CONTEXT: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported. OBJECTIVE: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. DESIGN AND SETTING: We conducted a cross-sectional case-control study at an academic referral center. PATIENTS: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied. MAIN OUTCOME MEASURES: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI. RESULTS: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion. CONCLUSIONS: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.
CONTEXT: The olfactory phenotype in patients with idiopathic hypogonadotropic hypogonadism (IHH) ranges from complete anosmia (Kallmann syndrome) to normosmia (normosmic IHH). However, the true prevalence of intermediary olfactory phenotypes (hyposmia) in IHH patients has not yet been assessed, and systematic correlations with anatomical and genetic abnormalities have not been reported. OBJECTIVE: The objective of this study was to evaluate olfactory function in a large IHH cohort and correlate these findings with olfactory magnetic resonance imaging (MRI) and underlying genetic etiology. DESIGN AND SETTING: We conducted a cross-sectional case-control study at an academic referral center. PATIENTS: A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied. MAIN OUTCOME MEASURES: We measured olfactory function using the University of Pennsylvania Smell Identification Test; in 208 subjects, the genetic etiology of IHH was ascertained by DNA sequencing; in a minor subset [39 of 286 subjects (13%)], olfactory structures were determined by MRI. RESULTS: In the IHH cohort, 31.5% were anosmic, 33.6% were hyposmic, and 34.9% were normosmic. Most hyposmic (seven of 11) subjects with MRI data exhibited olfactory structure abnormalities. Of hyposmic subjects, 39.5% harbored mutations in genes involved in either GnRH neuronal migration or GnRH secretion. CONCLUSIONS: IHH subjects display a broad spectrum of olfactory function, with a significant hyposmic phenotype in nearly one third of subjects. The hyposmic subjects harbor mutations in genes affecting GnRH neuronal migration and its secretion, suggesting a pathophysiological overlap between Kallmann syndrome and normosmic IHH. Accurate olfactory phenotyping in IHH subjects will inform the pathophysiology of this condition and guide genetic testing.
Authors: Cecilia Martin; Ravikumar Balasubramanian; Andrew A Dwyer; Margaret G Au; Yisrael Sidis; Ursula B Kaiser; Stephanie B Seminara; Nelly Pitteloud; Qun-Yong Zhou; William F Crowley Journal: Endocr Rev Date: 2010-10-29 Impact factor: 19.871
Authors: Elena Gianetti; Cintia Tusset; Sekoni D Noel; Margaret G Au; Andrew A Dwyer; Virginia A Hughes; Ana Paula Abreu; Jessica Carroll; Ericka Trarbach; Leticia F G Silveira; Elaine M F Costa; Berenice Bilharinho de Mendonça; Margaret de Castro; Adriana Lofrano; Janet E Hall; Erol Bolu; Metin Ozata; Richard Quinton; John K Amory; Susan E Stewart; Wiebke Arlt; Trevor R Cole; William F Crowley; Ursula B Kaiser; Ana Claudia Latronico; Stephanie B Seminara Journal: J Clin Endocrinol Metab Date: 2010-03-23 Impact factor: 5.958
Authors: Yee-Ming Chan; Adelaide de Guillebon; Mariarosaria Lang-Muritano; Lacey Plummer; Felecia Cerrato; Sarah Tsiaras; Ariana Gaspert; Hélène B Lavoie; Ching-Hui Wu; William F Crowley; John K Amory; Nelly Pitteloud; Stephanie B Seminara Journal: Proc Natl Acad Sci U S A Date: 2009-06-30 Impact factor: 11.205
