holoprosencephaly

Summary

Summary: Anterior midline brain, cranial, and facial malformations resulting from the failure of the embryonic prosencephalon to undergo segmentation and cleavage. Alobar prosencephaly is the most severe form and features anophthalmia; cyclopia; severe INTELLECTUAL DISABILITY; CLEFT LIP; CLEFT PALATE; SEIZURES; and microcephaly. Semilobar holoprosencepaly is characterized by hypotelorism, microphthalmia, coloboma, nasal malformations, and variable degrees of INTELLECTUAL DISABILITY. Lobar holoprosencephaly is associated with mild (or absent) facial malformations and intellectual abilities that range from mild INTELLECTUAL DISABILITY to normal. Holoprosencephaly is associated with CHROMOSOME ABNORMALITIES.

Top Publications

  1. Chen C, Chern S, Du S, Wang W. Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis. Prenat Diagn. 2002;22:5-7 pubmed
    We report the sonographic diagnosis and molecular analysis of holoprosencephaly (HPE) and premaxillary agenesis in a second-trimester fetus with a 46,XY karyotype...
  2. Aoto K, Shikata Y, Imai H, Matsumaru D, Tokunaga T, Shioda S, et al. Mouse Shh is required for prechordal plate maintenance during brain and craniofacial morphogenesis. Dev Biol. 2009;327:106-20 pubmed publisher
    In humans, holoprosencephaly (HPE) is a common birth defect characterized by the absence of midline cells from brain, facial, and oral structures...
  3. Jin L, Zhou Y, Kuang C, Lin L, Chen Y. Expression pattern of TG-interacting factor 2 during mouse development. Gene Expr Patterns. 2005;5:457-62 pubmed
    ..Mutations of TGIF have been found in holoprosencephaly, a genetic disease affecting forebrain and craniofacial developmental...
  4. Nagase T, Nagase M, Osumi N, Fukuda S, Nakamura S, Ohsaki K, et al. Craniofacial anomalies of the cultured mouse embryo induced by inhibition of sonic hedgehog signaling: an animal model of holoprosencephaly. J Craniofac Surg. 2005;16:80-8 pubmed
    The pathogenesis of holoprosencephaly is multifactorial, and blockage of Sonic hedgehog signaling is one of the most important causative factors in animal models and human cases...
  5. Lazaro L, Dubourg C, Pasquier L, Le Duff F, Blayau M, Durou M, et al. Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A. 2004;129A:21-4 pubmed
    ..Familial instances of typical and atypical holoprosencephaly (HPE) were found in 30% of cases...
  6. Dennis J, Kurosaka H, Iulianella A, Pace J, Thomas N, Beckham S, et al. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects. PLoS Genet. 2012;8:e1002927 pubmed publisher
    b>Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain...
  7. Takenouchi T, Okuno H, Kosaki R, Ariyasu D, Torii C, Momoshima S, et al. Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting. Am J Med Genet A. 2012;158A:2537-41 pubmed publisher
    The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity...
  8. Fernandez B, Siegel Bartelt J, Herbrick J, Teshima I, Scherer S. Holoprosencephaly and cleidocranial dysplasia in a patient due to two position-effect mutations: case report and review of the literature. Clin Genet. 2005;68:349-59 pubmed
    b>Holoprosencephaly (HPE) is a genetically heterogeneous developmental field defect in which midline cleavage of the forebrain and craniofacial structures is impaired...
  9. Seppala M, Depew M, Martinelli D, Fan C, Sharpe P, Cobourne M. Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest. 2007;117:1575-84 pubmed
    b>Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves...
  10. Geng X, Speirs C, Lagutin O, Inbal A, Liu W, Solnica Krezel L, et al. Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev Cell. 2008;15:236-47 pubmed publisher
    b>Holoprosencephaly (HPE), the most common forebrain malformation, is characterized by an incomplete separation of the cerebral hemispheres. Mutations in the homeobox gene SIX3 account for 1.3% of all cases of human HPE...

Detail Information

Publications98

  1. Chen C, Chern S, Du S, Wang W. Molecular diagnosis of a novel heterozygous 268C-->T (R90C) mutation in TGIF gene in a fetus with holoprosencephaly and premaxillary agenesis. Prenat Diagn. 2002;22:5-7 pubmed
    We report the sonographic diagnosis and molecular analysis of holoprosencephaly (HPE) and premaxillary agenesis in a second-trimester fetus with a 46,XY karyotype...
