Publications by authors named "Quinton R"

216 Publications

Hypogonadotropic hypogonadism due to variants in : expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

Cold Spring Harb Mol Case Stud 2020 06 12;6(3). Epub 2020 Jun 12.

Harvard Reproductive Endocrine Sciences Center, Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

Biallelic pathogenic variants in cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous variants were also reviewed. The ES identified pathogenic compound heterozygous variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.
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http://dx.doi.org/10.1101/mcs.a005033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304352PMC
June 2020

DLG2 variants in patients with pubertal disorders.

Genet Med 2020 08 28;22(8):1329-1337. Epub 2020 Apr 28.

Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.

Methods: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH.

Results: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH.

Conclusion: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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http://dx.doi.org/10.1038/s41436-020-0803-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510947PMC
August 2020

Maternal T Cells in the Human Placental Villi Support an Allograft Response during Noninfectious Villitis.

J Immunol 2020 06 22;204(11):2931-2939. Epub 2020 Apr 22.

Hospital Pathology Associates, Minneapolis, MN 55407.

During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8 T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis-placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.
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http://dx.doi.org/10.4049/jimmunol.1901297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307888PMC
June 2020

Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease.

Hum Genet 2021 Jan 21;140(1):77-111. Epub 2020 Mar 21.

Department of Clinical Sciences and Community Health, University of Milan, 20100, Milan, Italy.

A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the "pilot light" of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype-phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome-KS), other genes can be associated with both nCHH and KS-sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.
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http://dx.doi.org/10.1007/s00439-020-02147-1DOI Listing
January 2021

Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease.

Hum Genet 2021 Jan 21;140(1):77-111. Epub 2020 Mar 21.

Department of Clinical Sciences and Community Health, University of Milan, 20100, Milan, Italy.

A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the "pilot light" of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype-phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome-KS), other genes can be associated with both nCHH and KS-sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.
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http://dx.doi.org/10.1007/s00439-020-02147-1DOI Listing
January 2021

LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control.

Nat Cell Biol 2020 02 3;22(2):246-256. Epub 2020 Feb 3.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant growth-control pathways that dictate proper organ development. We therefore explored potential crosstalk between these two functionally relevant pathways to coordinate their growth-control functions. We found that the LATS1 and LATS2 kinases, the core components of the Hippo pathway, phosphorylate S606 of Raptor, an essential component of mTORC1, to attenuate mTORC1 activation by impairing the interaction of Raptor with Rheb. The phosphomimetic Raptor-S606D knock-in mutant led to a reduction in cell size and proliferation. Compared with Raptor mice, Raptor knock-in mice exhibited smaller livers and hearts, and a significant inhibition of elevation in mTORC1 signalling induced by Nf2 or Lats1 and Lats2 loss. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways to fine-tune organ growth.
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http://dx.doi.org/10.1038/s41556-020-0463-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076906PMC
February 2020

Psychological Aspects of Congenital Hypogonadotropic Hypogonadism.

Front Endocrinol (Lausanne) 2019 5;10:353. Epub 2019 Jul 5.

Newcastle-upon-Tyne Hospitals Foundation NHS Trust (Royal Victoria Infirmary) and Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom.

Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare, treatable form of infertility. Like other rare disease patients, individuals with CHH/KS frequently experience feelings of isolation, shame, and alienation. Unlike many rare diseases, CHH/KS is not life threatening and effective treatments are available. Nevertheless, it remains a profoundly life-altering condition with psychosocial distress on a par with untreatable or life-limiting disease. Patients with CHH/KS frequently express lasting adverse psychological, emotional, social, and psychosexual effects resulting from disrupted puberty. They also frequently experience a "diagnostic odyssey," characterized by distressing and convoluted medical referral pathways, lack-of-information, misinformation, and sometimes-incorrect diagnoses. Unnecessary delays in diagnosis and treatment-initiation can significantly contribute to poor body image and self-esteem. Such experiences can erode confidence and trust in medical professionals as well as undermine long-term adherence to treatment-with negative sequelae on health and wellbeing. This review provides a summary of the psychological aspects of CHH/KS and outlines an approach to comprehensive care that spans medical management as well as appropriate attention, care and referrals to peer-to-peer support and mental health services to ameliorate the psychological aspects of CHH/KS.
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http://dx.doi.org/10.3389/fendo.2019.00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624645PMC
July 2019

Defective AMH signaling disrupts GnRH neuron development and function and contributes to hypogonadotropic hypogonadism.

