Annales d'endocrinologie最新文献

The technical development of automated Sanger sequencing in the 2000s followed by next-generation sequencing (NGS) in the 2010s, has enabled significant advancements in the molecular diagnosis of inherited diseases. The launch of France's first National Rare Diseases Plan in 2011 further supported the establishment of rare disease centers and networks of rare diseases. Concurrently, NGS platform were integrated into molecular biology laboratories, enabling the first diagnoses using Targeted Exome Sequencing (TES) (gene panel). These approaches have been progressively implemented at very high throughput, evolving from Whole Exome Sequencing (WES, which analyzes all coding regions of the human genome) to Whole Genome Sequencing (WGS), the latter being integrated into the France Genomic Medicine 2025 plan initiated in 2016. In this review, we compare TES, WES, and WGS, and discuss their respective advantages, limitations, and future prospects, as well as their applications in the field of endocrinology.

Introduction: Non-invasive prenatal diagnosis for single-gene disorders (SGD-NIPD) has progressively emerged as a reliable alternative to invasive prenatal procedures in selected high-risk situations. In France, an exclusion strategy targeting paternal or de novo pathogenic variants has been implemented through a coordinated nationwide public network. We report five-year activity data, key technical performance indicators, and future perspectives of this model.

Methods: We conducted a retrospective multicenter study including all exclusion NIPD tests performed within the French public network between January 2017 and January 2026. Variant-specific assays were developed using droplet digital PCR (ddPCR). We analyzed activity trends, indication spectrum, assay availability, diagnostic reliability, and turnaround time.

Results: A total of 2,038 exclusion NIPD tests were performed. Annual activity increased elevenfold between 2017 and 2025, reaching 611 tests in 2025. Indications comprised de novo variants (52%), autosomal recessive conditions (34%), and autosomal dominant disorders (13%). Across four centers, 1,133 validated variant-specific assays are currently available, covering 478 genes. Assay development success rate reached approximately 94%. No false-positive or false-negative results have been reported. The mean turnaround time was 6 days.

Conclusion: Exclusion NIPD for single-gene disorders has achieved nationwide scalability within a public healthcare framework, combining analytical robustness, rapid result delivery, and broad disease coverage. Ongoing developments, including targeted haplotype-based approaches for maternally inherited variants within the national DANNIgene program, aim to extend the scope of non-invasive prenatal diagnosis. These advances may ultimately pave the way toward broader genomic inference strategies while maintaining structured clinical and ethical oversight.

Background: Genome-wide association studies (GWAS) emerged with expectations borrowed from Mendelian genetics, creating a gap between what the method can and cannot deliver. This gap has fuelled both unwarranted dismissal and unwarranted enthusiasm. For endocrine clinicians, the confusion is consequential because GWAS and clinical sequencing answer fundamentally different questions and serve different purposes.

Purpose: This review defines what GWAS is designed to do, clarifies the state of the "missing heritability" debate in 2026, and evaluates the contribution of GWAS to endocrine and cardiometabolic disease biology, including thyroid function, reproductive timing, adrenal steroid traits, type 2 diabetes, and lipid disorders. It also addresses methodological advances in the modern GWAS toolkit, the current status of polygenic risk scores, and the lessons from applying GWAS to understudied vascular diseases with endocrinological relevance.

Key findings: GWAS maps polygenic architecture, prioritizes biological pathways and tissues, and supports therapeutic target validation using human genetic evidence. It does not provide molecular diagnoses in individual patients. Large meta-analyses have identified hundreds of robust loci for thyroid-stimulating hormone, age at menarche, age at natural menopause, cortisol binding, primary aldosteronism, and type 2 diabetes subtypes. Multi-ancestry designs improve discovery and fine-mapping resolution. In rare but well-phenotyped vascular conditions such as spontaneous coronary artery dissection and fibromuscular dysplasia, GWAS has identified biologically coherent loci and tested hormonal hypotheses, demonstrating that rigorous phenotyping can partly compensate for modest sample sizes. Polygenic risk scores can identify individuals at high genetic risk for common endocrine traits, but portability across ancestry groups and clinical implementation remain unresolved challenges.