  2. Aoto K, Shikata Y, Imai H, Matsumaru D, Tokunaga T, Shioda S, et al. Mouse Shh is required for prechordal plate maintenance during brain and craniofacial morphogenesis. Dev Biol. 2009;327:106-20 pubmed publisher
    In humans, holoprosencephaly (HPE) is a common birth defect characterized by the absence of midline cells from brain, facial, and oral structures...
  3. Jin L, Zhou Y, Kuang C, Lin L, Chen Y. Expression pattern of TG-interacting factor 2 during mouse development. Gene Expr Patterns. 2005;5:457-62 pubmed
    ..Mutations of TGIF have been found in holoprosencephaly, a genetic disease affecting forebrain and craniofacial developmental...
  4. Nagase T, Nagase M, Osumi N, Fukuda S, Nakamura S, Ohsaki K, et al. Craniofacial anomalies of the cultured mouse embryo induced by inhibition of sonic hedgehog signaling: an animal model of holoprosencephaly. J Craniofac Surg. 2005;16:80-8 pubmed
    The pathogenesis of holoprosencephaly is multifactorial, and blockage of Sonic hedgehog signaling is one of the most important causative factors in animal models and human cases...
  5. Lazaro L, Dubourg C, Pasquier L, Le Duff F, Blayau M, Durou M, et al. Phenotypic and molecular variability of the holoprosencephalic spectrum. Am J Med Genet A. 2004;129A:21-4 pubmed
    ..Familial instances of typical and atypical holoprosencephaly (HPE) were found in 30% of cases...
  6. Dennis J, Kurosaka H, Iulianella A, Pace J, Thomas N, Beckham S, et al. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania-holoprosencephaly-agnathia craniofacial defects. PLoS Genet. 2012;8:e1002927 pubmed publisher
    b>Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain...
  7. Takenouchi T, Okuno H, Kosaki R, Ariyasu D, Torii C, Momoshima S, et al. Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting. Am J Med Genet A. 2012;158A:2537-41 pubmed publisher
    The combination of holoprosencephaly and ectrodactyly, also known as Hartsfield syndrome, represents a unique genetic entity...
  8. Fernandez B, Siegel Bartelt J, Herbrick J, Teshima I, Scherer S. Holoprosencephaly and cleidocranial dysplasia in a patient due to two position-effect mutations: case report and review of the literature. Clin Genet. 2005;68:349-59 pubmed
    b>Holoprosencephaly (HPE) is a genetically heterogeneous developmental field defect in which midline cleavage of the forebrain and craniofacial structures is impaired...
  9. Seppala M, Depew M, Martinelli D, Fan C, Sharpe P, Cobourne M. Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest. 2007;117:1575-84 pubmed
    b>Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves...
  10. Geng X, Speirs C, Lagutin O, Inbal A, Liu W, Solnica Krezel L, et al. Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev Cell. 2008;15:236-47 pubmed publisher
    b>Holoprosencephaly (HPE), the most common forebrain malformation, is characterized by an incomplete separation of the cerebral hemispheres. Mutations in the homeobox gene SIX3 account for 1.3% of all cases of human HPE...
  11. Shen J, Walsh C. Targeted disruption of Tgif, the mouse ortholog of a human holoprosencephaly gene, does not result in holoprosencephaly in mice. Mol Cell Biol. 2005;25:3639-47 pubmed
    ..Heterozygous nonsense and missense mutations of the human TGIF gene have been associated with holoprosencephaly, the most common congenital malformation of the forebrain...
  12. Orioli I, Castilla E. Epidemiology of holoprosencephaly: Prevalence and risk factors. Am J Med Genet C Semin Med Genet. 2010;154C:13-21 pubmed publisher
    The wide variation in cerebral and facial phenotypes and the recognized etiologic heterogeneity of holoprosencephaly (HPE) contribute to the observed inter-study heterogeneity...
  13. Richieri Costa A, Ribeiro L. Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil. Am J Med Genet C Semin Med Genet. 2010;154C:149-57 pubmed publisher
    ..de Anomalas Craniofaciais-Universidade de São Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype...
  14. Huang X, Litingtung Y, Chiang C. Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly. Hum Mol Genet. 2007;16:1454-68 pubmed
    b>Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain, and in its severe form, the cerebral hemispheres fail to completely separate into two distinct halves...
  15. Knepper J, James A, Ming J. TGIF, a gene associated with human brain defects, regulates neuronal development. Dev Dyn. 2006;235:1482-90 pubmed
    ..Mutations in TGIF have been detected in patients with holoprosencephaly (HPE), a severe brain malformation associated with mental retardation...
