[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.

The Olfactory Nerve: Anatomy and Pathology.

The human sense of smell is the unique sense through which the olfactory system can identify aromatic molecules within the air and provide a taste sensation. Still, also it plays an essential role in several other functions, warning about environmental safety and even impacts our emotional lives. Recently, olfactory impairment has become an issue of interest due to the COVID-19 pandemic. The dysfunction may vary from only reduced smell detection (hyposmia) to complete loss of it (anosmia) but also includes changes in the normal perception of odors (parosmia). Computed tomography and magnetic imaging resonance are the modalities of choice to evaluate the olfactory pathways. Computed tomography is the initial imaging modality for olfactory disturbances, allowing recognition of sinonasal pathologies, inflammatory processes, or bone-related tumors. Magnetic imaging resonance with dedicated protocols for olfactory disorders enables a detailed assessment of the sinonasal compartment and the anterior cranial fossa. Provides a better depiction of olfactory bulb volume, morphology and signal intensity, as well the status of signal intensity of the central olfactory projection areas. Several diseases can affect the olfactory nerve, such as congenital disorders, trauma, inflammatory or infectious diseases, neoplasms, and even post-operative involvement. This article aims to review the normal anatomy of the olfactory nerve pathway and highlight the spectrum of conditions that most commonly affect it.

[Analysis of clinical characteristics in the patient with olfactory disorders].

Objective:To analyze the etiology and clinical features of patients with olfactory disorders （OD） , and to explore the importance of gustatory testing in patients with OD. Methods:Clinical data of 335 consecutive patients with OD who seek medical consultation in the smell and taste center from the year 2015 to 2021 was retrospectively analyzed. The clinical characteristics of patients with OD were analyzed thorough a structured interview of medical history, otolaryngologic examinations, olfactory tests（Sniffin' Sticks test） and gustatory function test（whole-mouth taste test）. SPSS 17.0 software was used to analyze the clinical characteristics of patients with OD and related factors which have effect on gustatory function. Results:Among the patients， 36.4% of them caused by head trauma, 22.1% for upper respiratory tract infection（URTI）, 15.5% for rhinosinusitis diseases（RSD）, 11.9% for idiopathic, 9.6% for congenital anosmia, and 4.5% for other causes, respectively. The features were different in patients with different kinds of OD: most patients with head trauma were anosmic（χ²=27.958, P<0.001）, and no difference was found in gender and age（P>0.05 for both）; most patients with URTI were anosmic（χ²=21.568, P<0.001）, and female patients were more than male（χ²=5.898, P<0.05）, elder patients were more than younger（χ²=12.963, P<0.001）; most patients with RSD were anosmic（χ²=12.106, P<0.05）, and male patients were more than female（χ²=4.655, P<0.05）; elder patients were more than younger for idiopathic OD（χ²=5.284, P<0.05）, but no sex difference was found（P>0.05）; patients with congenital anosmia were all lost their smell since they were born, and no sex difference was found in the disease（P>0.05）. Fifty-seven of 146（39%） patients whose gustation was assessed had gustatory dysfunction. Gustatory function was significantly associated with the causes of OD（r=0.368, P<0.05）, but not related to olfactory function, age and sex（P>0.05 for all）. Conclusion:The leading causes of olfactory dysfunction were head trauma, URTI, RSD, and idiopathic causes. Each of OD had its own distinct clinical features. Gustatory dysfunction were common in patients with OD, and gustatory function was related to the causes of OD. High priority should be given to gustatory function evaluation for the patients with OD.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Anosmia congénita aislada: reporte de un caso clínico / Isolated congenital anosmia: a case report

RESUMEN Los trastornos del olfato son frecuentes, aunque la anosmia e hiposmia son síntomas poco referidos, suelen afectar de forma importante la calidad de vida de los pacientes. Las causas de anosmia pueden ser adquiridas o congénitas, y la prevalencia de anosmia congénita aislada en la población general se estima en 1:10.000. En estos casos, la anosmia es el único síntoma referido por el paciente. Se presenta el caso de un paciente de sexo masculino de 23 años, sin antecedentes mórbidos de importancia, diagnosticado con anosmia congénita aislada. La historia y evaluación clínica, evaluación neuroendocrinológica, y el uso de la resonancia magnética de cerebro permitió establecer el diagnóstico final.

ABSTRACT Disorders of olfaction are common, however, anosmia and hyposmia are not frequently self-reported, and these symptoms can lead to a significant impairment in quality of life. Causes of anosmia can be acquired or congenital, and the prevalence of isolated congenital anosmia is estimated to be 1:10000 in the general population. In these cases, anosmia is the only symptom referred by the patient. We hereby present the case of a 23-year-old male patient, with no prior medical history, diagnosed with isolated congenital anosmia. The findings from the medical history and physical examination, neuroendocrine evaluation, and the use of magnetic resonance imaging of the brain helped reach a final diagnosis.

