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Granular parakeratosis (GP) is a benign skin condition first described by Northcutt et al in 1991 as pruritic, red or brown, hyperkeratotic papules and plaques confined to one or both axillae of four patients.[[1]] Since the initial description, extra-axillary sites of involvement have also been reported. These include the inter- and infra-mammary areas, inguinal, groin, perianal and genital skin, beneath the abdominal pannus and in non-intertriginous sites such as the lumbosacral area.[[2–4]]

GP is thought to be a consequence of abnormal epidermal differentiation and keratinocyte maturation from the stratum granulosum to the stratum corneum[[1–3]] through a pathogenesis that is not yet fully understood. The process is possibly exacerbated by mechanical and chemical irritation, compounded by occlusive environments.[[2–4]] In recent years, there has been a greater recognition of the association between GP and chemical irritants found in antiseptics, especially laundry rinse aids and detergents containing benzalkonium chloride (BAC).[[5,6]] BAC is a quaternary ammonium cationic compound used as an antimicrobial preservative for a range of applications. It is active against a wide range of bacteria, yeasts and fungi, but it is increasingly being recognised as a skin irritant.[[7–9]] We have noticed a number of cases of GP in adults and children who share a common history of recent exposure to BAC in laundry rinse solutions commonly found on the New Zealand market.

Patients with GP often pose as a diagnostic challenge for clinicians and can have a long period of symptomatology with multiple presentations and investigations prior to correct diagnosis. In the context of increasing use of antiseptics and disinfectants during and beyond the era of the novel coronavirus (SARS-CoV-2) COVID-19 pandemic, we also anticipate the irritant effects of BAC to be heightened and that cases of GP will continue to rise. The aim of this study was to draw attention to the presentations and course of illness of patients with GP and examine the role of BAC as a possible aetiology.

Methods

We identified 13 cases of GP in adult and paediatric patients who presented to public and private Auckland dermatological clinics between 2015 to 2020. All diagnoses were made following specialist dermatologist consultation. Epidemiological data, clinical presentation, investigation results and treatment outcomes were collected from clinical records, and all patient information was de-identified. Skin biopsy findings were recorded for patients where available. Institutional approval for the report was granted by the Auckland District Health Board Research Office.

Results

Thirteen cases of GP (seven adults; six children) are included. Four patients (three adults; one child) were seen at the Auckland District Health Board public dermatology outpatient clinic, and nine patients (four adults; five children) were seen at a private dermatology clinic in Auckland. The duration from rash onset to GP diagnosis by the dermatologist ranged from two weeks to 18 months. All patients reported recent exposure to Dettol laundry additive (Reckett Benckiser, United Kingdom) or Canesten rinse solution (Bayer, New Zealand), both of which are laundry rinse aids that contain BAC (content described in Table 1). One child (patient five) also had further exposure to BAC in QV Flare Up Cream (Douglas Pharmaceuticals Ltd, New Zealand), which was applied topically after his rash had started, and this resulted in further exacerbation of his condition.

Table 1: Benzalkonium chloride concentrations in selected products available in New Zealand.

Clinical details of the 13 patients are summarised in Appendix Table 1. Patient ages ranged from eight months to 72 years (median=31 years). Ten of the 13 patients were of full or partial Asian ethnicity. Six patients had a personal (n=5) or family (n=1) history of atopic or irritant contact dermatitis. One patient also had active psoriasis at the time of diagnosis, which was confirmed histologically. The rashes shared a common theme of erythematous papules and plaques, accompanied by varying degrees of desquamation and scaling (Figures 1 and 2). There was associated lichenification (indicating chronicity) in eight patients. Four patients reported pruritus. The distribution included the axillae, groin, trunk, limbs, anterior neck and natal cleft. Interestingly, in one patient the rash was noticed on the helices of the ears. In two patients, the rash was predominantly in a pattern of distribution reflective of areas of close contact with clothing or fabric (neckline, nappy and waistband).

Figure 1: Granular parakeratosis in an adult. Close up of the back and left axilla, showing an erythematous rash with areas of hyperkeratosis at the peripheries of the eruption (a, b). Hyperkeratosis and fissuring in the left elbow flexure (c). Hyperpigmentation, fissuring and desquamation at the neckline (d).

Figure 2: Granular parakeratosis in a child. Clinical photography showing the morphology and distribution of the erythematous and brownish hyperkeratotic papules and plaques, around the umbilicus (e), in the front of the torso and axilla (f, g).

Blood tests were done on six patients and did not reveal any systemic involvement. Skin scrapings were taken from six patients and all yielded skin flora of insignificant growth. Nine 4mm skin biopsies of the affected areas were taken from four adults: seven of the nine specimens showed typical features of parakeratosis, acanthosis and mixed dermal inflammatory infiltrates. None of the nine biopsy specimens showed evidence of bacterial or fungal infection on serial stains. The most frequent histological diagnoses were dermatitis (eczema) or psoriasis. None of the paediatric patients had skin biopsies performed. Patch testing was completed for two patients and both were negative for a series of allergens including BAC, thereby excluding allergic contact dermatitis.

