Abstract Introduction: Patients with complex rare genetic syndromes (CRGS) have, by definition, combined medical problems affecting multiple organ systems. Intellectual disability (ID) is often part of the syndrome. During childhood, most patients with CRGS receive multidisciplinary (MD) and specialized pediatric care in tertiary centers. As improvement of medical care has improved life expectancy, more and more patients are now reaching adult age. While the complexity of the syndromes persist into adulthood, adequate multidisciplinary syndrome-specific care is rarely available for adults with CRGS. Although multiple organ systems are usually affected, internists are rarely involved. Pediatricians have expressed the urgent need for adequate, syndrome-specific, MD tertiary healthcare for adults with CRGS. Methods: In 2015 we have launched the Center for Adults with CRGS, a specialized MD outpatient clinic (MOPC) within the Endocrinology unit of the department of Internal Medicine. As adult manifestations are unknown for most CRGS, all CRGS patients who visit our MOPC undergo a systematic health screening (followed by treatment, if indicated). Before visiting the MOPC, caregivers fill out a medical questionnaire. We gathered the physical complaints, medication use and missed diagnoses of 726 adults with CRGS. Results: Between 2015 and 2020, 256 males and 470 females with over 60 syndromes visited the Center for Adults with CRGS. The main features of this population, as compared with general internal medicine patients, were intellectual disability, polypharmacy and use of psychotropic drugs. Missed diagnoses were common and many patients had undergone extensive diagnostic tests for symptoms that could actually be explained by their syndrome. Fatigue (52%), abdominal discomfort (23%) and hypertension (10%) were among the most frequent reasons for referral to Internal Medicine. Based on the literature and our clinical findings, 73% of the syndromes was associated with endocrine problems. We provide an algorithm for the clinical approach to CRGS adults, in order to prevent unnecessary diagnostics as well as missed diagnoses. Conclusion: Our overview of 726 adults with CRGS shows that missed diagnosed and needless invasive tests are common in this patient population. As more and more CRGS patients are now reaching adult age and transfer to Internal Medicine, internists and endocrinologists should be aware of the special needs of adults with CRGS and of the medical pitfalls. Knowledge about syndrome-specific health problems and multidisciplinary expert care is crucial to prevent the personal and financial burden of unnecessary diagnostics and under- and overtreatment.