Pediatric anosmia: A case series.

INTRODUCTION: Little is known about the etiology of olfactory dysfunction in the pediatric population. The aim of this study is to characterize the etiology and clinical features of anosmia and to explore evaluation options in a pediatric population. METHODS: Olfactory dysfunction was identified at a tertiary pediatric hospital between January 2003 and October 2014 using a text-based and ICD-9 search of the electronic health record system. Clinical information gathered included history, physical examination and imaging study. A phone questionnaire was completed to determine persistence and development of other rhinologic, endocrine, or neurologic symptoms. RESULTS: 37 children (male/female = 17/20) with mean/median ages of 13.28/14. 19 years were identified. The distribution of etiology was: rhinologic disease (N = 16), congenital (N = 4), trauma (N = 1), neoplasm (N = 1) and unknown (N = 15). Rhinologic disease included chronic rhinosinusitis (N = 3) and other nasal anatomic lesions. None of the four subjects with congenital anosmia had classic Kallmann syndrome. The utility of imaging in confirming an etiology of anosmia was noted in 1 of 8 CT and 5 of 22 MRI. The most significant finding of the questionnaire was confirmation of normal puberty in the congenital group. CONCLUSION: Similar to the adult population, rhinologic disease is the most common cause. Absence or hypoplasia of the olfactory bulbs without associated delayed puberty is the presentation of congenital anosmia in our cohort. MRI had a higher utility than CT in evaluating anosmia in general and congenital anosmia in specific. MRI to evaluate children with a history of congenital olfactory dysfunction is recommended.

Next-generation sequencing of patients with congenital anosmia.

We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare segregating variants that were predicted to be damaging, in 510 genes. Three Kallmann syndrome genes (FGFR1, SEMA3A, and CHD7) were identified. We performed permutation-based analysis to test for overall enrichment of these 510 genes carrying these 548 variants with genes mutated in Kallmann syndrome and with a control set of genes mutated in hypogonadotrophic hypogonadism without anosmia. The variants were found to be enriched for Kallmann syndrome genes (3 observed vs. 0.398 expected, p = 0.007), but not for the second set of genes. Among these three variants, two have been already reported in genes related to syndromic anosmia (FGFR1 (p.(R250W)), CHD7 (p.(L2806V))) and one was novel (SEMA3A (p.(T717I))). To replicate these findings, we performed targeted sequencing of 16 genes involved in Kallmann syndrome and hypogonadotrophic hypogonadism in 29 additional families, mostly singletons. This yielded an additional 6 variants in 5 Kallmann syndrome genes (PROKR2, SEMA3A, CHD7, PROK2, ANOS1), two of them already reported to cause Kallmann syndrome. In all, our study suggests involvement of 6 syndromic Kallmann genes in isolated anosmia. Further, we report a yet unreported appearance of di-genic inheritance in a family with congenital isolated anosmia. These results are consistent with a complex molecular basis of congenital anosmia.

On the mechanism of smell loss in patients with Type II congenital hyposmia.

BACKGROUND: Smell function has been initiated with theophylline treatment in 63% of patients with Type II congenital smell loss. Based upon a systematic evaluation of the protein components of nasal mucus we have demonstrated that interactions among four chemical moieties in nasal mucus may play significant roles in this initiation. Prior to treatment three of these moieties, cAMP, cGMP and sonic hedgehog (Shh), were significantly decreased in concentration whereas one of these moieties, TNFalpha, was increased in concentration. The mechanism(s) responsible for initiation of smell function in these patients, not immediately apparent, may depend upon understanding interactions among these moieties. METHODS: Measurements of cAMP, cGMP, Shh and TNFalpha in nasal mucus by specific spectrophotometric immunoassays before and after treatment with theophylline. RESULTS: Before theophylline treatment cAMP, cGMP and Shh in nasal mucus, which act as growth factors to support olfactory receptor function, were significantly decreased below normal levels whereas TNFalpha which acts as a "death factor" to inhibit olfactory receptor function was significantly increased above normal. After theophylline treatment cAMP, cGMP and Shh increased significantly whereas TNFalpha decreased significantly. CONCLUSIONS: These results indicate that there are specific biochemical changes associated with smell loss in patients with Type II congenital smell loss and that correction of these biochemical changes are associated with initiation of smell function in these patients. Understanding these relationships play an important role in understanding receptor action in smell function.

