Aquagenic Syringeal Acrokeratoderma Successfully Managed with Topical Glycopyrronium: A Case and Review of the Literature

1. Introduction

Aquagenic Syringeal Acrokeratoderma (ASA) is a rare dermatological condition characterised by the transient appearance of whitish papules and palmar or plantar wrinkling following water exposure [1,2]. This is often accompanied by pain, pruritus, or burning sensations [1]. While ASA is generally considered a benign and self-limiting condition, its clinical manifestations can cause functional impairment that negatively affects quality of life [1]. The aetiopathogenesis of ASA is unclear, and management of ASA remains challenging as treatment outcomes have been variable [1,2,3]. Here, we describe a case that helps elucidate the underlying pathogenesis of ASA and provides evidence to support the potential role of topical anticholinergic therapy in ASA.

2. Case Description

We report a case of a 21-year-old Indian male that presented to the dermatology clinic with a 2-year history of painful wrinkling of his palms upon exposure to water, accompanied by stinging and tingling of the palms. Symptoms developed approximately 15 minutes after water exposure and resolved upon drying of the hands. Prolonged hand washing or bathing resulted in pruritus, raised lesions, and peeling of skin involving the entire palmar surface. Similar but less severe lesions were reported on the soles follow-ing water exposure. No other abnormalities were identified. The patient had a history of palmar hyperhidrosis with a Hyperhidrosis Disease Severity Scale (HDSS) score of 2, and no known personal or family history of cystic fibrosis. He was employed part-time in warehouse work and reported concern that sweating during physical activities exacerbated his symptoms. Photographs provided by the patient following immersion of the hands in water demonstrated keratotic, macerated papules involving the palms, with greater prominence along the medial margins (Figure 1 and Figure 2). Laboratory investigations did not reveal evidence of an underlying systemic disorder. A diagnosis of acquired Aquagenic Syringeal Acrokeratoderma (ASA) of the palms was made.

Initial treatment with topical 20% aluminium chloride (Perspirex) was discontinued due to excessive dryness. Subsequently, topical glycopyrronium bromide 2% spray applied three times daily resulted in an approximate 50% reduction in symptom severity, without reported adverse effects. Prior to treatment, palmar wrinkling occurred after showers lasting less than 30 minutes, with pain persisting beyond 30 minutes. Following initiation of topical glycopyrronium bromide, pain developed only after showers exceeding 45 minutes in duration. The type of soap used did not influence symptom severity. The symptomatic improvement associated with topical glycopyrronium bromide has been sustained since treatment started 1.5 years ago.

3. Discussion

There are two forms of ASA: hereditary and acquired. Most reported cases are thought to be acquired, with onset typically occurring between 20 and 30 years of age, although some rare cases of inherited ASA with an onset during infancy have been reported [4,5,6]. ASA has been reported to have a higher prevalence among girls and women aged 8 to 65 years, although there has been a recent increase in case reports involving men [1,5].

ASA most commonly presents with symmetrical oedematous, white-translucent papules accompanied by wrinkling in palmar and occasionally plantar areas, after exposure to water [1,2]. Atypical sites for ASA include a single palm, the dorsal surface of the digits, heels, forehead, upper lip, nose, mouth, double ankle joints and calves [7,8]. These lesions and pathological wrinkling of the skin typically appear 3 to 5 minutes after exposure to water, in contrast to physiological wrinkling of the palmar skin which occurs after 11 minutes of water exposure [9]. Most cases resolve within 20 minutes of drying of the skin; however, some cases have been reported to last up to 2 or 3 hours [5,9]. Warm water seems to be more efficient in inducing the appearance of these lesions [5,10]. Associated symptoms may include pain, tingling, tightness, pruritus, and burning sensations [1].

Histological findings can include orthohyperkeratosis with acanthosis, spongiosis in the stratum corneum, dilation of acrosyringia and dermal eccrine ducts, and increased proliferation of capillaries surrounding the eccrine glands [2,3]. Dilatation of the eccrine ducts is the most common finding [11].

Diagnosis of ASA is based on the clinical history and physical findings as demonstrated by the ‘hand in the bucket’ sign, where patients immerse their hands in 15 °C water for 5 minutes to reproduce the clinical features of ASA [5,12,13]. Non-invasive adjunctive bedside tools including reflectance confocal microscopy and dermoscopy have also been used have also been described as adjunctive tools for diagnosis [14], and more recently Wood’s light has been proposed as a way to help confirm the diagnosis as well as rule out differential diagnoses [15]. However, as symptoms of ASA typically resolve rapidly upon drying of the skin and may exhibit a transient course, with variations in severity occurring throughout the patient’s lifetime, ASA can often go unrecognised [16].

