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Khyatisha Seejore, Marilena Giannoudi, Djoah Osborn, Julie M Lynch, Ahmed Al-Qaissi, Elaine Dunwoodie, Jane Hook, Maria Marples, and Robert D Murray

Context: Use of the CTLA4 inhibitor, ipilimumab, has proven efficacious in treatment of melanoma, renal carcinoma and non-small cell lung cancer, however, is associated with frequent immune-related adverse events (irAE). Ipililumab-induced hypophysitis (IIH) is a well-recognized and not infrequent endocrine irAE.

Objective: To investigate the timing of onset and severity of adrenal and thyroid hormone dysfunction around the development of IIH in patients treated for melanoma.

Design: Retrospectively review of hormone levels in consecutive adult patients treated with ipilimumab (3mg/kg) for advanced melanoma as monotherapy or in combination with a PD-1 inhibitor.

Results: Of 189 patients, 24 (13%; 13 males; 60.5±12.2 years) presented with IIH at a median of 16.1 (range: 6.7-160) weeks after commencing treatment, occurring in 14 (58%) after the fourth infusion. At presentation of IHH, corticotroph deficiency was characterised by an acute and severe decrease in cortisol levels to ≤83 nmol/l (≤3μg/dL) in all patients, often only days after a previously recorded normal cortisol level. Free T4 levels were observed to decline from 12 weeks prior to the onset of cortisol insufficiency, with recovery of thyroid hormone levels by 12 weeks after presentation of IIH. A median fall in fT4 level of 20% was observed at a median of 3 weeks (IQR: 1.5-6 weeks) prior to the diagnosis of IIH.

Conclusion: IIH is characterised by an acute severe decline in cortisol levels to ≤83 nmol/l at presentation. A fall in fT4 can herald the development of ACTH deficiency and can be a valuable early indicator of IIH.

Open access

Alessandro Prete, Richard J Auchus, and Richard J Ross

Background: Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.

Methods: Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.

Summary: Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two Corticotrophin Releasing Factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers whilst patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous subcutaneous infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone which was associated with patient reported benefit including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis blocking drug abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.

Conclusions: CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in those not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies, are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Open access

Alexandra Kautzky-Willer

In this SARS-COV2-pandemic, diabetes mellitus (DM) soon emerged as one of the most prominent risk factors for a severe course of corona virus disease-2019 (COVID-19) and increased mortality due to hyperglycemia/insulin resistance, obesity, inflammation, altered immune status, and cardiovascular complications. In general, men are at a higher risk of severe or fatal COVID-19 disease irrespective of age, region and despite comparable infection rates in both sexes. In COVID-19, there is also a male predominance among hospitalized patients with diabetes, however, overall, data among patients with diabetes are ambiguous so far. Of note, similar to cardiovascular complications, women with type 2 diabetes (DM2) appear to lose their biological female advantage resulting in comparable death rates to those of men. The complex interplay of biological and behavioral factors, which may put men at greater risk of a severe or fatal course of COVID-19, and gender-related psychosocial factors, which may cause disadvantage to women concerning the infection rates, might explain why sex-disaggregated data among infected patients with diabetes are conflicting. Better knowledge on biological factors leading to functionally different immune responses and of gender-sensitive sociocultural determinants of COVID-19 infection rates may help to optimize prevention and management in the high-risk groups of men and women with diabetes.

Open access

Yongze Li, Zhongyan Shan, and Weiping Teng

Objective: Longitudinal studies have investigated the effects of changing iodine status on thyroid disorders, but the effect of a transition from more than adequate iodine to adequate iodine on national changes in prevalence adjusted for changing risk factors remains unclear.

Design: Two repeat nationwide surveys were conducted from 2009-2010 to 2015-2017 to assess changes in thyroid disorder prevalence and iodine status in China.

Methods: A multistage stratified random sampling method was used to obtain a nationally representative sample of urban adults aged 18 and older in mainland China in 2009 (n=14925) and 2015 (n=12553). Changes in thyroid disorder prevalence, urinary iodine concentration (UIC), and thyroid-stimulating hormone (TSH) levels were assessed. Logistic regression models were used to examine changes in prevalence over time.

Results: The median UIC decreased significantly from 219.7 to 175.9 μg/L (P<0.0001). The weighted prevalence of overt hyperthyroidism, subclinical hyperthyroidism, Graves’ disease, and goitre decreased between 2009 and 2015 in the overall population (P<0.05 for all). Despite no significant changes in subclinical hyperthyroidism or hypothyroidism or anti-thyroid peroxidase or anti-thyroglobulin antibody positivity prevalence, a significant increase in thyroid nodule prevalence (P<0.0001) was found in the overall population. The 2.5th TSH percentile increased by 0.15 mIU/L (95%CI, 0.01 to 0.30 mIU/L, P=0.04) from 2009 to 2015.

