Kallmann syndrome and idiopathic hypogonadotropic hypogonadism: The role of semaphorin signaling on GnRH neurons

Abstract The first mutation in a gene associated with a neuronal migration disorder was identified in patients with Kallmann Syndrome, characterized by hypogonadotropic hypogonadism and anosmia. This pathophysiological association results from a defect in the development of the GnRH and the olfactory system. A recent genetic screening of Kallmann Syndrome patients revealed a novel mutation in CCDC141. Little is known about CCDC141, which encodes a coiled-coil domain containing protein. Here, we show that Ccdc141 is expressed in GnRH neurons and olfactory fibers and that knockdown of Ccdc141 reduces GnRH neuronal migration. Our findings in human patients and mouse models predict that CCDC141 takes part in embryonic migration of GnRH neurons enabling them to form a hypothalamic neuronal network to initiate pulsatile GnRH secretion and reproductive function.

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Clinicohormonal Parameters as a Primary Step to Differentiate Normosmic Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome in a Tertiary Care Hospital in Eastern India

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/48672.15128 ◽

2021 ◽

Author(s):

Ram Chandra Bhadra ◽

Dona Saha ◽

Arjun Baidya

Keyword(s):

Genetic Disorder ◽

Hormone Replacement ◽

Hypogonadotropic Hypogonadism ◽

Tertiary Care ◽

Serum Testosterone ◽

Kallmann Syndrome ◽

Care Hospital ◽

Cross Sectional ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

Male Predominance

Introduction: Idiopathic hypogonadotropic hypogonadism is a rare gonadal dysgenesis in which puberty does not take place naturally. It occurs due to insufficient pulsatile secretion of Gonadotrophin-Releasing Hormone (GnRH) and the resulting Follicle-Stimulating Hormone (FSH) and Luteinising Hormone (LH) deficiency leads to absence of or delayed sexual maturation. Kallmann syndrome is an uncommon genetic disorder characterised by hypogonadotropic hypogonadism associated with anosmia or hyposmia. When anosmia is absent, the same is referred as normosmic Idiopathic Hypogonadotropic hypogonadism (nIHH). Aim: To find out the significant differences between Kallmann syndrome and nIHH based on clinical features and biochemical assessment as a primary measure to initiate the treatment early. Materials and Methods: This hospital based cross-sectional observational cohort study was conducted in Department of Endocrinology, Nilratan Sircar Medical College and Hospital, Kolkata, India. The study was done on 55 cases of IHH presenting to the department with delayed secondary sexual characteristics. Results: Out of these 55 cases, 45 (81.8%) were of nIHH and only 10 (18.2%) cases were of Kallmann Syndrome. It was found that both the conditions show male predominance. Smell abnormalities were present only in Kallmann group. The level of serum testosterone was significantly higher (p<0.05) in nIHH subjects (mean-35.59 ng/dL) than patients with Kallmann Syndrome (mean-14.90 ng/dL). Patients with Kallmann syndrome showed significantly reduced pubic and axillary hair development and absence of gonadal development. Conclusion: Absence of puberty with anosmia/hyposmia with low serum FSH and LH, drastically reduced serum testosterone, are factors that point towards the diagnosis of Kallmann syndrome even in absence of genetic study, which is helpful for initiation of hormone replacement therapy for treatment.

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Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility

Endocrinology ◽

10.1210/en.2019-00113 ◽

2019 ◽

Vol 160 (9) ◽

pp. 2151-2164 ◽

Cited By ~ 3

Author(s):

Erica C Pandolfi ◽

Karen J Tonsfeldt ◽

Hanne M Hoffmann ◽

Pamela L Mellon

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Neuronal Cell ◽

Delayed Puberty ◽

Homeodomain Protein ◽

Gnrh Neuron ◽

Direct Role ◽

Hpg Axis ◽

Gnrh Neurons

Abstract Hypothalamic GnRH (luteinizing hormone–releasing hormone) neurons are crucial for the hypothalamic-pituitary-gonadal (HPG) axis, which regulates mammalian fertility. Insufficient GnRH disrupts the HPG axis and is often associated with the genetic condition idiopathic hypogonadotropic hypogonadism (IHH). The homeodomain protein sine oculis–related homeobox 6 (Six6) is required for the development of GnRH neurons. Although it is known that Six6 is specifically expressed within a more mature GnRH neuronal cell line and that overexpression of Six6 induces GnRH transcription in these cells, the direct role of Six6 within the GnRH neuron in vivo is unknown. Here we find that global Six6 knockout (KO) embryos show apoptosis of GnRH neurons beginning at embryonic day 14.5 with 90% loss of GnRH neurons by postnatal day 1. We sought to determine whether the hypogonadism and infertility reported in the Six6KO mice are generated via actions within the GnRH neuron in vivo by creating a Six6-flox mouse and crossing it with the LHRHcre mouse. Loss of Six6 specifically within the GnRH neuron abolished GnRH expression in ∼0% of GnRH neurons. We further demonstrated that deletion of Six6 only within the GnRH neuron leads to infertility, hypogonadism, hypogonadotropism, and delayed puberty. We conclude that Six6 plays distinct roles in maintaining fertility in the GnRH neuron vs in the migratory environment of the GnRH neuron by maintaining expression of GnRH and survival of GnRH neurons, respectively. These results increase knowledge of the role of Six6 in the brain and may offer insight into the mechanism of IHH.

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Parallel Multi-Gene Panel Testing for Diagnosis of Idiopathic Hypogonadotropic Hypogonadism/Kallmann Syndrome

Case Reports in Genetics ◽

10.1155/2019/4218514 ◽

2019 ◽

Vol 2019 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Manickavasagam Senthilraja ◽

Aaron Chapla ◽

Felix K. Jebasingh ◽

Dukhabhandhu Naik ◽

Thomas V. Paul ◽

...

Keyword(s):

Gene Mutation ◽

Hypogonadotropic Hypogonadism ◽

Cost Effective ◽

Kallmann Syndrome ◽

Causative Gene ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

Panel Testing ◽

Kal1 Gene ◽

Gene Panel Testing ◽

The Subject

Kallmann syndrome (KS)/Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia due to the abnormal migration of olfactory and gonadotropin releasing hormone producing neurons. Multiple genes have been implicated in KS/IHH. Sequential testing of these genes utilising Sanger sequencing is time consuming and not cost effective. The introduction of parallel multigene panel sequencing of small gene panels for the identification of causative gene variants has been shown to be a robust tool in the clinical setting. Utilizing multiplex PCR for the four gene KS/IHH panel followed by NGS, we describe herewith two cases of hypogonadotropic hypogonadism with a Prokineticin receptor 2 (PROKR2) gene and KAL1 gene mutation. The subject with a PROKR2 mutation had a normal perception of smell and normal olfactory bulbs on imaging. The subject with a KAL1 gene mutation had anosmia and a hypoplastic olfactory bulb.

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