Panhypopituitarism: Genetic Versus Acquired Etiological Factors

Coya, Raquel; Vela, Amaia; Nanclares, Guiomar Pérez de; Rica, Itxaso; Castaño, Luís; Busturia, Maria Angeles; Martul, P.

doi:10.1515/jpem.2007.20.1.27

Cited by 43 publications

(30 citation statements)

References 20 publications

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“…Two deleterious mutations were identified in two patients: a novel variation at the third base of the IVS2 (c.357C3 GOA) and the variation Q6H, previously reported by us (25), accounting for 0.8% of the total patients. These data are in agreement with other studies (3,14,21,22) and confirm the low frequency of HESX1 mutations in hypopituitarism.…”

Section: Discussionsupporting

confidence: 93%

“…Hesx1 shows a typical highly conserved 60 amino acids structural motif, the homeodomain (HD), which can bind DNA in a sequence-specific manner (9) and a basic repressive domain at the N-terminus (the engrailed homology domain, eh1) characterized by seven amino acidic residues (amino acids [21][22][23][24][25][26][27] (10). Both the functional domains of Hesx1 are involved in the repressive action by recruitment of the nuclear receptor co-repressor (NCOR) and by another co-repressor, the transducin-like enhancer of split 1 (TLE1) at the HD and at the repressive domain respectively (9,11,12).…”

Section: Introductionmentioning

confidence: 99%

“…To date, 13 mutations in the HESX1 gene have been reported in a broad spectrum of phenotypes ranging from IGHD to CPHD associated in some cases with anomalies such as SOD, pituitary malformations, like ectopy of the neurohypophysis or pituitary aplasia (16)(17)(18)(19)(20)(21)(22). Mutations in HESX1 may be present both at the homozygous (nZ3) and at the heterozygous states (nZ10).…”

Section: Introductionmentioning

confidence: 99%

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A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing

Vivenza¹,

Godi²,

Faienza³

et al. 2011

European Journal of Endocrinology

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Objective: Mutations in HESX1 represent a rare cause of GH deficiency (GHD) associated with a broad spectrum of other anomalies. We searched for causative mutations in a cohort of 244 Italian patients affected by combined and isolated GHD (IGHD). Methods: The HESX1 gene-coding region and exon-intron boundaries were screened by denaturing HPLC scanning. Results: A novel mutation adjacent to the invariant donor splice site of intron 2 (c.357C3GOA) was identified at the heterozygous state in an IGHD patient. The in vitro and in vivo mRNA analysis of the wild-type HESX1 allele revealed the presence of the whole cDNA and two isoforms lacking exon 2 and exons 2-3 respectively. The mutant HESX1 allele yielded only two splicing products, the whole cDNA and the cDNA missing exons 2-3, whereas the mRNA lacking exon 2 was absent. An in vitro assay demonstrated that the exon 2-deleted mRNA, predicting a prematurely truncated protein, is subjected to nonsense-mediated mRNA decay (NMD). Conclusions: The c.357C3GOA mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. The mutation is likely to cause IGHD in the heterozygous patient by interfering with the downregulation of HESX1 expression mediated by alternative splicing and NMD. Our results open new insight into the mechanism of HESX1 regulation suggesting that the coupling of alternative splicing and NMD might play a fundamental role in directing the HESX1 expression, and that the alteration of this process might lead to severe consequences.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing

Vivenza¹,

Godi²,

Faienza³

et al. 2011

European Journal of Endocrinology

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“…The multi-faceted interaction between these transcription factors and the environment is also likely to play a role in the significant variability in phenotype and penetrance associated with SOD. 1, 31 Further investigation of these intricate relationships may help us to better understand the aetiology of this complex disorder, possibly enabling us in the future to develop an improved diagnostic algorithm and to predict which children are likely to go on to develop hormonal abnormalities, developmental problems, and so on.…”

Section: Resultsmentioning

confidence: 99%

Septo-optic dysplasia

2009

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“…Patients with additional pituitary deficiencies diagnosed during follow-up had a higher incidence of breech presentation, perinatal asphyxia, and neonatal complications, and a trend toward greater delivery complications. Historically, these features have been recognized as more common among children who present initially with MPHD (23,24), although they are typically associated with organic rather than idiopathic GHD (25,26). Thus, there appears to be a spectrum of severity among patients with such perinatal histories, with the most severe presenting initially with MPHD and the less severe presenting initially with IGHD and later progressing to MPHD.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

Blum

Deal

Zimmermann

et al. 2014

European Journal of Endocrinology

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Objective: We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). Design: Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Methods: Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had R3.5 years, follow-up and continued to have IGHD (4-year cohort). Results: MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P!0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. Conclusions: MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

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Panhypopituitarism: Genetic Versus Acquired Etiological Factors

Cited by 43 publications

References 20 publications

A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing

A novel HESX1 splice mutation causes isolated GH deficiency by interfering with mRNA processing

Septo-optic dysplasia

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

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