GNRHR Mutations Research Articles

7407 Normosmic Idiopathic Hypogonadotropic Hypogonadism in Women: A Case Report and Comprehensive Review

Abstract Disclosure: E.G. Bustamante: None. M. Sulehri: None. I. Patoli: None. A. Karunakaran: None. Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH) in Women: A Case Report and Literature ReviewIntroduction: IHH is a rare genetic disorder affecting gonadotropic-releasing hormone (GnRH) production and/or action, resulting in diminished sex steroid levels. Characterized by the absence of spontaneous pubertal development. In women, it manifests with normal adrenarche but absent thelarche and menarche. Our case highlight a late diagnosis of IHH in a 34-year-old woman with primary amenorrhea. Case report: A 34 year old lady with a history of primary amenorrhea sought evaluation. At age 16, she underwent assessment for short stature and primary amenorrhea, denying anosmia, headache, visual disturbances. Evaluation revealed bone age concordant with chronological age and normal MRI Brain. Pelvic ultrasound (US) showed small premenarchal uterus and ovaries. She initiated oral contraceptive pills (OCP) and experienced regular menses. Seeking fertility assistance at age 24, a normal Hysterosalpingogram was followed by successful delivery of twins after ovarian stimulation. Post-delivery menses did not resume and OCP was not restarted. Family history revealed a sister with irregular periods requiring OCP.Subsequently workup at age 30 showed Estradiol 22 pg/ml, FSH/LH 4.1/2.3 mUI/mL; normal PRL, TFT, DHEAS, 17OHP. Repeat Pelvic US showed normal uterus, endometrial stripe normal at 0.24 cm and non-visualized ovaries. PCOS testing negative for hyperandrogenism. Progesterone challenge resulted in no withdrawal bleeding. Brain MRI demonstrated a 2.2 x 1.3 mm hypoenhancing ovoid mass in the pars Intermedia of the pituitary gland suggestive of pituitary microadenoma. Pituitary axis hormonal testing was normal. Karyotype revealed 46 XX (normal female). Genetic evaluation identified a pathogenic variant (p.R35C) in GNRH1 gene. Her final diagnosis: nIHH. Discussion HH is diagnosed in 5% of all women with primary amenorrhea and is divided into 2 major categories: Kallmann syndrome and nIHH. The majority of known causes of HH can be attributed to mutations in KAL1, FGFR1, or GNRHR. The p.R35C variant has been associated with autosomal dominant nIHH. Diagnosis involves clinical suspicious, low LH/FSH and sex steroid levels, normal hypothalamic–pituitary imaging, and exclusion of differentials.Treatment goal for female focus on regular breast and uterine development, as well as the capability to conceive. Use of hormonal replacement therapy and/or gonadotropins or pulsatile GnRH for ovarian stimulation are essential. ConclusionWhile IHH predominantly affects men, limited literature explores its manifestation in women and its impact on fertility. The identification of a GNRH1-related nIHH variant highlights the role of genetic testing in specific HH diagnoses. Failure to diagnose in adolescence may compromise women overall well-being Presentation: 6/1/2024

12413 Reversal Of Congenital Hypogonadotropic Hypogonadism (CHH) In A Woman With A Heterozygous Inactivating Variant In GnRHR Gene

