CONTEXT:Lipodystrophy and extreme insulin resistance syndrome are rare diseases with severe metabolic complications. Reported epidemiological data are conflicting. OBJECTIVE:We aimed to evaluate nationwide and regional prevalences of lipodystrophy and insulin resistance syndrome in France, and to study diagnostic and care-pathways. METHODS:We studied data from the French National Rare Disease Registry (BNDMR), which includes all patients attending rare disease reference centers in France. We analyzed demographic data and age at first signs and at diagnosis in patients with an ORPHA code of lipodystrophy or severe insulin resistance syndrome. RESULTS:The number of patients registered with lipodystrophy/insulin resistance syndrome doubled from 2017 to 2023, with the deployment of nationwide epidemiological tools in specialized rare diseases centers. Currently, 567 of the 652 patients (58% female) had a diagnosis of genetically determined disease with generalized (GL) or partial lipodystrophy (PL), giving an estimated national prevalence of 1.6 and 6.4 per million, respectively. Wide regional differences in estimated prevalence may be partly due to founder pathogenic variants, or local spread of clinical skills and knowledge. Median age at first signs and diagnosis were respectively 1 [IQR: 1-3] and 5 years [0-20] for GL, and 22 [14-35] and 40 years [25-52] for PL, with earlier first signs of PL in women than in men. CONCLUSION:The estimated prevalence of genetic lipodystrophy/extreme insulin resistance syndrome has increases with the use of dedicated epidemiological tools, suggesting persistent underdiagnosis. Knowledge of these diseases needs to be improved to decrease diagnostic delay and reduce regional and gender-associated diagnostic disparities.

Functional gonadotroph adenoma (FGA) is a rare condition associated with secretion of biologically active gonadotropins which affect reproductive organs. In women of reproductive age, it has been reported as a cause of spontaneous ovarian hyperstimulation syndrome (OHSS) occurring outside the context of assisted reproductive technology (ART). In rare instances, FGA may present as suspicious ovarian masses, leading to an overlooked pituitary disorder. We report the case of a 34-year-old woman initially suspected of having a bilateral ovarian tumor with a borderline component due to thick-walled cystic masses. She underwent pelvic surgery, resulting in an oophorectomy. However, a few weeks postoperatively, the sudden onset of galactorrhea prompted further investigation, revealing hyperprolactinemia, FSH hypersecretion, and low LH levels. Ultimately, the diagnosis of FGA was established. A literature review was conducted to analyze similar cases where patients underwent ovarian surgery without prior hormonal assessment or suspicion of pituitary pathology, only to be diagnosed with FGA later. Thirteen additional cases were identified, including ovarian cysts and two cases of suspicious ovarian masses, with diagnostic delays ranging from 1.5 to 10 years. This case highlights the importance of considering FGA in the differential diagnosis of bilateral ovarian masses to avoid unnecessary surgical procedures.

AIM:Advanced glycation end-products (AGEs) are known to play a role in the pathophysiology of type 1 diabetes (T1D) complications. The aim of this study was to assess the predictive value of AGEs indirectly evaluated by skin auto-fluorescence (SAF) on the occurrence of cardiovascular events (CVEs) in T1D. METHODS:We measured baseline SAF in T1D patients with at least 10 years history of diabetes and assessed incident CVEs. An optimum threshold of SAF was determined using ROC curve, and its predictive value was assessed by Cox proportional regression. RESULTS:The study included 179 patients, 53 % of whom were women. At baseline, the mean age was 47.7 ± 15.9 years, the mean duration of diabetes was 26.4 ± 12.2 years. Median HbA1c was 7.7 % (7.3-8.7) and median LDL cholesterol was 2.58 mmol/l (2.14-3.07). Median follow-up was 7.4 years (6.85 - 7.7) with 34 CVEs in 24 patients. The median SAF level was 2.7 (2.3-3.1) in patients with incident CVEs and 2.1 (1.8-2.6) in patients without CVEs. The optimum threshold of SAF to differentiate patients with or without incident CVEs was 2.2. The occurrence of CVE was predicted by the optimum SAF threshold in the unadjusted model (HR 6.46), but also after adjustment with different models (HR 3.15-5.05). CONCLUSION:SAF level is higher in people living with T1D who will present CVEs. Furthermore, SAF threshold of 2.2 predicted the occurrence of CVE. If these results are confirmed, SAF could be a useful marker in cardiovascular risk stratification in T1D.