Topical preparations (most commonly emollients and mild to moderate potency topical corticosteroids) had commonly been trialled prior to presentation to the dermatologist’s clinic, and systemic therapies, such as broad-spectrum antibiotics or anti-fungals, had also been prescribed in some cases. These yielded variable responses. At the time of diagnosis, patients were advised to avoid further contact with BAC and rewash clothing without the BAC-containing laundry rinses. Follow-up data were available for five cases, all of which reported improvement or resolution of skin rash following cessation of BAC exposure.

Discussion

The clinical features in our 13 patients fit well with the characteristic appearance of GP described in published literature.[[1,3,9–12]] Hyperkeratotic papules on an erythematous or brown base, often coalescing into plaques in a predominantly flexural distribution, are characteristic. Non-intertriginous involvement of the lumbosacral area, abdomen, limbs, face and neck was also noted in our cases. Involvement of the helices of the ears has not previously been reported and we postulate that this may be related to site of contact with traces of BAC on bedding.

GP has been described in all ages and both sexes, although it is more commonly reported in females.[[9–11]] In our series, the age of our patients at time of rash onset ranged widely from eight months to 72 years and just over half of cases were in females (7/13, 54%). Interestingly, 10/13 (77%) of our cohort were of full or partial Asian ethnicity. To the best of our knowledge, the occurrence of GP has not previously been described to have a particular geographical or racial predilection. Our finding may reflect local cultural practices related to laundry and hygiene.

There are many histopathologic variants of GP,[[11]] with the most common findings being hyperkeratosis, parakeratosis, epidermal acanthosis and hypergranulosis.[[2,3]] Mild to moderate capillary dilatation, proliferation of the upper papillary dermis and scattered perivascular inflammatory lymphohistiocytic infiltrate are also described.[[3,10,11]] Some histological features may overlap with psoriasis, and many of our cases also had spongiosis in the epidermis, which is classically seen in dermatitis (eczema). Of note, eczema and psoriasis were common histological misdiagnoses in our series. We propose that GP is unlikely to be diagnosed on histopathology alone; in most cases, GP should be a clinical diagnosis.

The precise aetiology and triggers of GP remain uncertain at present. Microscopic studies showing decreased cytoplasmic expression of filaggrin during cornification suggests that the primary underlying cause may be abnormal processing of profilaggrin to filaggrin (structures that maintain the keratohyalin granules in the stratum corneum during cornification).[[1–3]] Physical factors such as hyperhidrosis, obesity and friction are also thought to contribute to the evolvement of GP via chemical and or mechanical irritation, resulting in compromised epidermal maturation and barrier function.[[2,5,10]] A humid and occlusive environment, commonly found in cutaneous folds, may exacerbate penetration of irritants into the skin, which possibly explains the predominantly intertriginous distribution.[[2,4,13,14]] Five of our patients also had atopic dermatitis, which is a speculated risk factor for GP, as epidermal barrier dysfunction in atopic dermatitis may also facilitate increased penetration of irritants.[[13,15]] The skin microbiome is also important in mediating various processes involving immune responses and epidermal development and differentiation.[[16]] Previous studies have commented on how, in response to internal or external factors, altered skin microbial communities contribute to the disease pathology of a number of cutaneous conditions including acne, atopic dermatitis and psoriasis.[[17]]  Perhaps akin to the hypothesis of atopic dermatitis being associated with a loss of microbiome diversity secondary to overabundance of cutaneous Staphylococcus aureus,[[18]] Kumarasinghe et al postulate that flexural hyperkeratotic lesions such as GP could be triggered by an overgrowth of flora with a predominance of anaerobes.[[19]] In recent years GP has also been reported in association with chemotherapy for ovarian and breast carcinoma, as well as several keratinocytic neoplasms.[[9,20,21]]

Of the contact irritants that may contribute to development of GP, BAC is most widely reported.[[5,7–9,22,23]] BAC, an ammonium compound commercialised for more than 50 years, is used as an antiseptic and preservative[[7,23]] across a wide range of applications commonly found on the New Zealand market, including but not limited to eye drops, bath oils, skin cleansers, sanitisers and laundry rinse aids. These are alternative names for BAC:

  • N-Alkyl-N-benzyl-N
  • N-dimethylammonium chloride
  • Alkyldimethylbenzylammonium chloride
  • ADBAC
  • BC50
  • BC80
  • Alklbenzyldimethyl
  • Alkyl benzyldimethyl ammonium chloride
  • Ammonyx
  • Barquat MB-50
  • Barquat MB080
  • Benirol
  • Bradophen
  • BTC
  • Cequartyl
  • Drapolene
  • Dropolex
  • Enuclene
  • Germitol
  • Gesminol
  • Osuan
  • Paralkan
  • Parasterol
  • Quaternary ammonium compounds rodalon
  • Zephiran
  • Zephiran chloride
  • Zilkonium chloride