  16. Yoshikawa H, Nakano K, Watanabe S. Central tegmental tract lesion in a girl with holoprosencephaly presenting with West syndrome. Eur J Paediatr Neurol. 2009;13:376-9 pubmed publisher
    We described a 16-month-old female patient who developed West syndrome at 3 months of age. MRI revealed a holoprosencephaly with incomplete fusion of the cerebrum, associated with central tegmental tract (CTT) lesions...
  17. Heussler H, Suri M, Young I, Muenke M. Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch Dis Child. 2002;86:293-6 pubmed
    b>Holoprosencephaly (HPE) is a clinically variable and genetically heterogeneous central nervous system (CNS) malformation. Alobar HPE, which is its most severe form, is associated with a poor prognosis...
  18. Marcorelles P, Laquerriere A. Neuropathology of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:109-19 pubmed publisher
    b>Holoprosencephaly (HPE) is a brain malformation which results from a primary defect in induction and patterning of the rostral neural tube during early embryogenesis and usually considered as an impaired cleavage of the prosencephalon...
  19. Maurus D, Harris W. Zic-associated holoprosencephaly: zebrafish Zic1 controls midline formation and forebrain patterning by regulating Nodal, Hedgehog, and retinoic acid signaling. Genes Dev. 2009;23:1461-73 pubmed publisher
    b>Holoprosencephaly (HPE) is the most frequently observed human embryonic forebrain defect...
  20. Hahn J, Barnes P. Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation. Am J Med Genet C Semin Med Genet. 2010;154C:120-32 pubmed publisher
    b>Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation...
  21. Yamada S. Embryonic holoprosencephaly: pathology and phenotypic variability. Congenit Anom (Kyoto). 2006;46:164-71 pubmed
    b>Holoprosencephaly (HPE) is one of the major brain anomalies caused by the failure of cleavage of the prosencephalon during the early stage of development...
  22. Kjaer I, Keeling J, Fischer Hansen B, Becktor K. Midline skeletodental morphology in holoprosencephaly. Cleft Palate Craniofac J. 2002;39:357-63 pubmed
    The purpose of the present study was to analyze histologically the midline structures in a human fetus with holoprosencephaly and a single median maxillary central incisor...
  23. Lana Elola E, Tylzanowski P, Takatalo M, Alakurtti K, Veistinen L, Mitsiadis T, et al. Noggin null allele mice exhibit a microform of holoprosencephaly. Hum Mol Genet. 2011;20:4005-15 pubmed publisher
    b>Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide...
  24. Dupé V, Rochard L, Mercier S, Le Pétillon Y, Gicquel I, Bendavid C, et al. NOTCH, a new signaling pathway implicated in holoprosencephaly. Hum Mol Genet. 2011;20:1122-31 pubmed publisher
    Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway...
  25. Krauss R. Holoprosencephaly: new models, new insights. Expert Rev Mol Med. 2007;9:1-17 pubmed
    b>Holoprosencephaly (HPE) is a common congenital malformation that is characterised by a failure to divide the forebrain into left and right hemispheres and is usually accompanied by defects in patterning of the midline of the face...
  26. Simonis N, Migeotte I, Lambert N, Perazzolo C, De Silva D, Dimitrov B, et al. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. J Med Genet. 2013;50:585-92 pubmed publisher
    Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically...
  27. Zhang W, Hong M, Bae G, Kang J, Krauss R. Boc modifies the holoprosencephaly spectrum of Cdo mutant mice. Dis Model Mech. 2011;4:368-80 pubmed publisher
    b>Holoprosencephaly (HPE) is caused by a failure to form the midline of the forebrain and/or midface. It is one of the most common human birth defects, but clinical expression is extremely variable...
  28. Solomon B, Lacbawan F, Jain M, Domené S, Roessler E, Moore C, et al. A novel SIX3 mutation segregates with holoprosencephaly in a large family. Am J Med Genet A. 2009;149A:919-25 pubmed publisher
    b>Holoprosencephaly is the most common structural malformation of the forebrain in humans and has a complex etiology including chromosomal aberrations, single gene mutations and environmental components...
  29. Taniguchi K, Anderson A, Sutherland A, Wotton D. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet. 2012;8:e1002524 pubmed publisher
    b>Holoprosencephaly (HPE) is a severe human genetic disease affecting craniofacial development, with an incidence of up to 1/250 human conceptions and 1.3 per 10,000 live births...