Persistent primary hyperparathyroidism is defined as the persistence or recurrence of hypercalcemia within 6 months of parathyroid surgery. Recurrent primary hyperparathyroidism is defined as the recurrence of primary hyperparathyroidism more than 6 months after an initially curative parathyroidectomy. In these situations, it is essential to rule out differential diagnoses, and in particular secondary hyperparathyroidism and familial hypocalciuric hypercalcemia. Failure to remove the pathological parathyroid gland or glands during initial surgery for primary hyperparathyroidism is the most common situation in non-expert centers. In other situations, genetically determined multi-glandular primary hyperparathyroidism must be screened for. More rarely, a second sporadic adenoma is identified, or, exceptionally, a parathyroid carcinoma or parathyromatosis. Effective morphological evaluation, combining a morphological and functional imaging, is essential prior to any new parathyroid surgery. The indications for surgery must be discussed in a multidisciplinary team, assessing the risk/benefit ratio, since the risk of surgical complications is higher. Revision surgery should be performed using a suitable approach, after laryngoscopy, in an expert center, ideally with intraoperative PTH measurement and recurrent nerve neuromonitoring.

We describe for the first time the case of a woman presenting with Tatton-Brown-Rahman syndrome (TBRS) and multiple endocrine neoplasia (MEN). She developed primary hyperparathyroidism at age 13, a pituitary cyst at age 14, adrenal tumor at age 21, and metastatic insulinoma at age 34. In addition, she showed intellectual disability, obesity, multiple lipomas, facial dysmorphia, hemihypertrophy and kyphoscoliosis. At age 35, genome analysis revealed a pathogenic de-novo heterozygous germline DNMT3A variant, while classic MEN syndromes were ruled out by targeted somatic and germline genetic testing. This case highlights not only the importance of genomic analysis in patients with multiple and atypical conditions, but also the need for a multidisciplinary approach for TBRS patients, including in adulthood, involving endocrinologists to enhance understanding and optimize monitoring of this syndrome.

Objective The global increase in the prevalence of metabolic syndrome represents a significant public health concern. Rare biallelic pathogenic variants in ZMPSTE24 have been identified as the cause of mandibuloacral dysplasia type B, ie, a lipodystrophy syndrome associated with metabolic complications. The role of monoallelic pathogenic variants in ZMPSTE24 concerning metabolic syndrome remains uncertain.Design Case report and systematic review of literature.Methods We investigated a Wallisian family with FPLD and metabolic syndrome via whole-exome sequencing. We performed functional analyses of an identified rare ZMPSTE24 variant. To broadly assess the effect of heterozygous pathogenic ZMPSTE24 variants on FPLD-associated phenotypes, and metabolic syndrome, we used the Human Gene Mutation Database (HGMD) and 200 K exome data from UK Biobank.Results We investigated a Wallisian family where a 40-year-old female with metabolic syndrome was found to carry a rare heterozygous missense variant in ZMPSTE24. Functional assays showed a decreased prelamin to lamin A maturation and accelerated senescence. In silico analysis demonstrated that this variant might disrupt the lamin A binding site. We then analyzed the impact of monoallelic pathogenic ZMPSTE24 variants on metabolic traits using data from the HGMD and the UK Biobank. In HGMD, ZMPSTE24 variants carriers presented with dyslipidemia and hepatic steatosis. In the UK Biobank, monoallelic pathogenic variants were associated with an increased risk of hypertriglyceridemia, with a trend toward metabolic syndrome.Conclusions This study underscores the association of ZMPSTE24 rare variants with metabolic disorders and emphasizes the need for further research to clarify their clinical implications.

Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome caused by germline pathogenic variants involving the MYC Associated Factor X (MAX) gene. Affected individuals typically have pheochromocytomas, often bilateral, at a relatively early age. In MAX pheochromocytoma cohorts, pituitary adenomas are rarely reported. The role of MAX as a tumor suppressor gene in the pituitary gland has not been directly proven to date. The propositus came from a pheochromocytoma kindred with a germline pathogenic MAX variant c.97 C>T (p.R33*). In his late thirties he developed asynchronous bilateral pheochromocytomas and underwent bilateral adrenalectomy. At age 46, he developed hyperprolactinemia (45.1 μg/L; 3x ULN) and increased IGF-1 (460 ng/mL; 1.9x ULN). Total testosterone was low (1.5 ng/mL) as was LH (1.2 IU/L). Pituitary MRI showed a microadenoma (6 mm), which was resected and his prolactin, IGF-1, and testosterone levels normalized. A Pituitary adenoma was confirmed on pathology, which showed positivity for prolactin only and a Ki67 of 2

CONTEXT:Carney Complex (CNC) is a rare multiple endocrine neoplasia syndrome, due to PRKAR1A mutation, that causes GH-secreting pituitary adenomas (PA) in 10% of patients. PRKAR1A is not currently analyzed in patients with isolated sporadic or familial PA, in contrast to MEN1 or AIP. OBJECTIVE:We report the case of a young man diagnosed with a PA at age 21 during melanoma follow-up, with a family history of PA. He was initially misdiagnosed with FIPA due to a misclassified AIP mutation, before a final diagnosis of CNC was established. We subsequently retrospectively analysed PRKAR1A in a cohort of patients with PA to assess the relevance of includingPRKAR1A in PA predisposition gene panels. METHODS:After AIP variant reclassification and whole genome analysis of the patient, we performed a retrospective analysis of the genetic and clinical data of patients who underwent germline genetic testing for hereditary predisposition to PA. RESULTS:Two hundred and twenty patients were included, of whom 16 (7.3%) had a family history of PA, 162 (72.7%) had macro-PA, and 54 (24.6%) had GH- or GH/PRL-secreting PA. Four patients (1.8%) carried pathogenic variants in AIP or MEN1, but none in PRKAR1A. CONCLUSION:This case underscores the importance of periodically reassessing genetic variants, as reclassification can significantly impact patient management. It also highlights the clinical variability of CNC and the need to screen for CNC features in young patients with acromegaly. Further research is warranted to determine the value ofPRKAR1A testing in isolated GH- and GH/PRL-secreting PA.

OBJECTIVE:This updated French cost-utility analysis aimed to assess the efficacy of the second-line pharmacological treatment - pegvisomant, pasireotide or pegvisomant combined with first generation somatostatin analogues (FGSA) - considering first-line treatment (surgery, FGSA, cabergoline and combination), radiotherapy and the impact of treatment on tumor volume. METHODS:The original three-state Markov model was revised to include an additional health state, representing patients controlled without pharmacological treatment following successful radiotherapy. The model also accounted for the history of first-line treatments as additional costs upon patients' entry. A cohort of 1000 simulated patients was followed over a lifetime horizon from a collective perspective. Treatment efficacy is defined on normalization of insulin growth factor-1 and was determined through a network meta-analysis. Cost and utility data were sourced from French databases and literature. RESULTS:All the evaluated treatments were included in an efficiency frontier. The incremental cost-utility ratio (ICUR) of pegvisomant compared to pasireotide was 27,805€ per quality-adjusted life year (QALY) gained. The ICUR of pegvisomant combined with FGSA compared to pegvisomant was 253,854€/QALY. Sensitivity analyses showed the robustness of the results. The addition of radiotherapy has shown improved quality of life and lower costs for all second-line treatments. CONCLUSION:This model explores the cost-effectiveness of second-line pharmacological treatments of acromegaly accounting for the overall management recommended in France. Radiotherapy appears as a key therapeutic option allowing long-term remission of patients even after pharmacological treatment failure. This study is an additional tool for treatment choice including both a clinical and economic perspective. SIGNIFICANCE STATEMENT:The aim of this study is to assess the cost-utility of second-line treatments of acromegaly accounting for the overall management recommended in France, considering surgery, first-line treatments, radiotherapy and the impact of treatments on tumor volume, in addition to IGF-1 normalization. All evaluated treatments were included in an efficiency frontier. This addition has shown that radiotherapy and the impact on tumor volume are decisive in the management of second-line treatments for acromegaly. Indeed, radiotherapy enables patients to achieve complete remission, i.e. without the need for drug treatment. This is an important factor for patients, given that acromegaly treatments are chronic and usually lifelong. This study is an additional tool for treatment choice including both a clinical and economic perspective.

