{"doi":"10.1210/clinem/dgae918","title":"<i>PDE11A</i> Is a Phenotype Modulator of Primary Bilateral Macronodular Adrenal Hyperplasia: Results of a 334-Patient Series","abstract":"CONTEXT: Primary bilateral macronodular adrenal hyperplasia (PBMAH), the most common cause of Cushing syndrome due to bilateral nodules, is a heterogeneous disease at the clinical, hormonal, and morphological levels. ARMC5-inactivating pathogenic variants are causative of PBMAH, and rare variants of PDE11A have been associated with PBMAH. OBJECTIVE: The aim of this study, on a large cohort of individuals with PBMAH from Europe and America, was to study the ARMC5 and PDE11A genotype to determine the genotype/phenotype correlation and to investigate the hypothesis that PDE11A could be a modifying gene of the adrenal phenotype. METHODS: Leukocyte DNA of 354 PBMAH index cases was sequenced for ARMC5 and PDE11A genes by next-generation sequencing. Phenotypic characteristics of 334 of these patients were analyzed to study the genotype/phenotype correlations. RESULTS: Seven out of 16 PDE11A variants were considered damaging according to in silico predictions: 6 missense variants (p.Tyr727Cys, p.Met623Arg, p.Tyr658Cys, p.Ag867Trp, p.Asn298Ser, p.Glu840Lys) and 1 stop-gain variant (p.Arg307Ter). In the cohort, 11.4% of patients had one of these variants and 19.2% had ARMC5-pathogenic variants. There was no statistically significant difference in the distribution of PDE11A-damaging variants according to ARMC5 status (P = .83; OR = 0.79; 95% CI, 0.26-2.03) nor in the distribution of ARMC5 pathogenic variants according to PDE11A status (P = .83; OR = 0.81; 95% CI, 0.27-2.04). Patients with PDE11A-damaging variants had lower urinary free cortisol (0.7 vs 1.25 upper limit of normal; P = .0002), midnight plasma cortisol (157.81 vs 222.19 nmol/L, P = .016), and number of adrenal nodules (3.46 vs 4.74; P = .048) compared to PDE11A wild-type patients. Patients with ARMC5-pathogenic variants had a more severe phenotype with more frequent comorbidities and were more often treated by adrenalectomy (60%). CONCLUSION: PDE11A appears to be a modulator of PBMAH phenotype, damaging variants being associated with an attenuated form. This may contribute to the heterogeneity of PBMAH and could affect patient management.","journal":"The Journal of Clinical Endocrinology & Metabolism","year":2025,"id":514140,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9489,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1376127,"name":"Lucas Bouys","orcid":"0000-0003-1743-1598","position":1,"is_corresponding":false},{"id":1376128,"name":"Anne Jouinot","orcid":"0000-0002-7922-2065","position":2,"is_corresponding":false},{"id":373757,"name":"Stéphanie Espiard","orcid":"0000-0002-9584-4294","position":3,"is_corresponding":false},{"id":1376129,"name":"Albain Chansavang","orcid":"0000-0002-9835-2156","position":4,"is_corresponding":false},{"id":374113,"name":"Annabel Berthon","orcid":"0000-0002-5576-9525","position":5,"is_corresponding":false},{"id":1376717,"name":"Mario Néou","orcid":null,"position":6,"is_corresponding":false},{"id":510976,"name":"Anna Vaczlavik","orcid":null,"position":7,"is_corresponding":false},{"id":1376130,"name":"Florian Violon","orcid":"0000-0002-7990-3434","position":8,"is_corresponding":false},{"id":1376131,"name":"Helaine Laiz Silva Charchar","orcid":"0009-0004-6416-6103","position":9,"is_corresponding":false},{"id":28748,"name":"Matthias Kroiß","orcid":"0000-0002-7628-3161","position":10,"is_corresponding":false},{"id":1041514,"name":"Gérald Raverot","orcid":"0000-0002-9517-338X","position":11,"is_corresponding":false},{"id":1376132,"name":"Hélène Lasolle","orcid":"0000-0002-5027-7660","position":12,"is_corresponding":false},{"id":1376133,"name":"Laurence Guignat","orcid":"0000-0003-2782-5750","position":13,"is_corresponding":false},{"id":239627,"name":"Rossella Libé","orcid":"0000-0003-2881-6362","position":14,"is_corresponding":false},{"id":1104132,"name":"Guillaume Assié","orcid":"0000-0001-9590-0906","position":15,"is_corresponding":false},{"id":239614,"name":"Antoine Tabarin","orcid":"0000-0003-1231-3306","position":16,"is_corresponding":false},{"id":399745,"name":"Peter Kamenický","orcid":"0000-0002-1994-4226","position":17,"is_corresponding":false},{"id":228073,"name":"Éric Pasmant","orcid":"0000-0002-1881-8762","position":18,"is_corresponding":false},{"id":239625,"name":"Maria Candida Barisson Villares Fragoso","orcid":"0000-0001-6150-1915","position":19,"is_corresponding":false},{"id":287856,"name":"Constantine A. Stratakis","orcid":"0000-0002-4058-5520","position":20,"is_corresponding":false},{"id":1376134,"name":"Bruno Ragazzon","orcid":"0000-0001-9476-4973","position":21,"is_corresponding":false},{"id":239626,"name":"Jérôme Bertherat","orcid":"0000-0003-2551-3008","position":22,"is_corresponding":false},{"id":1376126,"name":"Patricia Vaduva","orcid":"0000-0003-3195-1629","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:48:23.284782Z","pmid":"39774659","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}