The main differential diagnoses for ASA would include hereditary papulotranslucent acrokeratoderma (HPA), which occurs soon after puberty and persists throughout life [10]. HPA exhibits a different clinical presentation characterised by persistent yellow-white translucent papules or plaques on palms or soles that may be associated with fine-textured scalp hair and atopic diathesis [5]. Focal hyperkeratosis, acanthosis and normal eccrine ducts may be seen on histological examination of HPA [5,10]. Eccrine angiomatous nevus (hamartoma) may also mimic ASA on histological examination, as both may demonstrate hyperplasia of the capillary vessels surrounding the dilated eccrine glands. However, this condition exhibits erythematous, brownish-yellow hyperhidrotic papules or plaques that are persistent, differing from the clinical presentation of ASA [5]. Other differential diagnoses of ASA are aquagenic pruritus and aquagenic urticaria [7].

ASA has classically been associated with cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1,2]. Multiple studies have drawn a link between ASA and CFTR dysfunction in around 75% of CF patients, and 25% of CF carriers with ASA [12]. This strong association has prompted other studies to suggest the presence of ASA as a sensitive screening tool for suspected CF or CF carrier patients [9,12]. ASA has also been associated with palmoplantar hyperhidrosis, atopic dermatitis, Raynaud disease and marasmus [7,9,12].

The aetiopathogenesis of ASA is unclear, however it has been proposed to involve an increase in the water binding capacity of the stratum corneum associated with increased sodium retention in the epidermal cells and aberrant function of the sweat glands [1,2,5]. In relation to CF, it has been hypothesised that ASA is due to an increased salt content in sweat [9,12,17]. The CFTR protein is normally present in eccrine ducts and regulates electrolyte transport. Mutations in the CFTR gene in CF patients lead to production of a defective CFTR protein which impairs electrolyte reabsorption, resulting in hypertonic sweat [9,12]. High concentration of salt accumulates within the exceptionally thick stratum corneum on acral skin and the eccrine ductal lumens, leading to increased fluid diffusion into palmar or plantar skin.

A similar pathogenic mechanism has been described in patients with ASA induced by certain drugs such as cyclooxygenase-2 (COX-2) inhibitors, aspirin, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers [9,17,18]. Carder and Weston reported a case of rofecoxib-induced ASA and hypothesised that selective COX-2 inhibition in epidermal cells causes increased sodium retention, similar to the mechanism of COX-2 inhibition in the kidneys [19]. Other drugs associated with ASA include isotretinoin which has been reported to cause aquagenic wrinkling possibly through increasing sympathetic activation, as well as by impairing skin barrier function and water absorption [20]. ASA has also been observed in patients taking aminoglycoside antibiotics, gabapentin, spironolactone, and a combination of ascorbic acid with clarithromycin and paracetamol [12,17].

Sympathetic overactivity of the autonomic nervous system and eccrine duct involvement are thought to play a role in eccrine gland dysfunction that contributes to the development of ASA [21,22]. Eccrine sweat glands are innervated by sympathetic postganglionic nerves with acetylcholine as the primary neurotransmitter driving sweat production. Heightened sympathetic activation of the eccrine gland is hypothesised to alter ductal function, promoting an osmotic influx of water into the eccrine ducts [21]. Mac Cormack et al. have also proposed an aberration of the sweat duct walls as a structural origin of ASA [23]. The proposed role of eccrine gland dysfunction is further supported by the clinical response observed with therapeutic modalities targeting sympathetic activity and eccrine function, including anticholinergic drugs, botulinum toxin and iontophoresis [3,21,22,24].

The exaggerated wrinkling response seen in ASA has also been attributed to sympathetic activation [3,25]. It has been shown that fingertip skin wrinkling is related to digit pulp vasoconstriction [26]. Wilder-Smith and Chow [27] proposed that the diffusion of water into eccrine ducts disrupts electrolyte balance which results in increased firing of the adjacent sympathetic nerve fibres and subsequent vasoconstriction [9,25]. Increased vasomotor activity induces contraction of small muscle fibres, while vasoconstriction leads to a reduction in tissue volume, resulting in wrinkling of the skin [9].

Other studies have suggested that the rapid yet transient effect of water contact in ASA points to the dysregulation of certain aquaporin (AQP) channels [3]. Aberrant expression of AQP5 in eccrine sweat glands as well as dysfunction of AQP3 and AQP10 in the epidermis are thought to contribute to rapid alterations in epidermal water-handling capacity mediated by AQPs and thus the transient oedema seen in ASA [3,28].

Additionally, it has been suggested that dysfunction in the osmosensitive transient vanilloid receptor type-1 (TVRT-1) expressed in human keratinocytes leads to dysregulation of water transport in the epidermis, causing higher stratum corneum water-binding capacity [3]. This mechanism has been proposed to account for cases of ASA associated with the COVID-19 pandemic, where hygiene practices like increased frequencies of handwashing may lead to keratinocyte swelling through TVRT-1 receptors [16].

Other postulated mechanisms include impaired stratum corneum barrier function similar to that observed in atopic dermatitis, obstruction of the eccrine duct openings, and structural weakness of the eccrine duct walls [1,2,17].

