Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

Werner F. Blum, Jürgen Klammt, Serge Amselem, Heike M. Pfäffle, Marie Legendre, Marie Laure Sobrier, Marie Pierre Luton, Christopher J. Child, Christine Jones, Alan G. Zimmermann, Charmian A. Quigley, Gordon B. Cutler, Cheri L. Deal, Jan Lebl, Ronald (Ron) Rosenfeld, John S. Parks, Roland W. Pfäffle

Research output: Contribution to journalArticle

Abstract

Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.

Original languageEnglish (US)
Pages (from-to)390-400
Number of pages11
JournalEBioMedicine
Volume36
DOIs
StatePublished - Oct 1 2018

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Pediatrics
Screening
Genes
Phenotype
Mutation
DNA
Growth
Pituitary Hormones
Testing
Regression analysis
Logistics
Labels
Blood
Cells
Neuroendocrinology
Mutation Rate
Genomics
Hypothyroidism
Industry
Registries

Keywords

  • Genetics
  • Growth hormone deficiency
  • Hypopituitarism
  • Pituitary
  • Short stature

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion : Frequencies, phenotypes and growth outcomes. / Blum, Werner F.; Klammt, Jürgen; Amselem, Serge; Pfäffle, Heike M.; Legendre, Marie; Sobrier, Marie Laure; Luton, Marie Pierre; Child, Christopher J.; Jones, Christine; Zimmermann, Alan G.; Quigley, Charmian A.; Cutler, Gordon B.; Deal, Cheri L.; Lebl, Jan; Rosenfeld, Ronald (Ron); Parks, John S.; Pfäffle, Roland W.

In: EBioMedicine, Vol. 36, 01.10.2018, p. 390-400.

Research output: Contribution to journalArticle

Blum, WF, Klammt, J, Amselem, S, Pfäffle, HM, Legendre, M, Sobrier, ML, Luton, MP, Child, CJ, Jones, C, Zimmermann, AG, Quigley, CA, Cutler, GB, Deal, CL, Lebl, J, Rosenfeld, RR, Parks, JS & Pfäffle, RW 2018, 'Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes', EBioMedicine, vol. 36, pp. 390-400. https://doi.org/10.1016/j.ebiom.2018.09.026
Blum, Werner F. ; Klammt, Jürgen ; Amselem, Serge ; Pfäffle, Heike M. ; Legendre, Marie ; Sobrier, Marie Laure ; Luton, Marie Pierre ; Child, Christopher J. ; Jones, Christine ; Zimmermann, Alan G. ; Quigley, Charmian A. ; Cutler, Gordon B. ; Deal, Cheri L. ; Lebl, Jan ; Rosenfeld, Ronald (Ron) ; Parks, John S. ; Pfäffle, Roland W. / Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion : Frequencies, phenotypes and growth outcomes. In: EBioMedicine. 2018 ; Vol. 36. pp. 390-400.
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T1 - Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion

T2 - Frequencies, phenotypes and growth outcomes

AU - Blum, Werner F.

AU - Klammt, Jürgen

AU - Amselem, Serge

AU - Pfäffle, Heike M.

AU - Legendre, Marie

AU - Sobrier, Marie Laure

AU - Luton, Marie Pierre

AU - Child, Christopher J.

AU - Jones, Christine

AU - Zimmermann, Alan G.

AU - Quigley, Charmian A.

AU - Cutler, Gordon B.

AU - Deal, Cheri L.

AU - Lebl, Jan

AU - Rosenfeld, Ronald (Ron)

AU - Parks, John S.

AU - Pfäffle, Roland W.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.

AB - Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.

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KW - Growth hormone deficiency

KW - Hypopituitarism

KW - Pituitary

KW - Short stature

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