Elife 2019 07 10;8. Epub 2019 Jul 10.

Jean-Pierre Aubert Research Center (JPArc), Laboratory of Development and Plasticity of the Neuroendocrine Brain, Inserm, UMR-S 1172, Lille, France.

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone () and its receptor, , in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of -deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.
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http://dx.doi.org/10.7554/eLife.47198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620045PMC
July 2019

Identification of the kinase STK25 as an upstream activator of LATS signaling.

Nat Commun 2019 04 4;10(1):1547. Epub 2019 Apr 4.

The Laboratory of Cancer Cell Biology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.

The Hippo pathway maintains tissue homeostasis by negatively regulating the oncogenic transcriptional co-activators YAP and TAZ. Though functional inactivation of the Hippo pathway is common in tumors, mutations in core pathway components are rare. Thus, understanding how tumor cells inactivate Hippo signaling remains a key unresolved question. Here, we identify the kinase STK25 as an activator of Hippo signaling. We demonstrate that loss of STK25 promotes YAP/TAZ activation and enhanced cellular proliferation, even under normally growth-suppressive conditions both in vitro and in vivo. Notably, STK25 activates LATS by promoting LATS activation loop phosphorylation independent of a preceding phosphorylation event at the hydrophobic motif, which represents a form of Hippo activation distinct from other kinase activators of LATS. STK25 is significantly focally deleted across a wide spectrum of human cancers, suggesting STK25 loss may represent a common mechanism by which tumor cells functionally impair the Hippo tumor suppressor pathway.
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http://dx.doi.org/10.1038/s41467-019-09597-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449379PMC
April 2019

Many women with Turner syndrome lack protective antibodies to common respiratory pathogens, Haemophilus influenzae type B and Streptococcus Pneumoniae.

Clin Endocrinol (Oxf) 2019 07 11;91(1):228-230. Epub 2019 Apr 11.

Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle Upon Tyne, UK.

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http://dx.doi.org/10.1111/cen.13978DOI Listing
July 2019

Congenital Hypogonadotrophic Hypogonadism: Minipuberty and the Case for Neonatal Diagnosis.

Front Endocrinol (Lausanne) 2019 21;10:97. Epub 2019 Feb 21.

Department of Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

Congenital hypogonadotrophic hypogonadism (CHH) is a rare but important etiology of pubertal failure and infertility, resulting from impaired gonadotrophin-releasing hormone secretion or action. Despite the availability of effective hormonal therapies, the majority of men with CHH experience unsatisfactory outcomes, including chronic psychosocial and reproductive sequelae. Early detection and timely interventions are crucial to address the gaps in medical care and improve the outlook for these patients. In this paper, we review the clinical implications of missing minipuberty in CHH and therapeutic strategies that can modify the course of disease, as well as explore a targeted approach to identifying affected male infants by integrating clinical and biochemical data in the early postnatal months.
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http://dx.doi.org/10.3389/fendo.2019.00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393341PMC
February 2019

Is calcium supplementation always needed in patients with hypoparathyroidism?

Clin Endocrinol (Oxf) 2019 06 19;90(6):775-780. Epub 2019 Mar 19.

The Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Oral calcium salts are recommended for the treatment of chronic hypoparathyroidism (HypoPT), although dosimetry is variable between individual patients and clinicians. However, patient feedback on calcium salts can be negative, particularly due to gastrointestinal side effects and hypercalciuria-related complications. We begin with a clinical case of a HypoPT patient taking oral calcium salts following thyroid surgery, who requested support in reducing her dose of these with a view to stopping entirely. To evaluate her request, we first describe the usual treatment of HypoPT according to current guidance and then present data from (a) a case note review of a cohort of 24 HypoPT patients managed with a "no calcium" treatment regimen by single physician (b) a comprehensive online survey of HypoPT patients' treatment and experiences (n = 330). The case note review found that target range serum calcium levels were successfully achieved in all 24 patients since transitioning to a "no calcium" regimen, without any breakthrough hypocalcaemia-related symptoms, the development of new renal stones, the occurrence of calcium-related hospital admissions or the finding of significant hypercalciuria. The online survey identified 36% of HypoPT patients who continued to take activated vitamin D, but had discontinued calcium supplements. HypoPT patients not currently taking calcium reported a significantly lower prevalence of adverse effects and outcomes, both compared with their previous experiences whilst taking calcium and also compared with the 64% of patients who continued to take oral calcium. We conclude that, subject to methodological limitations, there are significant issues of tolerability arising from conventional calcium-based treatment regimens for patients with chronic HypoPT. For selected patients, it may be reasonable to facilitate a managed therapeutic transition to "no calcium" regimen, and we also propose that calcium-based regimes be prospectively evaluated against calcium-free (or calcium-low) alternatives.
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http://dx.doi.org/10.1111/cen.13955DOI Listing
June 2019

