Prevalence and clinical correlates of clinical red flags for rare diseases in consecutive patients presenting with HCM phenotype

Abstract

Abstract Introduction For patients presenting with primary Left Ventricular Hypertrophy (LVH), the ESC recommends systematic search for diagnostic clues or “red flags” (cardiac and non-cardiac) that can identify particular treatable disorders and guide rational selection of diagnostic tests. To date, a systematic evaluation of this recommendation has not been performed Purpose We sought to determine prevalence and predictive accuracy of clinical markers (red flags, RF), known to be associated with specific systemic disease in a consecutive cohort of patients with hypertrophic cardiomyopathy (HCM). Methods We studied 210 consecutively genotyped patients (54±21 years, 118 (56% males) referred to our center for the suspicion of primary LVH. Pre-specified RF were categorized into four domains: family history; signs/symptoms; electrocardiography and imaging. Results Of the 210 patients, 84 (40%) were diagnosed with sarcomeric HCM, 56 (27%) with TTR amyloidosis, 44 (21%) with Fabry disease (FD), 7 (4%) with a mitochondrial disease, 4 (2%) with Pompe disease, 4 (2%) with PRKAG2 cardiomyopathy, 3 (1%) with Noonan, 3 (1%) with Friederich's Ataxia, 3 (1%) with LEOPARD and 2 (1%) with Danon disease. A total of 942 RF has been identified in the cohort. Concerning family history, autosomal dominant pattern was specific for sarcomeric HCM (66/84, 79%), whereas X-linked inheritance was frequently observed in Fabry disease (40/44, 91%). Non-sarcomeric causes of HCM were the most prevalent in ages <1yo and >55yo. Ophthalmological signs/symptoms (22/23) were specifically find in FD, whereas muscolo-skeletal RF were rare and non-specific. Neurological phenotype was prevalent in FD patients (38/44, 86%), as well as in TTR amyloidosis (carpal tunnel in 29/56, (52%)), in mithocondropathies and Friederich's Ataxia. Cutaneous involvement was frequent in FD (12 patients with angiokeratomata) (Tab.1). Giant T waves inversion was the most prevalent ECG alteration, but aspecific (61 patients, 32/84 sarcomeric HCM, 16/44 FD). Short PR interval was found in 24 (12%) of patients and specific for FD (15/44) and mitochondrial disease (3/7). Low QRS voltage was present in 17 (8%) patients, and of these 16 had TTR amyloidosis. Inferior leads Q waves was uncommon and non-specific. Mitral valve disease (SAM and anterior mitral leaflet elongation) and apical LVH were present respectively in 57/210 (28%) and 9/210 (4%) of the patient and were almost entirely observed in sarcomeric HCM. Concentric LVH and severe left posterior wall hypertrophy were extremely specific for non sarcomeric HCM (108/109 cases). Strain apical sparing was useful in the identification of TTR amyloidosis. Conclusions Clinical RF in patients with primary LVH are common and can be highly specific for correct phenotypisation of the patient. An extensive diagnostic work-up should therefore be conducted by the physician to identify potentially treatable primary LVH causes. Funding Acknowledgement Type of funding sources: None.