Gray matter alteration in isolated congenital anosmia patient: a voxel-based morphometry study.

Decreased volume of gray matter (GM) was observed in olfactory loss in patients with neurodegenerative disorder. However, GM volume has not yet been investigated in isolated congenital anosmia (ICA) people. We herewith investigated the volume change of gray matter of an ICA boy by morphometric analysis of magnetic resonance images (voxel-based morphometry), and compared with that of 20 age-matched healthy controls. ICA boy presented a significant decrease in GM volume in the orbitofrontal cortex, anterior cingulate cortex, middle cingulate cortex, thalamus, insular cortex, cerebellum, precuneus, gyrus rectus, subcallosal gyrus, middle temporal gyrus, fusiform gyrus and piriform cortex. No significant GM volume increase was detected in other brain areas. The pattern of GM atrophy was similar as previous literature reported. Our results identified similar GM volume alterations regardless of the causes of olfactory impairment. Decreased GM volume was not only shown in olfactory bulbs, olfactory tracts and olfactory sulcus, also in primary olfactory cortex and the secondary cerebral olfactory areas in ICA people. This is the first study to evaluate GM volume alterations in ICA people.

[Clinical observation of isolated congenital anosmia].

OBJECTIVE: To introduce 8 patients with isolated congenital anosmia and to discuss the clinical manifestations, imaging characteristics and family characteristics of this rarely seen disorder. METHODS: Eight patients with isolated congenital anosmia treated between April 2007 and April 2012 were reviewed retrospectively. There were 4 males and 4 females. A detailed medical history collection, physical examination, nasal endoscopy, T&T and Sniffin'Sticks subjective olfactory function tests, olfactory event-related potentials sinonasal computed tomography scan and sex hormones level monitoring were performed in all patients. Seven cases underwent magnetic resonance image of olfactory pathway examination. RESULTS: All patients were anosmia without evidence of other defects. ENT physical examination, nasal endoscopy and computed tomography scan were normal except 4 cases with obvious nasal septum deviation, 2 cases with concha bullosa. Subjective olfactory test indicated all of them were anosmia. Olfactory event-related potentials were obtained in only 1 patient. Magnetic resonance imaging revealed the smaller or atrophy olfactory bulb and olfactory tract in five cases, the absence of olfactory bulbs and tracts in two case. A female patient did not have MRI examination because of wearing IUDs. Detection of 8 patients of sex hormones were normal. Family characteristics: 3 patients showed family inheritance pattern. CONCLUSIONS: The diagnosis of isolated congenital anosmia should be based on chief complaint, medical history, physical examination, olfactory test, nasal endoscopy, olfactory testing, olfactory imaging and olfactory event-related potentials. Magnetic resonance image of olfactory pathway and olfactory event-related potentials have important value for the diagnosis. More attention should be paid to the genetic susceptibility of the family.

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency.

OBJECTIVE: Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders. DESIGN AND METHODS: In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced. RESULTS: Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations. CONCLUSIONS: This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.

Diagnosis and clinical characteristics of congenital anosmia: case series report.

OBJECTIVE: congenital anosmia is extremely rare and tends to present late. We report on a series of patients with congenital anosmia to analyze its clinical characteristics and present illustrative cases. DESIGN: retrospective chart review. SETTINGS: tertiary care centre. METHODS: thirty-five patients with congenital anosmia were reviewed. A thorough medical history taking, physical examination, and nasal endoscopy were performed in all patients. T&T olfactory testing (n = 33), olfactory event-related potentials (OERPs) (n = 33), and sinonasal computed tomography (CT) (n = 35) were carried out. Magnetic resonance images (MRIs) of the olfactory pathway (n = 34) were available. Serum sex hormones were tested (n = 33). MAIN OUTCOME MEASURES: physical examination, olfactory testing, MRI of the olfactory pathway, and serum sex hormones. RESULTS: twenty cases were isolated congenital anosmia (ICA). Fifteen cases were congenital anosmia with other anomalies, including 12 cases with Kallmann syndrome (KS), two with CHARGE syndrome, and one with hypoplasia of the nasal cavity and nasal sinus. T&T olfactory testing indicated anosmia (n = 33). No OERP was obtained (n = 33). CT scans indicated three abnormal patients, including two with unilateral choanal atresia and one with hypoplasia of the nasal cavity and sinus. MRI demonstrated aplasia or hypoplasia of the olfactory bulbs, tracts, and olfactory sulci (n = 34). Serum sex hormones were low in 12 patients with KS. CONCLUSIONS: early diagnosis of congenital anosmia on the basis of olfactory symptoms is difficult. MRI of the olfactory pathway plays an important role in anatomic location. ICA is the most common congenital anosmia. KS is the primary presentation of congenital anosmia with other anomalies.

