FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition

Genetic Predictors Of Long-term Response To Growth Hormone (gh) Therapy In Children With Gh Deficiency And Turner Syndrome: The Influence Of A Socs2 Polymorphism

Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47GHdeficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. CopyrightObjective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH).Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P=.016) and-202 A/C IGFBP3 (P=.013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001).Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS andGHDafter long-term rhGH therapy. Polymorphisms located inGHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.999E1808E1813Geffner, M.E., Dunger, D.B., Future directions: Growth prediction models (2007) Horm Res., 68, pp. 51-56Flores-Morales, A., Greenhalgh, C.J., Norstedt, G., Rico-Bautista, E., Negative regulation of growth hormone receptor signaling (2006) Mol Endocrinol., 20, pp. 241-253Greenhalgh, C.J., Rico-Bautista, E., Lorentzon, M., SOCS2 negatively regulates growth hormone action in vitro and in vivo (2005) J Clin Invest., 115, pp. 397-406Wassenaar, M.J., Dekkers, O.M., Pereira, A.M., Impact of the exon 3-deleted GH receptor polymorphism on baseline height and the growth response to recombinant human growth hormone therapy in growth hormone deficient(GHD)andnon-GHDchildren with short stature: A systematic review and meta-analysis (2009) J Clin Endocrinol Metab., 94, pp. 3721-3730Renehan, A.G., Solomon, M., Zwahlen, M., Growth hormone receptor polymorphism and growth hormone therapy response in children: A Bayesian meta-analysis (2012) AmJ Epidemiol., 175, pp. 867-877Costalonga, E.F., Antonini, S.R., Guerra-Junior, G., Mendonca, B.B., Arnhold, I.J., Jorge, A.A., The-202 A allele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency (2009) J Clin Endocrinol Metab., 94, pp. 588-595Braz, A.F., Costalonga, E.F., Montenegro, L.R., The interactive effect of GHR-exon 3 and-202 A/C IGFBP3 polymorphisms on rhGH responsiveness and treatment outcomes in patients with Turner syndrome (2012) J Clin Endocrinol Metab., 97, pp. E671-E677Weedon, M.N., Lango, H., Lindgren, C.M., Genome-wide association analysis identifies 20 loci that influence adult height (2008) Nat Genet., 40, pp. 575-583Gudbjartsson, D.F., Walters, G.B., Thorleifsson, G., Manysequence variants affecting diversity of adult human height (2008) Nat Genet., 40, pp. 609-615Chan, Y., Holmen, O.L., Dauber, A., Common variants show predicted polygenic effects on height in the tails of the distribution, except in extremely short individuals (2011) PLoS Genet., 7, p. e1002439Lou, X.Y., Chen, G.B., Yan, L., A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence (2007) Am J Hum Genet., 80, pp. 1125-1137Lango Allen, H., Estrada, K., Lettre, G., Hundreds of variants clustered in genomic loci and biological pathways affect human height (2010) Nature., 467, pp. 832-838Lanktree, M.B., Guo, Y., Murtaza, M., Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height (2011) Am J Hum Genet., 88, pp. 6-18Ranke, M.B., Lindberg, A., Albertsson-Wikland, K., Wilton, P., Price, D.A., Reiter, E.O., Increased response, but lower responsiveness, to growth hormone (GH) in very young children (aged 0-3 years) with idiopathicGHDeficiency: Analysis of data from KIGS (2005) J Clin Endocrinol Metab., 90, pp. 1966-1971Ranke, M.B., Lindberg, A., Chatelain, P., Prediction of long-term response to recombinant human growth hormone in Turner syndrome: Development and validation of mathematical models. KIGS International Board. Kabi International Growth Study (2000) J Clin Endocrinol Metab., 85, pp. 4212-4218Ranke, M.B., Lindberg, A., Cowell, C.T., Prediction of response to growth hormone treatment in short children born small for gestational age: Analysis of data from KIGS (Pharmacia International Growth Database) (2003) J Clin Endocrinol Metab., 88, pp. 125-131Clayton, P., Chatelain, P., Tato, L., Apharmacogenomic approach to the treatment of children withGHdeficiency or Turner syndrome (2013) Eur J Endocrinol., 169, pp. 277-289Stevens, A., Clayton, P., Tato, L., Pharmacogenomics of insulinlike growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome (2014) Pharmacogenomics J., 14, pp. 54-6

The Sitting Height/height Ratio For Age In Healthy And Short Individuals And Its Potential Role In Selecting Short Children For Shox Analysis

