Prevalence of severe growth hormone deficiency.

Vimpani, G V; Vimpani, A F; Lidgard, Graham P.; Cameron, E. H. D.; Farquhar, J W

doi:10.1136/bmj.2.6084.427

Cited by 223 publications

(109 citation statements)

References 14 publications

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“…Previous estimates of the prevalence of GH deficiency have varied from 1-2.5 Â 10 -4 [Vimpani et al, 1977;Rona and Tanner, 1977;Lacey and Parkin, 1974;Lindsay et al, 1993] although 90% of these cases were presumed to result from infection, environmental insults, or a secondary morbid condition rather than genetic variation [Rona and Tanner, 1977]. The data reported here therefore suggest that functionally significant GH1 gene mutations could be more frequent in the general population than previously recognized.…”

Section: Discussioncontrasting

confidence: 37%

“…Short stature associated with growth hormone (GH) deficiency has been estimated to occur with an incidence of between 1:4,000 and 1:10,000 live births [Vimpani et al, 1977;Lacey and Parkin, 1974;Rona and Tanner, 1977;Lindsay et al, 1993]. Most of these cases are both sporadic and idiopathic, but between 5% and 30% have an affected first-degree relative consistent with a genetic aetiology for the condition [Cogan and Phillips, 2001].…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

et al. 2003

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Communicated by Mark H. PaalmanSubtle mutations in the growth hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic growth hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1-132.2) and without (odds ratio 3.6; 95% CI, 1.0-12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature. Hum Mutat 21:424-440,

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Section: Discussioncontrasting

confidence: 37%

Section: Introductionmentioning

confidence: 99%

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

et al. 2003

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“…In most cases with sporadic isolated GH deficiency (GHD), the genetic cause is unknown. The estimated incidence of GHD is 1/4000-10 000 live births (9,10,11), and much lower of GH insensitivity and reduced bioactivity of the GH. The diagnosis of 'syndrome of bioinactive GH' has often been discussed and suggested in short children with the phenotype resembling isolated GHD with normal or even slightly elevated basal GH levels, low IGF1 concentration, and normal catch-up growth on GH replacement therapy.…”

Section: Introductionmentioning

confidence: 99%

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Petkovic

Miletta

Boot

et al. 2013

European Journal of Endocrinology

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Objective: Short stature caused by biologically inactive GH is clinically characterized by lack of GH action despite normal-high secretion of GH, pathologically low IGF1 concentrations and marked catch-up growth on GH replacement therapy. Design and methods: Adopted siblings (girl and a boy) of unknown family history were referred for assessment of short stature (K4.5 and K5.6 SDS) at the age of 10 and 8.1 years respectively. They had delayed bone ages (6.8 and 4.5 years), normal GH peaks at stimulation tests, and severely reduced IGF1 concentrations (K3.5 and K4.0 SDS). Genetic analysis of the GH1 gene showed a heterozygous P59S mutation at position involved in binding to GH receptor (GHR). Results: Isoelectric focusing analysis of secreted GH in patient serum revealed the presence of higher GH-P59S peak compared with that of wt-GH. Furthermore, computational simulation of GH-P59S binding to GHR suggested problems in correct binding of the mutant to the GHR. In vitro GHR binding studies revealed reduced binding affinity of GH-P59S for GHR (IC 50 , 30 ng/ml) when compared with the wt-GH (IC 50 , 11.8 ng/ml) while a significantly decreased ability of the mutant to activate the Jak2/Stat5 signaling pathway was observed at physiological concentrations of 25-100 ng/ml. Conclusions: The clinical and biochemical data of our patients support the diagnosis of partial bioinactive GH syndrome. The higher amount of GH-P59S secreted in their circulation combined with its impact on the wt-GH function on GHR binding and signaling may alter GHR responsiveness to wt-GH and could ultimately explain severe short stature found in our patients.

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“…Short stature associated with GH deficiency is reported to be between 1 in 4,000 and 1 in 10,000 of the population in several studies [5][6][7][8]. However, the exact incidence of severe short stature with severe GH deficiency (GHD) among total short stature patients (HtSDS below -2), and the proportion of GH-related gene abnormalities in severe short stature with severe GHD have yet to be clarified.…”

mentioning

confidence: 99%

Studies of Very Severe Short Stature with Severe GH Deficiency: From the Data Registered with the Foundation for Growth Science

Hanew¹,

Tachibana

Yokoya

et al. 2005

Endocr J

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Abstract. The ratio, clinical characteristics, and therapeutic efficacy of hGH treatment in patients with severe short stature (HtSDS below -4SD) with severe GHD (all peak GH values to provocation tests: below 2 mg/L) were studied. From March 1986 to January 1998, 23,110 patients with idiopathic GH deficiency (IGHD) were registered with the Foundation for Growth Science, Japan. These subjects were divided into 5 groups as follows: Group 1 (G1), all subjects; Group 2 (G2), at least one GH peak to provocative test ³5 mg/L; Group 3 (G3), 2 mg/L£GH peak<5 mg/L; Group 4 (G4), all GH peaks<2 mg/L and HtSDS>-4; Group 5 (G5), all GH peaks<2 mg/L and HtSDS£-4. The ratio of G5 was 139 patients (0.6%) out of 23,110 patients with IGHD. In G5, there were no significant differences in birth weight, birth length, gestational age and parental height between G2, G3 and G4. However, asphyxia at delivery was more frequent in G5 and G4 than G2 and G3. Chronological age (CA), bone age (BA) and BA/CA ratio at registration were significantly lower in G5 than G2, G3 and G4. Further, the IGF-I SD score in G5 was significantly lower than those in G2 and G3. After hGH treatment, the final height and final height SDS in G5 remained the lowest, while the DHtSDS value in G5 was the greatest among G2 to G5 groups. In conclusion, the ratio of severe short stature with severe GH deficiency (G5) is only 0.6% of all IGHD cases. Growth failure in G5 seems to occur after birth, and its etiology in G5 seems to be different from that of patients with other forms of IGHD. Early diagnosis and hGH treatment are needed to attain better final height.

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Prevalence of severe growth hormone deficiency.

Cited by 223 publications

References 14 publications

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature

Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH

Studies of Very Severe Short Stature with Severe GH Deficiency: From the Data Registered with the Foundation for Growth Science

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