SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.

The loss of smell in persistent allergic rhinitis is improved by levocetirizine due to reduction of nasal inflammation but not nasal congestion (the CIRANO study).

BACKGROUND: Persistent allergic rhinitis (PER) has a moderate impact on the sense of smell, but no controlled study has reported the effect of antihistamines on the loss of smell in patients with PER. METHODS: Patients with PER and subjective loss of the sense of smell (n = 27) were included in this pilot randomised, double-blind, placebo-controlled study. Nasal symptoms, nasal endoscopy, skin prick test, acoustic rhinometry, peak nasal inspiratory flow, nasal nitric oxide (nNO), and olfactometry (Barcelona Smell Test-24; BAST-24) were performed and evaluated in all PER patients at baseline and after 7 and 30 days of treatment with levocetirizine 5 mg or placebo. RESULTS: The study population was randomized into two homogeneous groups: levocetirizine (n = 14) and placebo groups (n = 13). The evolution of symptoms reflected the therapeutic effect of levocetirizine treatment on rhinorrhea, nasal itching, eye itching, sneezing, and the total symptoms score after 7 and 30 days. Significant improvement in loss of smell by a visual analog scale (VAS) was observed after 7 days of levocetirizine treatment (7.2 ± 4.3; p < 0.05) compared to placebo (-9.4 ± 6.2). Improvement in smell identification by BAST-24 was strongly correlated (r = 0.72; p < 0.05) with smell improvement by VAS after 30 days. After 7 days of treatment with levocetirizine, the nNO values decreased (-494 ± 188) compared to placebo (155 ± 284 ppb; p < 0.05). CONCLUSIONS: The CIRANO study suggests that levocetirizine is effective on PER symptoms, including a transient improvement in loss of smell, and that this improvement concurs more with reduction of nasal inflammation than of nasal patency.

A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes.

CONTEXT: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). OBJECTIVE: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. DESIGN AND PATIENTS: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. RESULTS: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. CONCLUSION: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.

Persistent allergic rhinitis has a moderate impact on the sense of smell, depending on both nasal congestion and inflammation.

OBJECTIVES/HYPOTHESIS: A degree of smell disturbance has been found in seasonal and perennial allergic rhinitis, but alterations in olfaction in patients with persistent allergic rhinitis (PER) have not yet been evaluated. The aims of the study were to evaluate the impact of PER on the sense of smell, and to characterize this impact based on self-reported hyposmia (SRH) and PER severity. STUDY DESIGN/METHODS: A prospective controlled study was performed on 49 consecutive patients with PER. PER patients were subclassified depending on severity and the presence of SRH. Olfactory function was evaluated by the Barcelona Smell Test-24 (BAST-24) olfactometry for smell detection, identification, and forced choice for first and fifth cranial nerve (CN) dependent odors in comparison to a group of 60 healthy volunteers. In patients with SRH, obstruction was evaluated by peak nasal inspiratory flow (PNIF) and acoustic rhinometry; and nasal inflammation was evaluated by nasal nitric oxide (nNO). RESULTS: Most patients with PER (67%) presented SRH. Moderate/severe PER (84.8%) predominated among patients with SRH, while mild PER (75%) predominated among patients without SRH. Smell detection, identification, and forced choice tests were significantly worse in PER patients (P < .05) than in healthy controls for the odors related to the first and fifth CN. Among subgroups, patients with moderate/severe PER and/or with SRH presented a significant reduction in smell detection (P < .05) compared to healthy controls. Nasal NO correlated (R: 0.4; P < .05) with loss of smell. CONCLUSIONS: Patients with PER have a moderate loss of smell (BAST-24) with a higher impairment in those with self-reported hyposmia and moderate-to-severe PER. These results suggest that the sense of smell should be further investigated in all patients with allergic rhinitis, both in a clinical setting and in clinical trials.