{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:41:34Z","timestamp":1793166094064,"version":"4.5.0"},"reference-count":56,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2004,8,4]],"date-time":"2004-08-04T00:00:00Z","timestamp":1091577600000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2004,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Holoprosencephaly (HPE) is one of the most common developmental disorders of the brain associated with specific craniofacial dysmorphogenesis. Although numerous postnatal cases have been reported, early phases of its pathogenesis are not well understood. We examined over 200 cases of HPE human embryos both grossly and histologically, and studied their phenotypic variability and stage\u2010specific characteristics.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Among over 44,000 human embryos in the Kyoto Collection of Human Embryos, 221 embryos have been diagnosed as HPE. Their developmental stages ranged from Carnegie stage (CS) 13 to CS 23. They were examined grossly and were also serially sectioned for detailed histological analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>HPE embryos after CS 18 were classified into complete (true) cyclopia, synophthalmia (partially fused eyes in a single eye fissure), closely apposed separate eyes (possible forerunners of ethmocephaly and cebocephaly), and milder HPE with median cleft lip (premaxillary agenesis). At CS 13\u201317, when facial morphogenesis is not completed, HPE embryos had some facial characteristics that are specific to these stages and different from those in older HPE embryos. The midline structures of the brain, including the pituitary gland, were lacking or seriously hypoplastic in HPE embryos. Complete cyclopia was found in two cases after CS 18 but none at earlier stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>The early development of HPE in human embryos was systematically studied for the first time. The pathogenesis of craniofacial abnormalities, especially eye anomalies, in HPE was discussed in the light of recent studies with mutant laboratory animals. Birth Defects Research (Part A), 2004. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.20048","type":"journal-article","created":{"date-parts":[[2004,8,4]],"date-time":"2004-08-04T17:00:29Z","timestamp":1091638829000},"page":"495-508","source":"Crossref","is-referenced-by-count":82,"title":["Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection"],"prefix":"10.1002","volume":"70","author":[{"given":"Shigehito","family":"Yamada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chigako","family":"Uwabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Fujii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Shiota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,8,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1400540204"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1400540205"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1400570204"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1086\/394504"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/394509"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/383407a0"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420400304"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320340232"},{"key":"e_1_2_6_10_1","first-page":"196","article-title":"Perspectives on holoprosencephaly: part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies","volume":"12","author":"Cohen MM","year":"1992","journal-title":"J Craniofac Genet Dev Biol"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10258"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1159\/000104278"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.34.2.256"},{"key":"e_1_2_6_14_1","first-page":"431","volume-title":"Handbook of clinical neurology","author":"DeMyer WE","year":"1977"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.2003.tb01022.x"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1090910103"},{"key":"e_1_2_6_17_1","first-page":"1","article-title":"The early development of morphology and patterns of the face in the human embryo","volume":"98","author":"Hinrichsen K","year":"1985","journal-title":"Adv Anat Embryol Cell Biol"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.126.21.4873"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(03)00205-7"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00698663"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00691523"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.4.388"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02162203"},{"key":"e_1_2_6_24_1","first-page":"222","article-title":"Human fetal pituitary gland in holoprosencephaly and anencephaly","volume":"15","author":"Kjaer I","year":"1995","journal-title":"J Craniofac Genet Dev Biol"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/110.1.237"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1177\/088307388600100102"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1000070207"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ar.1090030406"},{"key":"e_1_2_6_29_1","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1242\/dev.124.3.603","article-title":"A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate","volume":"124","author":"Li H","year":"1997","journal-title":"Development"},{"key":"e_1_2_6_30_1","first-page":"5","article-title":"Cyclopia in the human embryo","volume":"6","author":"Mall FP","year":"1917","journal-title":"Contrib Embryol"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420160304"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1086\/344412"},{"key":"e_1_2_6_33_1","series-title":"The metabolic and molecular basis of inherited disease","first-page":"6203","author":"Muenke M","year":"2001"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001850404"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.13.2479"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420010306"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420100102"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1159\/000396087"},{"key":"e_1_2_6_39_1","first-page":"637","volume-title":"Developmental stages in human embryos: including a revision of Streeter's \u201cHorizons\u201d and a survey of the Carnegie collection","author":"O'Rahilly R","year":"1987"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420400502"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.8.1593"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1196-357"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2235734100"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(63)90038-1"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1001150306"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn704"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(99)01742-4"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.1991.tb00360.x"},{"key":"e_1_2_6_49_1","first-page":"189","article-title":"Teratothanasia: prenatal loss of abnormal conceptuses and the prevalence of various malformations during human gestation","volume":"29","author":"Shiota K","year":"1993","journal-title":"Birth Defects Orig Artic Ser"},{"key":"e_1_2_6_50_1","first-page":"261","article-title":"Computerized three\u2010dimensional reconstruction of the brain of normal and holoprosencephalic human embryos","volume":"29","author":"Shiota K","year":"1993","journal-title":"Birth Defects Orig Artic Ser"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420420404"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-193811000-00047"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.28.718.455"},{"key":"e_1_2_6_54_1","first-page":"473","article-title":"The experimental production of various eye abnormalities and an analysis of the development of the primary parts of the eye","volume":"1","author":"Stockard CR","year":"1910","journal-title":"Arch Vergl Ophth"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00230088"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.3.377"},{"key":"e_1_2_6_57_1","first-page":"201","volume-title":"Congenital malformations. Notes and comments","author":"Warkany J","year":"1971"}],"container-title":["Birth Defects Research Part A: Clinical and Molecular Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.20048","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdra.20048","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T16:27:47Z","timestamp":1697473667000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdra.20048"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8]]},"references-count":56,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2004,8]]}},"alternative-id":["10.1002\/bdra.20048"],"URL":"https:\/\/doi.org\/10.1002\/bdra.20048","archive":["Portico"],"relation":{},"ISSN":["1542-0752","1542-0760"],"issn-type":[{"value":"1542-0752","type":"print"},{"value":"1542-0760","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,8]]}}}