Objectifs: Les grossesses non désirées sont plus fortement associées au risque de violences conjugales (et/ou sexuelles). Alors que les professionnels médicaux sont en première ligne du dépistage, et que les recommandations invitent à poser systématiquement la question des violences, celles-ci ne sont que rarement détectées.L’objectif de cet article est de mesurer l’impact du questionnaire WAST dans le dépistage des violences conjugales au cours des consultations pré-IVG et son acceptabilité par les professionnels.Méthode: Il s’agit d’une étude analytique rétrospective monocentrique portant sur les patientes en demande d’IVG au centre de santé sexuelle du CHU de Reims sur six mois, associée à une analyse des pratiques professionnelles. Nous avons comparé deux méthodes de dépistage : une question posée au cours de l’anamnèse et la remise du WATS.Résultats: Nous avons observé un meilleur dépistage avec le WAST qu’avec une question fermée, sans toutefois augmenter les violences déclarées. Nous retrouvons des facteurs significativement associés aux violences constituant des signes d’alerte : des IVG répétées, reportées ou à un terme avancé.Concernant les professionnels, il s’agissait d’un public averti qui s’accordait à penser qu’un questionnaire pouvait faciliter le dépistage. Après utilisation, ils en rapportent l’intérêt.Conclusion: Tous les professionnels de santé devraient être formés au dépistage des violences conjugales (et/ou sexuelles) et à leur prise en charge, afin que les patientes puissent se sentir en confiance pour en parler. De plus, durant la grossesse, il est possible d'avoir un impact sur la prise en charge médico-légale (signalement judiciaire, dépôt de plainte). Notre étude montre que l’utilisation du WAST a un impact positif sur le dépistage des violences conjugales et est jugé comme un bon outil par les professionnels dans le contexte d’une consultation pré-IVG.

In 2024, the French Society of Endocrinology, the French-speaking Association of Endocrine Surgery, and the French Society of Nuclear Medicine have elaborated a joint consensus statement on primary hyperparathyroidism, which was presented at the last congress of the French Society of Endocrinology, in October 2024, and subsequently published as 15 individual chapters in the Annals of Endocrinology. This consensus statement is a fruit of a joint effort by over 80 French-speaking experts in the field, including adult and pediatric endocrinologists, endocrine and pediatric surgeons, radiologists, nuclear medicine specialists, biologists and geneticists, and has been endorsed by the Belgian and Swiss endocrine societies. This document summarizes the recommendations, subdivided into 15 sections each preceded by a brief introduction. It aimed at covering systematically all areas of diagnosis and management of primary hyperparathyroidism throughout life in a comprehensive way, that we hope could be useful in particular to our younger colleagues in training.

