Molecular analysis of KAL-1 in a series of Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism patients from Northwestern China

We conducted an analysis of the Kallmann syndrome 1 （KAL-1） genotype in 17 patients with Kallmann syndrome （KS）, 9 patients with normosmic idiopathic hypogonadotropic hypogonadism （nlHH） and 20 age-matched normal men in Northwestern China. To do this, we used multiplex PCR analysis with exon-flanking primers and automated sequencing techniques with peripheral blood DNA samples. Intragenic deletions were found at the KAL-1 locus in two KS patients. One case with an atrial septal defect exhibited an intragenic deletion of exon 6. Another KS patient with cryptorchidism had intragenic deletions of exons 5 and 6. For the nlHH patients, no abnormalities were observed in the exonic and flanking sequences of KAL-1. This report describes two intragenic deletions of KAL-1 in two KS patients and suggests that KAL-1 deletion might be more prevalent in KS patients with other congenital organ abnormalities than those described previously in other series from Northwestern China.

Clinical assessment and genomic landscape of a consanguineous family with three Kallmann syndrome descendants

Although some genes that cause Kallmann syndrome （KS） have been identified by traditional linkage analysis and candidate gene techniques, the syndrome＇s molecular etiology in the majority of patients remains poorly understood. In this paper, we present the clinical assessments of a consanguineous Hart Chinese family with three KS descendants. To understand the molecular etiology of KS from a genome-wide perspective, we investigated the genome-wide profile of structural variation in this family using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. The results revealed that the three affected individuals had common copy number variants （microdeletions） on chromosomes lp21.1, 2q32.2, 8q21.13, 14q21.2 and Xp22.31. Moreover, the copy number variants on Xp22.31 were located in the intron of KAL 1, which causes X-linked KS. Two PCR assays were performed on these regions to validate the results obtained using the chips. In addition, genomic microdeletions in this region were verified in one of 29 Han Chinese sporadic KS cases and one of four other family cases, but not in 26 Han Chinese sporadic normosmic idiopathic hypogonadotropic hypogonadism cases and 100 unrelated Han Chinese normal controls. Our results provide a novel insight into the relative contributions of certain copy number variants to KS＇s molecular etiology and generate a list of interesting candidate regions for further studies.

Are there fibroblast growth factor receptor 1 mutations in a Chinese Kallmann syndrome family?

The present study examined 58 members of a Kallmann syndrome family and investigated whether there are fibroblast growth factor receptor 1 （FGFR1） gene mutations in this family. Genomic DNA from the proband and family members was subjected to PCR to amplify 18 exons of FGFR1, and the amplified products were sequenced to identify potential mutations. MRI of the olfactory bulb region was performed on suspected subjects. The patient and his father were diagnosed with Kallmann syndrome. A polymorphic site was found at 39542, with the proband and his parents being heterozygous （guanine ＋ cytosine）. However, healthy controls and the other members of this family were homozygous for guanine at this position.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.

Molecular diagnosis of Kallmann syndrome with diabetes by whole exome sequencing and bioinformatic approaches

BACKGROUND Kallmann syndrome(KS)is a hypogonadotropic hypogonadism accompanied by anosmia or hyposmia.It is associated with the low secretion of gonadotropins which can lead to other abnormal endocrine metabolism disorders such as diabetes.Through genetic and molecular biological methods,more than 10 KS pathogenic genes have been found.AIM To identify the existing mutation sites of KS with diabetes and reveal the relationship between genotype and phenotype.METHODS We studied KS pathogenesis through high-throughput exome sequencing on four diabetes’patients with KS for screening the potential pathogenic sites and exploring the genotype-phenotype correlation.Clinical data and peripheral blood samples were collected from the patients.White blood cells were separated and genomic DNA was extracted.High-throughput sequencing of all exons in the candidate pathogenic genes of probands was performed,and the results obtained were analyzed.RESULTS Sequencing revealed mutations in the KLB p.T313M,ANOS1 p.C172F,and IGSF10 gene(p.Lys1819Arg and p.Arg1035Thr)at different sites,which may have been associated with disease onset.CONCLUSION The diagnosis of KS is challenging,especially in early puberty,and the clinical manifestations reflect physical delays in development and puberty.Timely diagnosis and treatment can induce puberty,thereby improving sexual,bone,metabolic and mental health.

Comparing Women and Men’s Experiences with Kallmann Syndrome

Topic: Kallmann syndrome (KS) is a congenital olfacto-genital disease. Affected persons show an absence of physical pubertal development, and their sense of smell is reduced or absent (anosmia). The prevalence is 1:40,000 in women and 1:8000 to 1:10,000 in men. Development of gender identity corresponds to the assigned gender at birth. The cause of KS is a genetic defect. To date, only a few systematic investigations have delved into the psychological disstress and consequences of the somatic characteristics of KS. In order for affected persons to be appropriately informed, well-founded research results are necessary. The focus of the present study aims at examining the similarities and differences between the psychological disstress and consequences women and men experience through the development, on the one hand, and through its medical treatment on the other. The present text complements current findings on the psychological consequences of KS in men [1] and women, respectively [2]. Two questions lie at the center of the comparison: 1) Which similarities and which gender-specific differences are there concerning the perceived burdens? 2) Which coping strategies have been developed in dealing with the burdens and consequences caused by KS in the affected women and men? Which similarities and which gender-specific differences are there with respect to these coping strategies? Methodology: The survey has been carried out by means of topically focused narrative interviews of 16 men and 5 women. Based on the qualitative content analysis according to Mayring [3], categories have been generated and evaluated on the basis of the interview material. The results of the male and female samples have been contrasted and analyzed in gender-specific relevant key subjects [1,2]. Results: The comparison shows that the burdens women and men experience through KS go beyond the somato-medical problems, and that the psychosocial consequences are a heavy burden for the members of both groups. Men bear a heavier burden through insecurities and shame about the absence of virilization and subsequently suffer more from bullying and marginalization experiences. They also perceive mood changes more frequently and as more burdensome through the course of hormone treatment. Women also develop shame due to the absence of female body development;they do, however, perceive this as less burdensome than do men. They suffer particularly from a loss of libido before and also during hormone treatment. Differences occur concerning the gender-specific hormone treatment and its effects on mood and libido. Wellfounded statements relating to this do, however, require further-reaching studies. In women, KS is frequently misdiagnosed as simply estrogen deficiency, which could be an explanation for the differing degree of prevalence. The preferred coping strategies for both sexes include confidential talks with suitable people, such as parents, the partner, friends, or a psychotherapist. Using support from psychotherapists, sex education, and/or sexual therapists is recommended when necessary. Conclusion: Psychotherapeutic/psychological support is recommended for both women and men diagnosed with KS, taking into account the gender-specific differences in dealing with the burdens KS imposes. The focus for both sexes should be on developing and strengthening body image and self-esteem. In medical treatment for both women and men, normal or inconspicuous body development should be emphasized. Particularly in the case of women, sex therapy should be available for support due to loss of libido. For men, therapy should be recommended, so as to strengthen their social capabilities and self-confidence. Additional studies are necessary for examining the effects of hormonal treatment on mood and libido and phenotyp.

New understandings of the genetic basis of isolated diopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone （GnRH） action. Because reduced or normal luteinizing hormone （LH）/follicle-stimulating hormone （FSH） levels may be observed in the affected patients, the term idiopathic central hypogonadism （ICH） appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and ~s fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome （KS）. KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH （nlCH）, justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network.