Abstract Disclosure: S.W. Nyunt: None. M. Phylactou: None. K. Koysombat: None. J. Tsoutsouki: None. A.C. Yeung: None. M. Young: None. A. Newman: None. A.N. Comninos: None. Y. Mamoojee: None. N. Pitteloud: None. R. Quinton: None. W.S. Dhillo: None. A. Abbara: None. Introduction: Congenital Hypogonadotropic Hypogonadism (CHH) is a rare genetic condition with central hypogonadism and pubertal failure affecting both sexes. Reversal of CHH is far less commonly reported in women in the literature. We presented a case of reversal of CHH in a woman with heterozygous GnRHR mutation and the use of kisspeptin in interrogating hypothalamic function. Case history: Our patient presented with primary amenorrhea and incomplete puberty aged 15 yrs. Based on high BMI from early adolescence, clinical hyperandrogenism, family history of polycystic ovary syndrome (PCOS) and insulin resistance, she was diagnosed with PCOS and commenced on a combined oral contraceptive (COC), achieving breast development.Aged 21yrs, she was reassessed for amenorrhea off COC. Biochemical assessment revealed hypogonadotropic hypogonadism (HH): LH 0.2 IU/L, FSH 0.3 IU/L, estradiol <92 pmol/L. She had a normal sense of smell and Tanner 4 breasts; MRI demonstrated normal olfactory bulbs and pituitary. The diagnosis was therefore revised to CHH and COC was restarted, later changed to HRT due to hypertension. A 22-gene CHH panel (R148) identified a heterozygous pathogenic variant c.3171>Gp in GNRHR.At reassessment off HRT aged 32yrs, she remained amenorrheic. Ultrasound showed normal ovarian morphology, antral follicle counts 17 and endometrial thickness 5.8mm; hormonal assays: LH 5.0 IU/L, FSH 8.3 U/L, estradiol 162 pmol/L, AMH 12.2 pmol/L, testosterone 1.6 nmol/L (RR <2.0), SHBG 35 nmol/L (RR 30-100 nmol/L).She then achieved 20kg weight loss (BMI 41.8 to 35.2 kg/m2) on GLP-1 agonist. GnRH test (Gonadorelin 100mcg) incremented LH from 5.16 to 44.46 IU/L and FSH from 6.47 to 15.27 IU/L at 60 mins. After an intravenous kisspeptin (9.6nmol/kg) bolus, LH rose from 5.05 to 29.99 IU/L, FSH from 6.68 to 13.91 IU/L. Off HRT, she began having regular cycles (estradiol 800 pmol/L). Discussion: CHH was diagnosed based on primary amenorrhea, HH and pathogenic GnRHR variant that would not, however, be expected to result in a productive phenotype in the absence of a second deleterious allele (oligogenicity occurs in 20% of CHH), so whole exome sequencing is awaited. Kisspeptin is a potent stimulator of hypothalamic GnRH neurons and can be used to interrogate hypothalamic function. Typically, gonadotrophin responses to kisspeptin are minimal in CHH. Thus, her kisspeptin response was not consistent with CHH at time of assessment, indicating reversal of CHH (seen in 20% of CHH, particularly with GnRHR variants). Notably, her kisspeptin response was higher than in healthy women, consistent with decreased hypothalamic function and potentially a ‘Female Obesity-Related Hypogonadism’. Our case highlights the value of interrogating hypothalamic function using kisspeptin, both for the diagnosis of CHH, and to identify alternate pathology, as well as to identify recovery of reproductive function in CHH reversal. Presentation: 6/1/2024

12413 Reversal Of Congenital Hypogonadotropic Hypogonadism (CHH) In A Woman With A Heterozygous Inactivating Variant In GnRHR Gene

Abstract Disclosure: S.W. Nyunt: None. M. Phylactou: None. K. Koysombat: None. J. Tsoutsouki: None. A.C. Yeung: None. M. Young: None. A. Newman: None. A.N. Comninos: None. Y. Mamoojee: None. N. Pitteloud: None. R. Quinton: None. W.S. Dhillo: None. A. Abbara: None. Introduction: Congenital Hypogonadotropic Hypogonadism (CHH) is a rare genetic condition with central hypogonadism and pubertal failure affecting both sexes. Reversal of CHH is far less commonly reported in women in the literature. We presented a case of reversal of CHH in a woman with heterozygous GnRHR mutation and the use of kisspeptin in interrogating hypothalamic function. Case history: Our patient presented with primary amenorrhea and incomplete puberty aged 15 yrs. Based on high BMI from early adolescence, clinical hyperandrogenism, family history of polycystic ovary syndrome (PCOS) and insulin resistance, she was diagnosed with PCOS and commenced on a combined oral contraceptive (COC), achieving breast development.Aged 21yrs, she was reassessed for amenorrhea off COC. Biochemical assessment revealed hypogonadotropic hypogonadism (HH): LH 0.2 IU/L, FSH 0.3 IU/L, estradiol <92 pmol/L. She had a normal sense of smell and Tanner 4 breasts; MRI demonstrated normal olfactory bulbs and pituitary. The diagnosis was therefore revised to CHH and COC was restarted, later changed to HRT due to hypertension. A 22-gene CHH panel (R148) identified a heterozygous pathogenic variant c.3171>Gp in GNRHR.At reassessment off HRT aged 32yrs, she remained amenorrheic. Ultrasound showed normal ovarian morphology, antral follicle counts 17 and endometrial thickness 5.8mm; hormonal assays: LH 5.0 IU/L, FSH 8.3 U/L, estradiol 162 pmol/L, AMH 12.2 pmol/L, testosterone 1.6 nmol/L (RR <2.0), SHBG 35 nmol/L (RR 30-100 nmol/L).She then achieved 20kg weight loss (BMI 41.8 to 35.2 kg/m2) on GLP-1 agonist. GnRH test (Gonadorelin 100mcg) incremented LH from 5.16 to 44.46 IU/L and FSH from 6.47 to 15.27 IU/L at 60 mins. After an intravenous kisspeptin (9.6nmol/kg) bolus, LH rose from 5.05 to 29.99 IU/L, FSH from 6.68 to 13.91 IU/L. Off HRT, she began having regular cycles (estradiol 800 pmol/L). Discussion: CHH was diagnosed based on primary amenorrhea, HH and pathogenic GnRHR variant that would not, however, be expected to result in a productive phenotype in the absence of a second deleterious allele (oligogenicity occurs in 20% of CHH), so whole exome sequencing is awaited. Kisspeptin is a potent stimulator of hypothalamic GnRH neurons and can be used to interrogate hypothalamic function. Typically, gonadotrophin responses to kisspeptin are minimal in CHH. Thus, her kisspeptin response was not consistent with CHH at time of assessment, indicating reversal of CHH (seen in 20% of CHH, particularly with GnRHR variants). Notably, her kisspeptin response was higher than in healthy women, consistent with decreased hypothalamic function and potentially a ‘Female Obesity-Related Hypogonadism’. Our case highlights the value of interrogating hypothalamic function using kisspeptin, both for the diagnosis of CHH, and to identify alternate pathology, as well as to identify recovery of reproductive function in CHH reversal. Presentation: 6/1/2024

The GNRHR mutation: from delayed puberty to normosmic hypogonadotropic hypogonadism

The GNRHR mutation: from delayed puberty to normosmic hypogonadotropic hypogonadism

A partial loss-of-function variant in GNRNR gene in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.

BackgroundIdiopathic hypogonadotropic hypogonadism (IHH) is a rare genetic disease attributed to the disorder of hypothalamic-pituitary-gonadal axis. Mutations in the GNRHR gene are one of the most common genetic causes of IHH. Herein, we aimed to investigate GNRHR variants in a Chinese cohort with IHH, and to characterize them at the molecular level.MethodsA total of 153 IHH patients were recruited, and variants were detected using a tailored next-generation sequencing panel. GNRHR rare sequencing variant (RSV) was verified using Sanger sequencing. Phenotypic features and therapeutic outcomes of patients were followed up. In order to examine the pathogenicity of the GNRHR RSV, we performed conservative analysis, crystal structure prediction, expression analysis as well as the assessment of ERK1/2 activation and IP3/Ca2+ response.ResultsThe same heterozygous RSV (p.R240Q) in GNRHR was identified in four sporadic IHH patients. These patients exhibited different severity of testicular development and hormone profile. hCG treatment was effective in improving gonadal development, serum testosterone, and semen quality. The GNRHR RSV has no effect on the expression of mRNA and protein, whereas damaged ERK1/2 activation and inositol triphosphate/calcium signaling.ConclusionsThe study expands GNRHR mutation spectrum in IHH patients, and reveals that the GNRHR RSV is a partial loss-of-function mutation. Although this heterozygous RSV may not have a significant influence on the pathogenesis of IHH, but its homozygous/ compound status should be paid attention in this research field.

A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred.

Congenital hypogonadotrophic hypogonadism (CHH) is a challenging inherited endocrine disorder characterised by absent or incomplete pubertal development and infertility as a result of the low action/secretion of the hypothalamic gonadotrophin-releasing hormone (GnRH). Given a growing list of gene mutations accounting for CHH, the application of massively parallel sequencing comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. The present study proposes the use of whole exome sequencing (WES) to identify causative and modifying mutations based on a phenotype-genotype CHH analysis using an in-house exome pipeline. Based on 44 known genes related to CHH in humans, we were able to identify a novel homozygous gonadotrophin-releasing hormone receptor (GNRHR) p.Thr269Met mutant, which segregates with the CHH kindred and was predicted to be deleterious by in silico analysis. A functional study measuring intracellular inositol phosphate (IP) when stimulated with GnRH on COS-7 cells confirmed that the p.Thr269Met GnRHR mutant performed greatly diminished IP accumulation relative to the transfected wild-type GnRHR. Additionally, the proband carries three heterozygous variants in CCDC141 and one homozygous in SEMA3A gene, although their effects with respect to modifying the phenotype are uncertain. Because they do not segregate with reproductive phenotype in family members, we advocate they do not contribute to CHH oligogenicity. WES proved to be useful for CHH molecular diagnosis and reinforced its benefit with respect to identifying heterogeneous genetic disorders. Our findings expand the GnRHR mutation spectrum and phenotype-genotype correlation in CHH.

Recombinant Human FSH Treatment Outcomes in Five Boys With Severe Congenital Hypogonadotropic Hypogonadism.

ContextRecombinant human FSH (r-hFSH), given to prepubertal boys with hypogonadotropic hypogonadism (HH), may induce Sertoli cell proliferation and thereby increase sperm-producing capacity later in life.ObjectiveTo evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients.Design and SettingRetrospective review in three tertiary centers in Finland between 2006 and 2016.PatientsFive boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1 mutation in one, and homozygous GNRHR mutation in one. Prepubertal testicular volume (TV) varied between 0.3 and 2.3 mL; three boys had micropenis, three had undergone orchidopexy.InterventionsTwo boys received r-hFSH (6 to 7 months) followed by r-hFSH plus hCG (33 to 34 months); one received T (6 months), then r-hFSH plus T (29 months) followed by hCG (25 months); two received T (3 months) followed by r-hFSH (7 months) or r-hFSH plus T (8 months).Main Outcome MeasuresTV, inhibin B, anti-Müllerian hormone, T, puberty, sperm count.Resultsr-hFSH doubled TV (from a mean ± SD of 0.9 ± 0.9 mL to 1.9 ± 1.7 mL; P < 0.05) and increased serum inhibin B (from 15 ± 5 ng/L to 85 ± 40 ng/L; P < 0.05). hCG further increased TV (from 2.1 ± 2.3 mL to 8.6 ± 1.7 mL). Two boys with initially extremely small testis size (0.3 mL) developed sperm (maximal sperm count range, 2.8 to 13.8 million/mL), which was cryopreserved.ConclusionsSpermatogenesis can be induced with gonadotropins even in boys with HH who have extremely small testes, and despite low-dose T treatment given in early puberty. Induction of puberty with gonadotropins allows preservation of fertility.

Deficiency in GnRH receptor trafficking due to a novel homozygous mutation causes idiopathic hypogonadotropic hypogonadism in three prepubertal siblings

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by low levels of gonadotropins and delayed or absent sexual development. Most of the patients are diagnosed in late adolescence or early adulthood. Determining the diagnosis of IHH in prepubertal patients can be challenging. Making a timely, correct diagnosis has important clinical implications. Here we aimed to identify the genetic cause of IHH in three prepubertal siblings from a Chinese Han family and give appropriate treatment advice. Using whole exome sequencing (WES), we identified a novel homozygous GNRHR mutation (NM_000406; c.364C>T, p.L122F) in two prepubertal boys with cryptorchidism and micropenis. Sanger sequencing showed that their younger asymptomatic sister also had the homozygous GNRHR mutation. This mutation was inherited from the father and the mother. Immunofluorescence analysis showed that in permeabilized cells, expression of the mutant receptor on the cell membrane was significantly lower than that of wild-type. Calcium mobilization assays demonstrated that c.364C>T in the GNRHR gene is a complete loss-of-function mutation that caused IHH. These results may contribute to the genetic diagnosis of the three prepubertal siblings with IHH. According to this diagnosis, timely hormonal treatment can be given for the three prepubertal patients to induce pubertal development, especially for the asymptomatic female.

GnRH receptor gene mutations in adolescents and young adults presenting with signs of partial gonadotropin deficiency.

Biallelic, partial loss-of-function mutations in GNRHR cause a wide spectrum of reproductive phenotypes from constitutional delay of growth and puberty to complete congenital hypogonadotropic hypogonadism. We studied the frequency of GNRHR, FGFR1, TAC3, and TACR3 mutations in nine adolescent and young adult females with clinical cues consistent with partial gonadotropin deficiency (stalled puberty, unexplained secondary amenorrhea), and describe phenotypic features and molecular genetic findings of monozygotic twin brothers with stalled puberty.Two girls out of nine (22%, 95%CI 6–55%) carried biallelic mutations in GNRHR. The girl with compound heterozygous c.317A>G p.(Gln106Arg) and c.924_926delCTT p.(Phe309del) GNRHR mutations displayed incomplete puberty and clinical signs of hypoestrogenism. The patient carrying a homozygous c.785G>A p.(Arg262Gln) mutation presented with signs of hypoestrogenism and unexplained secondary amenorrhea. None of the patients exhibited mutations in FGFR1, TAC3, or TACR3. The twin brothers, compound heterozygous for GNRHR mutations c.317A>G p.(Gln106Arg) and c.785G>A p.(Arg262Gln), presented with stalled puberty and were discordant for weight, and the heavier of them had lower testosterone levels.These results suggest that genetic testing of the GNRHR gene should be offered to adolescent females with low-normal gonadotropins and unexplained stalled puberty or menstrual dysfunction. In male patients with partial gonadotropin deficiency, excess adipose tissue may suppress hypothalamic-pituitary-gonadal axis.

GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism.

ObjectiveNormosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare disorder characterised by lack of pubertal development and infertility, due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH) and, unlike Kallmann syndrome, is associated with a normal sense of smell. Mutations in the GNRHR gene cause autosomal recessive nCHH. The aim of this study was to determine the prevalence of GNRHR mutations in a group of 40 patients with nCHH.DesignCross-sectional study of 40 unrelated patients with nCHH.MethodsPatients were screened for mutations in the GNRHR gene by DNA sequencing.ResultsGNRHR mutations were identified in five of 40 patients studied. Four patients had biallelic mutations (including a novel frameshift deletion p.Phe313Metfs*3, in two families) in agreement with autosomal recessive inheritance. One patient had a heterozygous GNRHR mutation associated with a heterozygous PROKR2 mutation, thus suggesting a possible role of synergistic heterozygosity in the pathogenesis of the disorder.ConclusionsThis study further expands the spectrum of known genetic defects associated with nCHH. Although GNRHR mutations are usually biallelic and inherited in an autosomal recessive manner, the presence of a monoallelic mutation in a patient should raise the possibility of a digenic/oligogenic cause of nCHH.

Mutations in gonadotropin-releasing hormone signaling pathway in two nIHH patients with successful pregnancy outcomes

BackgroundAnomalous levels of gonadotropin-releasing hormone (GnRH) secretion result in a variety of reproductive phenotypes associated with infertility or subfertility. The normosmic isolated hypogonadotropic hypogonadism (nIHH) is due to a failure of either GnRH pulsatile secretion in hypothalamus or its reception in pituitary. The spectrum of nIHH-associated alterations continues to expand, especially when additional ethnic populations are investigated. The aim of this study was to uncover genetic causes for nIHH in patients of Russian origin.MethodsFor two nIHH patients referred to infertility clinic, both exons and promoter sequences of 6 GnRH signaling genes were sequenced.ResultsPatient 1 was a compound heterozygote for mutations in GnRH and its receptor encoding genes, while in Patient 2 GnRHR mutations were found in homozygous state. In both patients, the coding frame of GnRHR gene harbored missense-mutation Arg139His previously described as founder mutation in Polish and Brazilan patients. IVF/ET treatments were successful, with phenotypically healthy offsprings delivered.ConclusionPolish founder mutation Arg139His in GnRHR was found in two nIHH patients originating from Western region of Russia. Common variant of GnRH-encoding gene, Trp16Ser, could possibly contribute to reproductive phenotypes in patients with heterozygous mutations of other GnRH signaling pathway genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0183-8) contains supplementary material, which is available to authorized users.

Triallelic digenic mutation in the prokineticin 2 and GNRH receptor genes in two brothers with normosmic congenital hypogonadotropic hypogonadism

Purpose/aim of the study: To date, different genes have been identified as responsible for the presence of normosmic congenital hypogonadotropic hypogonadism (nCHH). Herein, we report the molecular findings regarding the analysis of PROK2, in two brothers with nCHH. Subjects and methods: Two siblings with nCHH, in whom mutations in GNRHR, PROKR2 and FGFR1 had been investigated previously, as well as their family were studied. DNA was amplified by PCR and sequenced for the PROK2 gene. Controls were analyzed by restriction fragment-length polymorphism. The structure of PROK2 and its mutant protein were compared using a protein molecular model. Results: Both affected siblings exhibited a heterozygous p.R117W mutation in PROK2, while their mother was a heterozygous carrier and their father, an unaffected brother and their sister were homozygous wild type. Besides, both patients presented a homozygous p.E90K mutation in GNRHR that had been previously reported. Conclusions: We found a novel mutation in PROK2 in two siblings in whom a mutation in the GNRHR gene had been previously reported.

Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay

To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). Molecular analysis and invitro experiments correlated with phenotype. Academic medical center. A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. GNRHR coding region was amplified and sequenced. Novel variants were submitted to invitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. Eleven IHH patients (10%) carried biallelic GNRHR mutations. Invitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP.

Genetics of congenital hypogonadotropic hypogonadism in Denmark

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by incomplete/absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life. We examined the genetics and clinical features of CHH in Denmark. Forty-one male patients were screened for mutations in KAL1, FGFR1, FGF8, PROK2, PROKR2, GNRHR, TAC3, TACR3, and KISS1R. CHD7 was screened in two patients with hearing loss. In 12 patients, a molecular genetic cause for CHH was found. Four patients had mutations in KAL1 (C105VfsX13, C53X, ex5-8del, R257X), and five in FGFR1 (G97S, R209C, A512V, R646W, and c.1614C>T, (p.I538I), predicted to affect splicing). All 9 had severe HH (cryptorchidism and/or micropenis), and 2 had cleft lip/palate. One patient with a previously reported homozygous R262Q mutation in GNRHR displayed fascinating temporal variation in his phenotype. Two patients with hearing loss had CHD7 mutations (c.7832_7841del (p.K2611MfsX25) and c.2443-2A>C), confirming that CHH patients with CHARGE syndrome-associated features should be screened for mutations in CHD7.

Hypogonadotropic hypogonadism presenting with arhinia: a case report.

IntroductionArhinia, congenital absence of the nose, is a rare malformation. We present the third reported case of arhinia accompanied by hypogonadism and demonstrate that this is due to gonadotropin deficiency.Case presentationA 13-year-old Caucasian boy with congenital arhinia presented for evaluation of delayed puberty and micropenis. We examined genes known to be associated with hypogonadotropic hypogonadism for mutations and performed a chromosomal microarray to assess copy number variation.ConclusionNo mutations in KAL1, FGFR1, PROK2, PROKR2, FGF8, CHD7 and GnRHR were identified in our patient and there were no copy number variations observed that would explain the phenotype. Though studies are limited in such patients, we suggest that hypogonadotropic hypogonadism is associated with arhinia and that the two entities likely result from a common genetic cause that affects early nasal development and gonadotropin-releasing hormone neuron formation or migration.

Responsiveness to a Physiological Regimen of GnRH Therapy and Relation to Genotype in Women With Isolated Hypogonadotropic Hypogonadism

