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dc.contributor.authorAlatzoglou, Kyriaki S
dc.contributor.authorTurton, James P
dc.contributor.authorKelberman, Daniel
dc.contributor.authorClayton, Peter E
dc.contributor.authorMehta, Ameeta
dc.contributor.authorBuchanan, Charles
dc.contributor.authorAylwin, Simon
dc.contributor.authorCrowne, Elizabeth C
dc.contributor.authorChristesen, Henrik T
dc.contributor.authorHertel, Niels T
dc.contributor.authorTrainer, Peter J
dc.contributor.authorSavage, Martin O
dc.contributor.authorRaza, Jamal
dc.contributor.authorBanerjee, Kausik
dc.contributor.authorSinha, Sunil K
dc.contributor.authorTen, Svetlana
dc.contributor.authorMushtaq, Talat
dc.contributor.authorBrauner, Raja
dc.contributor.authorCheetham, Timothy D
dc.contributor.authorHindmarsh, Peter C
dc.contributor.authorMullis, Primus E
dc.contributor.authorDattani, Mehul T
dc.date.accessioned2009-10-29T10:40:24Z
dc.date.available2009-10-29T10:40:24Z
dc.date.issued2009-09
dc.identifier.citationExpanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency. 2009, 94 (9):3191-9 J. Clin. Endocrinol. Metab.en
dc.identifier.issn1945-7197
dc.identifier.pmid19567534
dc.identifier.doi10.1210/jc.2008-2783
dc.identifier.urihttp://hdl.handle.net/10541/84997
dc.description.abstractCONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
dc.language.isoenen
dc.subject.meshAdolescent
dc.subject.meshChild
dc.subject.meshChild, Preschool
dc.subject.meshCohort Studies
dc.subject.meshGenetic Screening
dc.subject.meshHomeodomain Proteins
dc.subject.meshHuman Growth Hormone
dc.subject.meshHumans
dc.subject.meshInfant
dc.subject.meshLocus Control Region
dc.subject.meshMutation
dc.subject.meshPedigree
dc.subject.meshReceptors, Neuropeptide
dc.subject.meshReceptors, Pituitary Hormone-Regulating Hormone
dc.subject.meshSOXB1 Transcription Factors
dc.titleExpanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.en
dc.typeArticleen
dc.contributor.departmentDevelopmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.en
dc.identifier.journalThe Journal of Clinical Endocrinology and Metabolismen
html.description.abstractCONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.


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