Kallmann’s Syndrome: A Comparison of the Reproductive Phenotypes in Men Carrying KAL1 and FGFR1/KAL2 Mutations

Abstract Context: Kallmann’s syndrome (KS) is a genetically heterogeneous disorder consisting of congenital hypogonadotropic hypogonadism (CHH) with anosmia or hyposmia. Objective: Our objective was to compare the reproductive phenotypes of men harboring KAL1 and FGFR1/KAL2 mutations. Design and Patients: We studied the endocrine features reflecting gonadotropic-testicular axis function in 39 men; 21 had mutations in KAL1 and 18 in FGFR1/KAL2, but none had additional mutations in PROK-2 or PROKR-2 genes. Results: Puberty failed to occur in the patients with KAL1 mutations, all of whom had complete CHH. Three patients with FGFR1/KAL2 mutations had normal puberty, were eugonadal, and had normal testosterone and gonadotropin levels. Cryptorchidism was more frequent (14 of 21 vs. 3 of 15; P < 00.1) and testicular volume (2.4 ± 1.1 vs. 5.4 ± 2.4 ml; P < 0.001) was smaller in CHH subjects with KAL1 mutations than in subjects with FGFR1/KAL2 mutations. The mean basal plasma FSH level (0.72 ± 0.47 vs. 1.48 ± 0.62 IU/liter; P < 0.05), serum inhibin B level (19.3 ± 10.6 vs. 39.5 ± 19.3 pg/ml; P < 0.005), basal LH plasma level (0.57 ± 0.54 vs. 1.0 ± 0.6 IU/liter; P < 0.01), and GnRH-stimulated LH plasma level (1.2 ± 1.0 vs. 4.1 ± 3.5 IU/liter; P < 0.01) were significantly lower in the subjects with KAL1 mutations. LH pulsatility was studied in 13 CHH subjects with KAL1 mutations and seven subjects with FGFR1/KAL2 mutations; LH secretion was nonpulsatile in all the subjects, but mean LH levels were lower in those with KAL1 mutations. Conclusion: KAL1 mutations result in a more severe reproductive phenotype than FGFR1/KAL2 mutations. The latter are associated with a broader spectrum of pubertal development and with less severe impairment of gonadotropin secretion.

Download Full-text

Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype–phenotype relationships

Acta Endocrinologica ◽

10.1530/eje-10-0083 ◽

2010 ◽

Vol 162 (5) ◽

pp. 835-851 ◽

Cited By ~ 69

Author(s):

Frédéric Brioude ◽

Jérôme Bouligand ◽

Séverine Trabado ◽

Bruno Francou ◽

Sylvie Salenave ◽

...

Keyword(s):

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Genetic Alterations ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Gonadotropin Secretion ◽

Endocrine Disorder ◽

Congenital Hypogonadotropic Hypogonadism ◽

Kallmann's Syndrome ◽

Kallmann’S Syndrome

Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion, and it is characterized by impaired pubertal development. CHH is caused by defectiveGNRHrelease, or by a gonadotrope cell dysfunction in the pituitary. Identification of genetic abnormalities related to CHH has provided major insights into the pathways critical for the development, maturation, and function of the reproductive axis. Mutations in five genes have been found specifically in Kallmann's syndrome, a disorder in which CHH is related to abnormalGNRHneuron ontogenesis and is associated with anosmia or hyposmia.In combined pituitary hormone deficiency or in complex syndromic CHH in which gonadotropin deficiency is either incidental or only one aspect of a more complex endocrine disorder or a non-endocrine disorder, other mutations affectingGNRHand/or gonadotropin secretion have been reported.Often, the CHH phenotype is tightly linked to an isolated deficiency of gonadotropin secretion. These patients, who have no associated signs or hormone deficiencies independent of the deficiency in gonadotropin and sex steroids, have isolated CHH. In some familial cases, they are due to genetic alterations affectingGNRHsecretion (mutations inGNRH1,GPR54/KISS1RandTAC3andTACR3) or theGNRHsensitivity of the gonadotropic cells (GNRHR). A minority of patients with Kallmann's syndrome or a syndromic form of CHH may also appear to have isolated CHH, but close clinical, familial, and genetic studies can reorient the diagnosis, which is important for genetic counseling in the context of assisted reproductive medicine.This review focuses on published cases of isolated CHH, its clinical and endocrine features, genetic causes, and genotype–phenotype relationships.