Aims: To determine the presence of abnormal body proportion, assessed by sitting height/height ratio for age and sex (SH/H SDS) in healthy and short individuals, and to estimate its role in selecting short children for SHOX analysis. Methods: Height, sitting height and weight were evaluated in 1,771 healthy children, 128 children with idiopathic short stature (ISS), 58 individuals with SHOX defects (SHOX-D) and 193 females with Turner syndrome (TS). Results: The frequency of abnormal body proportion, defined as SH/H SDS >2, in ISS children was 16.4% (95% CI 10-22%), which was higher than in controls (1.4%, 95% CI 0.8-1.9%, p 2 were less common in children (48%, 95% CI 37-59%) and in adults (28%, 95% CI 20-36%) with TS. Conclusion: Abnormal body proportions were observed in almost all individuals with SHOX-D, 50% of females with TS and 16% of children considered ISS. Defects in SHOX gene were identified in 19% of ISS children with SH/H SDS >2, suggesting that SH/H SDS is a useful tool to select children for undergoing SHOX molecular studies. © 2013 S. 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C., Marttila, P., Kowal, K., Nass, A., Papenhausen, P., Abboudi, J., Zinn, A.R., Phenotypes associated with SHOX deficiency (2001) J Clin Endocrinol Metab, 86, pp. 5674-5680Binder, G., Ranke, M.B., Martin, D.D., Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufficiency in schoolage children with unexplained short stature (2003) J Clin Endocrinol Metab, 88, pp. 4891-4896Rappold, G., Blum, W.F., Shavrikova, E.P., Crowe, B.J., Roeth, R., Quigley, C.A., Ross, J.L., Niesler, B., Genotypes and phenotypes in children with short stature: Clinical indicators of SHOX haploinsufficiency (2007) J Med Genet, 44, pp. 306-313Jorge, A.A., Souza, S.C., Nishi, M.Y., Billerbeck, A.E., Liborio, D.C., Kim, C.A., Arnhold, I.J., Mendonca, B.B., SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: Frequency and phenotypic variability (2007) Clin Endocrinol (Oxf), 66, pp. 130-135Hirschfeldova, K., Solc, R., Baxova, A., Zapletalova, J., Kebrdlova, V., Gaillyova, R., Prasilova, S., Stekrova, J., SHOX gene defects and selected dysmorphic signs in patients of idiopathic short stature and Leri-Weill dyschondrosteosis (2012) Gene, 491, pp. 123-127Kant, S.G., Broekman, S.J., De Wit, C.C., Bos, M., Scheltinga, S.A., Bakker, E., Oostdijk, W., Losekoot, M., Phenotypic characterization of patients with deletions in the 3 ′ flanking SHOX region (2013) PeerJ, 1, pp. e35Fredriks, A.M., Van Buuren, S., Van Heel, W.J., Dijkman-Neerincx, R.H., Verloove-Vanhorick, S.P., Wit, J.M., Nationwide age references for sitting height, leg length, and sitting height/ height ratio, and their diagnostic value for disproportionate growth disorders (2005) Arch Dis Child, 90, pp. 807-812Kuczmarski, R.J., Ogden, C.L., Grummer-Strawn, L.M., Flegal, K.M., Guo, S.S., Wei, R., Mei, Z., Johnson, C.L., CDC growth charts: United States (2000) Adv Data, 314, pp. 1-27Silva, D.A., Pelegrini, A., Petroski, E.L., Gaya, A.C., Comparison between the growth of Brazilian children and adolescents and the reference growth charts: Data from a Brazilian project (2010) J Pediatr (Rio J), 86, pp. 115-120Funari, M.F., Jorge, A.A., Souza, S.C., Billerbeck, A.E., Arnhold, I.J., Mendonca, B.B., Nishi, M.Y., Usefulness of MLPA in the detection of SHOX deletions (2010) Eur J Med Genet, 53, pp. 234-238Lango Allen, H., Estrada, K., Lettre, G., Berndt, S.I., Weedon, M.N., Rivadeneira, F., Willer, C.J., Hirschhorn, J.N., Hundreds of variants clustered in genomic loci and biological pathways affect human height (2010) Nature, 467, pp. 832-838Shears, D.J., Vassal, H.J., Goodman, F.R., Palmer, R.W., Reardon, W., Superti-Furga, A., Scambler, P.J., Winter, R.M., Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis (1998) Nat Genet, 19, pp. 70-73Belin, V., Cusin, V., Viot, G., Girlich, D., Toutain, A., Moncla, A., Vekemans, M., Cormier-Daire, V., SHOX mutations in dyschondrosteosis (Leri-Weill syndrome) (1998) Nat Genet, 19, pp. 67-69Rappold, G.A., Fukami, M., Niesler, B., Schiller, S., Zumkeller, W., Bettendorf, M., Heinrich, U., Ogata, T., Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature (2002) J Clin Endocrinol Metab, 87, pp. 1402-1406Jorge, A.A., Arnhold, I.J., Anthropometric evaluation of children with SHOX mutations can be used as indication for genetic studies in children of short stature (2007) J Med Genet, 44, pp. e90. , author reply e91Kosho, T., Muroya, K., Nagai, T., Fujimoto, M., Yokoya, S., Sakamoto, H., Hirano, T., Ogata, T., Skeletal features and growth patterns in 14 patients with haploinsufficiency of SHOX: Implications for the development of turner syndrome (1999) J Clin Endocrinol Metab, 84, pp. 4613-4621Fukami, M., Nishi, Y., Hasegawa, Y., Miyoshi, Y., Okabe, T., Haga, N., Nagai, T., Ogata, T., Statural growth in 31 Japanese patients with SHOX haploinsufficiency: Support for a disadvantageous effect of gonadal estrogens (2004) Endocr J, 51, pp. 197-200Blum, W.F., Cao, D., Hesse, V., Fricke-Otto, S., Ross, J.L., Jones, C., Quigley, C.A., Binder, G., Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome (2009) Horm Res, 71, pp. 167-172Scalco, R.C., Melo, S.S., Pugliese-Pires, P.N., Funari, M.F., Nishi, M.Y., Arnhold, I.J., Mendonca, B.B., Jorge, A.A., Effectiveness of the combined recombinant human growth hormone and gonadotropin-releasing hormone analog therapy in pubertal patients with short stature due to SHOX deficiency (2010) J Clin Endocrinol Metab, 95, pp. 328-33