Publications by authors named "Andrew A Dwyer"

69 Publications

Evaluating co-created patient-facing materials to increase understanding of genetic test results.

J Genet Couns 2020 Oct 24. Epub 2020 Oct 24.

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

Patients often have difficulty understanding genetic test reports. Technical language and jargon can impede comprehension and limit patients using results to act on findings. One potential way to improve patient understanding of genetic test reports is to provide patient-facing materials. This study aimed to examine understandability and actionability of co-created patient-facing materials for genetic test results in a research context. We combined interprofessional perspectives and patient engagement to co-create patient-facing materials for patients undergoing research genetic testing for congenital hypogonadotropic hypogonadism (Kallmann syndrome). The iterative development process was guided by principles of health literacy and human-centered design (i.e., design thinking). Readability was assessed using eight validated algorithms. Patients and parents evaluated materials using a web-based survey. The gold standard Patient Education Materials Assessment Tool for print materials (PEMAT-P) was employed to measure understandability (content, style, use of numbers, organization, design, use of visual aids) and actionability. PEMAT-P scores >80% were considered high quality. Results were analyzed descriptively and correlations performed to identify relationships between education/health literacy and PEMAT-P ratings. A consensus score of eight algorithms indicated the materials were an 8 -9th grade reading level. Our findings are consistent with the U.S. Department of Health and Human Services 'average difficulty' classification (i.e., 7th-9th grade). In total, 61 patients/parents evaluated the materials. 'Visual Aids' received the lowest mean PEMAT-P rating (89%). All other parameters scored 90%-97%. PEMAT-P scores did not differ according to educational attainment (less than college vs. college or more, p = 0.28). Participants with adequate health literacy were more likely to approve of the 'organization' of information (p < 0.05). Respondents with low health literacy had more favorable views of 'visual aids' (p < 0.01). Involving patients in a co-creation process can produce high-quality patient-facing materials that are easier to understand.
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http://dx.doi.org/10.1002/jgc4.1348DOI Listing
October 2020

GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

Hum Reprod 2020 Oct;35(10):2312-2322

Univ Paris-Saclay, Paris-Saclay Medical School, Le Kremlin-Bicêtre, France.

Study Question: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life?

Summary Answer: Both parameters lack the specificity to discriminate CDGP from CHH.

What Is Known Already: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms.

Study Design, Size, Duration: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls.

Participants/materials, Setting, Methods: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test.

Main Results And The Role Of Chance: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold.

Limitations, Reasons For Caution: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here.

Wider Implications Of The Findings: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP.

Study Funding/competing Interest(s): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa185DOI Listing
October 2020

Parent of Origin Effects on Family Communication of Risk in + Women: A Qualitative Investigation of Human Factors in Cascade Screening.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Boston College, Department of Sociology, Chestnut Hill, MA 02467, USA.

Pathogenic germline variants in Breast Cancer 1/2 () genes confer increased cancer risk. Understanding status/risk can enable family cascade screening and improve cancer outcomes. However, more than half of the families do not communicate family cancer history/ status, and cancer outcomes differ according to parent of origin (i.e., maternally vs. paternally inherited pathogenic variant). We aimed to explore communication patterns around family cancer history/ risk according to parent of origin. We analyzed qualitative interviews ( = 97) using template analysis and employed the Theory of Planned Behavior (TPB) to identify interventions to improve communication. Interviews revealed sub-codes of 'male stoicism and 'paternal guilt' that impede family communication (template code: gender scripting). Conversely, 'fatherly protection' and 'female camaraderie' promote communication of risk. The template code 'dysfunctional family communication' was contextualized by several sub-codes ('harmful negligence', 'intra-family ignorance' and 'active withdrawal of support') emerging from interview data. Sub-codes 'medical misconceptions' and 'medical minimizing' deepened our understanding of the template code 'medical biases'. Importantly, sub-codes of 'informed physicians' and 'trust in healthcare' mitigated bias. Mapping findings to the TPB identified variables to tailor interventions aimed at enhancing family communication of risk and promoting cascade screening. In conclusion, these data provide empirical evidence of the human factors impeding communication of family risk. Tailored, theory-informed interventions merit consideration for overcoming blocked communication and improving cascade screening uptake.
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http://dx.doi.org/10.3390/cancers12082316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464326PMC
August 2020

Editorial: New Aspects in Hypogonadism.

Front Endocrinol (Lausanne) 2020 30;11:426. Epub 2020 Jun 30.

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

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http://dx.doi.org/10.3389/fendo.2020.00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338426PMC
June 2020

A sexual health course for advanced practice registered nurses: Effect on preparedness, comfort, and confidence in delivering comprehensive care.

Nurse Educ Today 2020 Sep 19;92:104506. Epub 2020 Jun 19.

Boston College, Connell School of Nursing, Chestnut Hill, MA, United States of America; The Fenway Institute, Boston, MA, United States of America; University of Hawaii at Manoa, School of Nursing and Dental Hygiene, Honolulu, HI, United States of America. Electronic address:

Background: Sexual healthcare is a critical component of well-being. Sexual health disparities persist nationally. Nurses and advanced practice nurses are well positioned to provide sexual healthcare to diverse patient populations. However, many nurses do not feel prepared to provide comprehensive care and sexual health curricula vary widely across schools of nursing.

Objectives: We aimed to evaluate the effectiveness of a new sexual health course for graduate students in improving nurses' knowledge, preparedness, comfort, and confidence in delivering comprehensive, culturally informed sexual healthcare.

Design: A pre-post-intervention survey study design was utilized to assess course effectiveness.

Setting: Medium-sized, private university.

Participants: Graduate nursing students enrolled in the course (intervention group, n = 30) were recruited. Graduate students enrolled at the institution but not enrolled in the course served as controls (n = 64).

Methods: Descriptive statistics and multivariate analysis were used to evaluate pre- to post-course changes in knowledge, preparedness, comfort, and confidence in the intervention group and differences between the intervention and control group at baseline.

Results: At baseline, all participants (n = 94) exhibited high objective clinical sexual health knowledge. The intervention group had significantly increased overall preparedness, comfort, and confidence in providing sexual healthcare to diverse patient populations. In particular, participants in the intervention group had statistically significant increases associated with care for marginalized minority populations (sexual minorities, gender minorities, sex workers, and persons with a history of sexual trauma).

Conclusions: The graduate-level course on sexual health and sexual health disparities effectively increased perceived preparedness, comfort, and confidence in delivering comprehensive and culturally informed care to diverse populations. Nursing programs should evaluate their curricula to determine whether graduates are optimally prepared.
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http://dx.doi.org/10.1016/j.nedt.2020.104506DOI Listing
September 2020

Psychosexual effects resulting from delayed, incomplete, or absent puberty.

Authors:
Andrew A Dwyer

Curr Opin Endocr Metab Res 2020 Oct 24;14:15-21. Epub 2020 Apr 24.

Boston College Connell School of Nursing & MGH Harvard Center for Reproductive Medicine, 140 Commonwealth Avenue, Maloney Hall 273, Chestnut Hill MA 02476.

Puberty is a remarkable period of postnatal development culminating in reproductive capacity. Biological changes of puberty are accompanied by social and emotional changes including psychosexual development. Developmental changes of adolescence are influenced by numerous biological, psychological and social influences. Work to date has identified associations between disrupted puberty (i.e. delayed, incomplete or absent) and psychosexual development. This brief review summarizes our current understanding of the psychosexual effects of delayed puberty and congenital hypogonadotropic hypogonadism (Kallmann syndrome). The importance of psychosocial support and transitional care is highlighted and future directions are discussed.
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http://dx.doi.org/10.1016/j.coemr.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286539PMC
October 2020

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

Neuroendocrinology 2021 20;111(1-2):99-114. Epub 2020 Feb 20.

University Paris-Saclay, Le Kremlin-Bicêtre, France,

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs.

Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met.

Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
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http://dx.doi.org/10.1159/000506640DOI Listing
February 2020

Symptom perception in heart failure - Interventions and outcomes: A scoping review.