Although spontaneous resolution or self-limitation have been reported in many cases, ASA can cause significant physical and psychological distress if persistent, thus necessitating treatment [5]. A range of therapeutic approaches have been considered, however most have yielded mixed results [1,2].

Aluminium-based topical therapy is commonly cited as a first-line treatment for ASA, with a 20% aluminium chloride solution shown to produce improvement in multiple cases [8,9,29]. However, some patients are unable to tolerate the irritant properties of this treatment, citing dryness and pain [30]. In such patients, a 15% aluminium chloride gel formulation which may be less drying can be considered as an alternative [31]. Recurrence of symptoms can also occur after discontinuation [7,8]. Other topical treatment options include 20% salicylic acid, 10% urea cream and formalin 3% in alcohol [9,12]. Topical corticosteroids, oral acitretin and oral antihistamines have been reported in the management of ASA as well, however their efficacy remains uncertain [9,17]. Ammonium lactate creams used alone or in combination with petroleum jelly, gloves and other measures that create a barrier to water exposure have been shown to be ineffective in treating ASA [5,9,30]. Topical calcineurin inhibitors such as pimecrolimus and tacrolimus have been proposed as a novel treatment option, however their efficacy requires validation by further studies [30,32].

In refractory cases where topical treatment modalities are ineffective, botulinum toxin A injections can be considered as a second-line therapy [3,9]. Used in the treatment of hyperhidrosis, it targets preganglionic sympathetic and parasympathetic nerves and postganglionic parasympathetic nerves [3]. Botulinum toxin injections have obtained good results in a few cases and can offer a disease remission period of up to 5 months [8,33,34]. Iontophoresis has also been described in a single case where it produced symptomatic improvement along with reduced sweating in a patient unresponsive to topical 20% aluminium chloride [12]. In severe or refractory cases of ASA, permanent treatment of ASA with endoscopic thoracic sympathectomy can be considered, especially when associated with severe palmar or plantar hyperhidrosis [35].

The use of various anticholinergic medications has also been explored in the treatment of ASA. Oral oxybutynin chloride, which has been effective in the treatment of hyperhidrosis, has been reported to produce substantial improvement in a case of atypical ASA and thus been proposed to be a a more affordable and less invasive treatment modality than botulinum toxin [21]. More recently, Medhus et al. reported complete resolution of palmar sweating, papule formation, and discomfort with once-daily topical glycopyrronium cloth 2.4% [22]. Similarly, our patient experienced substantial symptomatic improvement with topical glycopyrronium bromide 2% spray.

In line with the favourable response to treatments that modify sweating observed above, Pradas and Santacana noted that the most effective treatments to date are those that address both hyperhidrosis and ASA [8]. We propose that this points to sweat itself playing a direct role in the pathogenesis of ASA, with water entering epidermis and dermis causing the macerated keratoderma and pain, respectively. Similar to cystic fibrosis, we postulate that there may be an underlying eccrine transmembrane channelopathy in ASA, with impaired reabsorption of salt from sweat. This can lead to the accumulation of a high concentration of salt within the stratum corneum layer and ductal lumens of the exceptionally thick acral skin. When the skin is subsequently exposed to water externally or when sweat production increases, this elevated intracellular ionic strength acts as an osmotic draw for water. Subsequently, water diffuses up the concentration gradient from the eccrine ductal lumens into the high-solute cells of the stratum corneum and into the dermal interstitium, leading to macerated papules and plaques in the epidermis and pain within the dermis.

Given the available therapies, we suggest that topical glycopyrronium bromide can be considered as a viable treatment option for ASA, particularly when the patient proves to be intolerant or unresponsive to other therapies. Botulinum toxin injections on palms and soles are extremely painful, costly and require repeated administration for sustained results [8]. Iontophoresis has generally demonstrated limited therapeutic efficacy [8]. Sympathectomy, while effective, can be an overly aggressive choice and should be reserved for patients with concomitant severe hyperhidrosis [35]. Oral oxybutynin chloride appears to provide an efficacious and convenient treatment option in comparison, and if given at low doses (<10 mg/day) can reduce the risk of systemic anticholinergic adverse effects [8]. However, dry mouth was still a very commonly cited side effect among patients in a randomised controlled trial of oral oxybutynin as a treatment for generalised hyperhidrosis, even at low doses [36], and systemic anticholinergic side effects can develop over time with prolonged administration. The topical application of glycopyrronium bromide could potentially mitigate such side effects. and coupled with its ease of application and comparable efficacy. The delivery in the form of a spray described in our treatment of this case of ASA, rather than in the form of a cloth in the previous case of ASA treated with topical glycopyrronium bromide, further confers ease and convenience for patients to store and apply the therapy.

4. Conclusions

The favourable clinical response observed in this case of ASA following treatment with topical glycopyrronium bromide 2% supports the hypothesis that eccrine sweat dysfunction contributes to the pathogenesis of aquagenic syringeal acrokeratoderma and suggests that topical anticholinergic therapy may be a safe and effective therapeutic option for ASA.