Marco Bonomi1,2, Valeria Vezzoli2, Csilla Krausz3, Fabiana Guizzardi2, Silvia Vezzani4,5,6, Manuela Simoni4,5,6, Ivan Bassi2, Paolo Duminuco2, Natascia Di Iorgi7, Claudia Giavoli1,8, Alessandro Pizzocaro9, Gianni Russo10, Mirella Moro2, Letizia Fatti2, Alberto Ferlin11, Laura Mazzanti12, Maria Chiara Zatelli13, Salvo Cannavò14, Andrea M Isidori15, Angela Ida Pincelli16, Flavia Prodam17, Antonio Mancini18, Paolo Limone19, Maria Laura Tanda20, Rossella Gaudino21, Mariacarolina Salerno22, Pregnolato Francesca23, Mohamad Maghnie7, Mario Maggi3, Luca Persani1,2. 1. Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. 2. IRCCS Istituto Auxologico Italiano, Division of Endocrine and Metabolic Diseases & Laboratory of Endocrine and Metabolic Research, Milan, Italy. 3. Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Florence, Italy. 4. Department of Biomedical, Metabolic and Neural Sciences, Unit of Endocrinology, University of Modena and Reggio Emilia, Modena, Italy. 5. Department of Medicine, Endocrinology, Metabolism and Geriatrics, Azienda USL of Modena, Modena, Italy. 6. Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy. 7. Department of Pediatrics, IRCCS Giannina Gaslini, University of Genoa, Genoa, Italy. 8. Endocrinology and Metabolic Diseases Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. 9. Endocrinology Unit, IRCCS, Humanitas Research Hospital, Rozzano, Milan, Italy. 10. Department of Pediatrics, IRCCS San Raffaele Hospital, Milan, Italy. 11. Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy. 12. Department of Medical and Surgical Sciences, Alma Mater Studiourm, University of Bologna, Bologna, Italy. 13. Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy. 14. Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Messina, Messina, Italy. 15. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. 16. Division of Internal Medicine, Endocrinology and Diabetology Unit, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy. 17. Department of Health Sciences, University of Eastern Piedmont, Novara, Italy. 18. Operative Unit of Endocrinology, Catholic University of the Sacred Heart, Rome, Italy. 19. Endocrinology, Diabetes and Metabolic Disease Unit, A.O. Ordine Mauriziano di Torino, Torino, Italy. 20. Dipartimento di Medicina Clinica e Sperimentale, Università dell'Insubria sede di Varese, Varese, Italy. 21. Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy. 22. Department of Translational Medical Sciences, University of Naples 'Federico II', Naples, Italy. 23. IRCCS Istituto Auxologico Italiano, Experimental Laboratory of Immunological and Rheumatologic Researches, Milan, Italy.
Abstract
OBJECTIVE: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. DESIGN: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. METHODS: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). RESULTS: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. CONCLUSIONS: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.
OBJECTIVE:Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. DESIGN: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. METHODS: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). RESULTS: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. CONCLUSIONS:Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.
Authors: Bettina Toth; Dunja Maria Baston-Büst; Hermann M Behre; Alexandra Bielfeld; Michael Bohlmann; Kai Bühling; Ralf Dittrich; Maren Goeckenjan; Katharina Hancke; Sabine Kliesch; Frank-Michael Köhn; Jan Krüssel; Ruben Kuon; Jana Liebenthron; Frank Nawroth; Verena Nordhoff; Germar-Michael Pinggera; Nina Rogenhofer; Sabine Rudnik-Schöneborn; Hans-Christian Schuppe; Andreas Schüring; Vanadin Seifert-Klauss; Thomas Strowitzki; Frank Tüttelmann; Kilian Vomstein; Ludwig Wildt; Tewes Wischmann; Dorothea Wunder; Johannes Zschocke Journal: Geburtshilfe Frauenheilkd Date: 2019-12-11 Impact factor: 2.915
Authors: Alessandra Mancini; Sasha R Howard; Federica Marelli; Claudia P Cabrera; Michael R Barnes; Michael Je Sternberg; Morgane Leprovots; Irene Hadjidemetriou; Elena Monti; Alessia David; Karoliina Wehkalampi; Roberto Oleari; Antonella Lettieri; Valeria Vezzoli; Gilbert Vassart; Anna Cariboni; Marco Bonomi; Marie Isabelle Garcia; Leonardo Guasti; Leo Dunkel Journal: JCI Insight Date: 2020-06-04
Authors: Andrea Salonia; Giulia Rastrelli; Geoffrey Hackett; Stephanie B Seminara; Ilpo T Huhtaniemi; Rodolfo A Rey; Wayne J G Hellstrom; Mark R Palmert; Giovanni Corona; Gert R Dohle; Mohit Khera; Yee-Ming Chan; Mario Maggi Journal: Nat Rev Dis Primers Date: 2019-05-30 Impact factor: 52.329
Authors: Mary C Whitman; Brenda J Barry; Caroline D Robson; Flavia M Facio; Carol Van Ryzin; Wai-Man Chan; Tanya J Lehky; Audrey Thurm; Christopher Zalewski; Kelly A King; Carmen Brewer; Konstantinia Almpani; Janice S Lee; Angela Delaney; Edmond J FitzGibbon; Paul R Lee; Camilo Toro; Scott M Paul; Omar A Abdul-Rahman; Bryn D Webb; Ethylin Wang Jabs; Hans Ulrik Moller; Dorte Ancher Larsen; Jayne H Antony; Christopher Troedson; Alan Ma; Glad Ragnhild; Katrine V Wirgenes; Emma Tham; Malin Kvarnung; Timothy James Maarup; Sarah MacKinnon; David G Hunter; Francis S Collins; Irini Manoli; Elizabeth C Engle Journal: Hum Genet Date: 2021-10-15 Impact factor: 4.132
Authors: A Nordenström; S F Ahmed; E van den Akker; J Blair; M Bonomi; C Brachet; L H A Broersen; H L Claahsen-van der Grinten; A B Dessens; A Gawlik; C H Gravholt; A Juul; C Krausz; T Raivio; A Smyth; P Touraine; D Vitali; O M Dekkers Journal: Eur J Endocrinol Date: 2022-04-21 Impact factor: 6.558