Pituitary adenomas (PAs) are rare in pediatric patients, with limited data. The study aimed to describe the specific characteristics of pediatric PAs and highlight the challenges in their management. We conducted a retrospective review of patients diagnosed with PAs before age 18, who were followed at the reference center in Lyon, France, between 2010–2023. 29 patients (19 females) were identified. Median age at diagnosis was 14 years (range: 10-17). 19 patients had prolactinomas, 4 corticotropinomas, 3 somatotropinomas and 3 non-functioning pituitary adenomas (NFPAs). The mean diagnosis delay was 13 months (median: 6, range: 0-70). The most common symptoms were headaches (34

Objectives To analyse genetic mechanisms triggering familial sarcoidosis, whole exome screening of a family of six persons with four cases of sarcoidosis and two healthy controls was performed integrating progressive and spontaneous remission cases and evaluating involved genetic alterations that could potentially determine the individual course of the disease. Methods Clinical diagnostic criteria in patients of the selected sarcoidosis family were according to American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders guidelines. Exome screening of four patients and the two intrafamilial healthy relatives was performed by paired-end (2 x 100 bp) sequencing. We then selected the gene variants considered pathogenic on the basis of a series of prediction software applications and presence only in members of the family affected by sarcoidosis, after subtracting the common variations observed in healthy subjects. Results Four persons out of six family members were affected by sarcoidosis. Fifty genes with uncommon in silico pathogenic variants could be identified that differentiated affected and healthy family members. One patient with sarcoidosis showed spontaneous remission whereas the remaining three patients required immunosuppressive treatment. Subtraction analysis revealed 18 genes that distinguished the three progressive cases from the patient with spontaneous remission. Conclusion The genetic analysis of these cases with familial sarcoidosis identified several involved genes and functional pathways that could help in understanding the basic mechanisms that determine the development of the disease and that discriminate spontaneously regressive and progressive forms.

Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand whether macrophages from patients with nonresolving chronic sarcoidosis are predisposed to macrophage aggregation and granuloma formation and whether modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses and phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from patients with sarcoidosis and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas in vitro compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients.

Background: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France. Methods: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorit ' e de Sant ' e and following international guide-lines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases. Results: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lym-phangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications. Conclusion: These recommendations are intended to guide the diagnosis and practical management of pul-monary lymphangioleiomyomatosis. (c) 2023 SPLF and Elsevier Masson SAS. All rights reserved.

PDF file, 764K, BRCA2 exon 12 to exon 13 gene, transcript and protein sequences (Supp Fig 1); Enhancer motifs contained within the cryptic exon and the constitutive surrounding exons (Supp Fig 2); Conservation of the cryptic exon across species (Supp Fig 3); Primers used for BRCA1 and BRCA2 routine mRNA analyses (Supp Table 1).