Robinson et al described GP in a susceptible subset of patients following exposure to laundry wash containing BAC;[[ 5]] and a paediatric case study in Brazil reported six cases of GP following exposure to commonly used infant skincare products containing BAC.[[14]] In our series, all patients reported use of a laundry rinse containing BAC prior to development of the rash. BAC is thought to irritate the skin by disrupting cellular epidermal lipid bilayers and promoting inflammatory cell infiltration, leading to activation of leucocytes, granulocytes, inflammatory proteins and cytokines (tumour necrosis factor-alpha, prostaglandin E2, interleukins-1a, -1b, -6, and -8).[[7,8,22]] As an antiseptic, BAC may also contribute to disease pathology by means of inducing changes to resident microbiome populations and disrupting skin homeostasis. Although less frequently reported as a sensitiser, BAC is also listed as a contact allergen on the Australian Baseline Series (ABS). Prolonged exposure to BAC can potentially predispose individuals to sensitisation and induce allergic contact dermatitis.[[5,7,10,24]]

The Environmental Protection Authority (EPA), a Crown Agent established in 2011, regulates BAC in New Zealand. The EPA categorises BAC of different concentrations (>33%; >5–25%; >1–5%) into classification codes as per the Hazardous Substances and New Organisms Act 1996. All businesses selling goods containing chemicals must apply for hazardous-substances approval from the EPA, provide an accessible chemical-safety data sheet and comply with labelling in accordance with the hazards of the particular chemical concentration. As per the EPA’s most recent reassessment of BAC in June 2020, BAC at all concentrations is not classified as a skin sensitiser. This means that in New Zealand there is no mandatory requirement for goods containing BAC to display any labelling to warn consumers of potential irritant or sensitisation effects. There is currently no limit on BAC concentration in cleaning products, although for products directly in contact with skin, the EPA limits BAC content to 3% in hair products and 0.1% in other cosmetics, such as hand-sanitisers. In light of an increasing awareness of BAC’s irritant properties and association with GP, we hence propose closer surveillance and an updated review of BAC at its various commercially available concentrations, with a particular focus on cleaning products and other common household solutions and their potential role in dermal irritation or sensitisation.  

There is currently no optimal or standardised approach to treatment for GP. There is also a paucity of high-quality evidence and controlled trials. According to our experience and other reports, treatment in the form of topical and systemic corticosteroids, retinoids, vitamin D analogues (eg, calcipotriene), keratolytics (such as salicyclic acid and ammonium lactate), antifungals and antimycotics are all of variable efficacy.[[15,25–27]] Recently, the use of broad-spectrum oral antibiotic therapy has been reported, with the proposed mechanism being modification and correction of the skin microbiome.[[19]] However, this therapy was trialled in two of our cases without noticeable improvement. The use of neurotoxin Clostridium botulinum type A has been described in patients who also suffer from hyperhidrosis;[[29]] and destructive procedural treatments such as cryotherapy, YAG and carbon dioxide lasers are also reported.[[30]] Many patients demonstrate spontaneous improvement, although the course of the eruption varies from several weeks to years.[[3,4]] In general, we consider general skin cares, withdrawal of BAC-containing laundry rinses, and avoidance of irritants to be the mainstay of treatment.

The variability in time from rash onset to diagnosis of GP in our cases (two weeks to 18 months) may be reflective of the lack of familiarity with this condition among clinicians locally and perhaps even internationally. Of the 363,343 skin biopsies from flexural dermatoses submitted by dermatologists at a large institute of dermatopathology in New York, the frequency of GP on histology was 0.005% (18 of 363,343), with only one correct clinical diagnosis in the 18 histologically confirmed cases of GP.[[11]] Similarly, Braun Falco and colleagues found histopathological features of GP in ten of 250,000 skin biopsies (0.004%), but GP had not been considered as a clinical diagnosis in any of the ten cases.[[10]] Our cases demonstrated that histopathology is rarely definitive in GP, which may lead to alternative diagnoses being sought, contributing to further diagnostic delay.

The differential diagnoses of intertriginous rashes are broad and include seborrhoeic dermatitis, irritant or allergic contact dermatitis, acanthosis nigricans, Hailey–Hailey disease, Darier’s disease, pemphigus vegetans, candidiasis, dermatophytosis, flexural drug eruptions and Dowling–Degos disease.[[3,9–11]] In the paediatric population, differentials also include napkin dermatitis, acrodermatitis enteropathica, or Letterer–Siwe disease.[[12,13]] Clinical and investigative findings, histopathological subtleties, as well as limited or no response to targeted treatment(s) will help differentiate these from GP.

This report is a retrospective case series, which makes it difficult to prove causality. Only two of our patients received formal skin patch testing to exclude an allergic contact dermatitis; however, we consider patch testing to be unnecessary in most cases where the clinical presentation is classical as GP arises from irritant rather than allergic mechanisms. Patch testing should be reserved for patients who do not respond to avoidance of BAC and other irritants.

