Improved Clinical Diagnosis for Loeys–Dietz Syndrome. Separate Nosology is Required

All articles of this category (opens in new window) Background: Currently, the diagnosis of Loeys–Dietz syndrome (LDS) is based on genetic testing. In contrast to Marfan syndrome (MFS), for which the revised Ghent criteria (RGC) represent established clinical diagnostic guidelines, there is no comparable framework for the assessment of LDS manifestations. In addition, genetic analyses often provide inconclusive results, as variants of unclear significance are frequently identified. Our data form the basis for the development of a clinical nosology for LDS. Methods: We screened 1,006 children in our pediatric Marfan clinic and 30 patients were diagnosed with LDS (9.0 ± 6.0 years, m: 53%): 10/30 TGFBR1 (8.9 ± 6.3 years, m: 50%), 16/30 TGFBR2 (9.0± 6.1 years, m: 50%), 4/30 TGFB2 (9.4 ± 6.1 years, m: 75%). We established a set of criteria with proven LDS manifestations, including RGC criteria (cardiovascular, skeletal, ophthalmological, neurological, gastroenterological, integumentary, and others). We analyzed the prevalence in the entire LDS group and in TGFBR1/TGFBR2 subgroups and compared them with those of MFS patients. TGFB2 was not subanalyzed due to the small number of patients. Results: The most common LDS manifestations not mentioned in the RGC are tricuspid valve prolapse (TVP, 80%), abnormal uvula (71%), high gothic palate (58%), and transparent skin (55%). In TGFBR1 patients: TVP (80%), rheumatic disease/joint or bone pathology (60%), abnormal uvula (60%), gastroenterological abnormalities (57%). In TGFBR2 patients: abnormal uvula (89%), vascular elongation (82%), TVP (81%), transparent skin (64%). Regarding RGC, hypermobile joints were more frequent, and lens dislocations were less frequent in LDS ( p < 0.05). In TGFBR1, dilatation of the sinus valsalvae aortae, hernias, and hypermobile joints were more frequent ( p < 0.05). Hypermobile joints, thoracic asymmetry, retrognathia, and pectus carinatum were more common in TGFBR2 than in MFS ( p < 0.05). Conclusion: Pediatric patients with LDS present with a wide spectrum of extracardiac manifestations that are not detected by RGC, including abnormal uvula, translucent skin, vascular tortuosity, rheumatological features, skeletal abnormalities, and gastrointestinal involvement. As genetic diagnosis is not always readily available or feasible, clinical classification must be based on phenotype. Furthermore, accurate differentiation between LDS subtypes—with potentially different clinical courses—is essential for customized treatment. This emphasizes the need for a comprehensive, clinically applicable set of diagnostic criteria covering the entire phenotypic LDS spectrum. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany