ISSN: 2572-4142 Jean-Jacques et al. Int Arch Transl Med 2019, 5:008 DOI: 10.23937/2572-4142.1510008 Volume 5 | Issue 1 International Archives of Open Access Translational Medicine ORIGINAL ARTICLE Diagnostic Findings in 60 Cases of Isolated and Syndromic Congenital Olfactory Dysfunction Jean-Jacques Braun, MD1*, Marion Renaud, MD1, Sébastien Moliere, MD2, Vincent Noblet, MD3, Stéphane Kremer, MD2, Hélène Dollfus, MD4,5 and Sophie Riehm, MD6 1Service ORL-CCF, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, France 2 Check for Service de Radiologie 2, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, France updates 3Laboratoire ICUBE, UMR CNRS 7357, Université de Strasbourg, France 4Service de Génétique Médicale, Centre de référence pour les Affections rares en Génétique Ophtalmologique (CARGO), Fédération de Médecine Translationelle (FMTS), Hôpitaux Universitaires de Strasbourg, France 5Laboratoire de Génétique Médicale, INSERM U 11 12, Fédération de Médecine Translationelle de Strasbourg, Université de Strasbourg, France 6Service de Radiologie 1, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, France *Corresponding author: Jean Jacques Braun, MD, Service ORL-CCF, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière 67098 Strasbourg Cedex, France, Tel: +33(0)3-8822-1307 Abstract Conclusion: The pathophysiology involving peripheral and/or central olfactory abnormalities and the involved Background: Congenital anosmia (CA) is rare compara- genetic mechanisms remain poorly understood. Complete tively to acquired anosmia. The pathophysiology and the genomes sequencing in affected patients and families with genetic background remain poorly understood. This study well delineated CA (ENT workup, olfactometry, MRI) and aims to review the main clinical and Magnetic Resonance studies of different CA animal models constitute a challenge Imaging (MRI) findings to discuss the diagnostic strategy, for better understanding of this rare and heterogeneous the pathophysiology and the genetic basis of the different group of CA. forms of CA. Methods: A series of 60 patients with congenital anosmia Keywords was reviewed retrospectively out of 425 non-sinus-related Anosmia, Congenital anosmia, Bardet Biedl syndrome, anosmia and compared to the literature data. CA was Kallmann syndrome, MRI, Olfactory bulb assessed by Ear Nose Throat (ENT) workup, psychophysical olfactometry and MRI evaluation of olfactory bulbs (OB) and Abbreviations central olfactory structures. CA: Congenital Anosmia; MRI: Magnetic Resonance Imag- ing; ENT: Ear, Nose and Throat; OB: Olfactory Bulb; ICA: Results: The 60 cases of CA include 16 isolated congenital Isolated Congenital Anosmia; SCA: Syndromic Congenital anosmia and 44 syndromic congenital anosmia especially Anosmia; BBS: Bardet Biedl Syndrome; KS: Kallmann Syn- 20 Bardet Biedl syndrome and 22 Kallmann syndrome. The drome; STOE: Suprathreshold Evaluation of Olfaction diagnosis of CA is often overlooked or delayed especially for isolated CA with no or few complaints about olfaction impairment compared to acquired anosmia. MRI shows Introduction in most cases hypoplasia or aplasia of OB with a strong correlation between global OB visual evaluation and OB Loss of smell (anosmia) is common in the general volumetric evaluation for trained radiologists and often population (prevalence about 5%) and is associated central olfactory abnormalities needing 3D MRI imaging. with reduced quality of life [1]. The etiologies are Citation: Jean-Jacques B, Renaud M, Moliere S, Noblet V, Kremer S, et al. (2019) Diagnostic Findings in 60 Cases of Isolated and Syndromic Congenital Olfactory Dysfunction. Int Arch Transl Med 5:008. doi.org/10.23937/2572-4142.1510008 Accepted: April 13, 2019: Published: April 15, 2019 Copyright: © 2019 Jean-Jacques B, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Jean-Jacques et al. Int Arch Transl Med 2019, 5:008 • Page 1 of 10 • DOI: 10.23937/2572-4142.1510008 ISSN: 2572-4142 numerous and various, and the prevalence increases ophthalmologist, geneticist) according to the associated with age. Patients with congenital anosmia (CA) or clinical symptoms, (vi) Genetic analysis for all BBS pa- congenital olfactory dysfunction have no memory of tients and for six KS patients. ever being able to smell. CA remains rare (1% of the anosmia population) and can be isolated (Isolated Diagnosis of SCA Congenital Anosmia, ICA) or associated with various BBS is a well-recognized ciliopathy with early onset diseases (Syndromic Congenital Anosmia, SCA) like retinitis pigmentosa, polydactyly, obesity, hypogonad- Bardet Biedl syndrome (BBS) and Kallmann syndrome ism, renal