Kallmann Syndrome Research Articles

A rare case of a 34-year-old patient diagnosed late with Kallmann syndrome: case report.

Kallmann syndrome (KS) is a rare genetic disorder manifested by the combination of hypogonadotropic-hypogonadism and olfactory dysfunction. It is usually diagnosed at 14 - 16 years of age due to delayed puberty. However, delays in diagnosis have been reported in a few cases. We presented a 34-year-old man presented with primary infertility as the chief complaint. Physical examination revealed bilateral gynecomastia, Tanner stage 2, and anosmia. Hormonal studies show a hypogonadotropic hypogonadism profile. Genetic testing revealed a normal male karyotype. Abdominal ultrasonography (USG) revealed a small prostate, and testicular USG demonstrated small testicles. Neuroimaging study revealed olfactory bulb agenesis and hypoplasia of the olfactory sulcus. Treatment was done by testosterone replacement therapy, and the patient is now on a regular follow-up. In conclusion, suspected clinical features of KS may guide the diagnosis with comprehensive hormonal and imaging studies. However, the reported patient was diagnosed extremely late.

Diagnosis of Kallmann Syndrome Following a Femur Fracture in a Middle Age Male Patient

Diagnosis of Kallmann Syndrome Following a Femur Fracture in a Middle Age Male Patient

Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

Congenital hypothalamic hypogonadism — a Kallmann syndrome in boys. Clinical cases

Central hypogonadism (CH) is a rare disease that occurs with a frequency of 1 : 8000 in women and 1 : 4000 in men. In 60 % of cases of CH, it is caused by Kallmann syndrome (KS) — a disease in which hypogonadotropic hypogonadism is combined with olfactory disorders (hyposmia or anosmia).Aim — to study clinical features, principles of diagnosis of CH/KS and evaluation of the effectiveness of various treatment. Materials and methods. 4 cases with CH/KS from three families had been described. Laboratory and instrumental investigations were used to confirm the KS; genetic diagnosis was performed using targeted next-generation sequencing (tNGS hypogonadotropic panel).Results. Patients with CH/KS had a wide spectrum of genital disorders (micropenia, cryptorchidism, microorchidism), which appeared at different age. Extragenital pathology was found in three of four patients: namely disorders of kidney, eye, respiratory system, hypoparathyroidism, hypothyroidism and epilepsy. It should be noted that all patients had olfactory disorders, which appeared in two of them only during a detailed survey after receiving genetic testing. In all patients, the diagnosis of CH was confirmed by the test with triptorelin 0.1. Also, all patients who underwent densitometry were found to have significant osteoporosis. In three patients, genetic testing confirmed hemizygous pathogenic variants in ANOS1 gene, while in one patient a heterozygous variant in FGFR1 gene was confirmed. After treatment with chorionic gonadotropin (HCG), two patients responded positively, with a descent of the testicles into the scrotum and an increase of testosterone level and testicular volume. However, in the other two patients there was no positive trend in treatment with HCG, therefore, the use of recombinant human FSH (r-FSH) in the form of priming and then further — in combination with HCG may be considered. Although the presence of severe microorchidism, cryptorchidism, low levels of AMH, inhibin B, and an unsatisfactory response to the previous treatment with HCG indicates extremely unfavorable prognosis. Therefore, in order to achieve the fertility in some patients with CH/KS, the most likely attempt is the use of assisted reproductive technologies.Conclusions. The leading problem in the treatment of patients with KS is their different response to hormone therapy, including different manifestations of the disease.

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

BACKGROUNDKallmann 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. AIMTo identify the existing mutation sites of KS with diabetes and reveal the relationship between genotype and phenotype.METHODSWe 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. RESULTSSequencing 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. CONCLUSIONThe 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.

TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism.

BackgroundIsolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin‐releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans.MethodsThe aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis.ResultsWe identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH‐associated genes.ConclusionOur study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.

