scholarly journals Role of Genetic Analysis for the Differential Diagnosis of Delayed Puberty from the UK Puberty Cohort

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A669-A669
Author(s):  
Tansit Saengkaew ◽  
Leo Dunkel ◽  
Sasha R Howard
Keyword(s):  
Clinical Diagnosis ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Defect ◽  
Treatment Modalities ◽  
Delayed Puberty ◽  
Biochemical Tests ◽  
Pathogenic Variants ◽  
New Genes ◽  
Pubertal Delay ◽  
The Uk

Abstract Distinction between self-limited delayed puberty (DP) and idiopathic hypogonadotropic hypogonadism (IHH) is challenging. Several biochemical tests have been applied to differentiate these conditions; however, all have limitations resulting in some patients undergoing inappropriate investigations and treatment. This study investigated whether the identification of a genetic defect in patients presenting with pubertal delay in adolescence through whole exome sequencing (WES) can help in distinguishing these two conditions. The WES data of 47 pubertal delay patients from Paediatric Endocrinology and Paediatric services around the UK were analysed. The variants were filtered for rare, predicted deleterious variants in genes from a virtual panel reported in IHH (n= 36), both IHH and self-limited (n=6), and self-limited DP (n= 4) that segregated with trait. Pathogenic variants were verified by Sanger sequencing, computational bioinformatics, and review of inheritance pattern as compared to previous reported mutations in this gene, and assigned a genotypic diagnosis as self-limited DP, IHH or overlapping. Full clinical history, physical examination and basic laboratory and hormonal investigations were used to determine the clinical diagnosis. Clinically, 38% of patients had self-limited DP and 26% had IHH and the rest of uncertain diagnosis as they were still undergoing a period of follow up under the age of 18 years. Twenty-four variants in 17 genes, accounting for 43% of the tested cohort, were identified to be potentially pathogenic variants, with most inherited in a heterozygous manner. We found a good correlation between genotypic diagnosis and phenotype diagnosis with Cohen’s kappa (k) = 0.235 (95% IC, 0.031 to 0.429). Thus, patients who carry variants reported only in self-limited DP with heterozygous inheritance were likely to have a clinical diagnosis of definite self-limited DP. On the other hand, patients carrying homozygous or loss of function variants in genes reported with heterozygous mutations in IHH will be very likely to have IHH. In addition, we identified variants in patients with clinical self-limited DP to have variants, which had been previously reported only in IHH, including DMXL2, CHD7, OTUD4, and SEMA3E. In summary, this study shows that there is a good genotype-phenotype correlation in patients presenting with pubertal delay. Therefore, genetic investigation may help to distinguish these two conditions, resulting in more accurate diagnosis and appropriate treatment modalities. In addition, new genes, previously implicated only in IHH, have been identified in self-limited DP, which indicate that these two conditions share similar disease mechanisms.

scholarly journals Genetic Evaluation Supports Differential Diagnosis in Adolescent Patients with Delayed Puberty

2021 ◽  
Author(s):  
Tansit Saengkaew ◽  
Heena R Patel ◽  
Kausik Banerjee ◽  
Gary Butler ◽  
Mehul Tulsidas Dattani ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Exome Sequencing ◽  
Clinical Diagnosis ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Evaluation ◽  
Delayed Puberty ◽  
Diagnostic Challenge ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
Pubertal Delay

Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. Objective: To assess whether gene panel testing can assist with clinical differential diagnosis, to allow accurate and timely management of delayed puberty patients. Design: Retrospective study Methods: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rare, predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. Results: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only 3 patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. Conclusion:This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

Delayed Puberty

2020 ◽  
Author(s):  
Amanda French
Keyword(s):  
Pubertal Timing ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Process ◽  
Optimal Growth ◽  
Underlying Disease ◽  
Delayed Puberty ◽  
Hypergonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Constitutional Delay

Although common, delayed puberty can be distressing to patients and families.   Careful assessment is necessary to ensure appropriate physical and social development in patients that require intervention to reach pubertal milestones and achieve optimal growth.  Most pubertal delay is from lack of activation of the hypothalamic-pituitary-gonadal axis which then results in a functional or physiologic GnRH deficiency.  The delay may be temporary or permanent.  Constitutional delay (CDGP), also referred to as self-limited delayed puberty (DP), describes children on the extreme end of normal pubertal timing and is the most common cause of delayed puberty, representing about one third of cases.  Hypergonadotropic hypogonadism (primary hypogonadism) results from a failure of the gonad itself, and hypogonadotropic hypogonadism (secondary hypogonadism) results from a failure of the hypothalamic-pituitary axis, which is usually caused by another process, often systemic.  Diagnosis is based on history and examination.  Treatment is based on the underlying cause of pubertal delay and may include hormone replacement.  Involving a pediatric endocrinologist should be considered.  Appropriate counseling and ongoing support are important for all patients and families, regardless of underlying disease process.   This review contains 4 figures, 4 tables, and 32 references. Keywords: puberty, delayed puberty, hypogonadism, hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, menarche, thelarche, constitutional delay and growth in puberty, Turner syndrome

Delayed Puberty

2020 ◽  
Author(s):  
Amanda French
Keyword(s):  
Pubertal Timing ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Process ◽  
Optimal Growth ◽  
Underlying Disease ◽  
Delayed Puberty ◽  
Hypergonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Constitutional Delay

Although common, delayed puberty can be distressing to patients and families.   Careful assessment is necessary to ensure appropriate physical and social development in patients that require intervention to reach pubertal milestones and achieve optimal growth.  Most pubertal delay is from lack of activation of the hypothalamic-pituitary-gonadal axis which then results in a functional or physiologic GnRH deficiency.  The delay may be temporary or permanent.  Constitutional delay (CDGP), also referred to as self-limited delayed puberty (DP), describes children on the extreme end of normal pubertal timing and is the most common cause of delayed puberty, representing about one third of cases.  Hypergonadotropic hypogonadism (primary hypogonadism) results from a failure of the gonad itself, and hypogonadotropic hypogonadism (secondary hypogonadism) results from a failure of the hypothalamic-pituitary axis, which is usually caused by another process, often systemic.  Diagnosis is based on history and examination.  Treatment is based on the underlying cause of pubertal delay and may include hormone replacement.  Involving a pediatric endocrinologist should be considered.  Appropriate counseling and ongoing support are important for all patients and families, regardless of underlying disease process.   This review contains 4 figures, 4 tables, and 32 references. Keywords: puberty, delayed puberty, hypogonadism, hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, menarche, thelarche, constitutional delay and growth in puberty, Turner syndrome

DLG2 mutations in the etiology of pubertal delay and Idiopathic Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Ihsan Turan ◽  
Korcan Demir ◽  
Eda Mengen ◽  
Leman Damla Kotan ◽  
Fatih Gürbüz ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Allele Frequencies ◽  
The Other ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Uncertain Significance ◽  
Causal Variants ◽  
Independent Families ◽  
Flanking Regions

Introduction: Idiopathic Hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack proper genotype phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patients variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of the DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found one homozygous and two heterozygous missense variants in three independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance” the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in two of the three families there were no causal variants in other IHH-related genes. Conclusion: We detected three rare sequencing variants in DLG2 in five patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

scholarly journals Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

2020 ◽  
Author(s):  
Félixe Pelletier ◽  
Stefanie Perrier ◽  
Ferdy K Cayami ◽  
Amytice Mirchi ◽  
Stephan Saikali ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Autosomal Recessive Disorder ◽  
Cross Sectional Study ◽  
Delayed Puberty ◽  
Cross Sectional ◽  
Pathogenic Variants ◽  
Neurological Features ◽  
A Prospective Study ◽  
Growth Abnormalities

Abstract Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

scholarly journals Hypogonadotropic hypogonadism and pituitary hypoplasia as recurrent features in Ulnar-Mammary syndrome

2018 ◽  
Vol 7 (12) ◽  
pp. 1432-1441 ◽  
Author(s):  
Elena Galazzi ◽  
Paolo Duminuco ◽  
Mirella Moro ◽  
Fabiana Guizzardi ◽  
Nicoletta Marazzi ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Apocrine Gland ◽  
Pathogenic Variants ◽  
Academic Center ◽  
Midline Defects ◽  
Limb Malformations ◽  
Pituitary Hypoplasia ◽  
Renal Abnormalities

