Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians

Nair, Sandhya; Jadhav, Swati; Lila, Anurag; Jagtap, Varsha S.; Bukan, Amol; Pandit, Reshma; Ekbote, Alka V.; Dharmalingam, Mala; Kumar, Prasanna; Kalra, Pramila; Gandhi, Pramod; Walia, Rama; Sankhe, Shilpa; Raghavan, Vijaya; Shivane, Vyankatesh; Menon, P. S. N.; Bandgar, Tushar; Shah, Nalini

doi:10.1111/cen.13009

Cited by 17 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients with KS also had a higher percentage of associated developmental anomalies ( Table 2). Our data regarding the sensorineural hearing loss, which was present only in PPO groups and with a slightly higher percentage in patients with KS, were partially discordant with previous literature, reporting the presence of high percentage of hearing loss in patients with KS (25,26) and a total absence in nIHH (24). More importantly, the renal anomalies were only present in PPO groups and particularly in the male patients with KS.…”

Section: Discussionsupporting

confidence: 69%

“…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. All together, these findings support the idea of an hormonal condition that is generally worse among patients with KS.…”

Section: Discussionsupporting

confidence: 68%

See 1 more Smart Citation

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

Bonomi

Vezzoli

Krausz

et al. 2018

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 69%

Section: Discussionsupporting

confidence: 68%

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

Bonomi

Vezzoli

Krausz

et al. 2018

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Using Sanger sequencing, we detected a novel, de novo FGFR1 variant in exon 11 replacing the glycine residue at amino acid position 487 with a cysteine (p.Gly487Cys). Notably, a missense variant changing this glycine residue to an aspartic acid (p.Gly487Asp) was previously reported in an individual with Hartsfield syndrome and an individual with olfactogenital (Kallmann; MIM#147950) syndrome, the co-occurrence of congenital hypogonadotropic hypogonadism and anosmia (Hong et al 2016;Nair et al 2016). We modeled this variant in silico to assess its effect on the protein structure.…”

Section: Introductionmentioning

confidence: 99%

The Use of Variant Maps to Explore Domain-Specific Mutations ofFGFR1

et al. 2017

View full text Add to dashboard Cite

Here we describe the genotype-phenotype correlations of diseases caused by variants in Fibroblast Growth Factor Receptor 1 ( FGFR1) and report a novel, de novo variant in FGFR1 in an individual with multiple congenital anomalies. The proband presented with bilateral cleft lip and palate, malformed auricles, and bilateral ectrodactyly of his hands and feet at birth. He was later diagnosed with diabetes insipidus, spastic quadriplegia, developmental delay, agenesis of the corpus callosum, and enlargement of the third cerebral ventricle. We noted the substantial phenotypic overlap with individuals with Hartsfield syndrome, the rare combination of holoprosencephaly and ectrodactyly. Sequencing of FGFR1 identified a previously unreported de novo variant in exon 11 (p.Gly487Cys), which we modeled to determine its predicted effect on the protein structure. Although it was not predicted to significantly alter protein folding stability, it is possible this variant leads to the formation of nonnative intra- or intermolecular disulfide bonds. We then mapped this and other disease-associated variants to a 3-dimensional model of FGFR1 to assess which protein domains harbored the highest number of pathogenic changes. We observed the greatest number of variants within the domains involved in FGF binding and FGFR activation. To further explore the contribution of each variant to disease, we recorded the phenotype resulting from each FGFR1 variant to generate a series of phenotype-specific protein maps and compared our results to benign variants appearing in control databases. It is our hope that the use of phenotypic maps such as these will further the understanding of genetic disease in general and diseases caused by variation in FGFR1 specifically.

show abstract

“…Moreover, an activating mutation was identified in a girl with idiopathic central precocious puberty, under the autosomal dominant inheritance pattern [20]. Furthermore, oligogenic models of CHH transmission were reported in combination with heterozygous mutations of the KISS1R gene [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism

Moalla

Kacem

Al-Mutery

et al. 2019

J Assist Reprod Genet

View full text Add to dashboard Cite

Purpose Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease's pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. Participants and methods We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. Results At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8 years, one female exhibited a spontaneous recovery of the hypothalamic-pituitary-adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). Conclusions Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic-pituitary-gonadal, -adrenal, and -somatotropic axes.

show abstract

Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians

Cited by 17 publications

References 34 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)

The Use of Variant Maps to Explore Domain-Specific Mutations ofFGFR1

Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism

Contact Info

Product

Resources

About