OBJECTIVES:Unintended pregnancies are more strongly associated with the risk of intimate partner violence (and/or sexual violence). While healthcare professionals are on the front line of screening, and guidelines recommend systematically asking about violence, such cases are rarely detected. This article aims to measure the impact of the WAST questionnaire in screening for intimate partner violence during pre-abortion consultations and its acceptability among healthcare professionals. METHOD:This is a single-center retrospective analytical study involving patients seeking abortion at the sexual health center of the University Hospital of Reims over a six-month period, combined with an analysis of professional practices. We compared two screening methods: a direct question asked during the medical history and the use of the WAST questionnaire. RESULTS:We observed better screening results with the WAST than with a closed question, although it did not increase the number of reported cases of violence. We identified factors significantly associated with violence, serving as warning signs: repeated abortions, delayed requests, or advanced gestational age. Regarding healthcare professionals, this was an informed group that agreed a questionnaire could facilitate screening. After using it, they reported finding it useful. CONCLUSION:All healthcare professionals should be trained in screening for intimate partner (and/or sexual) violence and in its management, so that patients can feel confident to discuss it. Moreover, during pregnancy, it is possible to have an impact on medico-legal management (judicial reporting, filing a complaint). Our study shows that the use of the WAST has a positive impact on screening for intimate partner violence and is considered a useful tool by professionals in the context of pre-abortion consultations.

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

OBJECTIVE:Biallelic variants in the pro-opiomelanocortin gene (POMC) can cause hypocortisolism, hypopigmentation, and early-onset obesity. Following the identification of 2 patients of combined pituitary hormone deficiency (CPHD), we investigated the prevalence of this association among carriers of rare pathogenic or likely pathogenic (P/LP) POMC variants. DESIGN:This study is a case report and systematic literature review. METHODS:Genetic analysis was conducted in a family with 2 cousins with childhood-onset obesity and CPHD. We assessed CPHD in carriers for biallelic pathogenic POMC variants using data from the literature and Human Gene Mutation Database. Clinical and biological data were collected, including pituitary axis involvement, obesity onset age, and pituitary imaging results. RESULTS:The 2 cousins, compound heterozygous for POMC variants, developed CPHD following initial hypocortisolism, with subsequent hypothyroidism, growth hormone deficiency, and hypogonadism. Among 41 patients with biallelic POMC variants identified in the literature, 20 had rare homozygous/compound heterozygous P/LP POMC variants and detailed endocrine evaluations. Of these, 40% presented with CPHD, always associated with early-onset severe obesity and hypocortisolism. Growth hormone deficiency was the most frequent (75%), followed by thyrotropic and gonadotropic deficiencies (62.5%). No anomalies were revealed in pituitary imaging. Two patients recovered the gonadotropic axis after treatment with the MC4R agonist. CONCLUSION:These findings underscore the potential for CPHD to occur in carriers of biallelic pathogenic POMC variants. Sequencing the full POMC, including coding and regulatory regions, is crucial in CPHD cases, alongside evaluating all pituitary axes in neonatal hypocortisolism. Beyond weight regulation, setmelanotide may modulate hypothalamic-pituitary function, with implications for fertility.

BACKGROUND:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS:A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683). RESULTS:Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION:This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.

AIM:To describe the effects of Glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with familial partial lipodystrophy (FPLD) assessed in a real-life setting in a national reference network. PATIENTS AND METHODS:We retrospectively collected clinical and metabolic parameters in patients with FPLD in the French lipodystrophy reference network, who initiated GLP-1RA. Data were recorded before, at one-year (12 ± 6 months) and at the latest follow-up on GLP-1RA therapy (≥18 months). RESULTS:Seventy-six patients (89.4% of women), diagnosed with LMNA-related FPLD2 (n = 57), PPARG-related FPLD3 (n = 4), PLIN1-related FPLD4 (n = 5) or FPLD1 (n = 10) initiated GLP-1RA therapy between 2008 and 2024. Patients were aged a median (IQR) 48 years (34.5-57), body mass index (BMI) was 26.0 kg/m2 (23.9-29.5), HbA1c 8.3% (7.5-9.3), triglycerides 2.31 mmol/L (1.62-3.88). GLP-1RA were used in addition to previously used antidiabetics, 50% of patients being insulin-treated. After one year with GLP-1RA therapy, BMI, HbA1c and triglycerides significantly decreased to 25.6 kg/m2 (22.7-29.1), 7.3% (6.6-8.3) and 1.97 mmol/L (1.5-3.2) respectively (p < 0.001, p < 0.001 and p < 0.01, respectively), without significant changes in other antidiabetic and lipid-lowering drugs. Gamma-glutamyl-transferase and alanine-aminotransferase levels also significantly decreased. Effects on HbA1c, BMI and triglycerides persisted in the long term. One case of acute pancreatitis occurred during follow-up, associated with severe hypertriglyceridemia in a non-observant patient. Gastrointestinal symptoms affected 34% of patients, leading to GLP-1RA withdrawal in six patients. CONCLUSION:GLP-1RA significantly improved BMI, HbA1c and triglycerides in a large majority of patients with FPLD. Larger and prospective controlled studies are warranted for identification of predictive factors and safety.