Conclusion

Our case series describes the development of GP in a cohort of patients exposed to BAC via laundry rinses and provides further evidence for the hypothesis that GP is an irritant contact reaction pattern with BAC as a likely culprit. Our experience is that patients often have delayed diagnosis. We advocate that healthcare professionals maintain clinical suspicion for GP when encountering patients presenting with flexural dermatoses, and a history of recent exposure to BAC should be specifically sought. We anticipate this to be particularly relevant in the context of the COVID-19 pandemic and an anticipatory increased use of antiseptics. Heightened awareness of GP results in a more-timely diagnosis with reduced medical visits, investigations and unnecessary therapies. Clinical diagnosis is usually possible, and biopsy should only be considered to exclude differential diagnoses in selected cases. We propose that the mainstay of treatment remains as identification and removal of skin irritants including BAC, in combination with emollients.

Table 2: Characteristics of patients presenting with granular parakeratosis.

Summary

Abstract

AIM: Granular parakeratosis (GP) is a benign dermatosis characterised by a rash at intertriginous sites. The pathogenesis is uncertain although it is proposed to be an irritant contact reaction with cases related to benzalkonium chloride (BAC) reported. Our experience is that patients often have delayed diagnosis. This study aims to review the clinical presentation and histopathological features of GP. METHODS: This study is a retrospective case series of adult and paediatric patients seen at dermatology clinics in Auckland, New Zealand. Information was collected on patient demographics, presentation, investigations and management. RESULTS: Thirteen cases (seven adults; six children) are included. The typical presentation of GP was erythematous or brown, scaly papules and plaques with desquamation in a predominantly flexural distribution. All patients reported recent exposure to BAC in laundry rinse solution. Nine biopsies were taken from four patients. Psoriasiform and eczematous findings were common on histopathology. The mainstay of treatment was cessation of BAC exposure. CONCLUSION: GP has a distinct clinical pattern although histopathological findings are varied. Clinicians should have a high index of suspicion for GP in patients presenting with erythematous flexural eruptions and seek a history of BAC exposure, especially in the context of the COVID-19 pandemic and increased antiseptic use.

Aim

Method

Results

Conclusion

Author Information

Dr Catherine JL Tian: House Officer (Doctor), Auckland District Health Board, Auckland, New Zealand. Dr Diana Purvis: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand. Dr Harriet S Cheng: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand.

Acknowledgements

Correspondence

Dr Harriet S Cheng, Department of Dermatology, Auckland District Health Board, Private bag 92189, Auckland Mail Centre, Auckland 1142, (09) 367 0000

Correspondence Email

harrietc@adhb.govt.nz

Competing Interests

Nil.

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9. Wallace CA, Pichardo RO, Yosipovitch G, et al. Granular parakeratosis: a case report and literature review. J Cutan Pathol. 2003 May;30(5):332-5. doi: 10.1034/j.1600-0560.2003.00066.x. PMID: 12753175.

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11. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005 May;52(5):863-7. doi: 10.1016/j.jaad.2004.12.031. PMID: 15858479.

12. Pimentel DR, Michalany N, Morgado de Abreu MA, et al. Granular parakeratosis in children: case report and review of the literature. Pediatr Dermatol. 2003 May-Jun;20(3):215-20. doi: 10.1046/j.1525-1470.2003.20306.x. PMID: 12787269.

13. Patrizi A, Neri I, Misciali C, et al. Granular parakeratosis: four paediatric cases. Br J Dermatol. 2002 Nov;147(5):1003-6. doi: 10.1046/j.1365-2133.2002.04953.x. PMID: 12410715.

14. Giraldi, S, Abagge, KT, Carvalho, VOd, et al. Paraqueratose granular: relato de seis casos em crianças. Anais Brasileiros de Dermatologia, 81(1), 59-64. https://doi.org/10.1590/S0365-05962006000100008

15. Borok J, Matiz C, Goldenberg A, et al. Contact Dermatitis in Atopic Dermatitis Children-Past, Present, and Future. Clin Rev Allergy Immunol. 2019 Feb;56(1):86-98. doi: 10.1007/s12016-018-8711-2. PMID: 30225535.

16. Sanmiguel, Adam, Elizabeth A. Grice. Interactions between Host Factors and the Skin Microbiome. Cellular and Molecular Life Sciences 72, no. 8. 2014: 1499-515. doi:10.1007/s00018-014-1812-z.

17. Weyrich LS, Dixit S, Farrer AG et al. The skin microbiome: associations between altered microbial communities and disease. Australas. J. Dermatol. 2015; 56: 268–74.

18. Kong HH, Oh J, Deming C et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012; 22: 850–9.

19. Kumarasinghe SPW, Chandran V, Raby E, et al. Hyperkeratotic flexural erythema responding to amoxicillin-clavulanic acid therapy: Report of four cases. Australas J Dermatol. 2019 Nov;60(4):311-314. doi: 10.1111/ajd.13069. Epub 2019 May 2. PMID: 31049927.

20. Jaconelli L, Doebelin B, Kanitakis J, et al. Granular parakeratosis in a patient treated with liposomal doxorubicin for ovarian carcinoma. J Am Acad Dermatol. 2008 May;58(5 Suppl 1):S84-7. doi: 10.1016/j.jaad.2007.05.031. PMID: 18489055.

