G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. They play a fundamental role in the endocrine system, where they mediate the effects of several hormones and neurotransmitters. As a result, alterations of GPCR signalling are a major cause of endocrine disorders such as congenital hypothyroidism or Cushing’s syndrome. My group develops innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy, which allow us to investigate GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using this innovative approach, we have contributed to elucidate some long debated questions about the mechanisms of GPCR signalling and their involvement in human disease. Among other findings, these studies have led to the unexpected discovery that GPCRs are not only signalling at the cell surface, as previously assumed, but also at various intracellular sites. This has important implications to understand how hormones and neurotransmitters produce specific responses in our cells and might pave the way to innovative treatments for common diseases like diabetes or heart failure.
Alexander A Leung, Janice L Pasieka, Martin D Hyrcza, Danièle Pacaud, Yuan Dong, Jessica M Boyd, Hossein Sadrzadeh, and Gregory A Kline
Objective: Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data.
Design: Population-based cohort study in Alberta, Canada from 2012 to 2019.
Methods: Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100,000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated.
Results: A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5,196,368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100,000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60 to 79 years (8.85 and 14.68 cases per 100,000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >2-fold or normetanephrine >3-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100,000 people per year.
Conclusion: The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.
Stephanie A Roberts and Ursula B Kaiser
Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader–Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.
Grégory Mougel, Arnaud Lagarde, Frédérique Albarel, Wassim Essamet, Perrine Luigi, Céline Mouly, Magaly Vialon, Thomas Cuny, Frédéric Castinetti, Alexandru Saveanu, Thierry Brue, Anne Barlier, and Pauline Romanet
The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.
To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.
Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome.
A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.
We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.
Claudia Giavoli, Eriselda Profka, Noemi Giancola, Giulia Rodari, Federico Giacchetti, Emanuele Ferrante, Maura Arosio, and Giovanna Mantovani
Sara De Vincentis, Maria Chiara Decaroli, Flaminia Fanelli, Chiara Diazzi, Marco Mezzullo, Fabio Morini, Davide Bertani, Jovana Milic, Federica Carli, Gianluca Cuomo, Daniele Santi, Giulia Tartaro, Simonetta Tagliavini, Maria Cristina De Santis, Laura Roli, Tommaso Trenti, Uberto Pagotto, Giovanni Guaraldi, and Vincenzo Rochira
Hypogonadism is common in HIV-infected men. The relationship between health status, sex steroids and body composition is poorly known in HIV. The aim was to investigate the association between health status (comorbidities/frailty), body composition, and gonadal function in young-to-middle-aged HIV-infected men.
Prospective, cross-sectional, observational study.
HIV-infected men aged<50 years and ongoing Highly Active Antiretroviral Therapy were enrolled. Serum total testosterone (TT), estradiol (E2), estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, LH and FSH by immunoassay. Free testosterone (cFT) was calculated by Vermeulen equation. Body composition was assessed by dual-energy X-ray absorptiometry and abdominal CT scan. Multimorbidity (MM) and frailty were defined as ≥3 comorbidities and by a 37-item index, respectively.
A total of 316 HIV-infected men aged 45.3±5.3 years were enrolled. Body fat parameters were inversely related to cFT and TT, and directly related to E1 and E2/T ratio. Patients with MM had lower cFT (p<0.0001) and TT (p=0.036), and higher E1 (p<0.0001) and E2/T ratio (p=0.002). Frailty was inversely related to cFT (R2=0.057, p<0.0001) and TT (R2=0.013, p=0.043), and directly related to E1 (R2=0.171, p<0.0001), E2 (R2=0.041, p=0.004) and E2/T ratio (R2=0.104, p<0.0001).
Lower TT and cFT, higher E1, E2/T ratio and visceral fat were independently associated to poor health status and frailty, being possible hallmarks of unhealthy conditions in adult HIV-infected men. Overall, MM, frailty and body fat mass are strictly associated to each other and to sex steroids, concurring together to functional male hypogonadism in HIV.
Matteo Rottoli, Paolo Bernante, Angela Belvedere, Francesca Balsamo, Silvia Garelli, Maddalena Giannella, Alessandra Cascavilla, Sara Tedeschi, Stefano Ianniruberto, Elena Rosselli Del Turco, Tommaso Tonetti, Vito Marco Ranieri, Gilberto Poggioli, Lamberto Manzoli, Uberto Pagotto, Pierluigi Viale, and Michele Bartoletti
Specific comorbidities and old age create a greater vulnerability to severe Coronavirus Disease 19 (COVID-19). While obesity seems to aggravate the course of disease, the actual impact of the BMI and the cutoff which increases illness severity are still under investigation. The aim of the study was to analyze whether the BMI represented a risk factor for respiratory failure, admission to the intensive care unit (ICU) and death.
Research design and methods:
A retrospective cohort study of 482 consecutive COVID-19 patients hospitalised between March 1 and April 20, 2020. Logistic regression analysis and Cox proportion Hazard models including demographic characteristics and comorbidities were carried out to predict the endpoints within 30 days from the onset of symptoms.
Of 482 patients, 104 (21.6%) had a BMI ≥ 30 kg/m2. At logistic regression analysis, a BMI between 30 and 34.9 kg/m2 significantly increased the risk of respiratory failure (OR: 2.32; 95% CI: 1.31–4.09, P = 0.004) and admission to the ICU (OR: 4.96; 95% CI: 2.53–9.74, P < 0.001). A significantly higher risk of death was observed in patients with a BMI ≥ 35 kg/m2 (OR: 12.1; 95% CI: 3.25–45.1, P < 0.001).
Obesity is a strong, independent risk factor for respiratory failure, admission to the ICU and death among COVID-19 patients. A BMI ≥ 30 kg/m2 identifies a population of patients at high risk for severe illness, whereas a BMI ≥ 35 kg/m2 dramatically increases the risk of death.
Bastiaan Sol, Jeroen M.k. de Filette, Gil Awada, Steven Raeymaeckers, Sandrine Aspeslagh, C.e. Andreescu, Bart Neyns, and Brigitte Velkeniers
Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.
We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.
Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.
ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.
Cécile Thomas-Teinturier, Isabelle Oliver-Petit, Helene Pacquement, Brice Fresneau, Rodrigue Sétchéou Allodji, Cristina Veres, Stephanie Bolle, Delphine Berchery, Charlotte Demoor-Goldschmidt, Nadia Haddy, Ibrahima Diallo, and Florent de Vathaire
Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN).
To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986.
Design and setting:
Cohort study and nested case–control study.
Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years).
Main outcome measures:
Occurrence of SN
In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2–1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4–1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9–4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2–3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9–5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case–control study.
This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.
Camille Sollier, Emilie Capel, Caroline Aguilhon, Vasily Smirnov, Martine Auclair, Claire Douillard, Myriam Ladsous, Sabine Defoort-Dhellemmes, Jennifer Gorwood, Laura Braud, Roberto Motterlini, Camille Vatier, Olivier Lascols, Eric Renard, Corinne Vigouroux, and Isabelle Jéru
The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants.
A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue.
We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudolipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction.
Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.