  30. Hahn J, Plawner L. Evaluation and management of children with holoprosencephaly. Pediatr Neurol. 2004;31:79-88 pubmed
    ..contributed to our understanding of the spectrum of midline brain and craniofacial malformations known as holoprosencephaly. Neuroradiologic studies have provided detailed characteristics of four major types of holoprosencephaly: ..
  31. Marini M, Cusano R, De Biasio P, Caroli F, Lerone M, Silengo M, et al. Previously undescribed nonsense mutation in SHH caused autosomal dominant holoprosencephaly with wide intrafamilial variability. Am J Med Genet A. 2003;117A:112-5 pubmed
    b>Holoprosencephaly (HPE) is the most common developmental defect of the forebrain and midface in humans, with a frequency of 1/16,000 live births...
  32. Solomon B, Lacbawan F, Mercier S, Clegg N, Delgado M, Rosenbaum K, et al. Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. J Med Genet. 2010;47:513-24 pubmed publisher
    b>Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE...
  33. Monuki E. The morphogen signaling network in forebrain development and holoprosencephaly. J Neuropathol Exp Neurol. 2007;66:566-75 pubmed
    ..molecules known as morphogens, and morphogen signaling defects often lead to failed midline induction and holoprosencephaly (HPE), the most common malformation of the human forebrain...
  34. Bendavid C, Dubourg C, Gicquel I, Pasquier L, Saugier Veber P, Durou M, et al. Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Hum Genet. 2006;119:1-8 pubmed
    b>Holoprosencephaly (HPE), the most common structural malformation of the forebrain in humans, can be detected early during pregnancy using prenatal ultrasonography ...
  35. Ming J, Kaupas M, Roessler E, Brunner H, Golabi M, Tekin M, et al. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet. 2002;110:297-301 pubmed
    b>Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations...
  36. Lipinski R, Godin E, O Leary Moore S, Parnell S, Sulik K. Genesis of teratogen-induced holoprosencephaly in mice. Am J Med Genet C Semin Med Genet. 2010;154C:29-42 pubmed publisher
    Evidence from mechanical, teratological, and genetic experimentation demonstrates that holoprosencephaly (HPE) typically results from insult prior to the time that neural tube closure is completed and occurs as a consequence of direct or ..
  37. Lim A, Lim T, Kee S, Chia P, Raman S, Eu E, et al. Holoprosencephaly: an antenatally-diagnosed case series and subject review. Ann Acad Med Singapore. 2008;37:594-7 pubmed
    b>Holoprosencephaly (HPE) is an uncommon congenital failure of forebrain development...
  38. Corona Rivera J, Rea Rosas A, Santana Ramírez A, Acosta León J, Hernández Rocha J, Miguel Jiménez K. Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome. Am J Med Genet A. 2010;152A:1741-6 pubmed publisher
    ..penile curvature, vesicoureteral reflux, hydronephrosis, and severe CNS anomalies including semilobar holoprosencephaly (HPE)...
  39. Aoto K, Shikata Y, Higashiyama D, Shiota K, Motoyama J. Fetal ethanol exposure activates protein kinase A and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly. Birth Defects Res A Clin Mol Teratol. 2008;82:224-31 pubmed publisher
    In humans, fetal ethanol exposure can cause holoprosencephaly (HPE), one of the most common birth defects that is characterized by brain, facial, and oral abnormalities. However, the pathogenesis of HPE is not clear...
  40. Leoncini E, Baranello G, Orioli I, Anneren G, Bakker M, Bianchi F, et al. Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol. 2008;82:585-91 pubmed publisher
    b>Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central ..
  41. Vaz S, Chodirker B, Prasad C, Seabrook J, Chudley A, Prasad A. Risk factors for nonsyndromic holoprosencephaly: a Manitoba case-control study. Am J Med Genet A. 2012;158A:751-8 pubmed publisher
    b>Holoprosencephaly (HPE) is one of the most common developmental field defects, occurring in 1 in 250 conceptuses and in 1 in 10,000-20,000 live births. Nearly half of patients with HPE have a recognized syndrome or a single gene defect...
  42. Vilain C, Mortier G, Van Vliet G, Dubourg C, Heinrichs C, de Silva D, et al. Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review. Am J Med Genet A. 2009;149A:1476-81 pubmed publisher
    We report on five male subjects with a triad of signs compatible with Hartsfield syndrome: ectrodactyly, holoprosencephaly, and mental retardation...
  43. Bendavid C, Dupé V, Rochard L, Gicquel I, Dubourg C, David V. Holoprosencephaly: An update on cytogenetic abnormalities. Am J Med Genet C Semin Med Genet. 2010;154C:86-92 pubmed publisher
    b>Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure of midline cleavage early in gestation...
