Review of genetic and environmental factors leading to hypospadias

European Journal of Medical Genetics

Volumn 57, Issue 8, 2014, Pages 453-463

  Shih, Erin M ^a   Graham, John M ^b  

^a CHILDREN S HOSPITAL LOS ANGELES   (United States)

^b CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

Environmental factors; Genetics; Hypospadias; Low birth weight infants; Placental insufficiency; Syndromes

Indexed keywords

ENDOCRINE DISRUPTOR;

ARTICLE; DISEASE SEVERITY; ENVIRONMENTAL FACTOR; GENE MUTATION; GENETIC DISORDER; HEREDITY; HUMAN; HYPOSPADIAS; LOW BIRTH WEIGHT; NEWBORN CARE; PLACENTA INSUFFICIENCY; PREVALENCE; SINGLE NUCLEOTIDE POLYMORPHISM; SURVIVAL; ENVIRONMENT; GENETICS; MALE; RISK FACTOR;

ENVIRONMENT; HUMANS; HYPOSPADIAS; MALE; RISK FACTORS;

EID: 84907351898     PISSN: 17697212     EISSN: 18780849     Source Type: Journal    
DOI: 10.1016/j.ejmg.2014.03.003     Document Type: Article

References (118)

1. Adams S.V., Hastert T.A., Huang Y., Starr J.R. No association between maternal pre-pregnancy obesity and risk of hypospadias or cryptorchidism in male newborns. Birth Defects Res Part Clin Mol Teratol 2011, 91:241-248.
2. Aho M., Koivisto A.M., Tammela T.L., Auvinen A. Is the incidence of hypospadias increasing? Analysis of Finnish hospital discharge data 1970-1994. Environ Health Perspect 2000, 108:463-465.
3. Ajayi G.O., Fadiran E.O. The effect of combined iron therapy (Chemiron) and single iron therapy on the dexamethasone-estriol reaction test for placenta insufficiency during normal pregnancy. Clin Exp Obstetrics Gynecol 1999, 26:27-30.
4. Akre O., Lipworth L., Cnattingius S., Sparen P., Ekbom A. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology 1999, 10:364-369.
5. Akre O., Boyd H.A., Ahlgren M., Wilbrand K., Westergaard T., Hjalgrim H., et al. Maternal and gestational risk factors for hypospadias. Environ Health Perspect 2008, 116:1071-1076.
6. Allera A., Herbst M.A., Griffin J.E., Wilson J.D., Schweikert H.U., McPhaul M.J. Mutations of the androgen receptor coding sequence are infrequent in patients with isolated hypospadias. JClin Endocrinol Metabol 1995, 80:2697-2699.
7. Arpino C., Brescianini S., Robert E., Castilla E.E., Cocchi G., Cornel M.C., et al. Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 2000, 41:1436-1443.
8. Aschim E.L., Nordenskjold A., Giwercman A., Lundin K.B., Ruhayel Y., Haugen T.B., et al. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. JClin Endocrinol Metabolism 2004, 89:5105-5109.
9. Ban S., Sata F., Kurahashi N., Kasai S., Moriya K., Kakizaki H., et al. Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias. Hum Reprod 2008, 23:1466-1471.
10. Baskin L.S., Himes K., Colborn T. Hypospadias and endocrine disruption: is there a connection?. Environ Health Perspect 2001, 109:1175-1183.
11. Battin M., Albersheim S., Newman D. Congenital genitourinary tract abnormalities following cocaine exposure in utero. Am J perinatol 1995, 12:425-428.
12. Beleza-Meireles A., Omrani D., Kockum I., Frisen L., Lagerstedt K., Nordenskjold A. Polymorphisms of estrogen receptor beta gene are associated with hypospadias. JEndocrinol Invest 2006, 29:5-10.
13. Beleza-Meireles A., Barbaro M., Wedell A., Tohonen V., Nordenskjold A. Studies of a co-chaperone of the androgen receptor, FKBP52, as candidate for hypospadias. Reproductive Biol Endocrinol RB&E 2007, 5:8.
14. Beleza-Meireles A., Lundberg F., Lagerstedt K., Zhou X., Omrani D., Frisen L., et al. FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias. Eur J Hum Genet EJHG 2007, 15:405-410.
