Olfactory function and olfactory bulbs in patients with Kallmann syndrome

BACKGROUND: The majority of Kallmann patients have anosmia or hyposmia. This is how the disease is diagnosed. Some of them don’t have such complaints but olfactory dysfunction is diagnosed via olfactometry. Nowadays there is the lack of information about correlation between olfactometry results and subjective complaints. Correlation between olfactory bulbs size and olfactory dysfunction has been little studied.

AIM: To explore olfactory bulb size and olfactory function in patients with congenital isolated hypogonadotropic hypogonadism. To correlate olfactory bulb sizes and smell test scores.

MATERIALS AND METHODS: Single-centre comparative study. 34 patients were included. The main group consisted of 19 patients with hypogonadotropic (15 –with Kallmann syndrome, 4 — with normosmic hypogonadism). Olfactory bulbs MRI were provided to all the patients, olfactory test (Sniffin’ Sticks Test) and molecular-genetic studies were provided in all patients with hypogonadism. Control group consisted of 15 patients who were provided with orbits MRI. Olfactory bulbs were evaluated additionally in them.

RESULTS: Normal size of olfactory bulbs were only in 1 patient with hypogonadism. Olfactory bulbs height and width were significantly smaller in patients with hypogonadism in comparison with control group (p<0.01). Height median of right bulb was 1.0 mm [0.2; 1.8] in patients from the main group vs. 3.0 [2.5; 3.2] in controls, width median of right bulb was 1.0 mm [0.2; 1.9] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Height median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 3.0 [2.7; 3.2] in controls, width median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Correlation has been established between left bulb height (r=0.59) and width (r=0.67) and olfactometry results (p<0.05). 4 patients had no anosmia complaints but had olfactory dysfunction according to Sniffin’ Sticks Tests.

CONCLUSION: Olfactometry was able to diagnose olfactory dysfunction in 78.5% (i.e. in 15 out of 19 patients with congenital isolated hypogonadotropic hypogonadism. However, anosmia complaints had only 11 out of 19 patients. It is the first results of olfactory bulb sizes in patients with hypogonadotropic hypogonadism in Russia. Uni — or bilateral hypoor aplasia were diagnosed in 94.7% patients with hypogonadism regardless of olfactory dysfunction. Bilateral olfactory bulbs hypoplasia were the most common MRI-finding (36.8%). Unilateral hypoor aplasia was diagnosed in 31.6% patients.

1. Smith N, Quinton R. Kallmann syndrome. BMJ. 2012; 345(1):e6971-e6971. doi: https://doi.org/10.1136/bmj.e6971

2. Dodé C, Hardelin J-P. Kallmann syndrome. Eur J Hum Genet. 2009; 17(2):139-146. doi: https://doi.org/10.1038/ejhg.2008.206

3. Boehm U, Bouloux P-M, Dattani MT, et al. European Consensus Statement on congenital hypogonadotropic hypogonadism —pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015; 11(9):547-564. doi: https://doi.org/10.1038/nrendo.2015.112

4. Hummel T, Pietsch H, Kobal G. Kallmann’s syndrome and chemosensory evoked potentials. Eur Arch Oto-Rhino-Laryngology. 1991; 248(5):311-312. doi: https://doi.org/10.1007/BF00176762

5. Vakhrushev SG, Smbatyan AS. Diagnostic value of different olfactometry methods Russ. Otorhinolaryngol. 2016; 15(3):10-15. (In Russ.). doi: https://doi.org/10.18692/1810-4800-2016-3-48-53

6. Zhukova IA, Zhukova NG, Izhboldina OP, et al. Methods for evaluating of olfactory function in patients with Parkinson’s disease. Zhurnal Nevrol i psikhiatrii im SS Korsakova. 2015; 115(6):44-49. doi: https://doi.org/10.17116/jnevro20151156244-49

7. Ottaviano G, Cantone E, D’Errico A, et al. Sniffin’ Sticks and olfactory system imaging in patients with Kallmann syndrome. Int Forum Allergy Rhinol. 2015; 5(9):855-861. doi: https://doi.org/10.1002/alr.21550

8. Anık A, Çatlı G, Abacı A, et al. Olfactory dysfunction in children with Kallmann syndrome: relation of smell tests with brain magnetic resonance imaging. Hormones. 2015; 14(2):293-299. doi: https://doi.org/10.14310/horm.2002.1562

9. Goektas O, Fleiner F, Sedlmaier B, Bauknecht C. Correlation of olfactory dysfunction of different etiologies in MRI and comparison with subjective and objective olfactometry. Eur J Radiol. 2009; 71(3):469-473. doi: https://doi.org/10.1016/j.ejrad.2008.10.039

10. Hun Yang K. et al, MR Evaluation of the Olfactory Bulb in Normals and Patients with Decreased Sense of Smell. KISEP Orig Artic J Rhinol. 1998; 5(1):44-47

11. Rumeau C, Nguyen DT, Jankowski R. How to assess olfactory performance with the Sniffin’ Sticks test ®. Eur Ann Otorhinolaryngol Head Neck Dis. 2016; 133(3):203-206. doi: https://doi.org/10.1016/j.anorl.2015.08.004

12. Bogdanov VV, Skljar MA, Zavadskij AV. Osobennosti kul’tural’noj adaptacii obonjatel’nogo testa Sniffin’ Sticks dlja ispol’zovanija v russkojazychnoj srede. Rossijskaja rinologija. 2013; 21(2):41-42. (In Russ.).

13. Hand JL, Runke CK, Hodge JC. The phenotype spectrum of X-linked ichthyosis identified by chromosomal microarray. J Am Acad Dermatol. 2015; 72(4):617-627. doi: https://doi.org/10.1016/j.jaad.2014.12.020

14. Shandin AN, Tyulpakov AN. Genetics of isolated of hypogonadotropic hypogonadism. Problems of Endocrinology. 2008; 54(2):27-35. (In Russ.). doi: https://doi.org/10.14341/probl200854227-35

15. Niu Y, Zhou C, Xu H, et al. Novel interstitial deletion in Xp22.3 in a typical X-linked recessive family with Kallmann syndrome. Andrologia. 2018; 50(4):e12961. doi: https://doi.org/10.1111/and.12961

16. Maya‐Núñez G, Cuevas‐Covarrubias S, Carlos Zenteno J, et al. Contiguous gene syndrome due to deletion of the first three exons of the Kallmann gene and complete deletion of the steroid sulphatase gene. Clin Endocrinol (Oxf). 1998; 48(6):713-718. doi: https://doi.org/10.1046/j.1365-2265.1998.00406.x

17. Lawson-Yuen A, Saldivar J-S, Sommer S, Picker J. Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet. 2008; 16(5):614-618. doi: https://doi.org/10.1038/sj.ejhg.5202006

18. Coimbra C, Cunha A, Ferreira EC, Condé A. Isolated olfactory bulbs agenesis: An extremely rare entity. Acta Otorrinolaringológica Española. 2016; 67(4):242-244. doi: https://doi.org/10.1016/j.otorri.2015.07.004

19. Costa I, Rodrigues B, Dias L. Congenital agenesis of the olfactory bulbs: What to suspect? Cureus. 2021; 67(4):242-244. doi: https://doi.org/10.7759/cureus.12659

20. Hacquart T, Ltaief-Boudrigua A, Jeannerod C, et al. Reconsidering olfactory bulb magnetic resonance patterns in Kallmann syndrome. Ann Endocrinol (Paris). 2017; 78(5):455-461. doi: https://doi.org/10.1016/j.ando.2016.12.003

21. Yu B, Chen K, Mao J, et al. The diagnostic value of the olfactory evaluation for congenital hypogonadotropic hypogonadism. Front Endocrinol (Lausanne). 2022; (13):2236. doi: https://doi.org/10.3389/fendo.2022.909623