  44. Traggiai C, Stanhope R. Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr. 2002;140:252-5 pubmed
    ..palate was associated not only with growth hormone deficiency (GHD) but also with diabetes insipidus (DI); holoprosencephaly and optic nerve hypoplasia with absence of the septum pellucidum had a similar incidence of GHD and DI...
  45. Anderson R, Lawrence A, Stottmann R, Bachiller D, Klingensmith J. Chordin and noggin promote organizing centers of forebrain development in the mouse. Development. 2002;129:4975-87 pubmed
    ..The variable phenotypes include cyclopia, holoprosencephaly, and rostral truncations of the brain and craniofacial skeleton...
  46. Schell Apacik C, Rivero M, Knepper J, Roessler E, Muenke M, Ming J. SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet. 2003;113:170-7 pubmed
    b>Holoprosencephaly (HPE) is a common forebrain malformation associated with mental retardation and craniofacial anomalies. Multiple lines of evidence indicate that loss of ventral neurons is associated with HPE...
  47. Chen C, Shih J, Hsu C, Chen C, Huang J, Wang W. Prenatal three-dimensional/four-dimensional sonographic demonstration of facial dysmorphisms associated with holoprosencephaly. J Clin Ultrasound. 2005;33:312-8 pubmed
    ..use of 3-dimensional 4-dimensional (3D/4D) sonography to visualize the facial dysmorphisms associated with holoprosencephaly in 6 fetuses (2 with cyclopia, 1 with cebocephaly, and 3 with holoprosencephaly-premaxillary agenesis)...
  48. Yamada S, Uwabe C, Fujii S, Shiota K. Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection. Birth Defects Res A Clin Mol Teratol. 2004;70:495-508 pubmed
    b>Holoprosencephaly (HPE) is one of the most common developmental disorders of the brain associated with specific craniofacial dysmorphogenesis...
  49. Plawner L, Delgado M, Miller V, Levey E, Kinsman S, Barkovich A, et al. Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain. Neurology. 2002;59:1058-66 pubmed
    Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described.
  50. Ming J, Muenke M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet. 2002;71:1017-32 pubmed
  51. Cole F, Krauss R. Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr Biol. 2003;13:411-5 pubmed
    b>Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure to delineate the midline in these structures...
  52. Keaton A, Solomon B, van Essen A, Pfleghaar K, Slama M, Martin J, et al. Holoprosencephaly and ectrodactyly: Report of three new patients and review of the literature. Am J Med Genet C Semin Med Genet. 2010;154C:170-5 pubmed publisher
    b>Holoprosencephaly (HPE) and ectrodactyly represent congenital malformations of the developing forebrain and developing digits, respectively...
  53. Garavelli L, Zanacca C, Caselli G, Banchini G, Dubourg C, David V, et al. Solitary median maxillary central incisor syndrome: clinical case with a novel mutation of sonic hedgehog. Am J Med Genet A. 2004;127A:93-5 pubmed
    ..It is usually considered as a minor manifestation of holoprosencephaly (HPE). Some reported families had severe cases of HPE in some members and SMMCI in others...
  54. Higashiyama D, Saitsu H, Komada M, Takigawa T, Ishibashi M, Shiota K. Sequential developmental changes in holoprosencephalic mouse embryos exposed to ethanol during the gastrulation period. Birth Defects Res A Clin Mol Teratol. 2007;79:513-23 pubmed
    ..However, its teratogenic window for inducing holoprosencephaly is narrow, and the teratogenic mechanism is not well understood...
  55. Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:52-61 pubmed publisher
    b>Holoprosencephaly (HPE) has captivated the imagination of Man for millennia because its most extreme manifestation, the single-eyed cyclopic newborn infant, brings to mind the fantastical creature Cyclops from Greek mythology...
  56. Roessler E, Pei W, Ouspenskaia M, Karkera J, Velez J, Banerjee Basu S, et al. Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Mol Genet Metab. 2009;98:225-34 pubmed publisher
    ..g. left-right mis-specification phenotypes), and only rarely holoprosencephaly (HPE)...
  57. Polizzi A, Pavone P, Iannetti P, Gambardella A, Ruggieri M. CNS findings in three cases of septo-optic dysplasia, including one with semilobar holoprosencephaly. Am J Med Genet A. 2005;136A:357 pubmed
  58. Maity T, Fuse N, Beachy P. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A. 2005;102:17026-31 pubmed
    b>Holoprosencephaly (HPE), a human developmental brain defect, usually is also associated with varying degrees of midline facial dysmorphism...