21. Resnik KS, DiLeonardo M. Incidental granular parakeratotic cornification in carcinomas. Am J Dermatopathol. 2007 Jun;29(3):264-9. doi: 10.1097/DAD.0b013e3180465860. PMID: 17519624.

22. Roebrock K, Wolf M, Bovens S, et al. Inhibition of benzalkonium chloride-induced skin inflammation in mice by an indol-1-ylpropan-2-one inhibitor of cytosolic phospholipase A2 α. Br J Dermatol. 2012 Feb;166(2):306-16. doi: 10.1111/j.1365-2133.2011.10637.x. Epub 2011 Dec 6. PMID: 21929537.

23. Sadakane K, Ichinose T. Effect of the hand antiseptic agents benzalkonium chloride, povidone-iodine, ethanol, and chlorhexidine gluconate on atopic dermatitis in NC/Nga mice. Int. J. Med. Sci. 2015; 12: 116–25.

24. Isaac J, Scheinman PL. Benzalkonium Chloride: An Irritant and Sensitizer. Dermatitis. 2017 Nov/Dec;28(6):346-352. doi: 10.1097/DER.0000000000000316. PMID: 28885313.

25. Patel U, Patel T, Skinner RB Jr. Resolution of granular parakeratosis with topical calcitriol. Arch Dermatol. 2011 Aug;147(8):997-8. doi: 10.1001/archdermatol.2011.214. PMID: 21844474.

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Granular parakeratosis (GP) is a benign skin condition first described by Northcutt et al in 1991 as pruritic, red or brown, hyperkeratotic papules and plaques confined to one or both axillae of four patients.[[1]] Since the initial description, extra-axillary sites of involvement have also been reported. These include the inter- and infra-mammary areas, inguinal, groin, perianal and genital skin, beneath the abdominal pannus and in non-intertriginous sites such as the lumbosacral area.[[2–4]]

GP is thought to be a consequence of abnormal epidermal differentiation and keratinocyte maturation from the stratum granulosum to the stratum corneum[[1–3]] through a pathogenesis that is not yet fully understood. The process is possibly exacerbated by mechanical and chemical irritation, compounded by occlusive environments.[[2–4]] In recent years, there has been a greater recognition of the association between GP and chemical irritants found in antiseptics, especially laundry rinse aids and detergents containing benzalkonium chloride (BAC).[[5,6]] BAC is a quaternary ammonium cationic compound used as an antimicrobial preservative for a range of applications. It is active against a wide range of bacteria, yeasts and fungi, but it is increasingly being recognised as a skin irritant.[[7–9]] We have noticed a number of cases of GP in adults and children who share a common history of recent exposure to BAC in laundry rinse solutions commonly found on the New Zealand market.

Patients with GP often pose as a diagnostic challenge for clinicians and can have a long period of symptomatology with multiple presentations and investigations prior to correct diagnosis. In the context of increasing use of antiseptics and disinfectants during and beyond the era of the novel coronavirus (SARS-CoV-2) COVID-19 pandemic, we also anticipate the irritant effects of BAC to be heightened and that cases of GP will continue to rise. The aim of this study was to draw attention to the presentations and course of illness of patients with GP and examine the role of BAC as a possible aetiology.

Methods

We identified 13 cases of GP in adult and paediatric patients who presented to public and private Auckland dermatological clinics between 2015 to 2020. All diagnoses were made following specialist dermatologist consultation. Epidemiological data, clinical presentation, investigation results and treatment outcomes were collected from clinical records, and all patient information was de-identified. Skin biopsy findings were recorded for patients where available. Institutional approval for the report was granted by the Auckland District Health Board Research Office.

Results

Thirteen cases of GP (seven adults; six children) are included. Four patients (three adults; one child) were seen at the Auckland District Health Board public dermatology outpatient clinic, and nine patients (four adults; five children) were seen at a private dermatology clinic in Auckland. The duration from rash onset to GP diagnosis by the dermatologist ranged from two weeks to 18 months. All patients reported recent exposure to Dettol laundry additive (Reckett Benckiser, United Kingdom) or Canesten rinse solution (Bayer, New Zealand), both of which are laundry rinse aids that contain BAC (content described in Table 1). One child (patient five) also had further exposure to BAC in QV Flare Up Cream (Douglas Pharmaceuticals Ltd, New Zealand), which was applied topically after his rash had started, and this resulted in further exacerbation of his condition.

Table 1: Benzalkonium chloride concentrations in selected products available in New Zealand.

Clinical details of the 13 patients are summarised in Appendix Table 1. Patient ages ranged from eight months to 72 years (median=31 years). Ten of the 13 patients were of full or partial Asian ethnicity. Six patients had a personal (n=5) or family (n=1) history of atopic or irritant contact dermatitis. One patient also had active psoriasis at the time of diagnosis, which was confirmed histologically. The rashes shared a common theme of erythematous papules and plaques, accompanied by varying degrees of desquamation and scaling (Figures 1 and 2). There was associated lichenification (indicating chronicity) in eight patients. Four patients reported pruritus. The distribution included the axillae, groin, trunk, limbs, anterior neck and natal cleft. Interestingly, in one patient the rash was noticed on the helices of the ears. In two patients, the rash was predominantly in a pattern of distribution reflective of areas of close contact with clothing or fabric (neckline, nappy and waistband).