15. Beleza-Meireles A., Tohonen V., Soderhall C., Schwentner C., Radmayr C., Kockum I., et al. Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias. Eur J Endocrinol/Eur Fed Endocr Soc 2008, 158:729-739.
16. Bentvelsen F.M., Brinkmann A.O., van der Linden J.E., Schroder F.H., Nijman J.M. Decreased immunoreactive androgen receptor levels are not the cause of isolated hypospadias. Br J Urol 1995, 76:384-388.
17. Blomberg M.I., Kallen B. Maternal obesity and morbid obesity: the risk for birth defects in the offspring. Birth Defects Res Part Clin Mol Teratol 2010, 88:35-40.
18. Boisen K.A., Chellakooty M., Schmidt I.M., Kai C.M., Damgaard I.N., Suomi A.M., et al. Hypospadias in a cohort of 1072 Danish newborn boys: prevalence and relationship to placental weight, anthropometrical measurements at birth, and reproductive hormone levels at three months of age. JClin Endocrinol Metabol 2005, 90:4041-4046.
19. Brouwers M.M., Feitz W.F., Roelofs L.A., Kiemeney L.A., de Gier R.P., Roeleveld N. Risk factors for hypospadias. Eur J Pediatrics 2007, 166:671-678.
20. Brouwers M.M., van der Zanden L.F., de Gier R.P., Barten E.J., Zielhuis G.A., Feitz W.F., et al. Hypospadias: risk factor patterns and different phenotypes. BJU Int 2010, 105:254-262.
21. Browne M.L., Rasmussen S.A., Hoyt A.T., Waller D.K., Druschel C.M., Caton A.R., et al. Maternal thyroid disease, thyroid medication use, and selected birth defects in the National Birth Defects Prevention Study. Birth Defects Res Part Clin Mol Teratol 2009, 85:621-628.
22. Carlson W.H., Kisely S.R., MacLellan D.L. Maternal and fetal risk factors associated with severity of hypospadias: a comparison of mild and severe cases. JPediatric Urol 2009, 5:283-286.
23. Carmichael S.L., Shaw G.M., Nelson V., Selvin S., Torfs C.P., Curry C.J. Hypospadias in California: trends and descriptive epidemiology. Epidemiology 2003, 14:701-706.
24. Carmichael S.L., Shaw G.M., Laurent C., Lammer E.J., Olney R.S. Hypospadias and maternal exposures to cigarette smoke. Paediatr Perinat Epidemiol 2005, 19:406-412.
25. Carmichael S.L., Shaw G.M., Laurent C., Olney R.S., Lammer E.J. Maternal reproductive and demographic characteristics as risk factors for hypospadias. Paediatr Perinat Epidemiol 2007, 21:210-218.
26. Carmichael S.L., Shaw G.M., Lammer E.J. Environmental and genetic contributors to hypospadias: a review of the epidemiologic evidence. Birth Defects Res Part Clin Mol Teratol 2012, 94:499-510.
27. Carmichael S.L., Mohammed N., Ma C., Iovannisci D., Choudhry S., Baskin L.S., et al. Diacylglycerol kinase K variants impact hypospadias in a California study population. JUrol 2013, 189:305-311.
28. Carmichael S.L., Ma C., Choudhry S., Lammer E.J., Witte J.S., Shaw G.M. Hypospadias and genes related to genital tubercle and early urethral development. JUrology 2013, 190:1884-1892.
29. Carmichael S.L., Yang W., Roberts E.M., Kegley S.E., Wolff C., Guo L., et al. Hypospadias and residential proximity to pesticide applications. Pediatrics 2013, 132:e1216-1226.
30. Castro A., Codner E., Kaune H., Lopez P., Vantman D., Cassorla F. Absence of Y chromosome microdeletions in patients with cryptorchidism and hypospadias. JPediatric Endocrinol Metabol JPEM 2004, 17:143-148.
31. Caton A.R., Bell E.M., Druschel C.M., Werler M.M., Mitchell A.A., Browne M.L., et al. Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias. Birth Defects Res Part Clin Mol Teratol 2008, 82:34-40.
32. Chamberlain N.L., Driver E.D., Miesfeld R.L. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994, 22:3181-3186.
33. Chen T., Li Q., Xu J., Ding K., Wang Y., Wang W., et al. Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias. Eur J Hum Genet EJHG 2007, 15:23-28.