and cognitive impairment, congenital or early (KS) [1]. The pathophysiology and the genetic basis are in life dysosmia with genetic background [3]. BBS genes still poorly understood especially for non-syndromic CA. have been screened thanks to high throughput se- Complete study of olfactory bulbs, sulcus and olfactory quencing using a custom panel targeting depending on central structures with 3D MRI imaging and complete the version 31 genes or 58 genes including the 19 BBS sequencing of the genomes of CA patients and CA genes and other related pathologies such as Alstrom families constitute a challenge for better understanding syndrome, Meckel syndrome, nephronophthisis… [4]. for these different forms of CA. KS diagnosis was performed according to the criteria This review aims to describe the different forms of of the European Consensus Statement [5]. The associ- CA, the diagnosis difficulties, the olfactory evaluation ation of congenital hypogonadotropic hypogonadism with different technics and the main clinical and MRI (CHH) with absence of puberty and infertility associated findings (evaluation of olfactory bulb (OB) and central with anosmia or hyposmia is termed KS (50% of patients olfactory structure by 3D MRI) in a series of 60 cases of with CHH). More than 25 causal genes have been de- CA [2,3]. scribed to date [5]. Only in 6 KS cases molecular diagno- sis has been performed with detailed phenotype anal- Methods ysis and sequencing of the coding sequences of KAL1, This study for BBS patients received ethical approval FGFR1, FGF8, PROKR2 and PROK2 [6]. for the study PHRC national Bardet Biedl IDRCB 2007- Olfaction evaluation A00868-45. Olfaction evaluation was performed on the basis Study design and review items provided by previous work [2,3]. The suprathreshold For this retrospective single center study all patients evaluation was based on the perception and identifica- were evaluated by the same Ear Nose and Throat (ENT) tion of 10 odors in three trials with randomized order specialist over a period of 30 years through a university (53 patients) [3]. For the UPSIT evaluation, identification department of rhinology and a private ENT office. Out of the odors was made using the technique of multiple of a series of 425 patients with non-sinonasal-related forced choices of 40 odors (37 patients) [7]. There was a anosmia especially post-infectious (56%), posttraumatic strong correlation between the two tests [2,3]. (14%) and anosmia associated with toxins/medications, neurologic diseases and idiopathic anosmia (16%), 60 MRI evaluation CA patients (14%) were included for this study. For this study MRI evaluation was not available for A senior ENT specialist evaluated all CA according to all patients especially for the first included patients the following protocol: (i) Clinical evaluation of olfaction because access to MRI was limited at that time. Some and its dysfunction: history taking, onset, duration, fluc- rare patients refused MRI “being without any utility in tuation, other nasal associated symptoms, past medical the absence of treatment for CA” and in other patients history looking for head trauma, respiratory infections, MRI was focused on the pituitary gland especially by sinonasal surgery, neurosurgery, toxins/medications, suspicion for KS and did not retrospectively allow a occupational exposure, family history of CA, non-nasal precise and complete study of OB nor- central olfactory associated symptoms (ii) ENT examination with nasal structures needing 3D MRI imaging. endoscopy (iii) Olfaction evaluation using one or two Images were acquired on 1.5T (20 cases) or 3T (27 different psychophysical methods namely a suprath- cases) MRI unit. MRI protocols that included coronal T2- reshold evaluation of olfaction (STOE) and/or the UPSIT weighted sequence covering the nasal cavities allowed French version (Sensonics, Pennsylvania NJ), (iv) MRI evaluation of olfactory bulb and sulcus without real for nasal cavities, sinuses, OB and quantitative evalua- difference between 1, 5T and 3T MRI. MRI protocols tion of the morphological central olfactory structures that included whole-brain imaging allowed qualitative alterations (Voxel-Based Morphometry) when possible evaluation of cortical atrophy and central structures. or qualitative evaluation of overall brain morphology 3T MRI protocols that included T1-weighted SPACE (qualitative assessment of cortical atrophy, anomalies (Sampling Perfection with Application optimized of the central structures), (v) Evaluation of the non-nasal Contrasts using different flip angle Evolution) sequence associated symptoms by workup of different specialists