Managing congenital hypogonadotrophic hypogonadism: a contemporary approach directed at optimizing fertility and long-term outcomes in males.

Ther Adv Endocrinol Metab 2019 10;10:2042018819826889. Epub 2019 Feb 10.

Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.

Hormonal induction of spermatogenesis offers men with azoospermia due to hypogonadotrophic hypogonadism (HH) the promising prospect of fertility restoration. However, an important exception is the subset of individuals affected by congenital hypogonadotrophic hypogonadism (CHH), also known as Kallmann syndrome if associated with anosmia, who often display dismal responses to fertility induction, despite prolonged therapy. This primarily stems from the loss of minipuberty, which is a crucial phase of testicular maturation in early life that has a far-reaching impact on eventual spermatogenic capacity. Further exacerbating the compromised reproductive health is the failure to initiate timely pubertal induction in many CHH patients, resulting in suboptimal genital and psychosexual development. In this paper, the clinical implications and management of male HH across the lifespan is comprehensively reviewed, with a special focus on novel strategies that have the potential to modify disease severity and maximize fertility potential in CHH by addressing the inadequacies of conventional approaches.
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http://dx.doi.org/10.1177/2042018819826889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378644PMC
February 2019

Hormone replacement therapy: transgender studies show safety of estradiol.

BMJ 2019 02 11;364:l600. Epub 2019 Feb 11.

Singapore General Hospital, Singapore 169608.

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http://dx.doi.org/10.1136/bmj.l600DOI Listing
February 2019

Machine learning algorithms for predicting scapular kinematics.

Med Eng Phys 2019 03 4;65:39-45. Epub 2019 Feb 4.

Biomechanics and Movement Science Program, University of Delaware, Newark, DE, USA. Electronic address:

The goal of this study was to develop and validate a non-invasive approach to estimate scapular kinematics in individual patients. We hypothesized that machine learning algorithms could be developed using motion capture data to accurately estimate dynamic scapula orientation based on measured humeral orientations and acromion process positions. The accuracy of the algorithms was evaluated against a gold standard of biplane fluoroscopy using a 2D to 3D fluoroscopy/model matching process. Individualized neural networks were developed for nine healthy adult shoulders. These models were used to predict scapulothoracic kinematics, and the predicted kinematics were compared to kinematics obtained using biplane fluoroscopy to determine the accuracy of the machine learning algorithms. Results showed correlations between predicted kinematics and validation kinematics. Estimated kinematics were within 10 of validation kinematics. We concluded that individualized machine learning algorithms show promise for providing accurate, non-invasive measurements of scapulothoracic kinematics.
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http://dx.doi.org/10.1016/j.medengphy.2019.01.005DOI Listing
March 2019

CRISPR-Mediated Approaches to Regulate YAP/TAZ Levels.

Methods Mol Biol 2019 ;1893:203-214

Department of Pharmacology and Experimental Therapeutics, The Cancer Center, Boston University School of Medicine, Boston, MA, USA.

The advent of CRISPR has revolutionized genomic engineering, and harnessing its power to regulate levels of the transcriptional co-activators YAP and TAZ represents an exciting new opportunity in the field of Hippo signaling. Initially repurposed from the microbial immune system to perform highly specific gene knockouts, CRISPR technology has now been expanded to modulate the transcriptional activity of any gene of interest in mammalian systems. Here, we describe strategies to employ CRISPR to genetically knock out the genes encoding for YAP (YAP1) or TAZ (WWTR1) in mammalian cell lines, as well as briefly outline an approach for utilizing CRISPR to transcriptionally modulate YAP/TAZ levels.
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http://dx.doi.org/10.1007/978-1-4939-8910-2_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533617PMC
June 2019

Fertility induction in hypogonadotropic hypogonadal men.

