Anosmin-1 immunoreactivity during embryogenesis in a primitive eutherian mammal
Tammy DellovadeJean‐Pierre HardelinNadia Soussi‐YanicostasDonald W. PfaffMarlene Schwanzel‐FukudaChristine Petit
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Kallmann syndrome
Vomeronasal organ
Anosmia
Olfactory marker protein
Kallmann syndrome
Vomeronasal organ
Anosmia
Olfactory marker protein
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GnRH-secreting neurons are known to originate in the epithelium of the medial olfactory placode, whence they migrate along the axons of the terminal nerve via the forebrain and into the hypothalamus. Synaptic contact between the developing olfactory bulbs and fascicles of the vomeronasal, terminal, and olfactory nerves does not occur in Kallmann's syndrome. Consequently, there is migration arrest of GnRH cells and partial or complete failure of formation of the olfactory bulbs, resulting in severe olfactory deficit and hypogonadotropic hypogonadism. In the present study, using an immunofluorescent, double immunostaining technique and confocal laser scanning microscopy, we observed GnRH-immunoreactive neurons in the hypothalamus of a 14-week-old human fetus. However, migration of GnRH neurons was not complete, and indeed, such cells were seen to be migrating along terminal nerve fascicles beneath the cribriform plate in a 16-week-old fetus. The same immunofluorescent technique demonstrated the presence of GnRH cells in biopsies of nasal mucosa obtained from three adults with Kallmann's syndrome, one normosmic subject with hypogonadotropic hypogonadism, and a eugonadal male cadaver. These findings are consistent with two different interpretations: the nasal GnRH neurons may be vestigial, representing cells that failed to migrate during embryogenesis; alternatively, they may have been generated de novo later in life, a possibility consistent with the recognized plasticity of human postnatal olfactory neuroepithelium. They also reveal that subjects with the normosmic (i.e. non-Kallmann's) form of GnRH deficiency are able to synthesize immunologically recognizable GnRH, implying that failure of GnRH synthesis is not responsible for this type of hypogonadotropic hypogonadism.
Kallmann syndrome
Vomeronasal organ
Olfactory nerve
Olfactory mucosa
Terminal nerve
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Kallmann syndrome is a human genetic disorder characterized by the association of hypogonadism with the inability to smell, and is due to defects in the olfactory system development (i.e. incomplete migration of olfactory axons and of gonadotropin‐releasing hormone producing neurons from the olfactory epithelium to the forebrain; aplasia or hypoplasia of olfactory bulbs and tracts). The human X‐linked Kallmann syndrome gene and its chicken homologue have been cloned. Their protein products contain fibronectin type III repeats and a ‘four‐disulfide‐core’ domain also found in molecules that are involved in neural development. Consistent with the human phenotype, the chicken Kallmann gene is expressed in the developing olfactory bulb. At present the molecular and cellular mechanism of action of the Kallmann syndrome gene product is unknown. Based on expression studies and the characteristic domains of the predicted protein, it is hypothesized that the protein may be involved in targeting olfactory axons to the bulb. Alternatively, the Kalunann protein could be an extracellular matrix component required for the proper formation of the multilayered structure of the olfactory bulb.
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Abstract Congenital total loss of the sense of smell occurs as a part of a syndrome or isolated anosmia. Kallmann syndrome is the most well known congenital anosmia associated with hypogonadotropic hypogonadism. Isolated congenital anosmia (ICA) is a very rare condition and appears to be due to changes in the olfactory epithelium or to aplasia of the olfactory nerve, bulb, and tract. Here we report two unrelated Iranian families with ICA. One family consisted of nine affected members, and the other family contained three affected members. Clinical history, physical examination, and smell testing by intravenous injection of combined vitamins (Alinamin™, Takeda Pharmaceutical Co. Ltd., Japan) confirmed the disease in each affected member. No signs of hypogonadism or other neurological disorders were observed in any affected members. Family analysis with the complete ascertainment method under assumption of the same condition in the two families suggested that the disease is not inconsistent with an autosomal dominant mode with incomplete penetrance. The inheritance in one family appears unusual, i.e., there were no affected individuals in the third generation. When only two upper generations in the family are concerned, the segregation ratio was 0.39 ± 0.11. Male‐to‐male transmissions were observed and both sexes were affected in both families. Magnetic resonance imaging (MRI) of the olfactory bulb and sulcus revealed no evidence of morphological changes in all affected members, suggesting that these patients have either a defect in the olfactory epithelium or a functional defect in the olfactory cortex. © 2004 Wiley‐Liss, Inc.
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The olfactory system development and brain sexual maturation, in man and animals, are closely related. Currently the overlap between the formation of the olfactory system and the migration of neurons that synthesize gonadotropin-releasing hormone (GnRF) are described. The GnRF neurons migrate from the medial portion of the nasal epithelium through the olfactory nerves and the main olfactory bulb to the anterior hypothalamus. Furthermore, Kallmann syndrome (KS) is a genetic disorder in which combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is characterized by the absence or reduced levels of gonadotropin-releasing hormone and anosmia is due to aplasia of the olfactory bulb. The basic clinical manifestations of KS are: anosmia and the absence of puberty. The structures responsible for the maturation of the main and accessory olfactory systems, the sexual differentiation of the brain and its relationship with all the clinical manifestations of Kallmann syndrome are analyzed in this review.