Authors: Marcel Koenigkam-Santos; Antonio Carlos Santos; Beatriz R Versiani; Paula Rejane B Diniz; Jorge Elias Junior; Margaret de Castro Journal: Neuroendocrinology Date: 2011-05-21 Impact factor: 4.914
Authors: R Quinton; V M Duke; A Robertson; J M Kirk; G Matfin; P A de Zoysa; C Azcona; G S MacColl; H S Jacobs; G S Conway; M Besser; R G Stanhope; P M Bouloux Journal: Clin Endocrinol (Oxf) Date: 2001-08 Impact factor: 3.478
Authors: Yousef Bo-Abbas; James S Acierno; Jenna K Shagoury; William F Crowley; Stephanie B Seminara Journal: J Clin Endocrinol Metab Date: 2003-06 Impact factor: 5.958
Authors: Rong Li; Honglu Diao; Fei Zhao; Shuo Xiao; Ahmed E El Zowalaty; Elizabeth A Dudley; Mark P Mattson; Xiaoqin Ye Journal: Endocrinology Date: 2015-06-24 Impact factor: 4.736
Authors: Angela Delaney; Rita Volochayev; Brooke Meader; Janice Lee; Konstantinia Almpani; Germaine Y Noukelak; Jennifer Henkind; Laura Chalmers; Jennifer R Law; Kathleen A Williamson; Christina M Jacobsen; Tatiana Pineda Buitrago; Orlando Perez; Chie-Hee Cho; Angela Kaindl; Anita Rauch; Katharina Steindl; Jose Elias Garcia; Bianca E Russell; Rameshwar Prasad; Uttam K Mondal; Hallvard M Reigstad; Scott Clements; Susan Kim; Kaoru Inoue; Gazal Arora; Kathryn B Salnikov; Nicole P DiOrio; Rolando Prada; Yline Capri; Kosuke Morioka; Michiyo Mizota; Roseli M Zechi-Ceide; Nancy M Kokitsu-Nakata; Cristiano Tonello; Siulan Vendramini-Pittoli; Gisele da Silva Dalben; Ravikumar Balasubramanian; Andrew A Dwyer; Stephanie B Seminara; William F Crowley; Lacey Plummer; Janet E Hall; John M Graham; Angela E Lin; Natalie D Shaw Journal: J Clin Endocrinol Metab Date: 2020-05-01 Impact factor: 5.958
Authors: Erica E Davis; Ravikumar Balasubramanian; Zachary A Kupchinsky; David L Keefe; Lacey Plummer; Kamal Khan; Blazej Meczekalski; Karen E Heath; Vanesa Lopez-Gonzalez; Mary J Ballesta-Martinez; Gomathi Margabanthu; Susan Price; James Greening; Raja Brauner; Irene Valenzuela; Ivon Cusco; Paula Fernandez-Alvarez; Margaret E Wierman; Taibo Li; Kasper Lage; Priscila Sales Barroso; Yee-Ming Chan; William F Crowley; Nicholas Katsanis Journal: Hum Mol Genet Date: 2020-08-11 Impact factor: 6.150
Authors: Ulrich Boehm; Pierre-Marc Bouloux; Mehul T Dattani; Nicolas de Roux; Catherine Dodé; Leo Dunkel; Andrew A Dwyer; Paolo Giacobini; Jean-Pierre Hardelin; Anders Juul; Mohamad Maghnie; Nelly Pitteloud; Vincent Prevot; Taneli Raivio; Manuel Tena-Sempere; Richard Quinton; Jacques Young Journal: Nat Rev Endocrinol Date: 2015-07-21 Impact factor: 43.330
Authors: Flavia Amanda Costa-Barbosa; Ravikumar Balasubramanian; Kimberly W Keefe; Natalie D Shaw; Nada Al-Tassan; Lacey Plummer; Andrew A Dwyer; Cassandra L Buck; Jin-Ho Choi; Stephanie B Seminara; Richard Quinton; Dorota Monies; Brian Meyer; Janet E Hall; Nelly Pitteloud; William F Crowley Journal: J Clin Endocrinol Metab Date: 2013-03-26 Impact factor: 5.958
Authors: Valerie F Sidhoum; Yee-Ming Chan; Margaret F Lippincott; Ravikumar Balasubramanian; Richard Quinton; Lacey Plummer; Andrew Dwyer; Nelly Pitteloud; Frances J Hayes; Janet E Hall; Kathryn A Martin; Paul A Boepple; Stephanie B Seminara Journal: J Clin Endocrinol Metab Date: 2013-01-01 Impact factor: 5.958