Figure 1: Granular parakeratosis in an adult. Close up of the back and left axilla, showing an erythematous rash with areas of hyperkeratosis at the peripheries of the eruption (a, b). Hyperkeratosis and fissuring in the left elbow flexure (c). Hyperpigmentation, fissuring and desquamation at the neckline (d).

Figure 2: Granular parakeratosis in a child. Clinical photography showing the morphology and distribution of the erythematous and brownish hyperkeratotic papules and plaques, around the umbilicus (e), in the front of the torso and axilla (f, g).

Blood tests were done on six patients and did not reveal any systemic involvement. Skin scrapings were taken from six patients and all yielded skin flora of insignificant growth. Nine 4mm skin biopsies of the affected areas were taken from four adults: seven of the nine specimens showed typical features of parakeratosis, acanthosis and mixed dermal inflammatory infiltrates. None of the nine biopsy specimens showed evidence of bacterial or fungal infection on serial stains. The most frequent histological diagnoses were dermatitis (eczema) or psoriasis. None of the paediatric patients had skin biopsies performed. Patch testing was completed for two patients and both were negative for a series of allergens including BAC, thereby excluding allergic contact dermatitis.

Topical preparations (most commonly emollients and mild to moderate potency topical corticosteroids) had commonly been trialled prior to presentation to the dermatologist’s clinic, and systemic therapies, such as broad-spectrum antibiotics or anti-fungals, had also been prescribed in some cases. These yielded variable responses. At the time of diagnosis, patients were advised to avoid further contact with BAC and rewash clothing without the BAC-containing laundry rinses. Follow-up data were available for five cases, all of which reported improvement or resolution of skin rash following cessation of BAC exposure.

Discussion

The clinical features in our 13 patients fit well with the characteristic appearance of GP described in published literature.[[1,3,9–12]] Hyperkeratotic papules on an erythematous or brown base, often coalescing into plaques in a predominantly flexural distribution, are characteristic. Non-intertriginous involvement of the lumbosacral area, abdomen, limbs, face and neck was also noted in our cases. Involvement of the helices of the ears has not previously been reported and we postulate that this may be related to site of contact with traces of BAC on bedding.

GP has been described in all ages and both sexes, although it is more commonly reported in females.[[9–11]] In our series, the age of our patients at time of rash onset ranged widely from eight months to 72 years and just over half of cases were in females (7/13, 54%). Interestingly, 10/13 (77%) of our cohort were of full or partial Asian ethnicity. To the best of our knowledge, the occurrence of GP has not previously been described to have a particular geographical or racial predilection. Our finding may reflect local cultural practices related to laundry and hygiene.

There are many histopathologic variants of GP,[[11]] with the most common findings being hyperkeratosis, parakeratosis, epidermal acanthosis and hypergranulosis.[[2,3]] Mild to moderate capillary dilatation, proliferation of the upper papillary dermis and scattered perivascular inflammatory lymphohistiocytic infiltrate are also described.[[3,10,11]] Some histological features may overlap with psoriasis, and many of our cases also had spongiosis in the epidermis, which is classically seen in dermatitis (eczema). Of note, eczema and psoriasis were common histological misdiagnoses in our series. We propose that GP is unlikely to be diagnosed on histopathology alone; in most cases, GP should be a clinical diagnosis.

The precise aetiology and triggers of GP remain uncertain at present. Microscopic studies showing decreased cytoplasmic expression of filaggrin during cornification suggests that the primary underlying cause may be abnormal processing of profilaggrin to filaggrin (structures that maintain the keratohyalin granules in the stratum corneum during cornification).[[1–3]] Physical factors such as hyperhidrosis, obesity and friction are also thought to contribute to the evolvement of GP via chemical and or mechanical irritation, resulting in compromised epidermal maturation and barrier function.[[2,5,10]] A humid and occlusive environment, commonly found in cutaneous folds, may exacerbate penetration of irritants into the skin, which possibly explains the predominantly intertriginous distribution.[[2,4,13,14]] Five of our patients also had atopic dermatitis, which is a speculated risk factor for GP, as epidermal barrier dysfunction in atopic dermatitis may also facilitate increased penetration of irritants.[[13,15]] The skin microbiome is also important in mediating various processes involving immune responses and epidermal development and differentiation.[[16]] Previous studies have commented on how, in response to internal or external factors, altered skin microbial communities contribute to the disease pathology of a number of cutaneous conditions including acne, atopic dermatitis and psoriasis.[[17]]  Perhaps akin to the hypothesis of atopic dermatitis being associated with a loss of microbiome diversity secondary to overabundance of cutaneous Staphylococcus aureus,[[18]] Kumarasinghe et al postulate that flexural hyperkeratotic lesions such as GP could be triggered by an overgrowth of flora with a predominance of anaerobes.[[19]] In recent years GP has also been reported in association with chemotherapy for ovarian and breast carcinoma, as well as several keratinocytic neoplasms.[[9,20,21]]