Conclusions: GWAS remains a relevant and productive tool in endocrine genetics in 2026, provided its outputs are interpreted correctly. Its role is interpretive and mechanistic rather than diagnostic. Integrated with sequencing, functional genomics, and Mendelian randomization, it offers a structured framework for moving from statistical association to biological understanding and, in selected contexts, to risk stratification research.

Introduction: Genome sequencing (GS) is reshaping newborn screening (NBS) by enabling the early detection of a broader range of rare, treatable and/or actionable disorders. In the context of rapid therapeutic advances, international pilot programs-many coordinated within the International Consortium on Newborn Sequencing (ICoNS)-are evaluating genome-based NBS (gNBS) as a preventive public health strategy.

Materials and methods: We reviewed published international gNBS pilot studies, with particular attention to discussions related to endocrine disorders. We integrated insights from the French PERIGENOMED-CLINICS 1 (PGC1) project, including its curated gene list and collaboration mainly with the FIRENDO French network dedicated to rare endocrine diseases.

Results: No publications were identified specifically addressing gNBS in rare pediatric endocrine diseases as a unified domain. In comparative analyses of gNBS pilot programs, endocrine disorders represented approximately 10% of included conditions, with marked heterogeneity across initiatives and no primary endocrine disorder uniformly retained. Analysis of the PGC1 dataset identified 125 endocrine and endocrine-adjacent gene-disease dyads (14% of all project dyads), divided into list 1 ("treatable", n = 62) and list 2 ("actionable", n = 63). List 1 predominantly included early-onset, hormonally driven disorders, whereas list 2 extended toward obesity-related and multisystem syndromic conditions. Stratification by clinical actionability revealed four categories ranging from time-critical neonatal conditions to surveillance-driven and long-term risk phenotypes, underscoring substantial variability in timing of intervention, penetrance, and level of evidence supporting early benefit.

Conclusion: Genomic NBS is transforming rare disease management, including endocrine diseases, by enabling earlier diagnosis, precision care, and coordinated professional and family-based interventions, marking a paradigm shift in population health.

Imprinting disorders result from (epi)genetic abnormalities affecting genomic regions whose expression depends on parental origin. Among these, multilocus imprinting disturbances (MLID) constitute a specific entity characterised by simultaneous alterations in several imprinted regions, often leading to complex phenotypes. In recent years, the identification of maternal genetic factors, particularly within the maternal subcortical complex (SCMC), has led to a better understanding of the origin of certain cases of MLID. At the same time, rapid advances in molecular analysis-methylation arrays, targeted NGS panels, and long-read sequencing approaches-have profoundly renewed diagnostic capabilities. Together, these advances now offer a more integrated view of the mechanisms, phenotypes, and genetic determinants of imprinting-related diseases.

Patients with primary bilateral macronodular adrenal hyperplasia, recently reclassified as bilateral macronodular adrenal disease (BMAD) have bilateral benign large adrenocortical nodules and variable cortisol excess. BMAD is considered a rare cause of overt Cushing's syndrome but a more frequent cause of bilateral adrenal incidentalomas. Initially considered a sporadic disease, the bilateral nature of the adrenal nodules and familial aggregation suggested a genetic origin. Indeed, genomic studies have improved our understanding of BMAD pathogenesis and identified several genetic events responsible for BMAD. As rare syndromic presentations were described, non-syndromic etiologies were also identified, suggesting distinct molecular backgrounds among BMAD cases. Firstly, germline heterozygous inactivating mutations of the ARMC5 gene, discovered in 2013, are now known to account for around 20-25% of sporadic cases and most familial cases. A second molecular group was later identified, characterized by germline heterozygous pathogenic variants and loss of heterozygosity of the lysine demethylase 1A gene (KDM1A, or LSD1) in familial and sporadic GIP-dependent BMAD, representing less than 5% of BMAD cases. Similarly to ARMC5, the stepwise inactivation of KDM1A, an epigenetic regulator gene, supports a tumor suppressor model of tumorigenesis. The latter, more heterogeneous, molecular group remains globally unelucidated, with the exception of reports of pathogenic variants in genes involved in the PKA and cAMP signaling pathways. In all cases, genetic counseling should be offered to identify affected members and to screen for BMAD.

