracts, congenital heart disease, sacral neural tube Czeizel-Losonci syndrome, or split hand with obstruc- defects and growth and developmental retardation tive uropathy, spina bifida and diaphragmatic defects (OMIM 608227), is postulated to have an autosomal (OMIM 183802), is postulated to have an autosomal recessive pattern of inheritance [8]. Siegel-Bartlet et al dominant pattern of inheritance with variable expres- [8] reported two female sibs with sacral NTDs and teth- sivity [15]. Czeizel and Losonci [15] reported a woman ered cord, congenital heart defects, bilateral hyperopia, with right hydronephrosis, atresia of the ureter, cuta- rapid onset of cataracts, aphakic glaucoma, and abnor- neous syndactyly of both hands and feet, lumbar spina mal facial features. bifida occulta, and thoracolumbar scoliosis. Her first child was a stillborn male with lumbosacral spina bifida cystica, hydrocephalus, split hand/split foot malforma- Fetal Warfarin Syndrome tion, atresia of the right ureter, and hydronephrosis. Her second child was a liveborn male with split hand/foot Fetal warfarin syndrome is characterized by nasal hypo- malformation, megaureter, bilateral hydronephrosis, plasia, stippled epiphyses, chondrodysplasia punctata, and a right diaphragmatic defect of Bochdalek type. and first-trimester prenatal exposure to the vitamin K Genuardi et al [16] reported a baby with split hand/split antagonist, i.e. the anticoagulant warfarin (coumarin foot malformation, urinary tract obstruction, syndactyly, or Coumadin). Warfarin inhibits the synthesis of γ- lumbosacral myelomeningocele, and radial and dia- carboxyglutamic acid, which is involved in clotting and phragmatic defects, and suggested a case of Czeizel- calcification. Occasional central nervous system anom- Losonci syndrome. alies associated with fetal warfarin syndrome include microcephaly, hydrocephalus, Dandy-Walker malforma- tion, and agenesis of the corpus callosum [9]. Tejani Maternal Cocaine Abuse [10] reported nasal hypoplasia, occipital encephalo- cele, hydrocephalus, microphthalmia and persistent Reported malformations associated with cocaine abuse truncus arteriosus in a patient with warfarin syn- during pregnancy include hypertelorism, midfacial flat- drome. Warkany and Bofinger [11] reported occipital tening, neurobehavioral disorders, schizencephaly, cal- encephalocele and renal malformation in a patient losal agenesis, porencephaly, NTDs, vascular occlusion, with warfarin syndrome. fetal myocardial calcification, renal agenesis, hydrone- phrosis, ambiguous genitalia, ileal atresia, and prune- belly syndrome [17]. Mahalik et al [18] found that Craniotelencephalic Dysplasia nontoxic doses of cocaine caused exencephaly in mice. Bingol et al [19] found that cocaine abuse in human Craniotelencephalic dysplasia (OMIM 218670) is char- was significantly associated with congenital malfor- acterized by frontal encephalocele, craniosynostosis and mations (10% vs. 2% for the control group), including developmental delay, and is postulated to have an auto- one exencephaly, one parietal encephalocele and one somal recessive pattern of inheritance [12]. Daum et al skull dysraphism with parietal bone defects. Heier et al Taiwan J Obstet Gynecol • September 2008 • Vol 47 • No 3 277 C.P. Chen [20] found five central nervous system anomalies 168500) is caused by mutations in the MSX2 gene among 43 babies (12% vs. 0% for the control group) of (OMIM 123101) [27–30]. PFM2 (OMIM 609597) is cocaine-abusing mothers, including one towering ence- caused by mutations or haploinsufficiency in the ALX4 phalocele, one posterior encephalocele, one holopros- gene (OMIM 605420) [30–32]. PFM3 (OMIM 609566) encephaly, one hypoplastic cerebellum and one spinal is associated with a locus on chromosome 4q21–q23 teratoma, and postulated that placental or cerebral [33]. The MSX2 and ALX4 genes encode homeodomain artery vasoconstriction from cocaine in the first trimester transcription factors, which act as pleiotropic develop- results in the congenital malformations. Zimmerman mental regulators in vertebrates [34,35]. Mavrogiannis et al [21] found that cocaine-induced vascular disrup- et al [30] concluded that PFMs caused by mutations tion in early mouse development was mediated by mater- in ALX4 and MSX2 have similar prevalence and are usu- nal production of oxygen free radicals. However, Shaw ally clinical indistinguishable. PFM may be associated et al [22] found that periconceptional maternal use of with NTDs [36–39]. Terrafranca and Zellis [36] reported cocaine