Conclusions: With the iodine status transition from more than adequate to adequate, thyroid disorder (except for thyroid nodules) prevalence remained stable or even decreased after adjusting for confounding factors among adults in mainland China between 2009 and 2015. Additional studies are needed to explore the reasons for the increased thyroid nodule prevalence.

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Amanda Sampaio Mangolim, Leonardo de Andrade Rodrigues Brito, and Vania dos Santos Nunes-Nogueira

Objective: This systematic review evaluated the effect of testosterone replacement therapy (TRT) in men with obesity having low testosterone levels (LTLs).

Design and methods: Search strategies were performed in MEDLINE, Embase, LILACS, and CENTRAL databases. Two reviewers selected the studies, assessed the risk of bias, and extracted data from the included studies. A random-effects model was used to pool results across studies and the Grading of Recommendations Assessment, Development, and Evaluation to evaluate the certainty of evidence.

Results: A total of 16 randomized controlled trials were included. With moderate certainty of the evidence, no difference was found between TRT and placebo regarding total adverse events, TRT led to a 2-kg lean body mass gain and slightly improved low-density lipoprotein (LDL), without effects on the blood pressure. Due to imprecision/heterogeneity, effects in cardiovascular events (relative risk 0.52, 95% CI 0.26 to 1.05, 7 trials, 583 participants), high-density lipoprotein, hematocrit, prostate-specific antigen, HbA1c, and quality of life were unclear. TRT was effective for waist circumference and body mass index; however, large between-study heterogeneity was found, with 95% prediction intervals crossing the null effect line. Meta-regression revealed that the average age of participants was a significant modifier for both outcomes.

Conclusion: TRT slightly improved the lean body mass and LDL in men with obesity having LTLs, but did not affect the blood pressure. The effects of TRT on cardiovascular events, HbA1c, and quality of life are unclear. The mean age of participants significantly modified the effect of TRT on weight loss.

Open access

Tansit Saengkaew, Heena R Patel, Kausik Banerjee, Gary Butler, Mehul T Dattani, Michael McGuigan, Helen L Storr, Ruben H Willemsen, Leo Dunkel, and Sasha R Howard

Context

Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective

To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients.

Design

Retrospective study.

Methods

Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results

Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion

This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

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James Nolan, Purdey J Campbell, Suzanne J Brown, Gu Zhu, Scott Gordon, Ee Mun Lim, John Joseph, Simone M Cross, Vijay Panicker, Sarah E Medland, Phillip E Melton, Lawrence J Beilin, Trevor A Mori, Benjamin H Mullin, Craig E Pennell, Carol A Wang, Frank Dudbridge, John P Walsh, Nicholas G Martin, and Scott G Wilson

Objective

Genetic factors underpin the narrow intraindividual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance.

Methods

Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9–16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these individuals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study (n = 1115) followed by meta-analysis to maximise power for discovery.

Results

Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7–74.9%) for TSH, 67.5% (59.8–75.3%) for fT4, 59.7% (54.4–65.0%) for fT3 and 48.8% (40.6–56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3, and fT3 and rs12687280 near SERPINA7. Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4.

Conclusion

Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.

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Rui M. B. Maciel and Ana Luiza Maia

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98%, 50% and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants have been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

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Lucía Sentchordi-Montané, Sara Benito-Sanz, Miriam Aza-Carmona, Francisca Díaz-González, Silvia Modamio-Høybjør, Carolina de la Torre, Julián Nevado, Pablo Ruiz-Ocaña, Carolina Bezanilla-López, Pablo Prieto, Pilar Bahíllo-Curieses, Atilano Carcavilla, Inés Mulero-Collantes, Ana C Barreda-Bonis, Jaime Cruz-Rojo, Joaquín Ramírez-Fernández, José Antonio Bermúdez de la Vega, André M Travessa, Jesús González de Buitrago Amigo, Angela del Pozo, Elena Vallespín, Mario Solís, Carlos Goetz, Ángel Campos-Barros, Fernando Santos-Simarro, Isabel González-Casado, Purificación Ros-Pérez, Manuel Parrón-Pajares, and Karen E Heath

Objective

Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies.

Design

Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies.

Methods

A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect.

Results

Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without.

Conclusions

A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

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Daniele Cappellani, Alessandro Brancatella, Riccardo Morganti, Simona Borsari, Fulvia Baldinotti, Maria Adelaide Caligo, Martin Kaufmann, Glenville Jones, Claudio Marcocci, and Filomena Cetani

Background and objectives: CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia (IIH), a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies.

Methods: Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31st,2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants.

Results: Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P=0.0005), and nephrocalcinosis was more frequent in infancy (P<0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8%, and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%). The effect size of the most-used medications administered to control hypercalcemia ranged from 18 to 29%.

Conclusions: CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly-variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.