Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

• Klíčová slova
• combined pituitary hormone deficiency, genetics of short stature, growth hormone deficiency, next-generation sequencing, short stature,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• Genetics, Growth hormone deficiency, Hypopituitarism, Pituitary, Short stature,
• MeSH
• dítě MeSH
• fenotyp MeSH
• homeodoménové proteiny genetika   MeSH
• hypofýza růst a vývoj   metabolismus   MeSH
• hypofyzární nanismus genetika   metabolismus   patofyziologie   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• lidský růstový hormon genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• protein Gli2 s motivem zinkových prstů genetika   MeSH
• proteiny s homeodoménou LIM genetika   MeSH
• receptory hormonů regulujících hypofyzární hormony MeSH
• receptory neuropeptidů MeSH
• transkripční faktor Pit-1 genetika   MeSH
• transkripční faktory SOXB1 genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Názvy látek
• GHRHR protein, human MeSH Prohlížeč
• GLI2 protein, human MeSH Prohlížeč
• HESX1 protein, human MeSH Prohlížeč
• homeodoménové proteiny MeSH
• jaderné proteiny MeSH
• Lhx3 protein MeSH Prohlížeč
• LHX4 protein, human MeSH Prohlížeč
• lidský růstový hormon MeSH
• POU1F1 protein, human MeSH Prohlížeč
• Prophet of Pit-1 protein MeSH Prohlížeč
• protein Gli2 s motivem zinkových prstů MeSH
• proteiny s homeodoménou LIM MeSH
• receptory hormonů regulujících hypofyzární hormony MeSH
• receptory neuropeptidů MeSH
• SOX3 protein, human MeSH Prohlížeč
• transkripční faktor Pit-1 MeSH
• transkripční faktory SOXB1 MeSH
• transkripční faktory MeSH

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

• MeSH
• dítě MeSH
• dospělí MeSH
• haplotypy * MeSH
• homeodoménové proteiny genetika   MeSH
• hypopituitarismus genetika   MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenční delece * MeSH
• transkripční faktor Pit-1 genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• homeodoménové proteiny MeSH
• POU1F1 protein, human MeSH Prohlížeč
• Prophet of Pit-1 protein MeSH Prohlížeč
• transkripční faktor Pit-1 MeSH