34. Chen Y., Thai H.T., Lundin J., Lagerstedt-Robinson K., Zhao S., Markljung E., et al. Mutational study of the MAMLD1-gene in hypospadias. Eur J Med Genet 2010, 53:122-126.
35. Codner E., Okuma C., Iniguez G., Boric M.A., Avila A., Johnson M.C., et al. Molecular study of the 3 beta-hydroxysteroid dehydrogenase gene type II in patients with hypospadias. JClin Endocrinol Metabol 2004, 89:957-964.
36. Czeizel A.E., Kazy Z., Puho E. Apopulation-based case-control teratological study of oral nystatin treatment during pregnancy. Scand J Infect Dis 2003, 35:830-835.
37. de Kort C.A., Nieuwenhuijsen M.J., Mendez M.A. Relationship between maternal dietary patterns and hypospadias. Paediatr Perinat Epidemiol 2011, 25:255-264.
38. Deeb A., Mason C., Lee Y.S., Hughes I.A. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol 2005, 63:56-62.
39. Diav-Citrin O., Shechtman S., Bar-Oz B., Cantrell D., Arnon J., Ornoy A. Pregnancy outcome after in utero exposure to valproate: evidence of dose relationship in teratogenic effect. CNS Drugs 2008, 22:325-334.
40. Fredell L., Kockum I., Hansson E., Holmner S., Lundquist L., Lackgren G., et al. Heredity of hypospadias and the significance of low birth weight. JUrol 2002, 167:1423-1427.
41. Fujimoto T., Suwa T., Kabe K., Adachi T., Nakabayashi M., Amamiya T. Placental insufficiency in early gestation is associated with hypospadias. JPediatric Surg 2008, 43:358-361.
42. Fukami M., Wada Y., Miyabayashi K., Nishino I., Hasegawa T., Nordenskjold A., et al. CXorf6 is a causative gene for hypospadias. Nat Genet 2006, 38:1369-1371.
43. Gatti J.M., Kirsch A.J., Troyer W.A., Perez-Brayfield M.R., Smith E.A., Scherz H.C. Increased incidence of hypospadias in small-for-gestational age infants in a neonatal intensive-care unit. BJU Int 2001, 87:548-550.
44. Gearhart J.P., Linhard H.R., Berkovitz G.D., Jeffs R.D., Brown T.R. Androgen receptor levels and 5 alpha-reductase activities in preputial skin and chordee tissue of boys with isolated hypospadias. JUrol 1988, 140:1243-1246.
45. Gill S.K., Broussard C., Devine O., Green R.F., Rasmussen S.A., Reefhuis J. Association between maternal age and birth defects of unknown etiology: United States, 1997-2007. Birth Defects Res Part Clin Mol Teratol 2012, 94:1010-1018.
46. Giordano F., Carbone P., Nori F., Mantovani A., Taruscio D., Figa-Talamanca I. Maternal diet and the risk of hypospadias and cryptorchidism in the offspring. Paediatr Perinat Epidemiol 2008, 22:249-260.
47. Giordano F., Abballe A., De Felip E., di Domenico A., Ferro F., Grammatico P., et al. Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring. Birth Defects Res Part Clin Mol Teratol 2010, 88:241-250.
48. Hackshaw A., Rodeck C., Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update 2011, 17:589-604.
49. Hennekam R.C., Allanson J.E., Biesecker L.G., Carey J.C., Opitz J.M., Vilain E. Elements of morphology: standard terminology for the external genitalia. Am J Med Genet Part 2013, 161A:1238-1263.
50. Hernandez-Diaz S., Smith C.R., Shen A., Mittendorf R., Hauser W.A., Yerby M., et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012, 78:1692-1699.
51. Hiort O., Klauber G., Cendron M., Sinnecker G.H., Keim L., Schwinger E., et al. Molecular characterization of the androgen receptor gene in boys with hypospadias. Eur J Pediatrics 1994, 153:317-321.
52. Holmes L.B. Common malformations 2012, Oxford University Press, Oxford.
53. Huisma F., Thomas M., Armstrong L. Severe hypospadias and its association with maternal-placental factors. Am J Med Genet Part 2013, 161:2183-2187.
