ECEESPE2025 Poster Presentations Pituitary, Neuroendocrinology and Puberty (162 abstracts)
Genetic basis of patients with congenital gonadotropin deficiency
Yi Wang 1,2,3 , Jing Zhai 1,2 , Yassine Zouaghi 1,2 , Imen Habibi 1,2 , Fernanda De Azevedo Correa 1,2 , Cecilia Perdices-Lopez 1,2 , Tommaso Todisco 1,2 , Richard Quinton 4 , Adamo Michela 1,2 , Franziska Phan-Hug 1,2 , An Jacobs 1,2 , Bob Millar 5 , Adelina Ameti 1,2,6 , Zofia Kolesinska , Sandra Pekic Djurdjevic 7 , Pignatelli Duarte 8 , Marco Bonomi 9 , Martine Cools 10 , Anne de Paepe 11 , Mitchell Geffner 12 , Yaasir Mamoojee 13 , Luca Persani 14 , Vera Popovic 15 , Waljit Dhillo 16 , Naoko Sato 17 , Fatima Ambrin 18 , Muhammad Ansar 19 , Nicolas Niederlander 1,2 , James Acierno 1,2 , Andrea Messina 1,2 , Federico Santoni 1,2 & Nelly Pitteloud 1,2
1Service of Endocrinology, Diabetology and Metabolism, CHUV, Lausanne, Switzerland; 2Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; 3Beijing Children’s Hospital, Capital Medical University, Beijing, China; 4Department of Endocrinology, Diabetes & Metabolism, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle, UK; 5Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina, Pretoria, South Africa; 6CHUV, Service of Endocrinology, Diabetology and Metabolism, Lausanne, Switzerland; 7Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center Belgrade & School of Medicine, University of Belgrade, Belgrade, Serbia; 8Department of Endocrinology, Centro Hospitalar e Universitário de S. João, Porto, Portugal; 9Department of Endocrine and Metabolic Medicine, IRCCS Instituto Auxologico Italiano, Milan, Italy; 10Department of Paediatric Endocrinology, Ghent University Hospital, University of Ghent, Ghent, Belgium; 11Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, Ghent, Belgium; 12Keck School of Medicine of the University of Southern California, Los Angeles, USA; 13Department of Endocrinology, Newcastle-upon-Tyne, UK, Newcastle, UK; 14Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy; 15Institute of Endocrinology Department of Neuroendocrinology, Belgrade, Serbia; 16Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK; 17Department of Neuroscience, The Jikei University School of Medicine, Tokyo, Japan; 18Department of Allied Health Sciences, Iqra National University Swat Campus, Swat 19200, Pakistan, Swat, Pakistan; 19Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva, 1211, Switzerland, Geneva, Switzerland
JOINT1742
Background: Congenital gonadotropin (GN) deficiency is a condition that falls under the umbrella of hypogonadotropic hypogonadism (HH). The defect may occur either in the hypothalamus or the pituitary. Congenital GN deficiency can be a characteristic feature of several disorders: (i) congenital hypogonadotropic hypogonadism (CHH), further classified into normosmic CHH (nCHH) or Kallmann syndrome (KS); (ii) combined pituitary hormone deficiency (CPHD); and (iii) other GN deficiency associated syndromes (e.g. CHARGE syndrome, septo-optic dysplasia [SOD]). Herein, we investigated the clinical and genetic overlap between these clinical entities.
Methods: All probands with congenital GN deficiency (n=571) underwent detailed phenotyping. Pathogenic (P), likely pathogenic (LP), and variants of unknown significance (VUS) were depicted for known CHH and CPHD genes in respective conditions. Further, oligogenicity was assessed in the CHH cohort and controls (n=601). Genetic overlap between CHH, CPHD and syndromic GN deficiency was further studied.
Results: 276 KS, 248 nCHH, 29 CPHD, and 18 syndromic GN deficiency were included in the study. In addition to HH, skeletal anomalies, cleft lip and palate, and dental agenesis were observed in all subgroups. Notably, altered sense of smell and robust GN response to LHRH test in CPHD patients were observed. 53% of KS probands harbored rare variants in CHH genes (40% were P/lP, 13% VUS); while 33% of nCHH probands carried rare variants in CHH genes (23% P/lP, 10% VUS). FGFR1, ANOS1 and PROKR2 in KS and FGFR1, GNRHR and TAC3R in nCHH were the most mutated genes. Oligogenicity occurs in 25% of CHH probands with DMLX2, FGFR1, and PNPLA6 being significantly involved in gene pairings. Almost 10% of CHH patients without genetic diagnosis carried rare variants in CPHD genes (e.g. DCHS2, FAT2 and CDON in KS as well as ROBO1, FAT2, DCHS2 and KCNQ1 in nCHH). Additionally, CHH genes (e.g. FGFR1, CHD7 and FGF8) were mutated in CPHD and syndromic GN deficiency.
Conclusion: Herein, we demonstrated: (i) clinical and genetic overlap between patients exhibiting GN deficiency; (ii) altered sense of smell and robust response to LHRH test in CPHD suggesting a dual defect (pituitary and hypothalamus); (iii) 25% of oligogenic inheritance in CHH; and (iv) novel putative CPHD genes (ROBO1, DCHS2, FAT2 and KCNQ1) in CHH.
Volume 110
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2025 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more