Clin Endocrinol (Oxf) 2018 12 9;89(6):712-718. Epub 2018 Oct 9.

Institute of Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle upon Tyne, UK.

Men with hypogonadotropic hypogonadism (HH) are typically azoospermic, and yet HH is one of the few treatable forms of male infertility. Sperm induction protocols using gonadotrophins aim to replicate the natural endocrine control of spermatogenesis. Previously virilised men with adult-onset HH and normal testicular volume respond well to monotherapy in which human chorionic gonadotrophin (hCG) acts as a long-acting LH-analogue stimulating spermatogenesis. However, this approach is rarely successful for men with congenital HH (CHH) (eg, Kallmann syndrome), for whom combined gonadotrophin therapy (hCG + follicle-stimulating hormone [FSH]) is an absolute requirement to maximise fertility potential. Key baseline predictors of successful spermatogenesis-induction include prior spontaneous testicular development (ie, testicular volume [TV] > 4 mL), serum inhibin B (I ) concentration >60 pg/mL and no history of maldescended testes (cryptorchidism).
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http://dx.doi.org/10.1111/cen.13850DOI Listing
December 2018

Hiding in a plain sight: A high prevalence of androgen deficiency due to primary hypogonadism among acute medical inpatients with anaemia.

Clin Endocrinol (Oxf) 2018 10 2;89(4):527-529. Epub 2018 Aug 2.

Newcastle-upon-Tyne Hospitals NHS Foundation Trust, The Royal Victoria Infirmary, Newcastle-upon-Tyne, UK.

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http://dx.doi.org/10.1111/cen.13809DOI Listing
October 2018

The Metabolic Syndrome in Central Hypogonadotrophic Hypogonadism.

Front Horm Res 2018 5;49:156-169. Epub 2018 Apr 5.

The metabolic syndrome (MetS) is a term used to describe the constellation of cardiometabolic risk factors including central adiposity, dyslipidemia, insulin resistance, non-alcoholic fatty liver disease and arterial hypertension. Notably, a number of studies have shown high rates of testosterone (T) deficiency in men with MetS and type 2 diabetes mellitus (T2DM). Both hypogonadism and MetS confer increased health risk for morbidity and mortality as men with the MetS are at twice the risk for developing cardiovascular disease and at 5-fold higher risk for developing T2DM. Moreover, the inverse relationship between T and MetS is consistently observed across racial and ethnic groups. Thus, in the setting of growing obesity rates, this relationship between the reproductive endocrine axis and metabolism warrants renewed attention. This review specifically focuses on central hypogonadotrophic hypogonadism (CH) providing a concise overview of the metabolic implications of CH and identify the unanswered questions and future directions in this growing field.
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http://dx.doi.org/10.1159/000485998DOI Listing
January 2019

A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation.

Mol Biol Cell 2018 07 23;29(13):1682-1692. Epub 2018 May 23.

Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118.

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.
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http://dx.doi.org/10.1091/mbc.E18-02-0141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080710PMC
July 2018

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.

Eur J Endocrinol 2018 Apr 1;178(4):377-388. Epub 2018 Feb 1.

School of MedicineUniversity of Belgrade, Belgrade, Serbia.

Objective: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

Design: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.

Methods: Exome sequencing data were used to identify rare variants in known genes in CHH ( = 116), CDGP ( = 72) and control cohorts ( = 36 874 ExAC and  = 405 CoLaus).

Results: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%,  = 7.6 × 10) or controls (18%,  = 5.5 × 10). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%,  = 0.002) and controls (2%,  = 6.4 × 10).

Conclusions: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.
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http://dx.doi.org/10.1530/EJE-17-0568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863472PMC
April 2018

Safety and tolerability of one-year intramuscular testosterone regime to induce puberty in older men with CHH.