Introduction: Lipodystrophy syndromes are rare diseases characterized by a generalized or partial lipoatrophic morphotype and metabolic complications. Data on health-related quality of life and impact of genetic lipodystrophy on social or psychological well-being are lacking. Patients and Methods: Patients with genetic lipodystrophy were recruited throughout the French national reference network for rare diseases of insulin secretion and insulin sensitivity. Patients completed a self-reported questionnaire exploring their physical, psychological, and social well-being and perceived impact of the disease. Descriptive analyses and comparison with general population norms were conducted. Results: Of 175 eligible patients, 109 (84% of women) were included, either with familial partial (n = 93) or congenital generalized (n = 16) lipodystrophy. Health-related quality of life based on physical and mental scores was significantly decreased compared to the French general population of similar age and gender (P < .001 for both). Forty-one percent of patients reported moderate or severe depression and 69% dealt with chronic pain. Half of respondents had taken tranquilizers, sleeping pills, or antidepressants over their life. Female participants with genetic lipodystrophy were more frequently unemployed due to health issues as compared to the general population. Social discrimination was highly prevalent (73%), coming, in 34% of cases, from health professionals. More than half of affected women reported a very negative impact of lipodystrophy on body image, significantly associated with depressive symptoms. Conclusion: This study highlights the need of psychosocial support in patients with lipodystrophy. An integrated approach and evaluation of psychological and physical symptoms by physicians should be made available to organize specialized care and set up specific therapeutic educational programs.

Une patiente née en 1957 est adressée pour élévation majeure de l’ACTH plasmatique (>2000ng/mL N<60ng/mL) demandé devant une pigmentation cutanée acquise. La patiente présente une forme extrêmement rare de porphyrie, une coproporphyrie héréditaire à l’état homozygote diagnostiquée à l’âge de 10 ans devant des douleurs abdominales et une hyponatrémie à 113mmol/L. Elle évolue sans suivi, ni crise aiguë depuis de nombreuses années avec une fatigue chronique.La poursuite des investigations sans traitement montre une natrémie à 134mmol/L (Kaliémie non évaluable par l’hémolyse), une cortisolémie 8h à 138 nmol/L (N 166–507), une ACTH à 755ng/mL, une aldostéronémie à 112pg/mL (20–152) et une rénine à 68,5pg/mL (N<38). Le stéroidogramme montre un cortisol à la limite inférieure de la normale, DHA, androgènes, prégnenolone et DOC bas, tandis que les dérivés 11 hydroxylés sont retrouvés à une concentration élevée sans anomalie du gène codant pour la 11 hydroxylase. Le scanner surrénalien révèle de petites surrénales sans calcifications, les anticorps anti-21 hydroxylase étant absents. Les porphyrines sanguines, fécales et urinaires sont élevées, témoignant de l’activité de la maladie. La mise sous hydrocortisone améliore la fatigue.Des anomalies de la stéroïdogenèse ont déjà été décrites dans les porphyries hépatiques aiguës. Elles pourraient jouer un rôle dans les hyponatrémies sévères rencontrées au cours des crises aiguës, et trouver un traitement simple par la substitution en hydrocortisone. Une étude systématique est en cours au centre de référence des porphyries à ce sujet.

Objective: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine. Methods: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants. Results: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management. Conclusions: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.