IntroductionThe purpose of this study was to explore the literature on fatigue in patients with syndromic heritable thoracic aortic disease (sHTAD), including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers Danlos syndrome (vEDS) and other sHTADs, critically appraise and synthesize the relevant literature. We also aimed to investigate how adults with sHTAD experience and perceive fatigue, and to discuss clinical implications and direction for further research.MethodsFirst, a systematic review was performed by searching the published literature in all relevant databases and other sources until 20th October 2022. Second, a qualitative focus group interview study was conducted of 36 adults with sHTADs (LDS n = 11, MFS n = 14, vEDS n = 11).ResultsIn the systematic review, 33 articles satisfied the eligibility criteria (3 reviews and 30 primary studies). Of the primary studies: 25 dealt with adults (MFS n = 17, MFS/EDS n = 1, EDS n = 2, LDS/vEDS n = 3, different sHTADs n = 2), 5 with children (MFS n = 4, different sHTADs n = 1). Twenty-two were cross-sectional quantitative studies, 4 prospective and 4 qualitative studies. The quality of the included studies was mostly good, but many had small sample sizes, low response rates and/or participants without verified diagnosis. Despite these limitations, studies indicated high prevalence of fatigue (ranging from 37 to 89%), and fatigue was associated with both health and psychosocial aspects. Few studies found that fatigue was associated with disease-related symptoms. In the qualitative focus groups most of the participants reported that they had experienced fatigue which influenced several aspects of life. Four themes related to fatigue were elucidated: (1) different diagnoses–different fatigue?, (2) the nature of fatigue, (3) searches for causes of fatigue, (4) dealing with fatigue in daily life. The four themes seemed mutually interrelated in terms of barriers, strategies and facilitators for dealing with fatigue. The participants experienced fatigue as a consistent dilemma between self-assertion and inadequacy. Fatigue seems to influence several aspects of daily life and may be one of the most debilitating symptoms of having a sHTAD.ConclusionFatigue seems to negatively impact the lives of people with sHTADs and should be recognized as an important aspect in the lifelong follow-up of these patients. The life-threatening complications of sHTADs may result in emotional stress, including fatigue and the risk of developing a sedentary lifestyle. Research and clinical initiatives should consider rehabilitation interventions aiming at postponing the onset or reducing symptoms of fatigue.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13023-023-02709-2.