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.

scholarly journals A nonsense variant in FGFR1: a rare cause of combined pituitary hormone deficiency

2020 ◽  
Vol 33 (12) ◽  
pp. 1613-1615
Author(s):  
İbrahim Mert Erbaş ◽  
Ahu Paketçi ◽  
Sezer Acar ◽  
Leman Damla Kotan ◽  
Korcan Demir ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Growth Factor Receptor ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Pituitary Hormone ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Midline Defects ◽  
Relationship Of ◽  
The Relationship

AbstractObjectivesVariants in fibroblast growth factor receptor-1 (FGFR1) may either cause isolated hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS). Although the relationship of genes classically involved in IHH with combined pituitary hormone deficiency (CPHD) is well established, variants in FGFR1 have been presented as a rare cause of this phenotype recently.Case presentationHerein, we report an adopted 16-year-old male presented with delayed puberty and micropenis. He had undergone surgery for bilateral undescended testes in childhood. He was normosmic, and the pituitary imaging was normal. However, hypogonadotropic hypogonadism and growth hormone deficiency were detected, associated with a heterozygous nonsense variant (c.1864 C>T, p.R622X) in FGFR1.ConclusionsFGFR1 variants are among the causes of IHH and KS, which are inherited in an autosomal dominant manner and can be associated with midline defects. It should also be kept in mind that CPHD may be associated with FGFR1 variants in a subject with normal olfactory function.

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 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.

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.

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

scholarly journals Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Li ◽  
Belle W. X. Lim ◽  
Ella R. Thompson ◽  
Simone McInerny ◽  
Magnus Zethoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Candidate Genes ◽  
Familial Aggregation ◽  
Loss Of Function ◽  
Cancer Data ◽  
Pathogenic Variants ◽  
New Genes ◽  
Predisposing Genes ◽  
Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

MO039IDENTIFICATION OF A RECURRENT SYNONYMOUS GENETIC VARIANT IN NPHP3 LEADING TO NEPHRONOPHTHISIS AND CONGENITAL HEPATIC FIBROSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eric Olinger ◽  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Eissa Ali Faqeih ◽  
Mohamed Al Hamed ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rna Splicing ◽  
Donor Site ◽  
Saudi Arabian ◽  
Bioinformatic Analysis ◽  
Initial Assessment ◽  
Splice Donor Site ◽  
Uk Biobank ◽  
Pathogenic Variants ◽  
Exon 20

Abstract Background and Aims Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice and has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. Filtering of variants and scoring variants in terms of pathogenicity still represents a major challenge and may explain why ∼50% of patients remain without diagnosis after initial assessment. Method In this study, we performed WES to determine the genetic cause of a hepato-renal ciliopathy syndrome in a genetically unsolved consanguineous family from Oman with 2 affected children. For variants filtering and annotation Qiagen Clinical Insight tool was used. Database searches for identical alleles in patients with similar phenotypes were performed using Genomics England, UK Biobank and a Saudi Arabian cohort. RNA studies were used to confirm a splicing defect. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project and from UK Biobank, a major biomedical database. Results Initial bioinformatic analysis of WES data from 2 affected sibs excluded obvious pathogenic variants in known genes associated with primary ciliopathy syndromes with liver and kidney phenotypes. However, by manual curation of variants in candidate genes, a rare homozygous synonymous allele in NPHP3 was identified (c.2805C>T; p.(Gly935Gly)), mid-exon 20 and within a region of shared homozygosity on chromosome 3. Correct segregation was confirmed via Sanger sequencing in the parents and the 2 affected sibs. The variant was rare in gnomAD (2/251374 alleles) and was found heterozygously in just one individual within the UK Biobank cohort of 200,000 exomes. Using various in silico tools, the allele was shown to activate a cryptic splice donor site in the middle of exon 20. RT-PCR with sequencing of parental whole blood RNA confirmed alternative splicing leading to frameshift p.Gly935GlyfsTer47. The identical homozygous allele was identified in 2 additional unsolved families within the Genomics England 100,000 Genomes Project and in 1 Saudi Arabian family with similar hepato-renal phenotypes. Conclusion This study shows that automated filtering of WES data may exclude synonymous variants which are pathogenic, especially if they are mid-exon. Here we identified a recurrent synonymous NPHP3 variant leading to a splice defect as the cause of a hepato-renal ciliopathy phenotype in four families. In unsolved cases, rare synonymous alleles in candidate genes need to be reassessed for impact on RNA splicing and possible pathogenicity.

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

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