  59. Bendavid C, Haddad B, Griffin A, Huizing M, Dubourg C, Gicquel I, et al. Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet. 2006;43:496-500 pubmed
    b>Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain. At birth, nearly 50% of children with HPE have cytogenetic anomalies...
  60. Roessler E, Ma Y, Ouspenskaia M, Lacbawan F, Bendavid C, Dubourg C, et al. Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans. Hum Genet. 2009;125:393-400 pubmed publisher
    Defective function of the Sonic Hedgehog (SHH) signaling pathway is the most frequent alteration underlying holoprosencephaly (HPE) or its various clinical microforms...
  61. Kourti M, Pavlou E, Rousso I, Economou I, Athanassiadou F. Holoprosencephaly and diabetes insipidus in a 3-month-old infant. J Child Neurol. 2008;23:118-20 pubmed
    b>Holoprosencephaly is a developmental defect caused by incomplete cleavage of the embryonic forebrain structures during early embryogenesis...
  62. Yang Y, Anderson R, Klingensmith J. BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning. Hum Mol Genet. 2010;19:3030-42 pubmed publisher
    b>Holoprosencephaly (HPE) is the most common forebrain and craniofacial malformation syndrome in humans. The genetics of HPE suggest that it often stems from a synergistic interaction of mutations in independent loci...
  63. Kantaputra P, Limwongse C, Tochareontanaphol C, Mutirangura A, Mevatee U, Praphanphoj V. Contiguous gene syndrome of holoprosencephaly and hypotrichosis simplex: association with an 18p11.3 deletion. Am J Med Genet A. 2006;140:2598-602 pubmed
    ..Possible explanations include (1) the effects of a different deleted region, (2) a positional effect caused by a gene close by, or (3) by interruption of a different gene resulting from chromosomal translocation...
  64. Ribeiro L, Quiezi R, Nascimento A, Bertolacini C, Richieri Costa A. Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients. Am J Med Genet A. 2010;152A:1688-94 pubmed publisher
    b>Holoprosencephaly (HPE) is genetically heterogeneous. Variable phenotypic manifestations within families with normal and affected patients have been attributed to the number and type of HPE gene mutations...
  65. Arathi N, Mahadevan A, Santosh V, Yasha T, Shankar S. Holoprosencephaly with cyclopia--report of a pathological study. Neurol India. 2003;51:279-82 pubmed
    A rare case of a lobar holoprosencephaly with cyclopia, associated with non-nervous system anomalies is being reported.
  66. Szabo N, Gergev G, Kóbor J, Szucs P, Turi S, Sztriha L. Holoprosencephaly in hungary: birth prevalence and clinical spectrum. J Child Neurol. 2011;26:1029-32 pubmed publisher
    A retrospective population based survey of patients born with holoprosencephaly in South-Eastern Hungary between July 1, 1992 and June 30, 2006 was performed...
  67. Hehr U, Gross C, Diebold U, Wahl D, Beudt U, Heidemann P, et al. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Eur J Pediatr. 2004;163:347-52 pubmed
    Mutations in the human sonic hedgehog gene (SHH) are the most frequent cause of autosomal dominant inherited holoprosencephaly (HPE), a complex brain malformation resulting from incomplete cleavage of the developing forebrain into two ..
  68. Rollins N. Semilobar holoprosencephaly seen with diffusion tensor imaging and fiber tracking. AJNR Am J Neuroradiol. 2005;26:2148-52 pubmed
    A neonate with semilobar holoprosencephaly was studied with diffusion tensor imaging and fiber tracking...
  69. de la Cruz J, Bamford R, Burdine R, Roessler E, Barkovich A, Donnai D, et al. A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Hum Genet. 2002;110:422-8 pubmed
    ..The mutant protein is inactive in a zebrafish rescue assay, indicating a role for TDGF1 in human midline and forebrain development...
  70. Roessler E, El Jaick K, Dubourg C, Vélez J, Solomon B, Pineda Alvarez D, et al. The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis. Hum Mutat. 2009;30:E921-35 pubmed publisher
    ..or its related pathway components are the most common, and best understood, pathogenetic changes observed in holoprosencephaly patients; this fact is consistent with the essential functions of this gene during forebrain development and ..
  71. Sezgin I, Sungu S, Bekar E, Cetin M, Ceran H. Cyclopia-astomia-agnathia-holoprosencephaly association: a case report. Clin Dysmorphol. 2002;11:225-6 pubmed
    A female infant is described with cyclopia-astomia-agnathia-holoprosencephaly association. The authors discuss whether the use of salicylates in early pregnancy is implicated.
  72. Kamnasaran D, Chen C, Devriendt K, Mehta L, Cox D. Defining a holoprosencephaly locus on human chromosome 14q13 and characterization of potential candidate genes. Genomics. 2005;85:608-21 pubmed
    b>Holoprosencephaly (HPE) is the most common developmental field defect in patterning of the human prosencephalon and associated craniofacial structures. The genetics is complex, with 12 loci defined on 11 chromosomes...
  73. Domené S, Roessler E, El Jaick K, Snir M, Brown J, Vélez J, et al. Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet. 2008;17:3919-28 pubmed publisher
    b>Holoprosencephaly (HPE) is the most common developmental anomaly of the human forebrain; however, the genetics of this heterogeneous and etiologically complex malformation is incompletely understood...
  74. Schachter K, Krauss R. Murine models of holoprosencephaly. Curr Top Dev Biol. 2008;84:139-70 pubmed publisher
    b>Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure to delineate the midline in these structures...
  75. Roessler E, Vélez J, Zhou N, Muenke M. Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. Mol Genet Metab. 2012;105:658-64 pubmed publisher
    ..diagnostic centers routinely screen SHH, ZIC2, SIX3 and TGIF for mutations that can help to explain holoprosencephaly and related brain malformations...
  76. McCormack W, Shen J, Curry S, Berend S, Kashork C, Pinar H, et al. Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy-Walker malformation. Am J Med Genet. 2002;112:384-9 pubmed
    ..13, del(13)(13q21-q34) and del(13)(13q22-q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy-Walker malformation (DWM) are described...
  77. Hsieh T, Yu C, Kuo P, Chang F. Prenatal diagnosis of alobar holoprosencephaly with cystic hygroma. Taiwan J Obstet Gynecol. 2006;45:146-9 pubmed
    b>Holoprosencephaly is a kind of brain anomaly characterized by inadequate cleavage of the prosencephalon during early embryogenesis. In addition, holoprosencephaly associated with cystic hygroma and hydrops fetalis has never been reported...
  78. Coleta E, Siminel M, Gheonea M. Holoprosencephaly sequence. Rom J Morphol Embryol. 2011;52:725-8 pubmed
    b>Holoprosencephaly (HPE) sequence is a rare spectrum of cerebral and facial malformations resulting from incomplete division of the embryonic forebrain into distinct lateral cerebral hemisphere...
  79. Bendavid C, Dubourg C, Pasquier L, Gicquel I, Le Gallou S, Mottier S, et al. MLPA screening reveals novel subtelomeric rearrangements in holoprosencephaly. Hum Mutat. 2007;28:1189-97 pubmed
    b>Holoprosencephaly (HPE) is the most common developmental brain anomaly in human, associated with a wide spectrum of presentations. The etiology is heterogeneous, due to environmental and genetic factors...
  80. Singh S, Tokhunts R, Baubet V, Goetz J, Huang Z, Schilling N, et al. Sonic hedgehog mutations identified in holoprosencephaly patients can act in a dominant negative manner. Hum Genet. 2009;125:95-103 pubmed publisher
    ..Mutations in the SHH gene are the most common cause of sporadic and inherited holoprosencephaly (HPE), a developmental disorder that is characterized by defective prosencephalon development...
  81. Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis. 2007;2:8 pubmed
    b>Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face...
  82. Koolen D, Herbergs J, Veltman J, Pfundt R, van Bokhoven H, Stroink H, et al. Holoprosencephaly and preaxial polydactyly associated with a 1.24 Mb duplication encompassing FBXW11 at 5q35.1. J Hum Genet. 2006;51:721-6 pubmed
    b>Holoprosencephaly (HPE) is the most common developmental defect affecting the forebrain and midface in humans. The aetiology of HPE is highly heterogeneous and includes both environmental and genetic factors...
  83. Edison R, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. N Engl J Med. 2005;352:2759 pubmed
  84. Ginocchio V, De Brasi D, Genesio R, Ciccone R, Gimelli S, Fimiani F, et al. Sonic Hedgehog deletion and distal trisomy 3p in a patient with microphthalmia and microcephaly, lacking cerebral anomalies typical of holoprosencephaly. Eur J Med Genet. 2008;51:658-65 pubmed publisher
    About 20% of cases with 7q deletion syndrome is associated with holoprosencephaly (HPE), due to deletion of the Sonic Hedgehog (SHH) gene (mapping to 7q36)...
  85. Sepulveda W. Monosomy 18p presenting with holoprosencephaly and increased nuchal translucency in the first trimester: report of 2 cases. J Ultrasound Med. 2009;28:1077-80 pubmed
    ..The purpose of this series is to describe the first-trimester sonographic findings leading to the diagnosis of monosomy 18p...
  86. Paulussen A, Schrander Stumpel C, Tserpelis D, Spee M, Stegmann A, Mancini G, et al. The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes. Eur J Hum Genet. 2010;18:999-1005 pubmed publisher
    b>Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000...
  87. Kinsman S. White matter imaging in holoprosencephaly in children. Curr Opin Neurol. 2004;17:115-9 pubmed
    b>Holoprosencephaly is a disorder of forebrain development characterized by a failure of the brain to separate into two hemispheres during early development...
  88. Shiota K, Yamada S. Early pathogenesis of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:22-8 pubmed publisher
    b>Holoprosencephaly (HPE) is one of the most common malformations encountered in early human embryos. It is assumed that more than 90% of HPE embryos die in utero and are eliminated by spontaneous abortion...
  89. Bae G, Domené S, Roessler E, Schachter K, Kang J, Muenke M, et al. Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. Am J Hum Genet. 2011;89:231-40 pubmed publisher
    b>Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these ..
  90. Miller E, Rasmussen S, Siega Riz A, Frias J, Honein M. Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am J Med Genet C Semin Med Genet. 2010;154C:62-72 pubmed publisher
    b>Holoprosencephaly (HPE) is a complex structural brain anomaly that results from incomplete cleavage of the forebrain. The prevalence of HPE at birth is low, and risk factors have been difficult to identify...
  91. McCabe M, Gaston Massuet C, Tziaferi V, Gregory L, Alatzoglou K, Signore M, et al. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab. 2011;96:E1709-18 pubmed publisher
    ..Murine data suggest a role for Fgf8 in hypothalamo-pituitary development; however, its role in the etiology of wider hypothalamo-pituitary dysfunction in humans is unknown...
  92. Rosenfeld J, Ballif B, Martin D, Aylsworth A, Bejjani B, Torchia B, et al. Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE. Hum Genet. 2010;127:421-40 pubmed publisher
    b>Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans. Both environmental and genetic factors have been identified to play a role in the HPE phenotype...
  93. Chan E, Ng D, Chong A, Hui Y, Fu Y. Congenital nasal pyriform aperture stenosis with semilobar holoprosencephaly. Int J Pediatr Otorhinolaryngol. 2005;69:93-6 pubmed
    ..We describe a child who has congenital nasal pyriform aperture stenosis with single maxillary central incisor, holoprosencephaly and central diabetes insipidus without any apparent anterior pituitary dysfunction...
  94. Solomon B, Mercier S, Vélez J, Pineda Alvarez D, Wyllie A, Zhou N, et al. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:133-41 pubmed publisher
    Since the discovery of the first gene causing holoprosencephaly (HPE), over 500 patients with mutations in genes associated with non-chromosomal, non-syndromic HPE have been described, with detailed descriptions available in over 300...
  95. Chen L, Liao G, Yang L, Campbell K, Nakafuku M, Kuan C, et al. Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A. 2006;103:16520-5 pubmed
    ..the Cdc42-deficient telencephalon failed to bulge or separate into two cerebral hemispheres, resulting in holoprosencephaly. However, neither the midline expression of Sonic hedgehog nor the dorso-ventral patterning of the ..
  96. Lee Y, Lin M, Lee M, Lin L. Holoprosencephaly and cyclopia visualized by two- and three-dimensional prenatal ultrasound. Chang Gung Med J. 2002;25:207-10 pubmed
    We report on the ultrasound (US) detection of holoprosencephaly with cyclopia at a gestational age of 16 weeks...
  97. Hong M, Krauss R. Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice. PLoS Genet. 2012;8:e1002999 pubmed publisher
    b>Holoprosencephaly (HPE) is a remarkably common congenital anomaly characterized by failure to define the midline of the forebrain and midface...
  98. Ribeiro L, Bertolacini C, Quiezi R, Richieri Costa A. A novel heterozygous missense mutation G316D of SIX3 gene in a Brazilian patient with holoprosencephaly-like phenotype and Langerhans cell histiocytosis. Clin Dysmorphol. 2011;20:160-2 pubmed publisher
    Here we report on a Brazilian female patient with the clinical manifestations of the holoprosencephaly-like phenotype who also presented with a retroocular granuloma diagnosed as Langerhans cell histiocytosis in early infancy...