Int J Nurs Stud 2020 Jan 10:103524. Epub 2020 Jan 10.

School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland Fribourg, Haute Ecole de Santé Fribourg, Route des Arsenaux 16a, CH-1700 Fribourg, Switzerland. Electronic address:

Background: Symptom perception in heart failure has recently been described as essential in the self-care process bridging self-care maintenance and self-care management. Accordingly, symptom perception appears to be critical for improving patient outcomes such as decreased hospital readmission and increased survival.

Objectives: To explore what interventions have been reported on heart failure symptom perception and to describe outcomes responsive to symptom perception.

Design: We conducted a scoping review using PRISMA Extension for Scoping Reviews.

Data Sources: Structured searches of Medline, PubMed, Embase, CINAHL, PsychINFO, Web of Science, Cochrane, Joanna Briggs Institute and Grey literature databases.

Review Methods: Two authors independently screened references for eligibility. Eligible articles were written in English, French, German, Swedish, Italian or Spanish and concerned symptom perception in adults with heart failure. Data were extracted and charted in tables by three reviewers. Results were narratively summarized.

Results: We identified 99 eligible studies from 3055 references. Seven interventional studies targeted symptom perception as the single intervention component. Mixed results have been found: while some reported decreased symptom frequency, intensity and distress, enhanced health-related quality of life, improved heart failure self-care maintenance and management as well as a greater ability to mention heart failure symptoms, others found more contacts with healthcare providers or no impact on anxiety, heart failure self-care nor a number of diary reported symptoms. Additional interventional studies included symptom perception as one component of a multi-faceted intervention. Outcomes responsive to symptom perception were improved general and physical health, decreased mortality, heart failure decompensation, as hospital/emergency visits, shorter delays in seeking care, more consistent weight monitoring, improved symptom recognition as well as self-care management, decreased hospital length of stay and decreased costs.

Conclusions: While many studies allowed to map a comprehensive overview of interventions supporting symptom perception in heart failure as well as responsiveness to outcomes, only a few single component intervention studies targeting symptom perception have been reported and study designs preclude assessing intervention effectiveness. With regard to multiple component interventions, the specific impact of symptom perception interventions on outcomes remains uncertain to date. Well-designed studies are needed to test the effectiveness of symptom perception interventions and to elucidate relationships with outcomes.
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http://dx.doi.org/10.1016/j.ijnurstu.2020.103524DOI Listing
January 2020

Non-invasive assessment of coronary endothelial function in children and adolescents with type 1 diabetes mellitus using isometric handgrip exercise-MRI: A feasibility study.

PLoS One 2020 13;15(2):e0228569. Epub 2020 Feb 13.

Pediatric Endocrinology, Diabetology and Obesity Unit, Service of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

Background: Type 1 diabetes mellitus (T1DM) in children and adolescents is associated with significant cardiovascular morbidity and mortality. Early detection of vascular dysfunction is key to patient management yet current assessment techniques are invasive and not suitable for pediatric patient populations. A novel approach using isometric handgrip exercise during magnetic resonance imaging (IHE-MRI) has recently been developed to evaluate coronary endothelial function non-invasively in adults. This project aimed to assess endothelium-dependent coronary arterial response to IHE-MRI in children with T1DM and in age matched healthy controls.

Materials And Methods: Healthy volunteers and children with T1DM (>5 years) were recruited. IHE-MRI cross-sectional coronary artery area measurements were recorded at rest and under stress. Carotid intima media thickness (CIMT) and aortic pulse wave velocity (PWV) were assessed for comparison. Student's t-tests were used to compare results between groups.

Results And Discussion: Seven children with T1DM (3 female, median 14.8 years, mean 14.8 ± 1.9 years) and 16 healthy controls (7 female, median 14.8 years, mean 14.2 ± 2.4 years) participated. A significant increase in stress-induced cross-sectional coronary area was measured in controls (5.4 mm2 at rest to 6.39 mm2 under stress, 18.8 ± 10.7%, p = 0.0004). In contrast, mean area change in patients with T1DM was not significant (7.17 mm2 at rest to 7.59 mm2 under stress, 10.5% ± 28.1%, p = n.s.). There was no significant difference in the results for neither PWV nor CIMT between patients and controls, (5.3±1.5 m/s vs.4.8±0.7 m/s and 0.4±0.03mm vs.0.46 mm ± 0.03 respectively, both p = n.s.).