54. Hussain N., Chaghtai A., Herndon C.D., Herson V.C., Rosenkrantz T.S., McKenna P.H. Hypospadias and early gestation growth restriction in infants. Pediatrics 2002, 109:473-478.
55. Jentink J., Loane M.A., Dolk H., Barisic I., Garne E., Morris J.K., et al. Valproic acid monotherapy in pregnancy and major congenital malformations. NEngl J Med 2010, 362:2185-2193.
56. Jones K.L., Jones M.C., del Campo M. Smith's recognizable patterns of human malformation 2013, 984. Philadelphia. 7th Ed.
57. Kalfa N., Liu B., Klein O., Audran F., Wang M.H., Mei C., et al. Mutations of CXorf6 are associated with a range of severities of hypospadias. Eur J Endocrinol Eur Fed Endocr Soc 2008, 159:453-458.
58. Kalfa N., Liu B., Klein O., Wang M.H., Cao M., Baskin L.S. Genomic variants of ATF3 in patients with hypospadias. JUrol 2008, 180:2183-2188. discussion 2188.
59. Kallen K. Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring. Teratology 2002, 66:185-191.
60. Kallen B., Olausson P.O. No increased risk of infant hypospadias after maternal use of loratadine in early pregnancy. Int J Med Sci 2006, 3:106-107.
61. Kallen B., Olausson P.Otterblad Use of anti-asthmatic drugs during pregnancy. 3. Congenital malformations in the infants. Eur J Clin Pharmacol 2007, 63:383-388.
62. Kallen B., Nilsson E., Olausson P.Otterblad Maternal use of loperamide in early pregnancy and delivery outcome. Acta Paediatr 2008, 97:541-545.
63. Klip H., Verloop J., van Gool J.D., Koster M.E., Burger C.W., van Leeuwen F.E. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 2002, 359:1102-1107.
64. Kohler B., Lin L., Mazen I., Cetindag C., Biebermann H., Akkurt I., et al. The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency. Eur J Endocrinol Eur Fed Endocr Soc 2009, 161:237-242.
65. Kristensen V.N., Borresen-Dale A.L. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Mutat Res 2000, 462:323-333.
66. Kurahashi N., Sata F., Kasai S., Shibata T., Moriya K., Yamada H., et al. Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias. Mol Hum Reprod 2005, 11:93-98.
67. Lim H.N., Chen H., McBride S., Dunning A.M., Nixon R.M., Hughes I.A., et al. Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet 2000, 9:829-834.
68. Lipworth B.J. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999, 159:941-955.
69. Liu B., Wang Z., Lin G., Agras K., Ebbers M., Willingham E., et al. Activating transcription factor 3 is up-regulated in patients with hypospadias. Pediatric Res 2005, 58:1280-1283.
70. Makridakis N., Ross R.K., Pike M.C., Chang L., Stanczyk F.Z., Kolonel L.N., et al. Aprevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase. Cancer Res 1997, 57:1020-1022.
71. Makridakis N.M., di Salle E., Reichardt J.K. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 2000, 10:407-413.
72. Manson J.M., Carr M.C. Molecular epidemiology of hypospadias: review of genetic and environmental risk factors. Birth defects Res Part Clin Mol Teratol 2003, 67:825-836.
73. Moller H., Weidner I.S. Epidemiology of cryptorchidism and hypospadias. Epidemiology 1999, 10:352-354.
74. Morera A.M., Valmalle A.F., Asensio M.J., Chossegros L., Chauvin M.A., Durand P., et al. Astudy of risk factors for hypospadias in the Rhone-Alpes region (France). JPediatric Urology 2006, 2:169-177.
75. Muroya K., Sasagawa I., Suzuki Y., Nakada T., Ishii T., Ogata T. Hypospadias and the androgen receptor gene: mutation screening and CAG repeat length analysis. Mol Hum Reprod 2001, 7:409-413.
76. Nebert D.W., Gonzalez F.J. P450 genes: structure, evolution, and regulation. Annu Rev Biochem 1987, 56:945-993.
