scholarly journals Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism

2021 ◽  
Vol 9 ◽  
Author(s):  
Raja Brauner ◽  
Joelle Bignon-Topalovic ◽  
Anu Bashamboo ◽  
Ken McElreavey
Keyword(s):  
Exome Sequencing ◽  
Precocious Puberty ◽  
Vaginal Bleeding ◽  
Hypogonadotropic Hypogonadism ◽  
Plasma Concentrations ◽  
Rare Condition ◽  
Breast Development ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Peripheral Precocious Puberty

Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown.Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility.Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them.Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.

scholarly journals Congenital Hypothyroidism with Precocious Puberty-A Case Report

2011 ◽  
Vol 24 (1) ◽  
pp. 48-50
Author(s):  
M Sanaul Haque ◽  
SN Hasnain ◽  
MI Haque ◽  
MA Hossain ◽  
MI Bari
Keyword(s):  
Case Report ◽  
Congenital Hypothyroidism ◽  
Precocious Puberty ◽  
Vaginal Bleeding ◽  
Rare Case ◽  
Rare Condition ◽  
Bone Age ◽  
Pubic Hair ◽  
Breast Development

Congenital hypothyroidism with precocious puberty is a rare condition. In this report a rare case of congenital hypothyroidism with precocious puberty is described. A 10 years old girl presented with feature of hypothyroidism together with breast development, vaginal bleeding, lack of pubic hair and delayed bone age. She also had multicystic ovaries. She was treated with L-thyroxine and improved TAJ 2011; 24(1): 48-50

Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

2016 ◽  
Vol 87 (2) ◽  
pp. 88-94 ◽  
Author(s):  
Nelmar Valentina Ortiz-Cabrera ◽  
Rosa Riveiro-Álvarez ◽  
Miguel Ángel López-Martínez ◽  
Pilar Pérez-Segura ◽  
Isabel Aragón-Gómez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Pathogenic Variants ◽  
Idiopathic Central Precocious Puberty ◽  
Clinical Exome Sequencing

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor

2018 ◽  
Vol 2018 ◽  
Author(s):  
Philip D Oddie ◽  
Benjamin B Albert ◽  
Paul L Hofman ◽  
Craig Jefferies ◽  
Stephen Laughton ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Precocious Puberty ◽  
Adrenocortical Carcinoma ◽  
Endocrine Disruptor ◽  
Residual Disease ◽  
Bone Age ◽  
Breast Development ◽  
List Type ◽  
Estrogenic Effect ◽  
Peripheral Precocious Puberty

Summary Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP. Learning points: Adrenocortical carcinoma is an important differential diagnosis for virilization in young children Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults. Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

scholarly journals Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients

2017 ◽  
Vol 103 (2) ◽  
pp. 415-428 ◽  
Author(s):  
Nitash Zwaveling-Soonawala ◽  
Marielle Alders ◽  
Aldo Jongejan ◽  
Lidija Kovačič ◽  
Floor A Duijkers ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Variants ◽  
De Novo ◽  
Hypogonadotropic Hypogonadism ◽  
Reference Population ◽  
Pituitary Stalk ◽  
Polygenic Inheritance ◽  
Pathogenic Variants ◽  
Brain Anomalies ◽  
Posterior Pituitary Lobe

Abstract Context Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. Objective To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. Methods Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. Results We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. Conclusion Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.

Whole-exome sequencing of a large Chinese azoospermia and severe oligospermia cohort identifies novel infertility causative variants and genes

2020 ◽  
Vol 29 (14) ◽  
pp. 2451-2459
Author(s):  
Shitao Chen ◽  
Guishuan Wang ◽  
Xiaoguo Zheng ◽  
Shunna Ge ◽  
Yubing Dai ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Characteristics ◽  
Obstructive Azoospermia ◽  
Sequencing Data ◽  
Chinese Han ◽  
Functional Studies ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Rare coding variants have been proven to be one of the significant factors contributing to spermatogenic failure in patients with non-obstructive azoospermia (NOA) and severe oligospermia (SO). To delineate the molecular characteristics of idiopathic NOA and SO, we performed whole-exome sequencing of 314 unrelated patients of Chinese Han origin and verified our findings by comparing to 400 fertile controls. We detected six pathogenic/likely pathogenic variants and four variants of unknown significance, in genes known to cause NOA/SO, and 9 of which had not been earlier reported. Additionally, we identified 20 novel NOA candidate genes affecting 25 patients. Among them, five (BRDT, CHD5, MCM9, MLH3 and ZFX) were considered as strong candidates based on the evidence obtained from murine functional studies and human single-cell (sc)RNA-sequencing data. These genetic findings provide insight into the aetiology of human NOA/SO and pave the way for further functional analysis and molecular diagnosis of male infertility.

scholarly journals A 4-Year-Old Girl with Precocious Puberty

2016 ◽  
Vol 6 (3) ◽  
pp. 161-163
Author(s):  
Poly Begum ◽  
Dipti Rani Saha ◽  
Md Kamrul Hassan
Keyword(s):  
Precocious Puberty ◽  
Vaginal Bleeding ◽  
Pubertal Development ◽  
Tanner Stage ◽  
Female Child ◽  
Pubic Hair ◽  
Breast Development ◽  
Average Height ◽  
Gonadotrophin Secretion ◽  
Hypothalamic Pituitary Axis

Appearance of secondary sexual development before the age of nine in a male child and before the age of eight in a female child is called precocious puberty. Precocious puberty due to premature activation of the hypothalamic-pituitary axis is called central or complete precocious puberty. Incomplete precocious puberty is called if ectopic gonadotrophin secretion occurs in boys or autonomous sex steroid secretion occurs in either sex. Here we report a case of a 4-year-old girl brought to a gynecologist by her parents because of breast development, pubic hair and periodic per vaginal bleeding. Her medical history was unremarkable. The parents were of average height, and the mother reported first menstruation when she was 11 years. At physical examination, the girl was 100 cm tall, weighed 17 kg, and had a body mass index of 17. Her pubertal development is classified as Tanner stage 3 breast development and Tanner stage 2 pubic hair development.J Enam Med Col 2016; 6(3): 161-163

scholarly journals New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

2019 ◽  
Vol 181 (2) ◽  
pp. 103-119 ◽  
Author(s):  
Lorena Guimaraes Lima Amato ◽  
Luciana Ribeiro Montenegro ◽  
Antonio Marcondes Lerario ◽  
Alexander Augusto Lima Jorge ◽  
Gil Guerra Junior ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Splice Site Mutation ◽  
Rare Condition ◽  
Large Cohort ◽  
Site Mutation ◽  
Clinical Genetic ◽  
Pathogenic Variants ◽  
Congenital Hypogonadotropic Hypogonadism

Context Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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