La sarcoïdose est une maladie inflammatoire systémique caractérisée par la formation de granulomes épithélioïdes et gigantocellulaires dans divers organes, principalement le parenchyme pulmonaire et les ganglions lymphatiques intrathoraciques. La physiopathologie de la sarcoïdose et notamment son primum movens restent encore mal connus, mais l’hypothèse la plus largement acceptée aujourd’hui suppose un défaut de clairance antigénique (concernant des antigènes microbiens ou minéraux) chez des individus génétiquement prédisposés. Les avancées du séquençage à haut débit a par ailleurs permis la mise en évidence d’une accumulation de variants pathogènes dans les voies de signalisation de l’autophagie, de la mitophagie et de mTOR (inhibitrice de l’autophagie et de la mitophagie) chez les patients porteurs de sarcoïdose [1]. Des lignées de cellules lymphoblastoïdes ont été générées à partir de cellules mononucléées de sang périphérique de patients issue d’une famille porteuse de sarcoïdose (trois patients sarcoïdose, deux contrôles intrafamiliaux et un contrôle extra familial). Cette famille a été sélectionnée au sein de la cohorte SARCFAM (cohorte rassemblant des cas de sarcoïdose groupés sur le plan familial à l’échelon national). L’aspect au repos des lignées lymphoblastoïdes ont été évaluées en premier lieu par microscopie électronique à transmission. Le métabolisme mitochondrial dans ces lignées cellulaires a été évalué par technologie seahorse (consommation d’oxygène et glycolyse). Le pool d’ADN mitochondrial (mtDNA) de ces lignées a également été quantifié à l’état basal et en réponse à un stimulus chimique (arséniate de sodium). L’expression génique et protéique des gènes associés au stress oxydatif et à l’autophagie ont également été évalués respectivement en PCR quantitative et par Western Blot. En microscopie électronique, on notait la présence de cellules porteuses de mitochondries altérées (cristae irrégulières) était notée dans le groupe sarcoïdose. Les taux de consommation d’oxygène (OCR) étudiés en seahorse était inférieurs chez les contrôles en comparaison aux patients porteurs de sarcoïdose. Ces OCR étaient inférieurs dans toutes les configurations de mesures relatives aux OCR mitochondriaux (OCR basal, OCR lié à la synthèse d’ATP et l’OCR maximal, p < 0,05). L’OCR non mitochondrial (OCR lié aux réactions d’oxydoréduction intracellulaires) était similaire dans les deux groupes. La production totale d’ATP était diminuée dans le groupe sarcoïdose et était liée à une diminution de la production d’ATP glycolyse-dépendante (p < 0,01). La quantification du mtDNA avant et après la stimulation des lignées lymphoblastoïdes montrait une accumulation de mtDNA en réponse à la stimulation par arséniate chez les patients porteurs de sarcoïdose et cette différence n’était pas visualisée de manière significative chez les contrôles. Après stimulation par arséniate, on observait une augmentation de l’expression de gènes associés au stress oxydatif et à l’autophagie (SQSTM1/NRF2) dans le groupe sarcoïdose, sans que cette augmentation puisse être visualisée chez les contrôles (p < 0,01). En western blot, il a été mis en évidence un effondrement des taux de TOMM20 (un marqueur de membrane mitochondriale), de BNIP3L sous forme non monomérique (mitophagie PARKIN indépendante) et de PINK1 (mitophagie PARKIN dépendante) (p < 0,01). Des différences en termes de morphologie, de métabolisme et de respiration mitochondriale ont pu être mises en évidence au sein de cette famille chez les individus porteurs de sarcoïdose. Les anomalies de structure mitochondriale ont déjà pu être observées en microscopie électronique dans des cellules endothéliales bronchiques dans une population de patients avec sarcoïdose [2]. L’accumulation de mtDNA avait également déjà été mise en évidence dans la cohorte GRADS, dans le liquide de LBA de malades [3]. Ces résultats contribuent au faisceau d’argument impliquant la dysfonction mitochondriale dans la physiopathologie de la sarcoïdose. Il n’est pour le moment pas possible de dire si cette dysfonction est le primum movens de la génération du granulome ou si elle contribue à l’entretien de la réaction inflammatoire (notamment par l’accumulation des ROS cytosoliques, de mtDNA oxydé et par l’activation de NLRP3 et NFkB par ces derniers). Il existe chez les patients porteurs de sarcoïdose des différences en termes de morphologie et de métabolisme mitochondrial. Ces différences pourraient être liées à une mitophagie déficiente qui empêcherait la dégradation de mitochondries défectueuses.

The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.