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Kallmann syndrome
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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.
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Prenatal and one-two month postnatal testosterone influences human neural and behavioural development, since the prenatal and one-two month postnatal hormone environment clearly contributes to the development of sex-related variation in human behaviour, and plays a role in the development of the sexual brain and individual differences in behaviour within each sex, as well as differences between the sexes. Olfactory system development, brain sexual maturation and sexual behaviour in man and animals are closely related. Kallmann syndrome (KS) is a genetic disorder which combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is characterized by the absence or reduced levels of gonadotropin-releasing hormone, and anosmia is due to aplasia of the olfactory bulb. The overlap between the formation of the olfactory system and the migration of neurons that synthesize the gonadotropin-releasing hormone (GnRH) is common knowledge. GnRH neurons migrate from the medial portion of the nasal epithelium through the olfactory nerves and the main olfactory bulb to the anterior hypothalamus. Furthermore, the clinical manifestations of KS are: anosmia, the absence of puberty, and modifications in sexual behaviour. The structures responsible for the maturation of the main and accessory olfactory systems, the sexual differentiation of the brain and its relationship with clinical manifestations and sexual behaviour in Kallmann syndrome are analyzed in this review. The importance of the treatment of KS at early ages is suggested in order to improve brain sexual development and its clinical and sexual behaviour manifestations.
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Sexual Differentiation
Delayed puberty
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Hypogonadotropic hypogonadism (HH) refers to an endocrine defect of hypothalamic origin resulting in gonadal hypoplasia and frequently associated with anosmia or severely impaired olfactory function (Kallmann's syndrome). This apparently results from a disruption in the migration of neurons from the olfactory placode to the bulb and hypothalamus early in development, and so provides a unique opportunity to investigate olfactory function in human subjects with congenitally incomplete peripheral systems. Olfactory performance in 37 HH patients and 37 age-matched controls was compared using a modified version of the Munich Olfaction Test. This test is based on the sniff-bottle method and includes tests of (i) odor quality discrimination, (ii) intensity discrimination, (iii) detection thresholds, and (iv) recognition, hedonic evaluation and identification ability. The patients could be divided into two distinct groups differing significantly on all four subtests and showing no overlap in performance: 20 anosmics, conforming to Kallmann's syndrome, and 17 apparent normosmics whose performance was slightly poorer, but not significantly different to that of the controls. The unexpected failure to find a continuum of olfactory dysfunction now raises the question whether HH with or without anosmia represents two syndromes with distinct etiologies, or rather reflects the ability of the olfactory system to function well despite morphological impairment.
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The development of Gonadotropin releasing hormone-1 (GnRH) neurons is important for a functional reproduction system in vertebrates. Disruption of GnRH results in hypogonadism and if accompanied by anosmia is termed Kallmann Syndrome (KS). From their origin in the nasal placode, GnRH neurons migrate along the olfactory-derived vomeronasal axons to the nasal forebrain junction and then turn caudally into the developing forebrain. Although research on the origin of GnRH neurons, their migration and genes associated with KS has identified multiple factors that influence development of this system, several aspects still remain unclear. This review discusses development of the olfactory system, factors that regulate GnRH neuron formation and development of the olfactory system, migration of the GnRH neurons from the nose into the brain, and mutations in humans with KS that result from disruption of normal GnRH/olfactory systems development.
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A previous study has demonstrated that luteinizing hormone‐releasing hormone (LHRH) is localized in the human bilateral vomeronasal organs in the nasal septum during a 4‐week period of intrauterine life (22). The purpose of the present study was to elucidate the location of LHRH‐expressing cells outside the vomeronasal organs, with special emphasis on the submucosa of the medial wall and roof of the nasal cavity. An additional aim was to study the innervation pathways in the same regions. Both regions can be affected in Kallmann's syndrome, which is characterized by hypogonadotropic hypogonadism (lack of LHRH) and often associated with anosmia. Histological sections of craniofacial regions (49 normal human fetuses, 6–19 weeks) were examined by immunohistochemical techniques for LHRH and for neuronal tissue (protein gene product 9.5, PGP 9.5). LHRH reactions were only seen in the septal submucosa extending from the vomeronasal organs to the olfactory bulb. There was a close spatiotemporal association between the occurrence of LHRH and neuronal tissue. From the rhino‐olfactory epithelium separate nerve tissue extended to the olfactory bulb. It is suggested that the medial region of the nasal placode giving rise to the septal wall is always affected in Kallmann's syndrome, and in cases in which the phenotypic features are associated with anosmia, also the more lateral part of the nasal placode, from which the rhino‐olfactory region originates, is affected.
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Kallmann syndrome
Anosmia
CHARGE syndrome
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