title: Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications.
abstract: BACKGROUND
  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.
  
  
  METHODS
  We conducted a cross-sectional case-control study at an academic referral center.
  
  
  METHODS
  A total of 286 IHH patients (201 males and 85 females) and 2183 healthy historic controls (1011 males and 1172 females) were studied.
  
  
  METHODS
  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.affiliation: Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Hilana M
authors.initials: HM
authors.lastname: Lewkowitz-Shpuntoff
authors.forename: Virginia A
authors.initials: VA
authors.lastname: Hughes
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Au
authors.forename: Richard L
authors.initials: RL
authors.lastname: Doty
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D017436:Kallmann Syndrome / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000857:Olfaction Disorders / Q000145:classification* / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics*; D009833:Olfactory Pathways / Q000503:physiopathology; D010641:Phenotype; D055815:Young Adult
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