Hyperhidrosis: A New And Often Early Symptom In Fabry Disease. International Experience And Data From The Fabry Outcome Survey

O. Lidove; U. Ramaswami; R. Jaussaud; F. Barbey; T. Maisonobe; C. Caillaud; M. Beck; G. Sunder-Plassmann; A. Linhart; A Mehta On Behalf Of The Fos European Investigators

Disclosures

Int J Clin Pract. 2006;60(9):1053-1059. 

In This Article

Summary and Introduction

Hypohidrosis is a classic feature of Fabry disease; in contrast, hyperhidrosis has only been rarely described. The aim of the study is to characterise the baseline descriptive data on hyperhidrosis (frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy) in hemizygous male and heterozygous female patients with Fabry disease. We describe case histories of five patients with Fabry disease and hyperhidrosis seen at three different centres. We have also analysed a cohort of 21 paediatric patients in the UK and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three female, two male) with hyperhidrosis were originally identified, although each had additional symptoms related to Fabry disease. The age at onset of hyperhidrosis was less than 18 years in four cases. In the cohort of 21 paediatric patients (12 female, nine male), one female had hyperhidrosis; the age at onset of this symptom was 11 years. In the FOS cohort, 66 of 714 patients with Fabry disease had hyperhidrosis (44 of 369 females, 11.9%; 22 of 345 males, 6.4%). The female predominance was observed in seven of nine countries from which data were analysed. Hyperhidrosis is an increasingly recognised feature of the Fabry disease phenotype. It is more prevalent in females than in males and often appears in childhood or adolescence. The efficacy of enzyme replacement therapy on this recently recognised symptom should be assessed.

Fabry disease is the second most common of the 40 or so LSDs that have been described, with an estimated incidence varying from 1:117,000[1] to 1: 17,000.[2] It is an X-linked lysosomal storage disorder (LSD) caused by an inborn deficiency of α-galactosidase A. The resulting inability to catabolise glycosphingolipids causes progressive accumulation of globotriaosylceramide (Gb3) in diverse cells and tissues of the body. These include cells of the endothelium, vascular smooth muscle, myocardium, corneal epithelium and nervous system and organs such as the kidney, pancreas, bowel, lung and skin.[3] The resulting symptoms usually appear during childhood and adolescence and are typically followed by disease progression and premature death.

The early clinical phenotype of 35 European children and adolescents with Fabry disease has been reported.[4] Predominant symptoms were acroparaesthesia, hypohidrosis (with a prevalence of 93% in males and 25% in females), cornea verticillata, angiokeratoma and gastrointestinal symptoms. Hypohidrosis predisposes to acroparaesthesia by making sufferers intolerant of heat and exercise, which often leads to exercise-induced pain crises. A study of 366 patients in the Fabry Outcome Survey (FOS) reported dermatological symptoms in 78% of males and 50% of females, with angiokeratomas present from a mean age of 17.9 years in males and 29.1 years in females.[5]

Hyperhidrosis, or excessive sweating, is found in 1.0-2.8% of the general population in the USA.[6,7] Generalised hyperhidrosis involves the entire body and is usually part of an underlying condition, most often an infectious, endocrine or neurological disorder. Focal hyperhidrosis is usually idiopathic, occurring in otherwise healthy people, and affects one or more body areas, most often the palms, armpits, soles or face. It is twice as prevalent in women as in men and carries a substantial psychological and social burden, as it interferes with daily activities. Patients rarely seek help, however, because many are unaware that they have a treatable medical disorder. Early detection and management of hyperhidrosis can significantly improve an individual's quality of life. In 2003, Mohrenschlager et al.[8] identified hyperhidrosis as a cutaneous manifestation of Fabry disease, and it is increasingly being recognised that hyperhidrosis may be an early manifestation of the disease.

The pathogenesis of sweating abnormalities in patients with Fabry disease relates to abnormal nerve function and infiltration of the sweat glands by storage material. An ultrastructure study by electron microscopy in a patient with Fabry disease and hyperhidrosis showed characteristic cytoplasmic inclusions in the eccrine sweat glands, as well as lamellated inclusions in the unmyelinated axons innervating the eccrine sweat glands. The small blood vessels around the eccrine glands were narrowed by swollen endothelial cells with heavy inclusions.[9] An ischaemic process may also contribute, considering the poor nerve perfusion leading to depolarised axons in patients with Fabry disease.[10]

Autonomic nerves fibres are affected in most symmetrical peripheral neuropathies and clinical effects are usually mild or subclinical. However, small or unmyelinated autonomic fibres are prominently targeted in Fabry disease ( Table 1 ).[11] The extensive distribution of the autonomic nerves results in an impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor and pupillomotor autonomic function. Functional tests used to document the abnormalities include thermoregulatory sweat testing, quantitative sudomotor-axon-reflex test (QSART), sweat imprint methods and sympathetic skin response. Distal hyperhidrosis is known to be an early symptom in the course of autonomic peripheral neuropathy, whereas hyperhidrosis with a proximal distribution commonly occurs later in the course.

Autonomic manifestations of Fabry disease classically include hypohidrosis or anhidrosis, reduced saliva and tear formation, impaired cutaneous flare response to scratch and histamine, disordered intestinal motility and severe orthostatic hypotension.[12,13]

The aims of the present study were to document hyperhidrosis in patients with Fabry disease and to characterise baseline clinical data on hyperhidrosis [frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy (ERT)] in hemizygous and heterozygous patients.

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