Of the contact irritants that may contribute to development of GP, BAC is most widely reported.[[5,7–9,22,23]] BAC, an ammonium compound commercialised for more than 50 years, is used as an antiseptic and preservative[[7,23]] across a wide range of applications commonly found on the New Zealand market, including but not limited to eye drops, bath oils, skin cleansers, sanitisers and laundry rinse aids. These are alternative names for BAC:

  • N-Alkyl-N-benzyl-N
  • N-dimethylammonium chloride
  • Alkyldimethylbenzylammonium chloride
  • ADBAC
  • BC50
  • BC80
  • Alklbenzyldimethyl
  • Alkyl benzyldimethyl ammonium chloride
  • Ammonyx
  • Barquat MB-50
  • Barquat MB080
  • Benirol
  • Bradophen
  • BTC
  • Cequartyl
  • Drapolene
  • Dropolex
  • Enuclene
  • Germitol
  • Gesminol
  • Osuan
  • Paralkan
  • Parasterol
  • Quaternary ammonium compounds rodalon
  • Zephiran
  • Zephiran chloride
  • Zilkonium chloride

Robinson et al described GP in a susceptible subset of patients following exposure to laundry wash containing BAC;[[ 5]] and a paediatric case study in Brazil reported six cases of GP following exposure to commonly used infant skincare products containing BAC.[[14]] In our series, all patients reported use of a laundry rinse containing BAC prior to development of the rash. BAC is thought to irritate the skin by disrupting cellular epidermal lipid bilayers and promoting inflammatory cell infiltration, leading to activation of leucocytes, granulocytes, inflammatory proteins and cytokines (tumour necrosis factor-alpha, prostaglandin E2, interleukins-1a, -1b, -6, and -8).[[7,8,22]] As an antiseptic, BAC may also contribute to disease pathology by means of inducing changes to resident microbiome populations and disrupting skin homeostasis. Although less frequently reported as a sensitiser, BAC is also listed as a contact allergen on the Australian Baseline Series (ABS). Prolonged exposure to BAC can potentially predispose individuals to sensitisation and induce allergic contact dermatitis.[[5,7,10,24]]

The Environmental Protection Authority (EPA), a Crown Agent established in 2011, regulates BAC in New Zealand. The EPA categorises BAC of different concentrations (>33%; >5–25%; >1–5%) into classification codes as per the Hazardous Substances and New Organisms Act 1996. All businesses selling goods containing chemicals must apply for hazardous-substances approval from the EPA, provide an accessible chemical-safety data sheet and comply with labelling in accordance with the hazards of the particular chemical concentration. As per the EPA’s most recent reassessment of BAC in June 2020, BAC at all concentrations is not classified as a skin sensitiser. This means that in New Zealand there is no mandatory requirement for goods containing BAC to display any labelling to warn consumers of potential irritant or sensitisation effects. There is currently no limit on BAC concentration in cleaning products, although for products directly in contact with skin, the EPA limits BAC content to 3% in hair products and 0.1% in other cosmetics, such as hand-sanitisers. In light of an increasing awareness of BAC’s irritant properties and association with GP, we hence propose closer surveillance and an updated review of BAC at its various commercially available concentrations, with a particular focus on cleaning products and other common household solutions and their potential role in dermal irritation or sensitisation.  

There is currently no optimal or standardised approach to treatment for GP. There is also a paucity of high-quality evidence and controlled trials. According to our experience and other reports, treatment in the form of topical and systemic corticosteroids, retinoids, vitamin D analogues (eg, calcipotriene), keratolytics (such as salicyclic acid and ammonium lactate), antifungals and antimycotics are all of variable efficacy.[[15,25–27]] Recently, the use of broad-spectrum oral antibiotic therapy has been reported, with the proposed mechanism being modification and correction of the skin microbiome.[[19]] However, this therapy was trialled in two of our cases without noticeable improvement. The use of neurotoxin Clostridium botulinum type A has been described in patients who also suffer from hyperhidrosis;[[29]] and destructive procedural treatments such as cryotherapy, YAG and carbon dioxide lasers are also reported.[[30]] Many patients demonstrate spontaneous improvement, although the course of the eruption varies from several weeks to years.[[3,4]] In general, we consider general skin cares, withdrawal of BAC-containing laundry rinses, and avoidance of irritants to be the mainstay of treatment.

The variability in time from rash onset to diagnosis of GP in our cases (two weeks to 18 months) may be reflective of the lack of familiarity with this condition among clinicians locally and perhaps even internationally. Of the 363,343 skin biopsies from flexural dermatoses submitted by dermatologists at a large institute of dermatopathology in New York, the frequency of GP on histology was 0.005% (18 of 363,343), with only one correct clinical diagnosis in the 18 histologically confirmed cases of GP.[[11]] Similarly, Braun Falco and colleagues found histopathological features of GP in ten of 250,000 skin biopsies (0.004%), but GP had not been considered as a clinical diagnosis in any of the ten cases.[[10]] Our cases demonstrated that histopathology is rarely definitive in GP, which may lead to alternative diagnoses being sought, contributing to further diagnostic delay.

