Background: Congenital hypogonadotropic hypogonadism (CHH) is a condition with a strong genetic background, caused by a deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Published data on CHH cohorts indicate a male predominance, although this is not supported by our current understandings. Aims: In order to unravel the possible causes or contributors to such epidemiological sex difference, the aim of our study is to investigate differences in genetic background and clinical presentation between males and females in a large cohort of CHH patients. Materials and methods: We enrolled 338 CHH patients with absent or arrested pubertal development, referred to our Center from 01/2016. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a custom panel of 28 candidate genes. Results: Among 338 patients 94 were female (F) and 244 male (M), with a ratio of 1:2.6. We found that 36.09% (122/338) of patients harbored potentially pathogenic rare genetic variants (RVs) with no significant differences between sexes; on the other hand, a significantly higher frequency of oligogenicity was observed in females (F 9,57% 9/94 vs M 3,69% 9/244, P = 0.034). The prevalence of non-reproductive phenotypic features was significantly higher (P = 0.01) in males (53/228, 23.2%) than in females (10/93, 10.8%): in particular, kidney abnormalities affected only male patients and midline defects had a significantly higher prevalence in males (P = 0.010). Finally, BMI SDS was -0.04 ± 1.09 in females and 0.69 ± 1.51 in males, with a statistically significant difference between groups (P = <0.001). Conclusion: Our data confirm the male predominance in CHH and identify some differences with regard to the clinical presentation between males and females that could indicate a variable expression of genetic rare variants and a dimorphic modulation of phenotype according to metabolic/behavioral factors, which will need to be substantiated and investigated by further studies.

Genetic and phenotypic differences between sexes in congenital hypogonadotropic hypogonadism (CHH): Large cohort analysis from a single tertiary centre / S. Federici, B. Cangiano, G. Goggi, D. Messetti, E.V. Munari, M. Amer, L. Giovanelli, F. Hrvat, V. Vezzoli, L. Persani, M. Bonomi. - In: FRONTIERS IN ENDOCRINOLOGY. - ISSN 1664-2392. - 13:(2022), pp. 965074.1-965074.12. [10.3389/fendo.2022.965074]

Genetic and phenotypic differences between sexes in congenital hypogonadotropic hypogonadism (CHH): Large cohort analysis from a single tertiary centre

S. Federici
Primo
;
B. Cangiano
Secondo
;
G. Goggi;E.V. Munari;M. Amer;L. Giovanelli;L. Persani
Penultimo
;
M. Bonomi
Ultimo
Project Administration
2022

Abstract

Background: Congenital hypogonadotropic hypogonadism (CHH) is a condition with a strong genetic background, caused by a deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Published data on CHH cohorts indicate a male predominance, although this is not supported by our current understandings. Aims: In order to unravel the possible causes or contributors to such epidemiological sex difference, the aim of our study is to investigate differences in genetic background and clinical presentation between males and females in a large cohort of CHH patients. Materials and methods: We enrolled 338 CHH patients with absent or arrested pubertal development, referred to our Center from 01/2016. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a custom panel of 28 candidate genes. Results: Among 338 patients 94 were female (F) and 244 male (M), with a ratio of 1:2.6. We found that 36.09% (122/338) of patients harbored potentially pathogenic rare genetic variants (RVs) with no significant differences between sexes; on the other hand, a significantly higher frequency of oligogenicity was observed in females (F 9,57% 9/94 vs M 3,69% 9/244, P = 0.034). The prevalence of non-reproductive phenotypic features was significantly higher (P = 0.01) in males (53/228, 23.2%) than in females (10/93, 10.8%): in particular, kidney abnormalities affected only male patients and midline defects had a significantly higher prevalence in males (P = 0.010). Finally, BMI SDS was -0.04 ± 1.09 in females and 0.69 ± 1.51 in males, with a statistically significant difference between groups (P = <0.001). Conclusion: Our data confirm the male predominance in CHH and identify some differences with regard to the clinical presentation between males and females that could indicate a variable expression of genetic rare variants and a dimorphic modulation of phenotype according to metabolic/behavioral factors, which will need to be substantiated and investigated by further studies.
GnRH (gonadotropin releasing hormone); congenital hypogonadotropic hypogonadism (CHH); female; genetics; phenotype [mesh]; sex
Settore MED/13 - Endocrinologia
MIS18ACARI_01 - Combined Next-generation sequencing and in vivo approach to uncover the complex genetic basis of GnRH neuron deficiency - CARIBONI, ANNA MARIA - MIS - Bandi Ministero Salute - 2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/950416
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