Introduction: Sarcoidosis is a systemic inflammatory disease characterized by granuloma formation in various organs, primarily the lungs and intrathoracic lymph nodes. Its etiology remains unknown to this day, but recent omics data have allowed to target specific signaling pathways and to progress more rapidly in translational research. Methods: EBV-immortalized lymphoblastoid cell lines were obtained from B lymphocytes of patients from a family of the French SARCFAM cohort of familial sarcoidosis cases. These cell lines were used for a whole exome study (Calender et al. Eur Resp J 2019) showing an accumulation of mutations in the autophagy/mitophagy pathways. Autophagic flux as well as mitochondrial respiration were studied in LCLs from a patient family with 3 patients, 2 healthy internal controls and 1 external control. Results: Autophagy expression was studied by western blot and RTqPCR. No significant difference in flux could be demonstrated between patients and controls. However, an increase in the transcription of genes associated with oxidative stress and mitophagy was observed in RTqPCR in patients with sarcoidosis in response to sodium arseniate, to a greater extent than that observed in controls. There was also an accumulation of mitochondrial genetic material under chemical stress and impaired mitochondrial respiration among patients. Conclusion: Omics data and especially the whole exome with the study of genetic predisposition of patients allows progress from a translational research point of view. This approach is probably the most adapted to the study of multifactorial diseases for which genetic data should allow a better understanding of the host-environment interaction that is at the origin of the disease.

PALB2 (partner and localizer of BRCA2), as indicated by its name, is a BRCA2-interacting protein that plays an important role in homologous recombination (HR) and DNA double-strand break (DSB) repair. While pathogenic variants of PALB2 have been well proven to confer an increased risk of breast cancer, data on its involvement in prostate cancer (PrC) have not been clearly demonstrated. We investigated, using targeted next generation sequencing (NGS), a 59-year-old Caucasian man who developed synchronous breast and prostate cancers. This genetic investigation allowed to identify an intragenic germline heterozygous duplication in PALB2, implicating intronic repetitive sequences spanning exon 11. This variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints have been identified and characterized at the nucleotide level (c.3114-811_3202-1756dup) using an approach based on walking PCR, long range PCR, and Sanger sequencing. RT-PCR using mRNA extracted from lymphocytes and followed by Sanger sequencing revealed a tandem duplication r.3114_3201dup; p.(Gly1068Glufs * 14). This duplication results in the synthesis of a truncated, and most-likely, non-functional protein. These findings expand the phenotypic spectrum of PALB2 variants and may improve the yield of genetic diagnoses in this field.

Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours (NETs) and/or pituitary adenomas. MEN1 can predispose patients to other endocrine and non-endocrine tumours, such as cutaneous tumours, central nervous system tumours and breast cancer. Endocrine tumours in patients with MEN1 differ from sporadic tumours in that they have a younger age at onset, present as multiple tumours in the same organ and have a different clinical course. Therefore, patients with overt MEN1 and those who carry a MEN1 mutation should be offered tailored biochemical and imaging screening to detect tumours and evaluate their progression over time. Fortunately, over the past 10 years, knowledge about the clinical phenotype of these tumours has markedly progressed, thanks to the implementation of national registries, particularly in France and the Netherlands. This Review provides an update on the clinical management of MEN1-related tumours. Epidemiology, the clinical picture, diagnostic work-up and the main lines of treatment for MEN1-related tumours are summarized. Controversial therapeutic aspects and issues that still need to be addressed are also discussed. Moreover, special attention is given to MEN1 manifestations in children and adolescents.

Introduction: Previous genomic studies suggested that impaired autophagy could promote sarcoidosis (Pacheco et al. Trends Immunol 2020; 41: 286–299). Autophagy can be altered in nongranulomatous neurological disorders (NGND) such as frontotemporal dementia (FTD) or Parkinson’s disease (PD) in which the accumulation of proteins such as α-synuclein due to an mitophagy defect had been suggested. Methods: We performed a whole exome sequencing (WES) study of sarcoidosic patients in the SARCFAM (familial sarcoidosis) cohort (familial sarcoidosis). In order to distinguish potentially pathogenic variants, a genomic subtraction with internal controls among siblings in each family was performed. Results: We focused on seven patients with NGND and sarcoidosis association out of the SARCFAM cohort (Calender et al. Eur Respir J 2019; 54). Patients were experiencing various NGND such as neurodegenerative (FTD, PD) or inflammatory disorders (encephalomyelitis). Accumulation of rare (minor allele frequency < 0.01) pathogenic variants (SIFT score < 0.400, Polyphenv2 score < 0.05) were found in genes involved in mitophagy, interleukin-17 signaling, Ras signaling, lysosomal and autophagy pathways (respective OR=33.28, 23.01, 14.37, 17.28 and 16.59, p<0.05) according to the Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis. Several genes (LRRK2, PARK7, DDIT4) are also suspected to have a role in PD. Conclusion: These data suggest that sarcoidosis and NGND are at a crossroads of auto/mitophagy dysregulation and that the accumulation of pathogenic variants could promote both diseases.

