Isolated GNRH deficiency: genotypic and phenotypic characteristics of the genetically heterogeneous Greek population

Stamou, Maria; Varnavas, Petros; Kentrou, Machi; Adamidou, Fotini; Voutetakis, Antonis; Jing, Jenny W.; Plummer, Lacey; Koika, Vasiliki; Georgopoulos, Neoklis A.

doi:10.1530/eje-16-0505

Cited by 10 publications

(12 citation statements)

References 37 publications

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“…These data are in agreement with the more severe neonatal phenotype of patients with KS, and perhaps with a more frequent involvement of inheritable genetic defects with a higher degree of expressivity and penetrance. Some authors (21,22,23) reported a similar prevalence of cryptorchidism between KS and nIHH groups. In our cohort, congenital micropenis was present only in PPO groups, as expected (10,24,25), but the prevalence of male genital tract anomalies, including micropenis and cryptorchidism (Table 3), was significantly higher in patients with KS, thus indicating a more severe intrauterine androgen deficiency in patients with KS.…”

Section: Discussionmentioning

confidence: 82%

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Bonomi

Vezzoli

Krausz

et al. 2018

European Journal of Endocrinology

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Section: Discussionmentioning

confidence: 82%

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Bonomi

Vezzoli

Krausz

et al. 2018

European Journal of Endocrinology

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“…Inclusion criteria for IGD patients have been described before (1) and consisted of (i) clinical diagnosis of IGD: this was defined as delay or absence of pubertal development by the age of 18 years and low sex steroid levels in the presence of low or normal gonadotropins; (ii) normal other pituitary function and (iii) no neuroanatomic or functional cause of hypogonadotropic hypogonadism. A total of 87 probands participated in this study.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously described an enrichment of the normosmic phenotypic variation of the IGD phenotype in the Greek patients with IGD as well as low prevalence of genetic variation in the Greek IGD cohort and absence of oligogenicity, highlighting the possible presence of a yet unidentified genetic cause that contributes to the expression of the IGD phenotype in this ethnic subpopulation (1). Given that next-generation sequencing (NGS) has emerged a huge number of genes and variation in multiple diseases and disorders, we utilized whole exome sequencing (WES) to examine if application of NGS has any effect on the prevalence of genetic variation and oligogenicity identified in the cohort studied.…”

Section: Introductionmentioning

confidence: 91%

Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients

Stamou

Varnavas

Plummer

et al. 2019

Endocrine Connections

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Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non-reproductive clinical characteristics. Apart from the phenotypic heterogeneity, IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described. We have previously described low prevalence of genetic variation in the Greek IGD cohort discovered with utilization of Sanger sequencing in 14 known IGD genes. Here, we describe the expansion of genetic screening in the largest IGD Greek cohort that has ever been studied with the usage of whole-exome sequencing, searching for rare sequencing variants (RSVs) in 37 known IGD genes. Even though Sanger sequencing detected genetic variation in 21/81 IGD patients in 7/14 IGD genes without any evidence of oligogenicity, whole exome sequencing (WES) revealed that 27/87 IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic. Our findings suggest that next-generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.

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“…Because of the lack of minipuberty, a high proportion of male infants with congenital GnRH or gonadotrophin deficiencies are affected by cryptorchidism or micropenis. In the largest United Kingdom (UK) series of men with CHH, around 50% were cryptorchid at birth, of which one-third had bilateral disease, 23 compared with the UK birth prevalence of 5–6%, 24,25 whereas micropenis affects 4.6–25.4% 26–28 of CHH males compared with the general population birth prevalence of 0.015–0.35%. 29,30 Experienced parents may also observe the absence of erections on nappy change.…”

Section: Clinical Manifestations and Diagnostic Evaluationmentioning

confidence: 97%

Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males

Swee

Quinton

2019

Therapeutic Advances in Endocrinology

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Hormonal induction of spermatogenesis offers men with azoospermia due to hypogonadotrophic hypogonadism (HH) the promising prospect of fertility restoration. However, an important exception is the subset of individuals affected by congenital hypogonadotrophic hypogonadism (CHH), also known as Kallmann syndrome if associated with anosmia, who often display dismal responses to fertility induction, despite prolonged therapy. This primarily stems from the loss of minipuberty, which is a crucial phase of testicular maturation in early life that has a far-reaching impact on eventual spermatogenic capacity. Further exacerbating the compromised reproductive health is the failure to initiate timely pubertal induction in many CHH patients, resulting in suboptimal genital and psychosexual development. In this paper, the clinical implications and management of male HH across the lifespan is comprehensively reviewed, with a special focus on novel strategies that have the potential to modify disease severity and maximize fertility potential in CHH by addressing the inadequacies of conventional approaches.

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Isolated GNRH deficiency: genotypic and phenotypic characteristics of the genetically heterogeneous Greek population

Cited by 10 publications

References 37 publications

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Next-generation sequencing refines the genetic architecture of Greek GnRH-deficient patients

Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males

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