Conclusions: Our pilot study demonstrates the feasibility of using a totally non-invasive IHE-MRI technique in children and adolescents with and without T1DM. Preliminary results suggest a blunted endothelium-dependent coronary vasomotor function in children with T1DM (>5 years). Better knowledge and new methodologies may improve surveillance and care for T1DM patients to reduce cardiovascular morbidity and mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018029PMC
May 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Minipuberty: A Primer for Pediatric Nurses.

Authors:
Andrew A Dwyer

J Pediatr Nurs 2020 Jan - Feb;50:138-139. Epub 2019 Dec 24.

William F. Connell School of Nursing, Boston College, Boston, MA, United States of America; Yvonne Munn Center for Nursing Research, Massachusetts General Hospital, Boston, MA, United States of America. Electronic address:

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http://dx.doi.org/10.1016/j.pedn.2019.10.012DOI Listing
November 2020

Symptom perception in heart failure: a scoping review on definition, factors and instruments.

Eur J Cardiovasc Nurs 2020 02 29;19(2):100-117. Epub 2019 Nov 29.

School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland - Fribourg, Switzerland.

Background: Symptom perception in heart failure has been identified as crucial for effective self-care that is a modifiable factor related to decreased hospital readmission and improved survival.

Aims: To review systematically the heart failure symptom perception literature and synthesise knowledge on definition, description, factors and instruments.

Methods: We conducted a scoping review including studies reporting patient-reported symptom perception in adults with heart failure. Structured searches were conducted in Medline, PubMed, Embase, CINAHL, PsychINFO, Web of Science, Cochrane, JBI and grey literature. Two authors independently reviewed references for eligibility. Data were charted in tables and results narratively summarised.

Results: The search yielded 3057 references, of which 106 were included. The definition of heart failure symptom perception comprised body listening, monitoring signs, recognising, interpreting and labelling symptoms, and furthermore awareness of and assigning meaning to the change. Symptom monitoring, recognition and interpretation were identified as challenging. Symptom perception facilitators include prior heart failure hospitalisation, heart failure self-care maintenance, symptom perception confidence, illness uncertainty and social support. Barriers include knowledge deficits, symptom clusters and lack of tools/materials. Factors with inconsistent impact on symptom perception include age, sex, education, experiences of living with heart failure, comorbidities, cognitive impairment, depression and symptom progression. One instrument measuring all dimensions of heart failure symptom perception was identified.

Conclusion: Heart failure symptom perception definition and description have been elucidated. Several factors facilitating or hampering symptom perception are known. Further research is needed to determine a risk profile for poor symptom perception - which can then be taken into consideration when supporting heart failure self-care.
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http://dx.doi.org/10.1177/1474515119892797DOI Listing
February 2020

Congenital hypogonadotropic hypogonadism/Kallmann syndrome is associated with statural gain in both men and women: a monocentric study.

Eur J Endocrinol 2020 Feb;182(2):185

Paris-Saclay University, Paris-Saclay Medical School, Le Kremlin-Bicêtre, France.

Context: Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare condition characterized by gonadotropin deficiency and pubertal failure. Adult height (AH) in patients with CHH/KS has not been well studied.

Objective: To assess AH in a large cohort of patients with CHH/KS.

Patients: A total of 219 patients (165 males, 54 females). Parents and siblings were included.

Methods: AH was assessed in patients and family members. AH was compared to the general French population, mid parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered as the difference between AH and parental TH. ∆H was compared between patients and siblings, normosmic CHH and KS (CHH with anosmia/hyposmia), and according to underlying genetic defect. We examined the correlations between ∆H and age at diagnosis and therapeutically induced individual statural gain.