Introduction: Recent genetic studies by Whole Exome Sequencing (WES) in familial forms of sarcoidosis allowed the characterization of genes encoding factors involved in innate immunity and autophagy, mainly around mTOR and Rac1 hubs. The pandemic generated by the SARS CoV2 virus raises the question of the susceptibility of sarcoidosis patients with genetic defects to COVID-19. Aims and Objectives: We compared a panel of genes (named SARC-COV) mutated in familial forms of sarcoidosis to the 332 genes published in SARS-CoV2 interactome analysis (Gordon et al., Nature 2020; 583: 459-468), highlighting host-cell proteins which are targets of the structural and non-structural (NSP) proteins during the process of viral infection. Methods: WES was performed in 13 families with at least two first-degree related affected individuals. Selection of genes sharing pathogenic variants was done by various softwares (POLYPHENv2, ALAMUT VISUAL) and the functional evaluation established by ENRICH.R. Results: We have identified 30 SARC-COV genes common to the list of mutated genes in sarcoidosis families and those of the Gordon SARS CoV2 interactome. Gene-set enrichment analysis of the SARC-COV gene panel identified 4 over-represented signaling pathways mediated by 1) retinoic acid-inducible gene 1 (RIG1) like receptor; 2) Toll-like Receptor (TLR3); 3) Interferon Regulatory Factors (IRF3/7) and 4) mitochondrial complex I assembly model OXPHOS system, all closely related to the mitophagy pathway. Conclusion: Our study is the first one searching genetic factors which could be related to the susceptibility of sarcoidosis patients to SARS-CoV2 infection and mainly severe forms of COVID-19

Introduction: The incidence of Cryptococcus infections (CI) is increased in sarcoidosis (Bernard et al. QJM 2013;106). There is no explanation for this increased risk of opportunistic infections in sarcoidosis. Methods: We present the results of a whole exome sequencing (WES) of a patient with a history of sarcoidosis and CI at the age of 18. The sarcoidosis begun with lung and mediastinal involvement rapidly improving under corticosteroids (CS). The patient presented deep lymphopenia which intriguingly did not respond to CS. Seven months later, he developed neuro meningeal CI. Results: In the WES study, variants were considered to be relevant if their minor allele frequency was under 0.01. Pathogenicity was determined in silico with Sift and Polyphenv2. We found a pathogenic variant of FER which encodes a STAT3 regulating kinase and CARMIL2 which regulates Rac1, a major negative regulator of autophagy, and interleukin-2 (IL-2) pathway. Our patient presented impaired T-cell proliferation to phytohemagglutinin and/or IL-2 although IL-2R was normally expressed among T cells. He was unresponding to rhIL-2 suggesting an intracellular pathway deficiency. FER regulates IL-2 through STAT3 which activates IL-2 promoter. Moreover, CARMIL2 deficiency is associated with immunodeficiency in humans (Schober et al. Nat Commun 2017;8). Finally, CARMIL2 interacts with CD28, a co-signaling element in T cells, which function could be impaired in sarcoidosis patients. Conclusion: We speculate that IL-2 axis dysregulation through the accumulation of pathogenic variants in IL-2 regulating genes is responsible for our patient immunodeficiency. This provides clues to understand the subjacent immunosuppression in sarcoidosis.

