{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:12:18Z","timestamp":1791353538105,"version":"4.3.1"},"reference-count":24,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Context: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and\/or optic nerve abnormalities.<\/jats:p><jats:p>Objective: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome.<\/jats:p><jats:p>Main Outcome Measures: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured.<\/jats:p><jats:p>Results: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2T&amp;gt;C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity.<\/jats:p><jats:p>Conclusions: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.<\/jats:p>","DOI":"10.1210\/jc.2006-0426","type":"journal-article","created":{"date-parts":[[2006,8,30]],"date-time":"2006-08-30T08:31:02Z","timestamp":1156926662000},"page":"4528-4536","source":"Crossref","is-referenced-by-count":70,"title":["Novel HESX1 Mutations Associated with a Life-Threatening Neonatal Phenotype, Pituitary Aplasia, but Normally Located Posterior Pituitary and No Optic Nerve Abnormalities"],"prefix":"10.1210","volume":"91","author":[{"given":"Marie-Laure","family":"Sobrier","sequence":"first","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale U654 Ho\u0302pital Henri-Mondor (M.-L.S., M.-P.V.-L., S.A.), 94000 Cre\u0301teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (M.M., N.d.I., R.L.), Instituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genova, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pierre","family":"Vie\u0301-Luton","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale U654 Ho\u0302pital Henri-Mondor (M.-L.S., M.-P.V.-L., S.A.), 94000 Cre\u0301teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Secco","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (A.S.), University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascia","family":"di Iorgi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (M.M., N.d.I., R.L.), Instituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genova, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Lorini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (M.M., N.d.I., R.L.), Instituto di Ricovero e Cura a Carattere Scientifico G. Gaslini, University of Genova, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Amselem","sequence":"additional","affiliation":[{"name":"Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale U654 Ho\u0302pital Henri-Mondor (M.-L.S., M.-P.V.-L., S.A.), 94000 Cre\u0301teil, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614142644900_R1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1242\/dev.122.1.41","article-title":"Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke\u2019s pouch of the mouse embryo","volume":"122","author":"Hermesz","year":"1996","journal-title":"Development"},{"key":"2020071614142644900_R2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/477","article-title":"Mutations in the homeobox gene HESX1\/Hesx1 associated with septo-optic dysplasia in human and mouse","volume":"19","author":"Dattani","year":"1998","journal-title":"Nat Genet"},{"key":"2020071614142644900_R3","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1101\/gad.932601","article-title":"Temporal regulation of a paired-like homeodomain repressor\/TLE corepressor complex and a related activator is required for pituitary organogenesis","volume":"15","author":"Dasen","year":"2001","journal-title":"Genes Dev"},{"key":"2020071614142644900_R4","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/384327a0","article-title":"Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism","volume":"384","author":"Sornson","year":"1996","journal-title":"Nature"},{"key":"2020071614142644900_R5","doi-asserted-by":"crossref","first-page":"4832","DOI":"10.1210\/jc.2002-021868","article-title":"Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia","volume":"88","author":"Cohen","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614142644900_R6","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1006\/dbio.2000.9757","article-title":"The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation","volume":"223","author":"Martinez-Barbera","year":"2000","journal-title":"Dev Biol"},{"key":"2020071614142644900_R7","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1146\/annurev.neuro.24.1.327","article-title":"Signaling and transcriptional mechanisms in pituitary development","volume":"24","author":"Dasen","year":"2001","journal-title":"Annu Rev Neurosci"},{"key":"2020071614142644900_R8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1093\/hmg\/10.1.39","article-title":"Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia","volume":"10","author":"Thomas","year":"2001","journal-title":"Hum Mol Genet"},{"key":"2020071614142644900_R9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1210\/jc.2002-020818","article-title":"Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient","volume":"88","author":"Tajima","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614142644900_R10","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1172\/JCI18589","article-title":"A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction","volume":"112","author":"Carvalho","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071614142644900_R11","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/humu.9332","article-title":"Alu-element insertion in the homeodomain of HESX1 and aplasia of the anterior pituitary","volume":"25","author":"Sobrier","year":"2005","journal-title":"Hum Mutat"},{"key":"2020071614142644900_R12","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/76041","article-title":"Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency","volume":"25","author":"Netchine","year":"2000","journal-title":"Nat Genet"},{"key":"2020071614142644900_R13","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1086\/323764","article-title":"Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4","volume":"69","author":"Machinis","year":"2001","journal-title":"Am J Hum Genet"},{"key":"2020071614142644900_R14","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1126\/science.272.5264.1004","article-title":"Specification of pituitary cell lineages by the LIM homeobox gene Lhx3","volume":"272","author":"Sheng","year":"1996","journal-title":"Science"},{"key":"2020071614142644900_R15","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1126\/science.278.5344.1809","article-title":"Multistep control of pituitary organogenesis","volume":"278","author":"Sheng","year":"1997","journal-title":"Science"},{"key":"2020071614142644900_R16","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1016\/S0140-6736(04)16413-1","article-title":"Growth hormone deficiency and related disorders: insights into causation, diagnosis, and treatment","volume":"363","author":"Dattani","year":"2004","journal-title":"Lancet"},{"key":"2020071614142644900_R17","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/35093537","article-title":"Conditional control of gene expression in the mouse","volume":"2","author":"Lewandoski","year":"2001","journal-title":"Nat Rev Genet"},{"key":"2020071614142644900_R18","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1136\/bmj.299.6698.541","article-title":"Influence of past reproductive performance on risk of spontaneous abortion","volume":"299","author":"Regan","year":"1989","journal-title":"BMJ"},{"key":"2020071614142644900_R19","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.2105\/AJPH.90.9.1452","article-title":"Subfertility and risk of spontaneous abortion","volume":"90","author":"Gray","year":"2000","journal-title":"Am J Public Health"},{"key":"2020071614142644900_R20","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1080\/00016340500494887","article-title":"Spontaneous abortion: a prospective cohort study of younger women from the general population in Denmark. Validation, occurrence and risk determinants","volume":"85","author":"Buss","year":"2006","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2020071614142644900_R21","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S0022-3476(56)80210-2","article-title":"Hypopituitarism, hypoadrenalism, and hypogonadism in the newborn infant","volume":"48","author":"Blizzard","year":"1956","journal-title":"J Pediatr"},{"key":"2020071614142644900_R22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/S0022-3476(60)80341-1","article-title":"Congenital absence of the pituitary gland","volume":"56","author":"Reid","year":"1960","journal-title":"J Pediatr"},{"key":"2020071614142644900_R23","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.modgep.2004.07.003","article-title":"Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development","volume":"5","author":"Sobrier","year":"2004","journal-title":"Gene Expr Patterns"},{"key":"2020071614142644900_R24","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ydbio.2005.12.053","article-title":"Conserved regulatory elements establish the dynamic expression of Rpx\/HesxI in early vertebrate development","volume":"292","author":"Chou","year":"2006","journal-title":"Dev Biol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/11\/4528\/9063648\/jcem4528.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/11\/4528\/9063648\/jcem4528.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:19:36Z","timestamp":1627777176000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/91\/11\/4528\/2656744"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,11,1]]},"references-count":24,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2006,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2006-0426","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,11,1]]}}}