Cheng Xu1, Daniele Cassatella1, Almer M van der Sloot2, Richard Quinton3, Michael Hauschild4, Christian De Geyter5, Christa Flück6, Katrin Feller7, Deborah Bartholdi8, Attila Nemeth9, Irene Halperin10, Sandra Pekic Djurdjevic11, Philippe Maeder12, Georgios Papadakis1, Andrew A Dwyer1,13, Laura Marino1, Lucie Favre1, Duarte Pignatelli14,15,16, Nicolas J Niederländer1, James Acierno1, Nelly Pitteloud17. 1. Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland. 2. Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada. 3. Institute for Genetic Medicine, University of Newcastle-on-Tyne, Newcastle-on Tyne, UK. 4. Endocrinology-Diabetology Unit, Department of Paediatrics, Lausanne University Hospital, Lausanne, Switzerland. 5. Clinic of Gynecological Endocrinology and Reproductive Medicine, University Hospital, University of Basel, Basel, Switzerland. 6. Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, and Department of Clinical Research, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 7. Division of Endocrinology, Diabetes, and Clinical Nutrition, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland. 8. Department of Human Genetics, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland. 9. Department of Endocrinology, St John's Hospital, Budapest, Hungary. 10. Department of Endocrinology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 11. Clinic of Endocrinology, Diabetes, and Diseases of Metabolism, University Clinical Center, Belgrade, Serbia. 12. Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland. 13. Institute of Higher Education and Research in Healthcare, University of Lausanne, Lausanne, Switzerland. 14. Department of Endocrinology, Hospital S João, Porto, Portugal. 15. Department of Experimental Biology, Faculty of Medicine of the University of Porto, Porto, Portugal. 16. CGC Genetics-Clinical and Research Institute, Porto, Portugal. 17. Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland. nelly.pitteloud@chuv.ch.
Abstract
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined. METHODS: Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated. RESULTS: Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01). CONCLUSION: Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.
PURPOSE: Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined. METHODS: Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated. RESULTS: Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01). CONCLUSION: Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.
Entities:
Keywords:
CHARGE syndrome; Kallmann syndrome; chromodomain helicase DNA binding protein 7; congenital hypogonadotropic hypogonadism
Authors: Catarina Inês Gonçalves; Filipa Marina Patriarca; José Maria Aragüés; Davide Carvalho; Fernando Fonseca; Sofia Martins; Olinda Marques; Bernardo Dias Pereira; José Martinez-de-Oliveira; Manuel Carlos Lemos Journal: Sci Rep Date: 2019-02-07 Impact factor: 4.379