Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications

Abstract

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.

Figures

Fig. 1.

UPSIT scores in IHH and control subjects. A, The distribution of raw UPSIT scores of male subjects (IHH and controls); B, distribution of raw UPSIT scores of female subjects (IHH and controls); C, UPSIT ratings of all IHH subjects (males and females); D, UPSIT ratings of all control subjects (males and females).

Fig. 2.

Correlation between olfactory self-assessment and UPSIT. A, Self-assessment reports of olfactory function in patients with IHH. B, UPSIT rating distributions of IHH patients who report “no smell” during self-assessment of olfactory function. C, UPSIT rating distribution of IHH patients who report to have “reduced” or “good smell” during self-assessment of olfactory function.

Fig. 3.

IHH centile-derived data as mapped vs. age- and gender-matched normative population. Histogram showing percentage of all IHH subjects (black bars) lying within respective age- and gender-matched centiles of olfactory function (centile values calculated from Ref. 30). The percentage of control subjects lying within each defined centile range is shown by the red dotted line.

Fig. 4.

Olfactory phenotype of IHH subjects harboring monogenic and oligogenic mutations. Number of IHH subjects with protein altering mutations in each gene are shown with their respective olfactory function as determined by UPSIT (anosmic, red; hyposmic, yellow; normosmic, green). The genes are arranged on the x-axis and are divided using vertical dotted lines to represent genes previously linked only to KS (KAL1, NELF); genes previously linked to both KS and nIHH (PROK2, PROKR2, FGF8, FGFR1); and genes previously linked only to nIHH (GNRH1, GNRHR, TAC3, TACR3, KISS1, KISS1R). The last column represents the number of subjects with oligogenic changes and the individual genes with protein-altering variants found within each olfactory phenotype.