Patients' perspective on the medical pathway from first symptoms to diagnosis in genetic lipodystrophy.

OBJECTIVE: Underdiagnosis is an important issue in genetic lipodystrophies, which are rare diseases with metabolic, cardiovascular, gynecological, and psychological complications. We aimed to characterize the diagnostic pathway in these diseases from the patients' perspective. DESIGN: Cross-sectional study conducted through a self-reported patient questionnaire. 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 on disease symptoms, steps leading to the diagnosis, and healthcare professionals involved. Descriptive analyses were conducted. RESULTS: Out of 175 eligible patients, 109 patients (84% women) were included; 93 had partial familial lipodystrophy and 16 congenital generalized lipodystrophy. Metabolic comorbidities (diabetes 68%, hypertriglyceridemia 66%, hepatic steatosis 57%), cardiovascular (hypertension 54%), and gynecologic complications (irregular menstruation 60%) were frequently reported. Median age at diagnosis was 30 years (interquartile range [IQR] 23-47). The overall diagnostic process was perceived as "very difficult" for many patients. It extended over 12 years (IQR 5-25) with more than five different physicians consulted by 36% of respondents, before diagnosis, for lipodystrophy-related symptoms. The endocrinologist made the diagnosis for 77% of the patients. Changes in morphotype were reported as the first symptoms by the majority of respondents. CONCLUSIONS: Diagnostic pathway in patients with genetic lipodystrophy is rendered difficult by the multisystemic features of the disease and the lack of knowledge of non-specialized physicians. Training physicians to systematically include adipose tissue examination in routine clinical evaluation should improve diagnosis and management of lipodystrophy and lipodystrophy-associated comorbidities.

Dominant PDX1 deficiency causes highly penetrant diabetes at different ages, associated with obesity and exocrine pancreatic deficiency: Lessons for precision medicine.

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.

Heterozygous pathogenic variants in POMC are not responsible for monogenic obesity: Implication for MC4R agonist use.

PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity. METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank. RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels. CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.

SDHx mutation and pituitary adenoma: can in vivo 1H-MR spectroscopy unravel the link?

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the '3PAs' syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Systematic detection of mosaicism by using digital NGS reveals three new MEN1 mosaicisms.

Purpose: Mosaicism is a feature of several inherited tumor syndromes. Only a few cases of mosaicism have been described in multiple endocrine neoplasia type 1 (MEN1). Next-generation sequencing (NGS) offers new possibilities for detecting mosaicism. Here, we report the first study to systematically look for MEN1 mosaicism, using blood DNA, in MEN1-suspected patients but without MEN1 pathogenic variants (PV) in a heterozygous state. Methods: Digital targeted NGS, including unique molecular identifiers (UMIs), was performed in routine practice, and the analytic performance of this method was verified. Results: Among a cohort of 119 patients harboring from 2 to 5 MEN1 lesions, we identified 3 patients with MEN1 mosaic PVs. The allele frequencies ranged from 2.3 to 9.5%. The detection rate of MEN1 mosaicism in patients bearing at least 3 MEN1 lesions was 17% (3/18). No cases were detected in patients with two lesions. Conclusion: We report here three new cases with MEN1 mosaicism. This study examined the performance of UMI in the diagnosis of MEN1 mosaicism in routine practice, and our results underline that the frequency of mosaicism is probably underestimated in patients with suspected MEN1.

Early Detection of Relapse by ctDNA Sequencing in a Patient with Metastatic Thymic Tumor and MEN1 Mosaicism.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by inactivating mutations in the MEN1 gene. In the literature, few cases of MEN1 have been reported because of mosaic MEN1 mutations. OBJECTIVE: We performed an extensive molecular characterization in several lesions and blood samples, including plasmatic circulating cell-free DNA (ccfDNA) in an exceptional case of a patient with MEN1 mosaicism causing primary hyperparathyroidism, multiple pancreatic neuroendocrine tumors (NETs), and a metastatic thymic NET. METHODS: Blood, ccfDNA and multiple tissue analysis were performed by next-generation sequencing. RESULTS: MEN1 mosaicism was confirmed by multiple tissue analysis. Somatic analysis of the largest pancreatic NET revealed the same MEN1 second-hit mutation as found in the thymic lesion, demonstrating its metastatic origin from the thymic lesion. Moreover, in ccfDNA we found the mosaic MEN1 mutation but also the somatic second-hit mutation found in the thymic primary tumor, revealing the presence of circulating tumor DNA (ctDNA). After surgical removal of the pancreatic metastasis, the mutated fraction of both mutations decreased, before increasing again several weeks before a new clinical relapse, suggesting that thymic ctDNA may be used as an early tumor biomarker. CONCLUSION: This exceptional MEN1 case highlighted (1) the importance of looking for MEN1 mosaicism, (2) that MEN1 mosaicism can cause very aggressive disease, and (3) the interest in analyzing ccfDNA for confirming MEN1 mosaicism but also as a potential tumor biomarker for NET.

Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow-up and genetic counseling?

MEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper, we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling.

Compound genetic etiology in a patient with a syndrome including diabetes, intellectual deficiency and distichiasis.

BACKGROUND: We studied a young woman with atypical diabetes associated with mild intellectual disability, lymphedema distichiasis syndrome (LDS) and polymalformative syndrome including distichiasis. We used different genetic tools to identify causative pathogenic mutations and/or copy number variations. RESULTS: Although proband's, diabetes mellitus occurred during childhood, type 1 diabetes was unlikely due to the absence of detectable autoimmunity. DNA microarray analysis first identified a de novo, heterozygous deletion at the chr16q24.2 locus. Previously, thirty-three pathogenic or likely pathogenic deletions encompassing this locus have been reported in patients presenting with intellectual deficiency, obesity and/or lymphedema but not with diabetes. Of note, the deletion encompassed two topological association domains, whose one included FOXC2 that is known to be linked with LDS. Via whole-exome sequencing, we found a heterozygous, likely pathogenic variant in WFS1 (encoding wolframin endoplasmic reticulum [ER] transmembrane glycoprotein) which was inherited from her father who also had diabetes. WFS1 is known to be involved in monogenic diabetes. We also found a likely pathogenic variant in USP9X (encoding ubiquitin specific peptidase 9 X-linked) that is involved in X-linked intellectual disability, which was inherited from her mother who had dyscalculia and dyspraxia. CONCLUSIONS: Our comprehensive genetic analysis suggested that the peculiar phenotypes of our patient were possibly due to the combination of multiple genetic causes including chr16q24.2 deletion, and two likely pathogenic variants in WFS1 and USP9X.

A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features.

PURPOSE: We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene. METHODS: We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3. RESULTS: Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one. CONCLUSION: We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations.