Sections

Overview

Practice Essentials

Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks' gestation, with failed segmentation of the neural tube. This leads to incomplete separation of the prosencephalon (forebrain).^{[1, 2, 3, 4]}

Classification of holoprosencephaly

Holoprosencephaly has four subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly).^{[2, 5]}

Alobar holoprosencephaly is the most severe form, with no separation of the cerebral hemispheres; it is characterized by a single ventricle, absence of the corpus callosum and interhemispheric fissure, and fused thalami.

In semilobar holoprosencephaly, the cerebral hemispheres are fused anteriorly, while lobar holoprosencephaly is characterized by fusion of the cerebral hemispheres at the frontal lobes.

A middle interhemispheric fusion variant results from nonseparation of posterior frontal and parietal lobes.

Some researchers have attempted to incorporate degree of nonseparation of subcortical structures into the classification system.^[6]The term septopreoptic holoprosencephaly has been used to describe a mild subtype of lobar holoprosencephaly with nonseparation restricted to the septal or preoptic region.^[7]

Most cases of holoprosencephaly are characterized by various midline craniofacial malformations. The most severe craniofacial deformity is cyclopia, with a single or partially divided eye existing in a single orbit, along with a proboscis (tubular appendage) above the eye and an absent nose (arhinia). Several less severe midline malformations have been described, such as a single central maxillary incisor.^{[8, 9, 10]}

Microform of holoprosencephaly is a term assigned to the relatives of probands who have minor craniofacial anomalies but no cerebral abnormalities suggestive of holoprosencephaly on neuroimaging. They may have neurodevelopmental issues.^{[11, 12, 13, 14, 15]}

Symptoms of holoprosencephaly

Seizures are common in holoprosencephaly.^{[16, 17]}Patients often have feeding difficulties and resultant malnutrition.^[18]Pituitary dysfunction is also common.^[19]Other problems include temperature dysregulation, disturbed sleep cycle, brainstem dysfunction, and recurrent respiratory tract infections.^{[20, 21]}The severity of developmental delay depends on the severity of the brain malformation. Movement disorders include spasticity, hypotonia, choreoathetosis, and dystonia.^[22]

Workup

Prenatal diagnosis options include karyotype analysis, microarray testing, ultrasonography, and magnetic resonance imaging (MRI). It is possible to arrive at an etiologic diagnosis prenatally in many cases.^{[23, 24, 25]}Karyotype is abnormal in about a third of holoprosencephaly cases, with trisomy 13 being the most common such anomaly.^{[26, 27]}

Management

Medical care is necessary for problems commonly associated with holoprosencephaly, such as seizures, movement disorders, pituitary dysfunction, failure to thrive, feeding issues, and gastroesophageal reflux. Neurosurgical intervention is needed if hydrocephalus is present.

Anatomy

During early human brain development, the forebrain divides into telencephalon and diencephalon. Telencephalon develops into cerebral hemispheres and subcortical structures such as basal ganglia, amygdala, and hippocampus. Diencephalon gives rise to the thalamus and hypothalamus.

Pathophysiology

A combination of genetic and environmental factors is thought to be responsible for the pathogenesis of holoprosencephaly. Defective sterol metabolism leading to abnormalities in the sonic hedgehog (SHH) signaling pathway may have a role in its causation.^{[28, 29, 30, 31, 32]} However, many genes besides SHH have also been associated with holoprosencephaly.^[33]

Using a collection of over 44,000 human conceptuses from Kyoto University, in Japan, Abe et al reported that spontaneous abortions occurred in about 30% of women with a conceptus suffering from holoprosencephaly, approximately twice the rate found in pregnancies in general. The study also indicated that an association exists between bleeding in pregnancy and holoprosencephaly, with such bleeding experienced by 70% of women with a holoprosencephalic conceptus.^[34]

Environmental causes

Maternal diabetes mellitus is a known risk factor.^[35]Maternal use of alcohol, retinoic acid, aspirin, misoprostol, and cholesterol-lowering agents has been implicated, as has maternal smoking.^{[36, 37, 38, 39, 40, 41, 42, 43, 44, 45]}

Heritable causes

Holoprosencephaly is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, and triploidy.^{[46, 47, 48, 49, 50, 51]}It has been reported with Down syndrome, but the association is thought to be coincidental.^{[52, 53]} Many other chromosomal abnormalities have been reported as a cause.^{[54, 55, 56]}

Many syndromes are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Meckel-Gruber syndrome, Pallister-Hall syndrome, caudal dysgenesis, and Aicardi syndrome.^{[57, 58, 59, 60, 61, 62, 63, 64, 65]}

Mutations in various genes have been reported in nonsyndromic holoprosencephaly, including SHH, ZIC2, SIX3, and TGIF, and are inherited in an autosomal-dominant fashion. Autosomal-recessive and X-linked patterns have also been described.^{[66, 67, 68, 69, 70, 71, 72, 73, 74, 75]}

United States statistics

Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births.^{[26, 76, 77]}This is likely to be an underestimation.

International statistics

Holoprosencephaly occurs worldwide.^{[78, 79, 80, 81, 82, 83]}The frequency among all pregnancies has been reported to be 1 in 250 based on a study on embryos obtained through induced abortion, making this the most common human forebrain malformation.^[84]

Racial differences in incidence

Ethnic variations have been reported.^{[77, 80]}However, these may be due to lower prenatal detection rates in certain groups and lower rates of pregnancy terminations.^[85]

Sexual differences in incidence

Holoprosencephaly has been reported to be more common in females than in males.^{[81, 86]} ^[87]

Prognosis

The prognosis of holoprosencephaly depends on the severity of the malformation.

The recurrence risk is high if parental carrier state is established, although its exact quantification may not be possible.^[88]The recurrence risk is usually low if the genetic abnormalities occur de novo in the proband, although there is always the possibility of germline mosaicism.^[89]

Complications

Possible complications of holoprosencephaly include those due to secondary manifestations such as seizures and ventriculoperitoneal shunt malfunction.

Mortality/morbidity

Mortality and morbidity associated with holoprosencephaly depend on the severity of the malformations. Most affected pregnancies result in miscarriage. Among live births, those with the severe type often die within days of birth.^[79] Persons with milder malformations usually survive beyond infancy.^[90]