An Uncommon Association of Kallmann Syndrome and Arachnoid Cysts: A Case Report

Objective − To present a rare case of Kallmann syndrome associated with arachnoid cysts, and to emphasize the importance of correlation of radiological analysis with anamnestic data and clinical findings. Case Report − Kallmann syndrome (KS) is a form of hypogonadotropic hypogonadism in combination with a defect in the sense of smell. We report the case of KS in a 17-year old male. The patient presented with an absence of secondary sexual characteristics and anosmia. On the basis of anamnestic data, clinical findings and hormonal assay diagnosis of KS was likely but additional diagnostic workup, such as laboratory tests, karyotyping, scrotal and abdominal ultrasound, bone mineral density and X-ray of the wrist, were made to ensure the correct diagnosis. Brain MRI showed a morphologically normal pituitary gland, an arachnoid cyst on the right temporal lobe, a right frontal arachnoid cyst and hypoplastic olfactory bulbs. Androgen replacement with testosterone was started to induce virilisation. Our patient is now on regular follow-up to monitor his response to treatment. Conclusion − Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell. This is the sixth reported case of KS associated with arachnoid cysts. Due to the rarity of both KS and arachnoid cysts, it is difficult to establish a relationship between these two conditions. Early diagnosis of this syndrome is important to ensure a better quality of life.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Enigmatic Neural Pathways: Potentiating Viral Neuroinvasion Into the CNS.

Kallmann Syndrome with Brain Changes and Unilateral Renal Agenesis: A Rare Case Report

Kallmann syndrome (KS) is a rare inherited disorder. It is characterized by hypogonadotropic hypogonadism in association with anosmia or hyposmia, results from defective migration of gonadotropin-releasing hormone producing neurons and olfactory axons. Because KS is a disease due to mutation of genes, patients with KS often display midline head and brain abnormalities such as cleft lip and/or palate and corpus callosum dysgenesis, septo-optic dysplasia, renal agenesis and other phenotypic abnormalities. Here we report a case of 19 years old boy presented with non-development of secondary sex characters, small penis, anosmia and clubfoot. Karyotype was 46XY and hormonal measurement revealed hypogonadotropic hypogonadism. MRI of the brain revealed bilateral agenesis of the olfactory bulb and sulcus, corpus callosal dysgenesis, septo-optic dysplasia and smaller pituitary gland. USG of abdomen revealed right renal agenesis.

A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis

Semaphorin 7A (SEMA7A) is a membrane‐bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7AR148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC‐MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance‐associated protein‐2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report

BackgroundVariants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5–6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS.Case presentationA 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score − 3.0) and femoral neck (Z-score − 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient’s health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment.ConclusionExploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

Magnetic resonance imaging in Kallmann syndrome: A case report

Kallmann syndrome is a rare genetically inherited condition characterized by hypogonadotrophic hypogonadism and anosmia or hyposmia. It is due to failure of migration of gonadotrophic releasing hormone neuron and olfactory neuron to hypothalamus. This case reports a 39-year-old Maldivian adult with clinical features of Kallmann syndrome and magnetic resonance imaging brain showing absence of olfactory sulcus and bulb.

Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism

Congenital isolated hypogonadotropic hypogonadism includes a group of diseases related to the defects of secretion and action of gonadotropin-releasing hormone (GNRH) and gonadotropins. In a half of cases congenital hypogonadism is associated with an impaired sense of smell. It's named Kallmann syndrome. Now 40 genes are known to be associated with function of hypothalamus pituitary gland and gonads. Phenotypic features of hypogonadism and therapy effectiveness are related to different molecular defects. However clinical signs may vary even within the same family with the same molecular genetic defect. Genotype phenotype correlation in patients with congenital malformations prioritizes the search for mutations in candidate genes. There are data of significant contribution of oligogenicity into the phenotype of the disease are presented in the review. Moreover, an issue of current isolated hypogonadotropic hypogonadism definition and classification revision is raised in the review due to hypogonadotropic hypogonadism development while there are mutations in genes not associated with GNRH neurons secretion and function.

Feedback-Related Beta-Band Power Predicts Risky Choices in a Probabilistic Gambling Task

SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.

Oligogenic Inheritance Underlying Incomplete Penetrance of PROKR2 Mutations in Hypogonadotropic Hypogonadism

The role of the prokineticin 2 pathway in human reproduction, olfactory bulb morphogenesis, and gonadotropin-releasing hormone secretion is well established. Recent studies have highlighted the implication of di/oligogenic inheritance in this disorder. In the present study, we aimed to identify the genetic mechanisms that could explain incomplete penetrance in hypogonadotropic hypogonadism (HH). This study involved two unrelated Tunisian patients with HH, which was triggered by identifying a homozygous p.(Pro290Ser) mutation in the PROKR2 gene in a girl (HH1) with Kallmann syndrome (KS). The functional effect of this variant has previously been well demonstrated. Unexpectedly, her unaffected father (HH1P) and brother (HH1F) also carried this genetic variation at a homozygous state. In the second family, we identified a heterozygous p.(Lys205del) mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (c.2803C > T) was involved in 18 pathogenic digenic combinations. The CCDC141 variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between DUSP6 and SEMA7A genes, predicted as “dual molecular diagnosis.” The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome. Sanger validation revealed the absence of this variant in the healthy mother. We hypothesize that disease expression in HH12 could be induced by the digenic transmission of the SEMA7A and DUSP6 variants or a monogenic inheritance involving only the SEMA7A VUS if further functional assays allow its reclassification into pathogenic. Our findings confirm that homozygous loss-of-function genetic variations are insufficient to cause KS, and that oligogenism is most likely the main transmission mode involved in Congenital Hypogonadotropic Hypogonadism.