Hypothalamic syndrome (HS) is a rare and severe complication of craniopharyngioma (CP). Diagnostic criteria have been reported for pediatric patients, but no validated criteria exist for adults, limiting clinical recognition and comparability between studies. The present study applied van Santen et al.'s pediatric criteria for HS to an adult cohort with CP, assessing clinical relevance and estimating HS prevalence in this population. We performed a cross-sectional study of adults with histologically confirmed CP followed in a tertiary center. Clinical, biochemical and neuroimaging data were extracted from medical records. Hypothalamic involvement was classified on Müller grade. HS was assessed on van Santen criteria; weight trajectory, hyperphagia, sleep dysregulation, behavioral symptoms, autonomic dysfunction and daytime somnolence. Effect sizes and proportions were calculated accordingly. Twenty-one patients (57.1% female; median age at diagnosis 24.0 years) were included. Most tumors showed limited hypothalamic involvement, with 76.2% Müller grade 0 and no grade 2. Obesity was common (47.6%), but with no hyperphagia. Only 1 patient (4.8%) met the full diagnostic definition of HS. In this adult cohort, characterized by predominantly non-invasive tumors with minimal hypothalamic involvement, prevalence of HS was low on pediatric-derived diagnostic criteria. These findings suggest that van Santen et al.'s criteria have limited sensitivity in adults and that cohort composition, particularly a low rate of hypothalamic invasion, strongly influences HS detection. Larger and more heterogeneous adult cohorts are needed to validate and refine diagnostic criteria for HS in adulthood.

Hyperglycemia is very common in critical care and is the focus of intense clinical research. To date, more than 24,000 patients have been enrolled in interventional randomized trials. The pioneering studies by the Louvain group reported remarkable benefits of intensive insulin therapy in intensive care units; however, subsequent large multicenter trials failed to confirm these findings. Recent evidence suggests that pre-admission glycemic status should be taken into account in defining glucose targets, through new parameters such as the stress hyperglycemia ratio and relative hypoglycemia, which include pre-admission glycemic control. Continuous glucose monitoring and individualization of glycemic targets according to these new parameters and the patient's clinical context are likely to bring major advances in the management of hyperglycemia in critically ill patients.

Ectopic ACTH-secreting pituitary adenoma, arising outside the sella turcica from residual cells of Rathke's pouch, is an exceptionally rare cause of Cushing's syndrome. Diagnosis is often challenging and may be late despite extensive clinical and biochemical work-up. We report here an ectopic corticotroph tumor of the maxillary sinus, which was finally localized by 18F-FDG PET/CT and somatostatin receptor scintigraphy. A 38-year-old woman was referred for suspicion of ACTH-dependent Cushing's syndrome. Biological testing was indicative of ectopic ACTH secretion; however, extensive investigation failed to identify any culprit tumor. In contrast, pituitary MRI revealed a doubtful 4-mm right-side pituitary lesion, leading to hypophysectomy, without clinical or biochemical remission. After pituitary surgery, medical therapy was initiated but had limited efficacy, and bilateral adrenalectomy was subsequently performed. Following the adrenalectomy, the patient developed hyperpigmentation due to elevated ACTH levels. ¹⁸F-FDG PET/CT and somatostatin receptor scintigraphy (Octreoscan®), years after initial diagnosis, revealed a hypermetabolic lesion in the maxillary sinus. Surgical resection identified an ectopic ACTH-secreting pituitary adenoma expressing ACTH and T-Pit; a marked decrease in plasma ACTH was observed postoperatively. In conclusion, we report a case of ACTH-dependent Cushing's syndrome, caused by an ectopic corticotroph adenoma located in the maxillary sinus. This case illustrates the diagnostic challenges in localizing ectopic ACTH-secreting pituitary adenomas and highlights the value of nuclear medicine imaging in identifying these unusual lesions.