Isolated hypogonadotropic hypogonadism (IHH) is caused by defective GnRH secretion or action resulting in absent or incomplete pubertal development and infertility. Most women with IHH ovulate with physiological GnRH replacement, implicating GnRH deficiency as the etiology. However, a subset does not respond normally, suggesting the presence of defects at the pituitary or ovary. The objective of the study was to unmask pituitary or ovarian defects in IHH women using a physiological regimen of GnRH replacement, relating these responses to genes known to cause IHH. This study is a retrospective analysis of 37 IHH women treated with iv pulsatile GnRH (75 ng/kg per bolus). Serum gonadotropin and sex steroid levels were measured, and 14 genes implicated in IHH were sequenced. During their first cycle of GnRH replacement, normal cycles were recreated in 60% (22 of 37) of IHH women. Thirty percent of women (12 of 37) demonstrated an attenuated gonadotropin response, indicating pituitary resistance, and 10% (3 of 37) exhibited an exaggerated FSH response, consistent with ovarian resistance. Mutations in CHD7, FGFR1, KAL1, TAC3, and TACR3 were documented in IHH women with normal cycles, whereas mutations were identified in GNRHR, PROKR2, and FGFR1 in those with pituitary resistance. Women with ovarian resistance were mutation negative. Although physiological replacement with GnRH recreates normal menstrual cycle dynamics in most IHH women, hypogonadotropic responses in the first week of treatment identify a subset of women with pituitary dysfunction, only some of whom have mutations in GNRHR. IHH women with hypergonadotropic responses to GnRH replacement, consistent with an additional ovarian defect, did not have mutations in genes known to cause IHH, similar to our findings in a subset of IHH men with evidence of an additional testicular defect.

Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH.Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared.

When Genetic Load Does Not Correlate with Phenotypic Spectrum: Lessons from the GnRH Receptor (GNRHR)

A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.

Reversible Congenital Hypogonadotropic Hypogonadism in Patients with CHD7, FGFR1 or GNRHR Mutations

BackgroundCongenital hypogonadotropic hypogonadism (HH) is a rare cause for delayed or absent puberty. These patients may recover from HH spontaneously in adulthood. To date, it is not possible to predict who will undergo HH reversal later in life. Herein we investigated whether Finnish patients with reversal of congenital hypogonadotropic hypogonadism (HH) have common phenotypic or genotypic features.Methods and FindingsThirty-two male HH patients with anosmia/hyposmia (Kallmann Syndrome, KS; n = 26) or normal sense of smell (nHH; n = 6) were enrolled (age range, 18–61 yrs). The patients were clinically examined, and reversal of HH was assessed after treatment withdrawal. KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, WDR11, GNRHR, GNRH1, KISS1R, KISS1, TAC3, TACR3, and LHβ were screened for mutations. Six HH patients (2 KS, 4 nHH) were verified to have reversal of HH. In the majority of cases, reversal occurred early in adulthood (median age, 23 yrs; range, 21–39 yrs). All had spontaneous testicular growth while on testosterone replacement therapy (TRT). One nHH subject was restarted on TRT due to a decline in serum T. Two reversal variants had a same GNRHR mutation (R262Q), which was accompanied by another GNRHR mutation (R139H or del309F). In addition, both of the KS patients had a mutation in CHD7 (p.Q51X) or FGFR1 (c.91+2T>A).ConclusionsConsiderable proportion of patients with HH (8% of KS probands) may recover in early adulthood. Spontaneous testicular enlargement during TRT was highly suggestive for reversal of HH. Those with the GNRHR mutation R262Q accompanied by another GNRHR mutation may be prone to reversal, although even patients with a truncating mutation in CHD7 or a splice-site mutation in FGFR1 can recover. We recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal.

Isolated cryptorchidism: No evidence for involvement of genes underlying isolated hypogonadotropic hypogonadism

Mutations in FGFR1, GNRHR, PROK2, PROKR2, TAC3, or TACR3 underlie isolated hypogonadotropic hypogonadism (IHH) with clinically variable phenotypes, and, by causing incomplete intrauterine activation of the hypothalamic–pituitary–gonadal axis, may lead to cryptorchidism. To investigate the role of defects in these genes in the etiology of isolated cryptorchidism, we screened coding exons and exon–intron boundaries of these genes in 54 boys or men from 46 families with a history of cryptorchidism. Control subjects (200) included 120 males. None of the patients carried mutation(s) in FGFR1, PROK2, PROKR2, TAC3 or TACR3. Two of the 46 index subjects with unilateral cryptorchidism were heterozygous carriers of a single GNRHR mutation (Q106R or R262Q), also present in male controls with a similar frequency (3/120; p = 0.62). No homozygous or compound heterozygous GNRHR mutations were found. In conclusion, cryptorchidism is not commonly caused by defects in genes involved in IHH.