P–044 A non-classical splice site variant in ANOS1 gene leading to Kallmann syndrome

Abstract Study question Genetic risk of the non-classical splice site variant in ANOS1 gene Summary answer A non-classical ANOS1 splice site variant, c.1062 + 4T&amp;gt;C, causes Kallmann syndrome. What is known already Genetic abnormalities play a key role in the development of Kallmann syndrome. Although an overwhelming majority of missense and nonsense mutations occur in the exons of a gene, intron mutations can also be pathogenic. Study design, size, duration The research object is a family. Eight patients of the family were recruited in this study, three of them were diagnosed with Kallmann syndrome. Participants/materials, setting, methods Genomic DNA was extracted from peripheral blood and whole-exome sequencing (WES) was performed to identify the genetic abnormalities. PCR was performed to verify the WES results. The functional splicing reporter mini gene assay was performed to assess the impact of sequence variants on splicing. Main results and the role of chance The proband and other two patients exhibited the typical clinical features of KS. A non-classical splice site variant, c.1062 + 4T&amp;gt;C in ANOS1 gene was identified, whereas the other unaffected family members did not have this mutation. This mutation caused the disappearance of the splicing site of intron 7 and the splicing position became the 156th base of exon 7, which caused a frame-shift mutation, leading to a premature termination of translation. Limitations, reasons for caution Since the ANOS1 gene is almost not expressed in the blood, in order to uncover the effect of this splice site variant of ANOS1, we carried out a functional splicing reporter mini gene assay in the mini gene vector pEGFP-N1. Wider implications of the findings: This study shows that mutations in non-classical splicing regions are also pathogenic. Therefore, it is recommended that the detection and analysis of this gene should pay attention to the non-classical splice site variant. Trial registration number Not applicable

Врожденный изолированный гипогонадотропный гипогонадизм: клинический и молекулярно-генетический полиморфизм

Congenital isolated hypogonadotropic hypogonadism includes a group of diseases related to the defects of secretion and action of gonadotropin-releasing hormone (GNRH) and gonadotropins. In a half of cases congenital hypogonadism is associated with an impaired sense of smell. It’s named Kallmann syndrome. Now 40 genes are known to be associated with function of hypothalamus pituitary gland and gonads. Phenotypic features of hypogonadism and therapy effectiveness are related to different molecular defects. However clinical signs may vary even within the same family with the same molecular genetic defect. Genotype phenotype correlation in patients with congenital malformations prioritizes the search for mutations in candidate genes. There are data of significant contribution of oligogenicity into the phenotype of the disease are presented in the review. Moreover, an issue of current isolated hypogonadotropic hypogonadism definition and classification revision is raised in the review due to hypogonadotropic hypogonadism development while there are mutations in genes not associated with GNRH neurons secretion and function.

Hypogonadotropic-hypogonadism (Kallman Syndrome) in Young Adult

Background: Kallmann syndrome (KS) is a rare disorder first described in 1856 and later studied by Kallmann in 1944. It is now designated as olfactogenital dysplasia with an association between agenesis of the olfactory bulbs and hypogonadism. The prevalence of KS is still unknown. The reported incidence is 1 in 8000 to 1 in 10 000 in men and rare in women. More than 24 genes are underlying KS that have been identified. Mutations in these genes are thought to interfere with the expression of cell markers that guide migrating neurons, leading to failed migration of GnRH neurons and olfactory neurons to the forebrain during fetal development. The main clinical characteristics of KS include hypogonadotropic hypogonadism and anosmia or hyposmia. Less common phenotypes include cardiovascular anomalies, unilateral renal agenesis, cleft palate and cleft lip, cryptorchidism and osteoporosis. Magnetic resonance imaging (MRI) can show abnormalities of the olfactory system and other forebrain structures. Other exceptions may be discovered using MRI because of its high resolution and multiplanar capabilities, such as pituitary abnormalities.

Prenatal genetic screening and the evolving quest for "perfect babies": at what cost for genetic diversity?

Commercial screening services for inheritable diseases raise concerns about pressure on parents to terminate "imperfect babies".