Results: Mean AH in men and women with CHH/KS was greater than that in the French general population. Patients of both sexes had AH > TH. Males with CHH/KS were significantly, albeit moderately, taller than their brothers. ∆H was higher in CHH/KS compared to unaffected siblings (+6.2 ± 7.2 cm vs +3.4 ± 5.2 cm, P < 0.0001). ∆H was positively correlated with age at diagnosis. Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual growth during replacement therapy inversely correlated with the age at initiation of hormonal treatment (P < 0.0001).

Conclusions: CHH/KS is associated with higher AH compared to the general population and mid-parental TH. Greater height in CHH/KS than siblings indicates that those differences are in part independent of an intergenerational effect.
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http://dx.doi.org/10.1530/EJE-19-0537DOI Listing
February 2020

Patient perceptions of peripheral artery disease: A cross-sectional study of hospitalized adults.

J Vasc Nurs 2019 Sep 14;37(3):188-193. Epub 2019 May 14.

University of Lausanne (UNIL), Institute of Higher Education and Research in Healthcare, Lausanne, Switzerland; Boston College William F. Connell School of Nursing, Chestnut Hill, Massachusetts.

Patients with peripheral artery disease (PAD) have increased risk for complications of cardiovascular disease. Smoking cessation, physical activity, and adherence to treatment are critical for limiting the progression of this chronic disease and improving health-related quality of life in patients with PAD.The aim of the study was to explore patient perceptions of PAD and views on medication, tobacco use, and physical activity. This descriptive, cross-sectional study included patients with PAD admitted to a vascular surgery unit at a tertiary academic medical center (October 2017 to January 2018). Sociodemographic data and medical information were collected during hospitalization. Patients completed the Brief Illness Perception Questionnaire, Beliefs about Medicines Questionnaire, and Cigarette Dependence Scale. Additional questions examined physical activity. In total, 32 patients participated in the study. About half (16/30) were active smokers, whereas the remainder had smoked in the past. Only half of patients (16/32) considered smoking as contributing to PAD. Most patients (18/30) perceived PAD as a chronic problem, yet 8/30 (27%) considered PAD a rather acute illness. Patients reported significant cognitive and emotional consequences of PAD (mean 6.2 ± 1.8 and 8.3 ± 2.9, maximum score 10, respectively). They rated relatively low perceived personal control (mean 4.8 ± 2.8, maximum score 10) and weak beliefs about the necessity of medication (mean 12.5 ± 3.3, maximum score 25). Most patients (21/32) perceived physical activity as a protective factor for PAD. Patients perceive PAD as having significant impact on their life and report low levels of personal control in managing PAD. Understanding patient health beliefs may inform more tailored therapeutic education and health promoting interventions to limit disease progression.
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http://dx.doi.org/10.1016/j.jvn.2019.04.001DOI Listing
September 2019

Parent of origin differences in psychosocial burden and approach to BRCA risk management.

Breast J 2020 04 28;26(4):734-738. Epub 2019 Oct 28.

Department of Measurement, Evaluation, Statistics and Assessment, Boston College, Chestnut Hill, MA, USA.

We conducted a mixed-method study to examine coping response in BRCA+ women based on parent of origin (maternally vs paternally inherited BRCA mutation). Quantitative findings (n = 408) revealed paternally inherited cases had genetic testing later and were more likely to have a cancer diagnosis. Having a maternally inherited mutation was the strongest predictor of proactive risk management response. Qualitative interviews (n = 56) identified proactive responses among maternally inherited cases compared to reactive responses in paternally inherited cases. Findings underscore the importance of unbiased pedigree analysis to determine cancer risk. Women with paternally inherited BRCA mutations may benefit from additional psychosocial support.
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http://dx.doi.org/10.1111/tbj.13633DOI Listing
April 2020

Developing a rare disease chronic care model: Management of systemic sclerosis (MANOSS) study protocol.

J Adv Nurs 2019 Dec 13;75(12):3774-3791. Epub 2019 Sep 13.

Institute of Nursing Science (INS), Department Public Health (DPH), Faculty of Medicine, University of Basel, Basel, Switzerland.