Download Full-text

A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic–pituitary–gonadal axis but deteriorating oligospermia during long-term follow-up

Acta Endocrinologica ◽

10.1530/eje-12-1055 ◽

2013 ◽

Vol 168 (4) ◽

pp. K45-K50 ◽

Cited By ~ 13

Author(s):

Marie-Laure Raffin-Sanson ◽

Bérénice Oudet ◽

Sylvie Salenave ◽

Sylvie Brailly-Tabard ◽

Martine Pehuet ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Hypogonadotropic Hypogonadism ◽

Growth Spurt ◽

Gonadotropin Secretion ◽

Lh Pulsatility ◽

Long Term Follow Up ◽

Human Spermatogenesis ◽

Lh Secretion

ObjectiveDAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation. The aim of the study was to prospectively investigate gonadotrope and testicular functions in a patient carrying a DAX1 mutation, who had spontaneous puberty and normal virilization but oligospermia.Case reportThe proband was referred for infertility at the age of 32 years. He reported adrenal insufficiency diagnosed at the age of 19 years. Puberty started at the age of 13 years, with spontaneous virilization, growth spurt, and testicular growth. He reported normal libido and sexual function. Physical examination showed normal virilization, penile length, and testicular volume. However, semen samples showed severe oligospermia. Hormonal measurements confirmed adrenal insufficiency but showed a preserved hypothalamic–pituitary–gonadal axis with normal testosterone and inhibin B; basal and GNRH-stimulated gonadotropin levels and LH pulsatility were also normal. He fathered a first boy by in vitro fertilization and a second boy without medical assistance. As a nephew also had early adrenal insufficiency, the possibility of DAX1 mutation was raised. The same recurrent hemizygous nonsense mutation W39X was found in the proband, his nephew, and in an apparently asymptomatic brother who was found to have adrenal insufficiency, mild HHG, and azoospermia. Several evaluations of the proband over 20 years showed preserved testosterone levels and LH secretion but deteriorating oligospermia.ConclusionLong-term preservation of normal hypothalamic–pituitary–gonadal function in this patient, contrasting with his severe oligospermia, strongly suggests that DAX1 is required for human spermatogenesis, independently of its known role in gonadotropin secretion.

Download Full-text

Hypogonadotropic Hypogonadism With Anosmia—Kallmann's Syndrome

Archives of Internal Medicine ◽

10.1001/archinte.1973.00320100029002 ◽

1973 ◽

Vol 131 (4) ◽

pp. 501 ◽

Cited By ~ 30

Author(s):

James L. Males

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Kallmann's Syndrome ◽

Kallmann’S Syndrome

Download Full-text

Craniofacial Morphology in Patients with Kallmann's Syndrome with and without Cleft Lip and Palate

The Cleft Palate-Craniofacial Journal ◽

10.1597/1545-1569_1997_034_0417_cmipwk_2.3.co_2 ◽

1997 ◽

Vol 34 (5) ◽

pp. 417-424 ◽

Cited By ~ 9

Author(s):

Kirsten Mølsted ◽

Inger Kjær ◽

Aleksander Giwercman ◽

Søren Vesterhauge ◽

Niels Erik Skakkebæk

Keyword(s):

Luteinizing Hormone ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Hypogonadotropic Hypogonadism ◽

Craniofacial Morphology ◽

Endocrine Treatment ◽

Anterior Cranial Base ◽

Kallmann's Syndrome ◽

Maxilla And Mandible ◽

Kallmann’S Syndrome

Objective: Kallmann's syndrome is characterized by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. The principal endocrine defect of hypogonadotropic hypogonadism is a failure to secrete luteinizing hormone-releasing hormone (LHRH), resulting in underdevelopment of the pituitary gonadotropes and an inability to synthesize and release luteinizing hormone and follicle-stimulating hormone. The purpose of the present investigation was to describe the dentition and the craniofacial morphology in patients diagnosed with Kallmann's syndrome. Design: The sample consisted of 11 patients, 2 of whom also had bilateral cleft lip and palate. Radiographic investigations, including cephalometry, were performed. Comparisons were made to normal individuals and to cleft lip individuals without Kallmann's syndrome. Results: Dentition: tooth agenesis occurred more frequently in patients with Kallmann's syndrome. Craniofacial morphology: Increased mandibular inclination and mandibular angulation were seen in Kallmann patients. When clefting also occurred, extreme retrognathism of both maxilla and mandible was seen, a deviation which seemingly worsened during growth. The anterior cranial base and the sphenoid bone showed an altered morphology in one of the patients with Kallman's syndrome. Conclusions: An early diagnosis of Kallmann's syndrome is very important because the prognosis for endocrine treatment thereby improves, and therefore, it is recommended that the sense of smell be evaluated in patients with the craniofacial morphology described.

Download Full-text

Exogenous Kisspeptin Administration as a Probe of GnRH Neuronal Function in Patients With Idiopathic Hypogonadotropic Hypogonadism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2014-2233 ◽

2014 ◽

Vol 99 (12) ◽

pp. E2762-E2771 ◽

Cited By ~ 15

Author(s):

Yee-Ming Chan ◽

Margaret F. Lippincott ◽

James P. Butler ◽

Valerie F. Sidhoum ◽

Cindy X. Li ◽

...

Keyword(s):

Neuronal Network ◽

Functional Capacity ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Fundamental Property ◽

Neuronal Function ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

The Subject ◽

Lh Secretion ◽

Robust Response

Context: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion. Objective: We probed the functional capacity of the GnRH neuronal network in patients with IHH. Participants: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1). Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h). Results: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin. Conclusions: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.

Download Full-text

Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann's Syndrome): Pathophysiological and Genetic Considerations

Endocrine Reviews ◽

10.1210/er.19.5.521 ◽

1998 ◽

Vol 19 (5) ◽

pp. 521-539 ◽

Cited By ~ 95

Author(s):

S. B. Seminara

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Gonadotropin Releasing Hormone ◽

Hormone Deficiency ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

Releasing Hormone ◽

Kallmann's Syndrome ◽

Kallmann’S Syndrome

Download Full-text

Characterization of the Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide, the Natural Ligand of GPR54

Endocrinology ◽

10.1210/en.2004-0836 ◽

2005 ◽

Vol 146 (1) ◽

pp. 156-163 ◽

Cited By ~ 298

Author(s):

V. M. Navarro ◽

J. M. Castellano ◽

R. Fernández-Fernández ◽

S. Tovar ◽

J. Roa ◽

...

Keyword(s):

Excitatory Amino Acid ◽

Hypogonadotropic Hypogonadism ◽

Mrna Levels ◽

Central Administration ◽

Experimental Conditions ◽

Gonadotropin Secretion ◽

Neuroendocrine Control ◽

Lh Secretion

Loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been recently associated with hypogonadotropic hypogonadism, in both rodents and humans. Yet the actual role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion remains largely unexplored. To initiate such analysis, the effects of KiSS-1 peptide on LH secretion were monitored using in vivo and in vitro settings under different experimental conditions. Central intracerebroventricular administration of KiSS-1 peptide potently elicited LH secretion in vivo over a range of doses from 10 pmol to 1 nmol. The effect of centrally injected KiSS-1 appeared to be mediated via the hypothalamic LHRH. However, no effect of central administration of KiSS-1 was detected on relative LHRH mRNA levels. Likewise, systemic (ip and iv) injection of KiSS-1 markedly stimulated LH secretion. This effect was similar in terms of maximum response to that of central administration of KiSS-1 and might be partially attributed to its ability to stimulate LH secretion directly at the pituitary. Finally, the LH-releasing activity of KiSS-1 was persistently observed after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant neurotransmitters in the neuroendocrine control of LH secretion. In summary, our results provide solid evidence for a potent stimulatory effect of KiSS-1 on LH release, acting at central levels (likely the hypothalamus) and eventually at the pituitary, and further document a novel role of the KiSS-1/GPR54 system as a relevant downstream element in the neuroendocrine network governing LH secretion.

Download Full-text

Ovarian Function and Reproductive Hormone Levels in Girls with Prader-Willi Syndrome: A Longitudinal Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-1595 ◽

2012 ◽

Vol 97 (9) ◽

pp. E1766-E1773 ◽

Cited By ~ 17

Author(s):

Elbrich P. C. Siemensma ◽

A. A. E. M. (Janielle) van Alfen-van der Velden ◽

Barto J. Otten ◽

Joop S. E. Laven ◽

Anita C. S. Hokken-Koelega

Keyword(s):

Ovarian Function ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Primordial Follicle ◽

Inhibin B ◽

Female Adolescents ◽

Prader Willi Syndrome ◽

Longitudinal Assessment ◽

Reference Levels ◽

Lh Secretion

Context: The etiology of hypogonadism in girls with Prader-Willi syndrome (PWS) remains uncertain. Objectives: The aim of the study was to evaluate gonadal function longitudinally in girls and female adolescents with PWS. Measurements: We performed a longitudinal assessment of anti-Müllerian hormone (AMH), gonadotropins, estradiol (E2), inhibin B and A, and pubertal development in girls and female adolescents with PWS. Patients and Methods: Sixty-one girls participating in the Dutch PWS Cohort study participated in the study. Serum AMH, gonadotropins, E2, and inhibin B and A levels were compared with reference values. Results: AMH levels in girls and female adolescents with PWS were comparable to reference levels between 6 months and 22 yr of age. From 10 yr of age, FSH and LH levels increased to above the 5th percentile compared to reference levels. E2 and inhibin B levels were in the low normal range in the majority, and inhibin A levels were low but detectable in almost half the female adolescents with PWS. The median age at puberty onset was comparable, but the median ages at attaining Tanner M3 (P = 0.05) and M4 (P < 0.0001) were significantly higher in girls with PWS than in healthy references. Conclusion: Our study shows that the primordial follicle pool and number of small antral follicles are conserved in girls and female adolescents with PWS. We found no classical hypogonadotropic hypogonadism. However, maturation of follicles and progression of pubertal development are impaired, which might be due to dysregulation of LH secretion. Because these impairments are not absolute, ovulation and thus conception cannot be ruled out in individual female adolescents with PWS.

Download Full-text