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In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS\u2010HPE. These manifestations have been described in case reports and in large cohorts of patients with \u201csingle\u2010gene\u201d mutations, suggesting that the NCNS\u2010HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS\u2010HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS\u2010HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation\u2010positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families.<\/jats:p>","DOI":"10.1002\/ajmg.c.31616","type":"journal-article","created":{"date-parts":[[2018,5,15]],"date-time":"2018-05-15T07:36:53Z","timestamp":1526369813000},"page":"246-257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly"],"prefix":"10.1002","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4109-1928","authenticated-orcid":false,"given":"Ariel F.","family":"Martinez","sequence":"first","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-0875","authenticated-orcid":false,"given":"Paul S.","family":"Kruszka","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Muenke","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,15]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24530"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02550"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM.2002.15.9.1525"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000302285"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/archotol.1992.01880090105027"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.27.3.192"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.07.001"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.22767"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2995"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-102249"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(84)80485-0"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01606.x"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1995.0010"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10221"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/2484"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13277-016-5463-6"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0714-06.2006"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/383407a0"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20532"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004290000114"},{"issue":"4","key":"e_1_2_7_22_1","first-page":"706","article-title":"GLI2 mutations as a cause of hypopituitarism","volume":"9","author":"Cohen L. 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