Clinical Presentation

Winter TC, Kennedy AM, Woodward PJ. Holoprosencephaly: a survey of the entity, with embryology and fetal imaging. Radiographics. 2015 Jan-Feb. 35 (1):275-90. [Medline]. [Full Text].
DEMYER W, ZEMAN W. Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: clinical, electroencephalographic and nosologic considerations. Confin Neurol. 1963. 23:1-36. [Medline].
De Catte L, De Keersmaeker B, Claus F. Prenatal neurologic anomalies: sonographic diagnosis and treatment. Paediatr Drugs. 2012 Jun 1. 14 (3):143-55. [Medline].
Icenogle DA, Kaplan AM. A review of congenital neurologic malformations. Clin Pediatr (Phila). 1981 Sep. 20 (9):565-76. [Medline].
Barkovich AJ, Quint DJ. Middle interhemispheric fusion: an unusual variant of holoprosencephaly. AJNR Am J Neuroradiol. 1993 Mar-Apr. 14(2):431-40. [Medline].
Simon EM, Hevner R, Pinter JD, Clegg NJ, Miller VS, Kinsman SL, et al. Assessment of the deep gray nuclei in holoprosencephaly. AJNR Am J Neuroradiol. 2000 Nov-Dec. 21(10):1955-61. [Medline].
Hahn JS, Barnes PD, Clegg NJ, Stashinko EE. Septopreoptic holoprosencephaly: a mild subtype associated with midline craniofacial anomalies. AJNR Am J Neuroradiol. 2010 Oct. 31(9):1596-601. [Medline].
Burck U, Hayek HW, Zeidler U. Holoprosencephaly in monozygotic twins - clinical and computer tomographic findings. Am J Med Genet. 1981. 9(1):13-7. [Medline].
Martin RA, Jones KL. Absence of the superior labial frenulum in holoprosencephaly: a new diagnostic sign. J Pediatr. 1998 Jul. 133(1):151-3. [Medline].
Chang LH. Alobar holoprosencephaly: report of two cases with unusual findings. Chang Gung Med J. 2003 Sep. 26(9):700-6. [Medline].
Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Am J Med Genet. 2001 Jul 22. 102(1):1-10. [Medline].
Heussler HS, Suri M, Young ID, Muenke M. Extreme variability of expression of a Sonic Hedgehog mutation: attention difficulties and holoprosencephaly. Arch Dis Child. 2002 Apr. 86(4):293-6. [Medline].
Solomon BD, 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 May. 149A(5):919-25. [Medline]. [Full Text].
Johnson VP. Holoprosencephaly: a developmental field defect. Am J Med Genet. 1989 Oct. 34(2):258-64. [Medline].
Arlis H, Ward RF. Congenital nasal pyriform aperture stenosis. Isolated abnormality vs developmental field defect. Arch Otolaryngol Head Neck Surg. 1992 Sep. 118(9):989-91. [Medline].
Ko JM, Kim SH. Clinical features and outcomes of holoprosencephaly in Korea. Pediatr Neurol. 2010 Oct. 43(4):245-52. [Medline].
Yoshikawa H, Nakano K, Watanabe S. Central tegmental tract lesion in a girl with holoprosencephaly presenting with West syndrome. Eur J Paediatr Neurol. 2009 Jul. 13(4):376-9. [Medline].
Kawame H, Kurosawa K, Akatsuka A, Ochiai Y. [Clinical spectrum and management of holoprosencephaly]. No To Hattatsu. 2000 Jul. 32(4):301-6. [Medline].
Traggiai C, Stanhope R. Endocrinopathies associated with midline cerebral and cranial malformations. J Pediatr. 2002 Feb. 140(2):252-5. [Medline].
Levey EB, Stashinko E, Clegg NJ, Delgado MR. Management of children with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010 Feb 15. 154C(1):183-90. [Medline].
Barr M Jr, Cohen MM Jr. Holoprosencephaly survival and performance. Am J Med Genet. 1999 Jun 25. 89(2):116-20. [Medline].
Hahn JS, Barkovich AJ, Stashinko EE, Kinsman SL, Delgado MR, Clegg NJ. Factor analysis of neuroanatomical and clinical characteristics of holoprosencephaly. Brain Dev. 2006 Aug. 28(7):413-9. [Medline].
Dill P, Poretti A, Boltshauser E, Huisman TA. Fetal magnetic resonance imaging in midline malformations of the central nervous system and review of the literature. J Neuroradiol. 2009 Jun. 36(3):138-46. [Medline].
Machado IN, Heinrich JK, Barini R. Genomic imbalances detected through array CGH in fetuses with holoprosencephaly. Arq Neuropsiquiatr. 2011 Feb. 69(1):3-8. [Medline].
Petracchi F, Crespo L, Michia C, Igarzabal L, Gadow E. Holoprosencephaly at prenatal diagnosis: analysis of 28 cases regarding etiopathogenic diagnoses. Prenat Diagn. 2011 Jun 27. [Medline].
Croen LA, Shaw GM, Lammer EJ. Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet. 1996 Aug 23. 64(3):465-72. [Medline].
Olsen CL, Hughes JP, Youngblood LG, Sharpe-Stimac M. Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984-1989. Am J Med Genet. 1997 Dec 12. 73(2):217-26. [Medline].
Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC. Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog?. Am J Med Genet. 1996 Dec 30. 66(4):478-84. [Medline].
Cooper MK, Wassif CA, Krakowiak PA, Taipale J, Gong R, Kelley RI. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet. 2003 Apr. 33(4):508-13. [Medline].
Haas D, Morgenthaler J, Lacbawan F, Long B, Runz H, Garbade SF. Abnormal sterol metabolism in holoprosencephaly: studies in cultured lymphoblasts. J Med Genet. 2007 May. 44(5):298-305. [Medline].
Maity T, Fuse N, Beachy PA. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A. 2005 Nov 22. 102(47):17026-31. [Medline].
Choudhry Z, Rikani AA, Choudhry AM, et al. Sonic hedgehog signalling pathway: a complex network. Ann Neurosci. 2014 Jan. 21 (1):28-31. [Medline]. [Full Text].
Kakar N, Ahmad J, Morris-Rosendahl DJ, et al. STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly. Hum Genet. 2015 Jan. 134 (1):45-51. [Medline].
Abe Y, Kruszka P, Martinez AF, et al. Clinical and Demographic Evaluation of a Holoprosencephaly Cohort From the Kyoto Collection of Human Embryos. Anat Rec (Hoboken). 2018 Jun. 301 (6):973-86. [Medline]. [Full Text].
Barr M Jr, Hanson JW, Currey K, Sharp S, Toriello H, Schmickel RD, et al. Holoprosencephaly in infants of diabetic mothers. J Pediatr. 1983 Apr. 102(4):565-8. [Medline].
Coulter CL, Leech RW, Schaefer GB, Scheithauer BW, Brumback RA. Midline cerebral dysgenesis, dysfunction of the hypothalamic-pituitary axis, and fetal alcohol effects. Arch Neurol. 1993 Jul. 50(7):771-5. [Medline].
Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med. 2004 Apr 8. 350(15):1579-82. [Medline].
Edison RJ, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly. N Engl J Med. 2005 Jun 30. 352(26):2759. [Medline].
Su PH, Chen JY, Lee IC, Ng YY, Hu JM, Chen SJ. Pfeiffer-like syndrome with holoprosencephaly: a newborn with maternal smoking and alcohol exposure. Pediatr Neonatol. 2009 Oct. 50(5):234-8. [Medline].
Kotzot D, Weigl J, Huk W, Rott HD. Hydantoin syndrome with holoprosencephaly: a possible rare teratogenic effect. Teratology. 1993 Jul. 48(1):15-9. [Medline].
Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG. 2000 Apr. 107(4):519-23. [Medline].
Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA,. Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am J Med Genet C Semin Med Genet. 2010 Feb 15. 154C(1):62-72. [Medline].
Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3. 313(14):837-41. [Medline].
Corona-Rivera JR, 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 Jul. 152A(7):1741-6. [Medline].
Vaz SS, Chodirker B, Prasad C, Seabrook JA, Chudley AE, Prasad AN. Risk factors for nonsyndromic holoprosencephaly: a Manitoba case-control study. Am J Med Genet A. 2012 Apr. 158A (4):751-8. [Medline].
Agbata IA, Kovi J, Parshad R, Kovi E. Holoprosencephaly and trisomy 13 in a cyclops. JAMA. 1979 Mar 16. 241(11):1109. [Medline].
Papp C, Beke A, Ban Z, Szigeti Z, Toth-Pal E, Papp Z. Prenatal diagnosis of trisomy 13: analysis of 28 cases. J Ultrasound Med. 2006 Apr. 25(4):429-35. [Medline].
Lang AF, Schlager FM, Gardner HA. Trisomy 18 and cyclopia. Teratology. 1976 Oct. 14(2):195-203. [Medline].
Emberger JM, Marty-Double C, Pincemin D, Caderas de Kerleau J. [Holoprosencephaly by triploidy 69 XXX in a 5 month old fetus]. Ann Genet. 1976 Sep. 19(3):191-3. [Medline].
Solomon BD, Rosenbaum KN, Meck JM, Muenke M. Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2010 Feb 15. 154C(1):146-8. [Medline].
Syngelaki A, Guerra L, Ceccacci I, Efeturk T, Nicolaides KH. Impact of holoprosencephaly, exomphalos, megacystis and increased nuchal translucency on first-trimester screening for chromosomal abnormalities. Ultrasound Obstet Gynecol. 2017 Jul. 50 (1):45-8. [Medline].
Pi SY, Fineman RM, Wing SD, Grunnet M, Chan G. Holoprosencephaly in a Down syndrome child. Am J Med Genet. 1980. 5(2):201-6. [Medline].
Epstein CJ, Seto S, Golabi M. Chance vs. causality in the association of Down syndrome and holoprosencephaly. Am J Med Genet. 1988 Aug. 30(4):939-42. [Medline].
Santolaya J, McCorquodale MM, Torres W, Meyer WJ, Gauthier D, Lemery D. Ultrasonographic prenatal diagnosis of the 13q-syndrome. Fetal Diagn Ther. 1993 Jul-Aug. 8(4):261-7. [Medline].
Quélin C, Bendavid C, Dubourg C, de la Rochebrochard C, Lucas J, Henry C. Twelve new patients with 13q deletion syndrome: genotype-phenotype analyses in progress. Eur J Med Genet. 2009 Jan-Feb. 52(1):41-6. [Medline].
Weiss K, Kruszka P, Guillen Sacoto MJ, et al. In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. Genet Med. 2017 Jun 22. [Medline].
Nöthen MM, Knöpfle G, Födisch HJ, Zerres K. Steinfeld syndrome: report of a second family and further delineation of a rare autosomal dominant disorder. Am J Med Genet. 1993 Jun 1. 46(4):467-70. [Medline].
Cunniff C, Kratz LE, Moser A, Natowicz MR, Kelley RI. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet. 1997 Jan 31. 68(3):263-9. [Medline].
Balci S, Teksen F, Dökmeci F, Cengiz B, Cömert RB, Can B. Prenatal diagnosis of Meckel-Gruber syndrome and Dandy-Walker malformation in four consecutive affected siblings, with the fourth one being diagnosed prenatally at 22 weeks of gestation. Turk J Pediatr. 2004 Jul-Sep. 46(3):283-8. [Medline].
Verloes A, Dodinval P, Beco L, Bonnivert J, Lambotte C. Lambotte syndrome: microcephaly, holoprosencephaly, intrauterine growth retardation, facial anomalies, and early lethality--a new sublethal multiple congenital anomaly/mental retardation syndrome in four sibs. Am J Med Genet. 1990 Sep. 37(1):119-23. [Medline].
Sills IN, Rapaport R, Desposito F, Lieber C. Familial Pallister-Hall syndrome: three affected offspring. Am J Med Genet. 1994 Aug 15. 52(2):251. [Medline].
Sato N, Matsuishi T, Utsunomiya H, Yamashita Y, Horikoshi T, Okudera T. Aicardi syndrome with holoprosencephaly and cleft lip and palate. Pediatr Neurol. 1987 Mar-Apr. 3(2):114-6. [Medline].
Martínez-Frías ML, Bermejo E, García A, Galán E, Prieto L. Holoprosencephaly associated with caudal dysgenesis: a clinical-epidemiological analysis. Am J Med Genet. 1994 Oct 15. 53(1):46-51. [Medline].
Tsai FJ, Tsai CH. Pseudo-trisomy 13 syndrome: report of one case. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1992 Nov-Dec. 33(6):441-5. [Medline].
Camera G, Lituania M, Cohen MM Jr. Holoprosencephaly and primary craniosynostosis: the Genoa syndrome. Am J Med Genet. 1993 Dec 1. 47(8):1161-5. [Medline].
Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov. 14(3):357-60. [Medline].
Brown LY, Odent S, David V, Blayau M, Dubourg C, Apacik C. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet. 2001 Apr 1. 10(8):791-6. [Medline].
Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, et al. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999 Jun. 22(2):196-8. [Medline].
Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet. 2000 Jun. 25(2):205-8. [Medline].
Rahimov F, Ribeiro LA, de Miranda E, Richieri-Costa A, Murray JC. GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum?. Am J Med Genet A. 2006 Dec 1. 140(23):2571-6. [Medline].
Ribeiro LA, Murray JC, Richieri-Costa A. PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI. Am J Med Genet A. 2006 Dec 1. 140(23):2584-6. [Medline].
Ribeiro LA, Quiezi RG, Nascimento A, Bertolacini CP, Richieri-Costa A. Holoprosencephaly and holoprosencephaly-like phenotype and GAS1 DNA sequence changes: Report of four Brazilian patients. Am J Med Genet A. 2010 Jul. 152A(7):1688-94. [Medline].
McCabe MJ, Gaston-Massuet C, Tziaferi V, Gregory LC, Alatzoglou KS, Signore M. Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J Clin Endocrinol Metab. 2011 Oct. 96(10):E1709-18. [Medline].
Mercier S, Dubourg C, Garcelon N, Campillo-Gimenez B, Gicquel I, Belleguic M. New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J Med Genet. 2011 Nov. 48(11):752-60. [Medline].
Dubourg C, Lazaro L, Pasquier L, et al. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Hum Mutat. 2004 Jul. 24 (1):43-51. [Medline].
Rasmussen SA, Moore CA, Khoury MJ, Cordero JF. Descriptive epidemiology of holoprosencephaly and arhinencephaly in metropolitan Atlanta, 1968-1992. Am J Med Genet. 1996 Dec 18. 66(3):320-33. [Medline].
Forrester MB, Merz RD. Epidemiology of holoprosencephaly in Hawaii, 1986-97. Paediatr Perinat Epidemiol. 2000 Jan. 14(1):61-3. [Medline].
Whiteford ML, Tolmie JL. Holoprosencephaly in the west of Scotland 1975-1994. J Med Genet. 1996 Jul. 33(7):578-84. [Medline].
Bullen PJ, Rankin JM, Robson SC. Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol. 2001 May. 184(6):1256-62. [Medline].
Ong S, Tonks A, Woodward ER, Wyldes MP, Kilby MD. An epidemiological study of holoprosencephaly from a regional congenital anomaly register: 1995-2004. Prenat Diagn. 2007 Apr. 27(4):340-7. [Medline].
Orioli IM, Castilla EE. Clinical epidemiologic study of holoprosencephaly in South America. Am J Med Genet A. 2007 Dec 15. 143A(24):3088-99. [Medline].
Leoncini E, Baranello G, Orioli IM, Annerén G, Bakker M, Bianchi F. Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol. 2008 Aug. 82(8):585-91. [Medline].
Szabó N, Gergev G, Kóbor J, Szucs P, Túri S, Sztriha L. Holoprosencephaly in hungary: birth prevalence and clinical spectrum. J Child Neurol. 2011 Aug. 26(8):1029-32. [Medline].
Matsunaga E, Shiota K. Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology. 1977 Dec. 16(3):261-72. [Medline].
Orioli IM, Castilla EE. Epidemiology of holoprosencephaly: Prevalence and risk factors. Am J Med Genet C Semin Med Genet. 2010 Feb 15. 154C(1):13-21. [Medline].
Roach E, Demyer W, Conneally PM, Palmer C, Merritt AD. Holoprosencephaly: birth data, benetic and demographic analyses of 30 families. Birth Defects Orig Artic Ser. 1975. 11(2):294-313. [Medline].
Michalski AM, Richardson SD, Browne ML, et al. Sex ratios among infants with birth defects, National Birth Defects Prevention Study, 1997-2009. Am J Med Genet A. 2015 May. 167A (5):1071-81. [Medline].
Mercier S, Dubourg C, Belleguic M, Pasquier L, Loget P, Lucas J. Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE). Am J Med Genet C Semin Med Genet. 2010 Feb 15. 154C(1):191-6. [Medline].
Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999 Dec. 8(13):2479-88. [Medline].
Kaliaperumal C, Ndoro S, Mandiwanza T, et al. Holoprosencephaly: antenatal and postnatal diagnosis and outcome. Childs Nerv Syst. 2016 May. 32 (5):801-9. [Medline].
Cohen MM Jr. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology. 1989 Sep. 40(3):211-35. [Medline].