Endocr Connect 2018 Jan;7(1):133-138

Department of EndocrinologyNewcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK

We present herein our 20-year experience of pubertal induction in apubertal older (median age 56 years; range 38.4-69.5) men with congenital hypogonadotrophic hypogonadism ( = 7) using a simple fixed-dose and fixed-interval intramuscular testosterone that we originally pioneered in relation to achieving virilisation of natal female transgender men. This regime was effective and well tolerated, resulting in complete virilisation by around 1 year after treatment initiation. No physical or psychological adverse effects were encountered in this group of potentially vulnerable individuals. There were no abnormal excursions of laboratory parameters and extended follow-up beyond the first year of treatment revealed remarkable improvements in bone density. We highlight advantages to both patients and physicians of this regime in testosterone-naïve older men with congenital hypogonadism and discourage the over-rigid application to such patients of treatment algorithms derived from paediatric practice in relation to the evaluation and management in younger teenagers with delayed puberty of uncertain cause.
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http://dx.doi.org/10.1530/EC-17-0241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754506PMC
January 2018

DCC/NTN1 complex mutations in patients with congenital hypogonadotropic hypogonadism impair GnRH neuron development.

Hum Mol Genet 2018 01;27(2):359-372

Endocrinology, Diabetes & Metabolism Service, Centre Hospitalier Universitaire Vaudois (CHUV), Faculty of Biology & Medicine, University of Lausanne, 1005 Lausanne, Switzerland.

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.
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http://dx.doi.org/10.1093/hmg/ddx408DOI Listing
January 2018

Child Death Review: Past, Present, and Future.

Authors:
Reade A Quinton

Acad Forensic Pathol 2017 Dec 1;7(4):527-535. Epub 2017 Dec 1.

Southwestern Institute of Forensic Sciences - Forensic Pathology.

This article describes the current state of child death reviews (CDR) in the United States. The CDR process has evolved over almost 40 years from informal local meetings to a coordinated effort involving all 50 states. Child death review programs across the country vary in the level of financial and administrative support, legislation, and review processes. While there is still a long way to go in standardizing the practice between states, great strides have been made in data collection, education, and prevention initiatives.
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http://dx.doi.org/10.23907/2017.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474434PMC
December 2017

Hypernatraemic hypovolaemia with anaemia: an unusual presentation of primary testicular insufficiency.

Endocrinol Diabetes Metab Case Rep 2017 10;2017. Epub 2017 Nov 10.

Department of Endocrinology, Newcastle-upon-Tyne Hospitals, Newcastle upon Tyne, UK.

Hypogonadal men may experience intense vasomotor symptoms, and vasomotor sweating can occasionally be associated with profound fluid losses. We describe a 37-year-old male, who exhibited persistent hypovolaemic hypernatraemia that was challenging to treat despite a continuous high fluid input (>4-5 L/day). He was noted to have drenching sweats and normochromic anaemia. He had recent traumatic head injury, which resulted in neurocognitive dysfunction, so pituitary function tests were done which showed primary hypogonadism. After exclusion of all other possible causes of excess sweating, hypernatraemia and anaemia, a trial of testosterone therapy was instituted. Sweating dramatically ceased within hours of his first testosterone injection, hydration status normalised within days and anaemia and neurocognitive function progressively improved with continued testosterone replacement. This case demonstrates how, in a susceptible individual, hypovolaemic hypernatraemia can arise from insensible cutaneous fluid loss through eccrine sweating, mediated by vasomotor symptoms of untreated hypogonadism. Although this scenario has not been described in the literature, we felt it needed to be shared with the wider medical community because of how the diagnosis and treatment utterly transformed this patient's functional status and outcome.

Learning Points: Hypogonadal men may experience intense vasomotor symptoms and vasomotor sweating can occasionally be associated with profound fluid losses.Whether or not there is also hyperosmolar hypernatraemia, clinicians should always consider the possibility of underlying hypogonadism in men with normocytic anaemia and excessive sweating.Androgen (testosterone) replacement in hypogonadal men can have a dramatic effect on vasomotor sweating and hot flushes.
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http://dx.doi.org/10.1530/EDM-17-0121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683299PMC
November 2017

Evaluating CHARGE syndrome in congenital hypogonadotropic hypogonadism patients harboring CHD7 variants.

Genet Med 2018 08 16;20(8):872-881. Epub 2017 Nov 16.

Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.

Purpose: Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined.

Methods: Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated.

Results: Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01).

Conclusion: Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.
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http://dx.doi.org/10.1038/gim.2017.197DOI Listing
August 2018
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