How can Fabry disease be misdiagnosed?

Fabry disease can commonly be misdiagnosed in patients. In a study published in 2004 of 366 patients enrolled in the Fabry Outcome Survey (FOS; sponsored by Shire, now part of Takeda), 25% of patients had previously been misdiagnosed.1 Initiated in 2001, FOS is an ongoing disease registry available to patients with Fabry disease.2 The mean delay from symptom onset to correct diagnosis of Fabry disease was 13.7 years in males and 16.3 years in females. Previous misdiagnoses included: rheumatological disease or rheumatic fever (39%), arthritis (15%), neuropsychological disease (13%), fibromyalgia syndrome (chronic pain associated with weakness, fatigue and sleep disturbances; 7%)3, dermatomyositis (inflammatory muscle disease usually accompanied by pain and weakness; 5%),4 erythromelalgia (throbbing and burning pain affecting the hands and feet often exacerbated by exertion or heat; 5%),6 Osler’s disease (hereditary haemorrhagic telangiectasia characterised by vascular lesions formed by dilatation of small blood vessels; 5%),5 Ménière’s disease (vertigo, hearing loss in one or more ears, tinnitus and a sense of fullness in the ear; 3%)7 or other (49%).1 In some cases, Fabry disease can also be misdiagnosed as multiple sclerosis, because patients with either disease can present with pain and white matter lesions on magnetic resonance imaging.8

In a separate retrospective, observational study of 58 patients (males, n=23; females, n=35) with Fabry disease referred to 10 internal medicine departments in France, the average time of diagnosis was 27.6 years in males (range, 10‒60 years) and 42.2 years in females (range, 9‒77 years). In this study, alternative diagnoses were considered prior to Fabry disease diagnosis in 18 patients (8 males and 10 females).9 One female patient received four different diagnoses (tuberculosis, multiple sclerosis, hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome [abnormality in the electrical functioning of the heart causing a rapid heart rate])10 throughout her life before Fabry disease was established.9 In the 58 patients, the most common clinical presentation which led to a diagnosis of Fabry disease was family history (males, n=12; females, n=27), followed by pain in the extremities (males, n=10; females, n=5) and angiokeratomas (males, n=8; females, n=4). As recommended by Lidove et al. Clin Genet 2012, clinicians should consider a diagnosis of Fabry disease when presented with a cluster of symptoms that may be either specific to the disease (both classical and late-onset) or non-specific but which may match the phenotype of Fabry disease.9

An evaluation of 55 patients with Fabry disease (males, n=25; females, n=30) in Argentina was performed to assess the most frequent diagnostic errors made in patients and to identify the medical specialists who were initially consulted. The mean age of enrolled females (38 years [range, 15‒73 years]) was older than males (27.5 years [range, 10‒43 years]). Of the 45 patients with available data, six were aged <18 years (two women were asymptomatic, and eight symptomatic patients had never consulted a physician for Fabry disease-related symptoms and were excluded from the study).11

In 40 patients (88.9%), symptoms of Fabry disease manifested before patients were aged 18 years. The mean age at symptom onset was 9.8 years for males, with a mean delay in Fabry disease diagnosis of 15.3 years (range, 3 months‒32 years). In females, the mean age at symptom onset was 10.9 years, with a mean delay in Fabry disease diagnosis of 24.7 years (range, 1‒52 years). The most commonly reported disease manifestation was acroparaesthesia (an abnormal sensation such as tingling, numbness, or pins and needles in the hands and fingers),12 which affected 34 patients. In 12 patients, acroparaesthesia was misdiagnosed as rheumatic fever. Symptoms, misdiagnoses and subsequent treatments for Fabry disease manifestations in this study are presented in Table 1. Internal medicine physicians and paediatricians were the most frequently consulted speciality for Fabry disease clinical manifestations, followed by orthopaedics, dermatologists, rheumatologists or others.11

Table 1.
Misdiagnosis of Fabry disease: symptoms, misdiagnoses and subsequent treatments. Reproduced with permission from Marchesoni CL et al. J Pediatr 2010; 156: 828-831.11



The findings from this study suggest that misdiagnosis of Fabry disease is common. Fabry disease should be included in the differential diagnosis of patients presenting with acroparaesthesia, hypohidrosis and recurrent abdominal pain in childhood or adolescence.11


C-ANPROM/INT/FAB/0016; Date of preparation: March 2021