Ulnar-mammary syndrome (UMS) is characterized by ulnar defects, and nipple or apocrine gland hypoplasia, caused by TBX3 haploinsufficiency. Signs of hypogonadism were repeatedly reported, but the mechanisms remain elusive. We aim to assess the origin of hypogonadism in two families with UMS. UMS was suspected in two unrelated probands referred to an academic center with delayed puberty because of the evident ulnar ray and breast defects in their parents. Clinical, biochemical and genetic investigations proved the existence of congenital normosmic IHH (nIHH) associated with pituitary hypoplasia in the two probands who were heterozygous for novel TBX3 pathogenic variants. The mutations co-segregated with delayed puberty, midline defects (nose, teeth and tongue anomalies) and other variable features of UMS in the two families (absent axillary hairs and nipple hypoplasia, asymmetrical features including unilateral ulnar or renal abnormalities). The combined analysis of these findings and of the previous UMS reports showed delayed puberty and other signs of hypogonadism in 79 and 37% of UMS males, respectively. Proband 1 was followed up to adulthood with persistence of nIHH. In conclusion, UMS should be suspected in patients with delayed puberty and midline defects, including pituitary hypoplasia, in the presence of mild cues for TBX3 mutation, even in the absence of limb malformations. In addition, TBX3 should be included among candidate genes for congenital nIHH.

Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias

2021 ◽  
pp. 1-7
Author(s):  
Barbara Leitao Braga ◽  
Nathalia Lisboa Gomes ◽  
Mirian Y. Nishi ◽  
Bruna L. Freire ◽  
Rafael L. Batista ◽  
...  
Keyword(s):  
Gestational Age ◽  
Small For Gestational Age ◽  
Massively Parallel Sequencing ◽  
Genetic Defect ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Mulibrey Nanism ◽  
New Genes ◽  
Whole Exome ◽  
Undetermined Etiology

Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region <i>H19/IGF2</i> was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the <i>CUL7</i> gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in <i>TRIM37</i> was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.

Delayed Puberty

2020 ◽  
Author(s):  
Amanda French
Keyword(s):  
Pubertal Timing ◽  
Hormone Replacement ◽  
Hypogonadotropic Hypogonadism ◽  
Disease Process ◽  
Optimal Growth ◽  
Underlying Disease ◽  
Delayed Puberty ◽  
Hypergonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Constitutional Delay

Although common, delayed puberty can be distressing to patients and families.   Careful assessment is necessary to ensure appropriate physical and social development in patients that require intervention to reach pubertal milestones and achieve optimal growth.  Most pubertal delay is from lack of activation of the hypothalamic-pituitary-gonadal axis which then results in a functional or physiologic GnRH deficiency.  The delay may be temporary or permanent.  Constitutional delay (CDGP), also referred to as self-limited delayed puberty (DP), describes children on the extreme end of normal pubertal timing and is the most common cause of delayed puberty, representing about one third of cases.  Hypergonadotropic hypogonadism (primary hypogonadism) results from a failure of the gonad itself, and hypogonadotropic hypogonadism (secondary hypogonadism) results from a failure of the hypothalamic-pituitary axis, which is usually caused by another process, often systemic.  Diagnosis is based on history and examination.  Treatment is based on the underlying cause of pubertal delay and may include hormone replacement.  Involving a pediatric endocrinologist should be considered.  Appropriate counseling and ongoing support are important for all patients and families, regardless of underlying disease process.   This review contains 4 figures, 4 tables, and 32 references. Keywords: puberty, delayed puberty, hypogonadism, hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, menarche, thelarche, constitutional delay and growth in puberty, Turner syndrome

scholarly journals Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings

2020 ◽  
Vol 2020 ◽  
Author(s):  
Satyanarayana V Sagi ◽  
Hareesh Joshi ◽  
Emily Whiles ◽  
Mondy Hikmat ◽  
Vijith R Puthi ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Genetic Disorder ◽  
Hypogonadotropic Hypogonadism ◽  
Clinical Manifestations ◽  
Gonadotropin Releasing Hormone ◽  
Delayed Puberty ◽  
List Type ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Releasing Hormone ◽  
Pathogenic Variants

Summary Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. Learning points: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism

2015 ◽  
Author(s):  
Sasha Howard ◽  
Ariel Poliandri ◽  
Helen Storr ◽  
Louise Metherell ◽  
Claudia Cabrera ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism
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