Aim: The aim of the management of systemic sclerosis (MANOSS) study described in this protocol is to develop a chronic care model, based on a contextual analysis and stakeholder involvement, for patients living with the rare disease systemic sclerosis (SSc) in Switzerland.

Design: Applying an implementation science approach, this study starts with an explanatory sequential mixed method study for contextual analysis, followed by broad stakeholder involvement for model development and a Delphi study to reach consensus.

Methods: First, a quantitative cross-sectional survey with patients and healthcare professionals (HPs) will be conducted to identify current practice patterns of chronic illness management and technology readiness. Second, qualitative interviews with patients, family members and HPs will be performed to gain a deeper understanding of care needs identified in the quantitative survey. Third, a model of care will be co-created with input from patients, HPs and other experts. The eHealth enhanced Chronic Care Model will serve as a guiding framework. The new model and corresponding outcome parameters will be refined using a Delphi-study approach to reach consensus on a testable model of care for persons living with SSc. The protocol has received research ethics committee approval in September 2018 by the Swiss Ethics Committee.

Discussion: The MANOSS study's participatory approach is essential for contextual fit of the model for patients with SSc in this setting. Subsequent feasibility testing and implementation are planned to evaluate the model's value in relation to health disparities faced by this patient population.

Impact: Patients living with this rare disease lack access to coordinated, specialized care and self-management support from qualified HPs. Reengineering of current care, with consideration for technological opportunities, is warranted to meet patients' and families' needs.
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http://dx.doi.org/10.1111/jan.14185DOI Listing
December 2019

Genetic Competencies for Effective Pediatric Endocrine Nursing Practice.

J Pediatr Nurs 2019 Sep - Oct;48:127-128. Epub 2019 Aug 10.

William F. Connell School of Nursing and Yvonne L. Munn Center for Nursing Research, Massachusetts General Hospital, MA, United States of America.

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http://dx.doi.org/10.1016/j.pedn.2019.06.006DOI Listing
June 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

Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History.

J Clin Endocrinol Metab 2019 08;104(8):3403-3414

Harvard Reproductive Endocrine Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Context: After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men.

Objective: To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH.

Design: Retrospective study in an academic medical center.

Participants: Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls.

Interventions: Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency.

Main Outcome Measures: Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants.

Results: Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH.

Conclusions: FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.
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http://dx.doi.org/10.1210/jc.2018-02697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594303PMC
August 2019

Thigh and abdominal adipose tissue depot associations with testosterone levels in postmenopausal females.

Clin Endocrinol (Oxf) 2019 03 9;90(3):433-439. Epub 2019 Jan 9.

Aging and Muscle Metabolism Laboratory, Department of Physiology, School of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Objective: Research findings on the relationship between serum androgens and adipose tissue in older females are inconsistent. We aimed to clarify the relationship using state-of-the-art techniques to evaluate associations between body fat distribution and plasma testosterone (T) levels in older postmenopausal women.

Design: Observational, cross-sectional study of healthy, community dwelling postmenopausal women.

Patients And Measurements: Postmenopausal women (60-80 years old) were included in this study. Overall body composition was evaluated by dual-energy X-ray absorptiometry. Abdominal and thigh fat depots were measured by magnetic resonance imaging. Circulating T concentrations were analysed by liquid chromatography-tandem mass spectrometry.

Results: Thirty-five women (66.6 ± 0.8 years) participated in this study. T levels were positively associated with clinical proxy measures of adiposity including weight (ρ = 0.39), BMI (ρ = 0.43) and waist circumference (ρ = 0.39) (all P < 0.05). Fat mass and % body fat were correlated with T levels (ρ = 0.42 and 0.38 respectively, both P < 0.05). T correlated with overall and superficial abdominal fat (ρ = 0.34 and 0.37 respectively, both P < 0.05) but not with visceral adipose tissue. T increased with greater thigh fat (ρ = 0.49, P < 0.05) in both superficial and deep depots (ρ = 0.50 and 0.35 respectively, both P < 0.05).