Sepulveda W, Wong AE, Andreeva E, Odegova N, Martinez-Ten P, Meagher S. Biparietal diameter-to-crown-rump length disproportion in first-trimester fetuses with holoprosencephaly. J Ultrasound Med. 2014 Jul. 33 (7):1165-9. [Medline].
Plawner LL, Delgado MR, Miller VS, Levey EB, Kinsman SL, Barkovich AJ. Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain. Neurology. 2002 Oct 8. 59(7):1058-66. [Medline].
Simon EM, Hevner RF, Pinter J, Clegg NJ, Delgado M, Kinsman SL. The dorsal cyst in holoprosencephaly and the role of the thalamus in its formation. Neuroradiology. 2001 Sep. 43(9):787-91. [Medline].
Arnold WH, Sperber GH, Machin GA. Anatomy of the circle of Willis in three cases of human fetal synophthalmic holoprosencephaly. Ann Anat. 1996 Dec. 178(6):553-8. [Medline].
Barkovich AJ, Simon EM, Clegg NJ, Kinsman SL, Hahn JS. Analysis of the cerebral cortex in holoprosencephaly with attention to the sylvian fissures. AJNR Am J Neuroradiol. 2002 Jan. 23(1):143-50. [Medline].
McCormack WM Jr, Shen JJ, Curry SM, Berend SA, 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 Nov 1. 112(4):384-9. [Medline].
Mittelbronn M, Beschorner R, Capper D, Haist M, Meyermann R, Meyer-Wittkopf M. Coincidence of semilobar holoprosencephaly and Chiari II malformation: correlation of prenatal diagnostics and neuropathologic findings. J Child Neurol. 2006 May. 21(5):426-9. [Medline].
Kumar S, Jaiswal AK, Rastogi M. Aventriculi associated with holoprosencephaly. J Clin Neurosci. 2006 Apr. 13(3):378-80. [Medline].
Martínez-Frías ML, Egüés X, Puras A, Hualde J, de Frutos CA, Bermejo E. Thanatophoric dysplasia type II with encephalocele and semilobar holoprosencephaly: Insights into its pathogenesis. Am J Med Genet A. 2011 Jan. 155A(1):197-202. [Medline].
Ramocki MB, Scaglia F, Stankiewicz P, Belmont JW, Jones JY, Clark GD. Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2. Am J Med Genet A. 2011 Jul. 155A(7):1574-80. [Medline].
Bendavid C, Rochard L, Dubourg C, Seguin J, Gicquel I, Pasquier L. Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci. Hum Mutat. 2009 Aug. 30(8):1175-82. [Medline].
Honey EM, Butow KW, Zwahlen RA. Holoprosencephaly with Clefts: Data of 85 Patients, Treatment and Outcome: Part 1: History, Subdivisions, and Data on 85 Holoprosencephalic Cleft Patients. Ann Maxillofac Surg. 2019 Jan-Jun. 9 (1):140-5. [Medline]. [Full Text].
Butow KW, Zwahlen RA. Holoprosencephaly with Clefts: Data of 85 Patients, Treatment, and Outcome: Part 2: Management, Surgical Treatment, and Unexpected Aspects of Holoprosencephaly Cleft Patients. Ann Maxillofac Surg. 2019 Jan-Jun. 9 (1):146-51. [Medline]. [Full Text].

Media Gallery

Early fetal magnetic resonance image shows alobar holoprosencephaly. Courtesy of Dorothy I. Bulas, MD.

of 1

Holoprosencephaly

Practice Essentials

Classification of holoprosencephaly

Symptoms of holoprosencephaly

Workup

Management

Anatomy

Pathophysiology

Etiology

Environmental causes

Heritable causes

Epidemiology

United States statistics

International statistics

Racial differences in incidence

Sexual differences in incidence

Prognosis

Complications

Mortality/morbidity

About

Membership

Apps

WebMD Network

Editions

Holoprosencephaly

Practice Essentials

Classification of holoprosencephaly

Symptoms of holoprosencephaly

Workup

Management

Anatomy

Pathophysiology

Etiology

Environmental causes

Heritable causes

Epidemiology

United States statistics

International statistics

Racial differences in incidence

Sexual differences in incidence

Prognosis

Complications

Mortality/morbidity

References

Tables

Contributor Information and Disclosures

What would you like to print?

Find Us On

About

Membership

Apps

WebMD Network

Editions