Anosmia congênita associada à hipospádia: relato de caso / Congenital anosmia associated with hypospadia: a case report

Introdução: A incidência de distúrbios olfatórios nos Estados Unidos da América é de cerca de 200 mil pacientes por ano, sendo as doenças sinusais as causas mais comuns. A anosmia congênita é rara e pode ocorrer como parte de uma síndrome ou como anosmia isolada. O objetivo deste trabalho é relatar um caso raro de anosmia congênita associada à hipospádia. Descrição do caso: Paciente masculino com 20 anos de idade e quadro de anosmia congênita, apresentando gustação e sensibilidade olfatória para odores irritantes preservadas. Refere hipospádia operada aos 13 anos de idade. Negava antecedentes familiares de anosmia. Apresentava exame otorrinolaringológico e nasofibroscopia sem alterações. Ao exame neurológico constatou-se anosmia pelo Cross Culture Smell Test. Ao exame geniturinário, apresentava orifício fistuloso em face ventral de terço médio do pênis, testículos tópicos e de tamanho normal, e desenvolvimento normal dos caracteres sexuais secundários. Observou-se, na tomografia computadorizada dos seios paranasais, presença de concha média bolhosa à esquerda. A ressonância magnética apresentava-se dentro dos padrões de normalidade. Uma análise hormonal foi realizada, cujos resultados foram: hormônio luteinizante de 5,02 mUI/mL, Hormônio folículo-estimulante de 0,8 mUI/mL e testosterona total de 887 ng/dL. Discussão: O relato deste caso é importante pela existência de apenas dois casos relatados na literatura de anosmia congênita associada à hipospádia. O relato de um novo caso e da associação da anosmia com outras anormalidades, como a hipospádia, pode auxiliar na aquisição de novos conhecimentos sobre o assunto e a despertar interesse na descoberta de algum fator etiológico comum às duas anormalidades.

Introduction: The incidence of olfactory disorders in the United States is approximately 200,000 patients per year. Sinus diseases are the most common causes. The congenital anosmia is rare and may occur as part of a syndrome or isolated. The purpose of this paper is to report a case of congenital anosmia associated with hypospadia. Case report: Male, 20 years old, reporting congenital anosmia. The taste and olfactory perception for irritant odors were preserved. He was submitted to hypospadia repair surgery at the age of 13 years old. Family history of anosmia was negative. Otolaryngologyc exam and nasofibroscopy were normal. In the neurologic exam, anosmia was determined by Cross Culture Smell Test. Genitourinary exam showed: fistular orificium in ventral face of medium third section of penis, topic and normal size testicles and full development of secondary sexual characters. On computed tomography of paranasal sinuses, a concha bullosa was observed on the left. The magnetic resonance was normal. Hormonal tests: LH 5.02 mUI/mL, FSH 0.8 mUI/mL and total testosterone 887 ng/dL. Discussion: This case report is important because there are only two cases reported in the literature about congenital anosmia associated with hypospadia. The report of a new case and the association of anosmia with others abnormalities such as hypospadia may lead to additional knowledge about the subject and may raise interest on the discovery of common etiological factors of these abnormalities (anosmia and hypospadia).

Taste perception in kallmann syndrome, a model of congenital anosmia.

OBJECTIVE: To investigate taste, a component of flavor perception, using electrogustometry (EG) in patients with congenital anosmia associated with Kallmann syndrome (KS). METHODS: Four patients with KS and 4 control subjects participated in this study. During the first phase of the investigation, the study subjects were administered the University of Pennsylvania Smell Identification Test. During the second phase of the study, EG testing of 2 regions on the anterior tongue tip was performed through an electrode. RESULTS: Patients with KS, as expected, scored in the anosmic range on the University of Pennsylvania Smell Identification Test, whereas the control group had a normal sense of smell. The difference in the olfaction scores was significant between the 2 study groups (P<0.015). The result of taste assessment of patients with KS and control subjects with use of EG was not significantly different between the 2 study groups (P = 0.874). CONCLUSION: The current study demonstrates that patients with KS have a normal sense of taste, as determined by EG. This finding is consistent with the fact that the deficit in KS is purely olfactory. Because flavor perception is not a common complaint in patients with this condition, it may be postulated that persons with KS compensate for the absent sense of smell. Further studies need to be undertaken to explore how patients with KS compensate for the olfactory dysfunction, information that should contribute to the understanding of the interplay of the various components of flavor perception.

Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia.

Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.