Conclusion: Our results suggest that postmenopausal women with higher circulating T levels have both higher regional and overall body adiposity. These findings underscore the sexual dimorphism in the relationship between serum androgen levels and adiposity.
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http://dx.doi.org/10.1111/cen.13921DOI Listing
March 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

Acceptance of the Advanced Practice Nurse in Lung Cancer Role by Healthcare Professionals and Patients: A Qualitative Exploration.

J Nurs Scholarsh 2018 09 22;50(5):540-548. Epub 2018 Jul 22.

Institute of Higher Education and Research in Healthcare, Faculty of Biology and Medicine, University of Lausanne, and Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland.

Purpose: The purpose of this study was to explore the acceptance of a novel role, the advanced practice nurse in lung cancer (APNLC), from the perspective of patients and healthcare professionals in a country lacking a regulatory oversight for advanced practice nursing (APN) roles.

Methods And Design: This study utilized a qualitative methodology using focus groups and semistructured interviews. Participants were purposively sampled in a Swiss academic medical center. Two focus groups were conducted: the first included nurses (n = 5) and the social worker, while the second targeted physicians (n = 6). The APNLC and patients (n = 4) were interviewed using semistructured interviews. Data were analyzed using thematic content analysis.

Findings: Three main themes were identified: APNLC role identification, APNLC role-specific contributions, and APNLC flexible service. Physicians and patients clearly recognized the APNLC role, noting contributions to continuity of care, psychosocial support, and enabling symptom self-management. Nurses perceived the APNLC role as overlapping with the oncology nurse role. Flexibility in providing care was seen as the strength of the APNLC role, yet this also posed organizational challenges.

Conclusions: The new role appears to be well accepted by patients and physicians, yet barriers posed by nursing colleagues remain challenging.

Clinical Relevance: Based on existing literature and the present findings, we propose a model to guide future implementation and enhance acceptance of the APNLC role. This model comprises three actions: (a) formalizing nursing role expectations, (b) providing appropriate support and resources, and (c) promoting a national plan for APN regulation.
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http://dx.doi.org/10.1111/jnu.12411DOI Listing
September 2018

Accuracy, satisfaction and usability of a flash glucose monitoring system among children and adolescents with type 1 diabetes attending a summer camp.

Pediatr Diabetes 2018 11 31;19(7):1276-1284. Epub 2018 Jul 31.

Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.

Background: The study aimed to assess accuracy, satisfaction and usability of a flash glucose monitoring system (FGM) in children and adolescents with type 1 diabetes mellitus (T1DM) attending a diabetes summer camp.

Methods: Sixty-six children and adolescents with T1DM aged 6 to 17 years participating in a 7-day medically supervised summer camp were enrolled. Capillary blood glucose (BG) and flash glucose (FG) values were measured simultaneously at breakfast, lunch, and dinner and for any given FG value <72 mg/dL (<4.0 mmol/L) during daytime, <108 mg/dL (<6.0 mmol/L) at nighttime, >270 mg/dL (>15.0 mmol/L) or when patient symptoms were discordant with sensor readings. Sensor-related issues were documented and patients' and healthcare professionals' (HCPs) satisfaction was evaluated.

Results: FGM demonstrated satisfactory clinical accuracy compared to reference capillary BG values with 98.8% of values falling within the clinically acceptable zones (A and B) of the consensus error grid. Overall mean absolute relative difference (MARD) was 16.7% ± 16.1%. Specific calculations of mean absolute difference (MAD), mean relative difference (MRD), and mean difference (MD) demonstrated that FGM overestimated BG values across all glycemic ranges. Overall satisfaction with the FGM was high in 91.7% participants and 95.0% HCPs, although confidence in the system was low in 18.0% participants and 40.0% HCPs.

Conclusions: The FGM exhibited satisfactory clinical accuracy. However, based on the present data, we conclude that no decision should be taken on the basis of a single, non-verified, FGM value alone. Our study highlights the need for revised therapeutic education for patients/families and further investigation on the integration of sensor readings in clinical decision-making.
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http://dx.doi.org/10.1111/pedi.12723DOI Listing
November 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

Transition of Care from Childhood to Adulthood: Congenital Hypogonadotropic Hypogonadism.