77. Negulescu R.I., Strecker J.R., Lauritzen C., Pal S. The influence of betamethasone on the feto-placental unit: a preliminary report. JPerinat Med 1977, 5:120-132.
78. Nordenskjold A., Friedman E., Tapper-Persson M., Soderhall C., Leviav A., Svensson J., et al. Screening for mutations in candidate genes for hypospadias. Urol Res 1999, 27:49-55.
79. Norgaard M., Wogelius P., Pedersen L., Rothman K.J., Sorensen H.T. Maternal use of oral contraceptives during early pregnancy and risk of hypospadias in male offspring. Urology 2009, 74:583-587.
80. North K., Golding J. Amaternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int 2000, 85:107-113.
81. Ormond G., Nieuwenhuijsen M.J., Nelson P., Toledano M.B., Iszatt N., Geneletti S., et al. Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study. Environ Health Perspect 2009, 117:303-307.
82. Palmer J.R., Wise L.A., Robboy S.J., Titus-Ernstoff L., Noller K.L., Herbst A.L., et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero. Epidemiology 2005, 16:583-586.
83. Paulozzi L.J., Erickson J.D., Jackson R.J. Hypospadias trends in two US surveillance systems. Pediatrics 1997, 100:831-834.
84. Pedersen L., Skriver M.V., Norgaard M., Sorensen H.T. Maternal use of Loratadine during pregnancy and risk of hypospadias in offspring. Int J Med Sci 2006, 3:21-25.
85. Pedersen L., Norgaard M., Rothman K.J., Sorensen H.T. Loratadine during pregnancy and hypospadias. Epidemiology 2008, 19:359-360.
86. Pierik F.H., Burdorf A., Deddens J.A., Juttmann R.E., Weber R.F. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect 2004, 112:1570-1576.
87. Pons J.C., Papiernik E., Billon A., Hessabi M., Duyme M. Hypospadias in sons of women exposed to diethylstilbestrol in utero. Prenat Diagn 2005, 25:418-419.
88. Porter M.P., Faizan M.K., Grady R.W., Mueller B.A. Hypospadias in Washington State: maternal risk factors and prevalence trends. Pediatrics 2005, 115:e495-499.
89. Radpour R., Rezaee M., Tavasoly A., Solati S., Saleki A. Association of long polyglycine tracts (GGN repeats) in exon 1 of the androgen receptor gene with cryptorchidism and penile hypospadias in Iranian patients. JAndrol 2007, 28:164-169.
90. Reinisch J.M., Simon N.G., Karow W.G., Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 1978, 202:436-438.
91. Rocheleau C.M., Romitti P.A., Dennis L.K. Pesticides and hypospadias: a meta-analysis. JPediatric Urol 2009, 5:17-24.
92. Rodriguez-Pinilla E., Mejias C., Prieto-Merino D., Fernandez P., Martinez-Frias M.L. Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case-control study in Spain. Drug Saf Int J Med Toxicol Drug Exp 2008, 31:537-543.
93. Sata F., Kurahashi N., Ban S., Moriya K., Tanaka K.D., Ishizuka M., et al. Genetic polymorphisms of 17 beta-hydroxysteroid dehydrogenase 3 and the risk of hypospadias. JSex Med 2010, 7:2729-2738.
94. Schnack T.H., Zdravkovic S., Myrup C., Westergaard T., Christensen K., Wohlfahrt J., et al. Familial aggregation of hypospadias: a cohort study. Am J Epidemiol 2008, 167:251-256.
95. Schweikert H.U., Schluter M., Romalo G. Intracellular and nuclear binding of [3H]dihydrotestosterone in cultured genital skin fibroblasts of patients with severe hypospadias. JClin Invest 1989, 83:662-668.
96. Sekaran P., O'Toole S., Flett M., Cascio S. Increased occurrence of disorders of sex development, prematurity and intrauterine growth restriction in children with proximal hypospadias associated with undescended testes. JUrol 2013, 189:1892-1896.
97. Silver R.I., Russell D.W. 5alpha-reductase type 2 mutations are present in some boys with isolated hypospadias. JUrol 1999, 162:1142-1145.