La sarcoïdose est une granulomatose systémique d’étiologie indéterminée [1]. De nombreux cas et des séries d’infections opportunistes (IO) chez des patients atteints de sarcoïdose sont rapportés dans la littérature médicale [2], [3]. Sont généralement exclues les aspergilloses cavitaires et les tuberculoses, associées respectivement à la fibrose et à des éléments démographiques communs. Les agents opportunistes rapportés sont variés (Cryptococcus neoformans, JC virus, mycobactéries atypiques, Nocardia spp.) mais actuellement aucun facteur de risque d’infection opportuniste n’est décrit au cours de la sarcoïdose. Nous avons effectué un recueil de la littérature médicale via le moteur de recherche Medline et réalisé un appel à observations via le groupe sarcoïdose francophone à la recherche d’associations « infection opportuniste » et « sarcoïdose ». Les caractéristiques cliniques des IO ont été comparées à une population témoin constituée de patients porteurs d’une sarcoïdose sans IO issus d’une cohorte de notre service. La revue de la littérature a permis de recenser 164 cas d’infections qualifiées d’opportunistes chez des patients porteurs d’une sarcoïdose. Parmi ces 164 infections, 83 étaient des cryptococcoses (51 %) et 39 étaient des leuco-encéphalopathies multifocales progressives (LEMP) (24 %). Notre appel à observations a permis de recenser 50 IO chez 49 patients, incluant : 24 cryptococcoses (49 %), 12 LEMP (24 %), 7 pneumocystoses (14 %) et 7 autres infections (14 %) dont 3 mycobactérioses atypiques, 2 nocardioses et 2 infections à cytomégalovirus. Ces 49 patients avec IO ont été comparés à 135 contrôles porteurs d’une sarcoïdose sans IO. Dans le groupe infection opportuniste, le compte lymphocytaire moyen était de 1000/mm3 (100-2680/mm3) et 14 patients ne présentaient pas de lymphopénie (29 %). Les facteurs de risques identifiés en analyse univariée étaient : le sexe masculin (OR = 4,76; IC95 % [2,12 ; 10,00]), la présence d’adénopathies périphériques (OR = 3,45 ; [1,49 ; 8,04]), d’une hépatomégalie (OR = 8,10 ; [1,91 ; 40,41]) ou d’une splénomégalie (OR = 9,00, [1,80 ; 58,86]), la présence d’une atteinte pulmonaire de stade ≥2 (OR = 6,66 ; [2,80 ; 17,74]), d’une atteinte neurologique centrale (OR = 8,73 ; [1,98 ; 53,52]) ou d’une insuffisance rénale (OR = 5,65 ; [1,33 ; 25,24]), la corticothérapie (OR = 10,26 ; [4,15 ; 29,22]) et l’utilisation du cyclophosphamide (OR = 9,42 ; [1,61 ; 98,92]) ou d’un anti-TNFα (OR = 7,68 ; [1,21 ; 83,62]). En analyse multivariée (ajustement sur l’âge et le sexe), les facteurs de risque identifiés étaient l’utilisation de corticoïdes (OR = 10,60 ; [4,31 ; 29,57]) ou d’un anti-TNFα (OR = 13,47 ; [2,05 ; 129,43]), la présence d’une hépatomégalie (OR = 9,91 ; [2,23 ; 55,85]), une atteinte pulmonaire de stade 2 ou supérieur (OR = 5,65 ; [2,34 ; 15,36]) et l’insuffisance rénale (OR = 11,76 ; [2,32 ; 68,35]). La lymphopénie < 1500/mm3 n’était pas un facteur de risque (OR = 1,49 ; [0,72 ; 3,16]) alors que l’absence de traitement immunosuppresseur ou d’une corticothérapie était un facteur protecteur (OR= 0,13, [0,04 ; 0,33]). Trois patients ont développé une infection opportuniste en l’absence de lymphopénie, de traitement immunosuppresseur ou de corticothérapie (6 %). Chez 11 patients (22 %), l’infection opportuniste et le diagnostic de sarcoïdose ont été concomitants. Les facteurs de risque d’IO dans notre étude sont associés à la gravité de la sarcoïdose et/ou à sa diffusion systémique. Il existe un facteur confondant lié à l’utilisation des immunosuppresseurs chez des patients avec une sarcoïdose plus sévère. Dans notre série, 6 % des patients ont développé une infection opportuniste sans aucun facteur de risque, suggérant néanmoins une immunosuppression propre à la sarcoïdose dans ces cas.