Endocr Dev 2018 8;33:82-98. Epub 2018 Jun 8.

Passage from childhood to adult life involves biological changes culminating in full reproductive capacity as well as psychosocial development. For patients with congenital hypogonadotropic hypogonadism (CHH), this can be an emotionally challenging time as their pubertal failure results in striking physical differences from their peers. CHH is difficult to differentiate from common disorders of puberty such as constitutional delay of growth and puberty. As such, delays in diagnosis are frequent, and it is a common source of stress and frustration for these adolescents. While effective treatments are available for inducing puberty and attaining fertility is possible in most cases, patients may find it difficult to cope with living with CHH. A critical issue for adolescents with CHH is the risk for being lost to follow-up during the transition from pediatric-centered care to adult care. This article will review the state of the art in diagnosis and treatment of patients with CHH with a particular focus on supporting an effective transition from pediatric-centered care to adult-oriented endocrine services. A synthesis of best practices is offered to help guide clinicians in supporting patients and families during this challenging period of care.
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http://dx.doi.org/10.1159/000487527DOI Listing
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.

Service of EndocrinologyDiabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland

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

Patient Perspectives on Nurse-led Consultations Within a Pilot Structured Transition Program for Young Adults Moving From an Academic Tertiary Setting to Community-based Type 1 Diabetes Care.

J Pediatr Nurs 2018 Jan - Feb;38:99-105. Epub 2017 Dec 6.

University of Lausanne Institute of Higher Education and Research in Healthcare, Lausanne, Switzerland; Centre Hospitalier Universitaire Vaudois (CHUV) Endocrinology, Diabetes and Metabolism Service, Lausanne, Switzerland. Electronic address:

Purpose: We aimed to evaluate patient self-management activities, patient perceptions of the therapeutic relationship and satisfaction with nurse-led consultations as part of a structured, pilot program transitioning young adults with type 1 diabetes (T1DM) to adult-oriented community-based practices.

Design And Methods: A descriptive, cross-sectional study of patients receiving nurse-led consultations. Patients provided sociodemographic/health information, glycated hemoglobin (HbA1c) measures and completed questionnaires assessing self-management (Revised Self-Care Inventory) and the therapeutic relationship (Caring Nurse-Patient Interaction - short scale). HbA1c values were compared to guideline recommendations.

Results: Twenty patients participated. HbA1c was ≤7.5% in 3/14 (21%) and 5/14 (36%) exhibited poor glycemic control (≥9.5%). The greatest concordance for self-care was in relation to insulin therapy (4.5±0.5) while patients reported the lowest adherence to diet recommendations (2.9±0.8). Overall satisfaction with nurse-led consultations was high (4±0.5 out of 5). Patients considered diabetes knowledge and technical competence as very important and were most pleased with the humanistic aspects of nursing care. Respect for privacy was deemed the most important (and most frequently observed) nursing attitude/behavior during consultations.

Conclusions: Young adults found the nurse-led consultations with therapeutic education to develop T1DM self-care skills are an important complement to medical management during transition.

Practice Implications: Patient autonomy and privacy should be respected during this developmental period. Nurses taking a humanistic approach towards accompanying and supporting the patient can enhance the therapeutic relationship during transition and promote continuity of care. Transition nurses can use technical competence and therapeutic education to empower patients for self-management.
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http://dx.doi.org/10.1016/j.pedn.2017.11.015DOI Listing
September 2018

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing.

Eur J Endocrinol 2018 Mar 12;178(3):R55-R80. Epub 2018 Jan 12.

University of Paris-Sud, Paris-Sud Medical School, Le Kremlin-Bicêtre, France.

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women. However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation. These are genetic diseases that can be transmitted to patients' offspring. Importantly, patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex; oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing and is increasingly being used in medical practice. Thus, it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission and also its role in incomplete penetrance and variable expressivity in a perspective of genetic counseling.
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http://dx.doi.org/10.1530/EJE-17-0749DOI Listing
March 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

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