<i>HESX1</i>Mutations Are an Uncommon Cause of Septooptic Dysplasia and Hypopituitarism

McNay, David; Turton, James; Kelberman, Daniel; Woods, Kathryn S.; Brauner, Raja; Papadimitriou, Anastasios; Keller, E; Keller, Alexandra; Haufs, Nele; Krude, Heiko; Shalet, Stephen M; Dattani, Mehul

doi:10.1210/jc.2006-1609

Cited by 141 publications

(104 citation statements)

References 29 publications

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“…Etiology of the SOD Most SOD cases are sporadic and several etiologies have been postulated, like viral infections, gestational diabetes, environmental teratogens, vascular or degenerative injury and genetic mutations 10,12,[14][15][16] . The association of low maternal age with SOD is not consensus 3,15,16 .…”

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Septo-optic dysplasia

Ferran

Paiva

Gilban

et al. 2010

Arq. Neuro-Psiquiatr.

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Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction. We report 5 children with SOD, originally referred to be evaluated due to short stature, who also presented bilateral optic nerve hypoplasia, nystagmus and development delay. In 4 of the patients, we identified neuroimaging abnormalities of the hypothalamo-pituitary axis such as anterior pituitary hypoplasia (3/5), ectopic posterior pituitary (4/5), thin or absent stalk (3/5) and empty sella (1/5). We also encountered diverse pituitary deficiencies: growth hormone (3/5), adrenocorticotropic hormone (3/5), thyroid-stimulating hormone (2/5) and antidiuretic hormone (1/5). Only one child presented intact pituitary function and anatomy. Although rare, SOD is an important cause of congenital hypopituitarism and it should be considered in children with optic nerve hypoplasia or midline brain abnormalities for early diagnosis and treatment. Key words: septo-optic dysplasia, optic nerve/abnormalities, hypopituitarism. Displasia septo-óptica resumoA displasia septo-óptica (DSO, síndrome de Morsier) é uma condição congênita rara definida por dois critérios da tríade: defeitos de linha média, hipoplasia de nervo óptico e insuficiência hipotálamo-hipofisária. Descrevemos 5 casos de DSO, encaminhados por baixa estatura, com hipoplasia dos nervos ópticos, nistagmo e atraso global do desenvolvimento. Destes, 4 possuem alteração na ressonância magnética de sela túrcica e insuficiência hipotálamo-hipofisária, tendo sido observada adeno-hipófise hipoplásica (3/5), neuro-hipófise ectópica (4/5), haste afilada/ausente (3/5) e sela vazia (1/5), além de déficit dos eixos somatotrófico (3/5), adrenocorticotrófico (3/5), tireotrófico (2/5) e do hormônio antidiurético (1/5). Apenas um paciente não apresenta alteração anatômica ou funcional do eixo hipotálamo-hipofisário. Embora rara, a DSO é causa importante de hipopituitarismo congênito, devendo ser considerada em crianças com hipoplasia de nervo óptico ou defeito de linha média para seu diagnóstico e tratamento precoces, evitando seqüelas graves. Palavras-chave: displasia septo-óptica, nervo óptico/anormalidades., hipopituitarismo.

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“…The association of low maternal age with SOD is not consensus 3,15,16 . A revision study of 100 patients with ONH identified association with prematurity in 21%, fetal alcohol syndrome in 9%, maternal diabetes in 6% and endocrine abnormalities in 6% 17 .…”

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Septo-optic dysplasia

Ferran

Paiva

Gilban

et al. 2010

Arq. Neuro-Psiquiatr.

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“…According to Morishima & Aranoff (11), w30% of SOD cases have complete manifestations, 62% have the complication of hypopituitarism and 60% have an absent septum pellucidum. The condition is thought to be more frequent in children born to younger mothers (mean maternal age 22 years) (8,12), although this has been disputed (13), and in some studies, there is a preponderance of primigravida mothers (13,14). Recently, cases of both isolated ONH and SOD have been shown to cluster in high population density, inner city areas with high rates of unemployment and teenage pregnancy (10).…”

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Hypothalamic and pituitary development: novel insights into the aetiology

Kelberman¹,

Dattani²

2007

eur j endocrinol

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The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.European Journal of Endocrinology 157 S3-S14

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“…At present, eleven mutations of the gene have been described. The patients presented with midline defects, optic nerve hypoplasia, neuro-pituitary ectopia and pituitary hypoplasia associated with hormonal deficiencies (8). Individuals homozygous for the recessive mutation R160C presented with septo-optic dysplasia (SOD/Morsier's syndrome) with agenesis of the corpus callosum and CPHD (9).…”

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confidence: 99%

“…For example, mutations in the SOX3 and SOX2 genes in combination with environmental factors such as very young maternal age, have been identified in individuals with SOD (8). Furthermore, mutations in other transcription factors such as PROP1; PIT1, LHX3 and LHX4 can cause CPHD, whereas mutations in the growth hormone releasing receptor (GHRHR) gene are responsible for the majority of cases of GHD (12,13).…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

Cruz

Nunes

Clara

et al. 2010

Arq Bras Endocrinol Metab

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Objective: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined -CPHD; isolated GH deficiency -GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. Subjects and methods: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. Results: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. Conclusion: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process. Arq Bras Endocrinol Metab. 2010;54(5):482-7 Keywords DNA mutational analysis; septo-optic dysplasia; pituitary hormonal deficiency RESUMO Objetivo: O presente estudo teve como objetivo avaliar os genes PROP1 e HESX1 em um grupo de pacientes com displasia septo-óptica (DSO) e deficiência hormonal hipofisária (combinada -DHHC; ou deficiência isolada de GH -DGH). Onze pacientes com apresentação clínica e bioquí-mica consistente com DHHC, DGH ou DSO foram avaliados. Subjects and methods: Em todos os pacientes, o gene HESX1 foi analisado pelo sequenciamento direto e, nos casos de DHHC, o gene PROP1 foi também sequenciado. Resultados: Um polimorfismo no gene HESX1 (1772 A > G; N125S) foi identificado em um paciente com DSO. Foram encontrados três pacientes portadores da variação alélica 27 T > C; A9A e 59 A > G; N20S no éxon 1 do gene PROP1. Mutações no gene PROP1 e HESX1 não foram identificadas nesses pacientes com DGH, DHHC e DSO esporádicos. Conclusão: Alterações genéticas em um ou diversos outros genes ou mecanismos não genéticos devem estar implicados nesse processo patogênico. Arq Bras Endocrinol Metab. 2010;54(5):482-7 Descritores Análise mutacional do DNA; displasia septo-óptica; deficiência hormonal hipofisária

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HESX1Mutations Are an Uncommon Cause of Septooptic Dysplasia and Hypopituitarism

Cited by 141 publications

References 29 publications

Septo-optic dysplasia

Septo-optic dysplasia

Hypothalamic and pituitary development: novel insights into the aetiology

Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

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