98. Sorensen H.T., Pedersen L., Norgaard M., Wogelius P., Rothman K.J. Maternal asthma, preeclampsia and risk of hypospadias. Epidemiology 2005, 16:806-807.
99. Stoll C., Alembik Y., Roth M.P., Dott B. Genetic and environmental factors in hypospadias. JMed Genet 1990, 27:559-563.
100. Sun G., Tang D., Liang J., Wu M. Increasing prevalence of hypospadias associated with various perinatal risk factors in chinese newborns. Urology 2009, 73:1241-1245.
101. Sutherland R.W., Wiener J.S., Hicks J.P., Marcelli M., Gonzales E.T., Roth D.R., et al. Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. JUrol 1996, 156:828-831.
102. Tateno T., Sasagawa I., Ashida J., Nakada T., Ogata T. Absence of Y-chromosome microdeletions in patients with isolated hypospadias. Fertility Steril 2000, 74:399-400.
103. Terakawa T., Shima H., Yabumoto H., Koyama K., Ikoma F. Androgen receptor levels in patients with isolated hypospadias. Acta Endocrinol 1990, 123:24-29.
104. Thai H.T., Kalbasi M., Lagerstedt K., Frisen L., Kockum I., Nordenskjold A. The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. JClin Endocrinol Metabol 2005, 90:6695-6698.
105. Toppari J., Virtanen H.E., Main K.M., Skakkebaek N.E. Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Res Part Clin Mol Teratol 2010, 88:910-919.
106. van der Zanden L.F., van Rooij I.A., Feitz W.F., Vermeulen S.H., Kiemeney L.A., Knoers N.V., et al. Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation?. JClin Endocrinol Metabol 2010, 95:2384-2390.
107. van der Zanden L.F., van Rooij I.A., Feitz W.F., Knight J., Donders A.R., Renkema K.Y., et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet 2011, 43:48-50.
108. van der Zanden L.F., van Rooij I.A., Feitz W.F., Franke B., Knoers N.V., Roeleveld N. Aetiology of hypospadias: a systematic review of genes and environment. Hum Reprod Update 2012, 18:260-283.
109. Waller D.K., Shaw G.M., Rasmussen S.A., Hobbs C.A., Canfield M.A., Siega-Riz A.M., et al. Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatrics Adolesc Med 2007, 161:745-750.
110. Wang Y., Li Q., Xu J., Liu Q., Wang W., Lin Y., et al. Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur J Hum Genet EJHG 2004, 12:706-712.
111. Wang Z., Liu B.C., Lin G.T., Lin C.S., Lue T.F., Willingham E., et al. Up-regulation of estrogen responsive genes in hypospadias: microarray analysis. JUrol 2007, 177:1939-1946.
112. Watanabe M., Yoshida R., Ueoka K., Aoki K., Sasagawa I., Hasegawa T., et al. Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities. Hum Reprod 2007, 22:1279-1284.
113. Watts D.H., Li D., Handelsman E., Tilson H., Paul M., Foca M., et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. JAcquir Immune Defic Syndr 2007, 44:299-305.
114. Whitlock J.P. Genetic and molecular aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin action. Annu Rev Pharmacol Toxicol 1990, 30:251-277.
115. Wogelius P., Horvath-Puho E., Pedersen L., Norgaard M., Czeizel A.E., Sorensen H.T. Maternal use of oral contraceptives and risk of hypospadias - a population-based case-control study. Eur J Epidemiol 2006, 21:777-781.
116. Wyszynski D.F., Nambisan M., Surve T., Alsdorf R.M., Smith C.R., Holmes L.B. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005, 64:961-965.
117. Yinon Y., Kingdom J.C., Proctor L.K., Kelly E.N., Salle J.L., Wherrett D., et al. Hypospadias in males with intrauterine growth restriction due to placental insufficiency: the placental role in the embryogenesis of male external genitalia. Am J Med Genet Part 2010, 152A:75-83.
118. Yucel S., Desouza A., Baskin L.S. In utero prednisone exposure affects genital development. JUrol 2004, 172:1725-1730. discussion 1730.