Sarcoidosis is a multi-system disease of unknown etiology characterized by the formation of granulomas in various organs. It affects people of all ethnic backgrounds and occurs at any time of life but is more frequent in African Americans and Scandinavians and in adults between 30 and 50 years of age. Sarcoidosis can affect any organ with a frequency varying according to ethnicity, sex and age. Intrathoracic involvement occurs in 90% of patients with symmetrical bilateral hilar adenopathy and/or diffuse lung micronodules, mainly along the lymphatic structures which are the most affected system. Among extrapulmonary manifestations, skin lesions, uveitis, liver or splenic involvement, peripheral and abdominal lymphadenopathy and peripheral arthritis are the most frequent with a prevalence of 25–50%. Finally, cardiac and neurological manifestations which can be the initial manifestation of sarcoidosis, as can be bilateral parotitis, nasosinusal or laryngeal signs, hypercalcemia and renal dysfunction, affect less than 10% of patients. The diagnosis is not standardized but is based on three major criteria: a compatible clinical and/or radiological presentation, the histological evidence of non-necrotizing granulomatous inflammation in one or more tissues and the exclusion of alternative causes of granulomatous disease. Certain clinical features are considered to be highly specific of the disease (e.g., Löfgren’s syndrome, lupus pernio, Heerfordt’s syndrome) and do not require histological confirmation. New diagnostic guidelines were recently published. Specific clinical criteria have been developed for the diagnosis of cardiac, neurological and ocular sarcoidosis. This article focuses on the clinical presentation and the common differentials that need to be considered when appropriate.

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7-10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mainly affects the lungs. Sarcoidosis is an autoinflammatory disease characterized by the diffusion of granulomas in the lungs and other organs. Here, we discuss how the two diseases might involve some common mechanistic cellular pathways around the regulation of autophagy.

Introduction: Sarcoidosis is a systemic granulomatous disease of unknown etiology mostly affecting lungs and lymph nodes. Previous whole-exome sequencing (WES) studies have shown that autophagy and especially Ras-related C3 botulinum toxin substrate 1 (RAC1) and mammalian target of rapamycin (mTOR) pathways were possibly implicated in sarcoidosis (Pacheco et al. Trends Immunol 2020 Accepted manuscript). Aims: The SARCFAM (familial sarcoidosis) cohort gathered families aggregating sarcoidosis cases. We hypothesized that relevant genes variants in patients with sarcoidosis and uveitis phenotype were also related to autophagy. Methods: A WES study was performed on 20 patients in 6 families out of the SARCFAM cohort compared with 10 internal controls among siblings. 2 genomic subtractions were performed to compare uveitis and sarcoidosis phenotype to sarcoidosis without uveitis phenotype and to healthy controls. Results: 4 of the 20 patients presented uveitis phenotype. In 3 different families, 38, 142 and 104 variants concerning autophagy were found and respectively 12, 40 and 34 were associated with the uveitis clinical phenotype. Most relevant genes were NOD2, UNC93B, NLRP14, UBQLNL and those related to Toll-like receptors (TLR5). All genes were shown to be related to autophagy/mTOR/RAC1 pathways. NLRP14/NOD2 polymorphisms were respectively found to be related to Behçet uveitis and Blau syndrome. These proteins are targets for various environmental antigens (viruses, mycobacteria) suggesting imbrication of genetic predisposition and environmental triggers. Conclusion: Autophagy could be a major key point in the pathophysiology of sarcoidosis and mTOR may represent an interesting target to treat sarcoidosis.