The differential diagnoses of intertriginous rashes are broad and include seborrhoeic dermatitis, irritant or allergic contact dermatitis, acanthosis nigricans, Hailey–Hailey disease, Darier’s disease, pemphigus vegetans, candidiasis, dermatophytosis, flexural drug eruptions and Dowling–Degos disease.[[3,9–11]] In the paediatric population, differentials also include napkin dermatitis, acrodermatitis enteropathica, or Letterer–Siwe disease.[[12,13]] Clinical and investigative findings, histopathological subtleties, as well as limited or no response to targeted treatment(s) will help differentiate these from GP.

This report is a retrospective case series, which makes it difficult to prove causality. Only two of our patients received formal skin patch testing to exclude an allergic contact dermatitis; however, we consider patch testing to be unnecessary in most cases where the clinical presentation is classical as GP arises from irritant rather than allergic mechanisms. Patch testing should be reserved for patients who do not respond to avoidance of BAC and other irritants.

Conclusion

Our case series describes the development of GP in a cohort of patients exposed to BAC via laundry rinses and provides further evidence for the hypothesis that GP is an irritant contact reaction pattern with BAC as a likely culprit. Our experience is that patients often have delayed diagnosis. We advocate that healthcare professionals maintain clinical suspicion for GP when encountering patients presenting with flexural dermatoses, and a history of recent exposure to BAC should be specifically sought. We anticipate this to be particularly relevant in the context of the COVID-19 pandemic and an anticipatory increased use of antiseptics. Heightened awareness of GP results in a more-timely diagnosis with reduced medical visits, investigations and unnecessary therapies. Clinical diagnosis is usually possible, and biopsy should only be considered to exclude differential diagnoses in selected cases. We propose that the mainstay of treatment remains as identification and removal of skin irritants including BAC, in combination with emollients.

Table 2: Characteristics of patients presenting with granular parakeratosis.

Summary

Abstract

AIM: Granular parakeratosis (GP) is a benign dermatosis characterised by a rash at intertriginous sites. The pathogenesis is uncertain although it is proposed to be an irritant contact reaction with cases related to benzalkonium chloride (BAC) reported. Our experience is that patients often have delayed diagnosis. This study aims to review the clinical presentation and histopathological features of GP. METHODS: This study is a retrospective case series of adult and paediatric patients seen at dermatology clinics in Auckland, New Zealand. Information was collected on patient demographics, presentation, investigations and management. RESULTS: Thirteen cases (seven adults; six children) are included. The typical presentation of GP was erythematous or brown, scaly papules and plaques with desquamation in a predominantly flexural distribution. All patients reported recent exposure to BAC in laundry rinse solution. Nine biopsies were taken from four patients. Psoriasiform and eczematous findings were common on histopathology. The mainstay of treatment was cessation of BAC exposure. CONCLUSION: GP has a distinct clinical pattern although histopathological findings are varied. Clinicians should have a high index of suspicion for GP in patients presenting with erythematous flexural eruptions and seek a history of BAC exposure, especially in the context of the COVID-19 pandemic and increased antiseptic use.

Aim

Method

Results

Conclusion

Author Information

Dr Catherine JL Tian: House Officer (Doctor), Auckland District Health Board, Auckland, New Zealand. Dr Diana Purvis: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand. Dr Harriet S Cheng: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand.

Acknowledgements

Correspondence

Dr Harriet S Cheng, Department of Dermatology, Auckland District Health Board, Private bag 92189, Auckland Mail Centre, Auckland 1142, (09) 367 0000

Correspondence Email

harrietc@adhb.govt.nz

Competing Interests

Nil.

1. Northcutt AD, Nelson DM, Tschen JA. Axillary granular parakeratosis. J Am Acad Dermatol. 1991 Apr;24(4):541-4. doi: 10.1016/0190-9622(91)70078-g.

2. Mehregan DA, Thomas JE, Mehregan DR. Intertriginous granular parakeratosis. J Am Acad Dermatol. 1998 Sep;39(3):495-6. doi: 10.1016/s0190-9622(98)70333-0. PMID: 9738790.

3. Metze D, Rütten A. Granular parakeratosis - a unique acquired disorder of keratinization. J Cutan Pathol. 1999 Aug;26(7):339-52. doi: 10.1111/j.1600-0560.1999.tb01855.x. PMID: 10487291.

4. Wohlrab J, Lüftl M, Wolter M. Submammary granular parakeratosis: an acquired punctate hyperkeratosis of exogenic origin. J Am Acad Dermatol. 1999 May;40(5 Pt 2):813-4. PMID: 10321622.

5. Robinson AJ, Foster RS, Halbert AR, et al. Granular parakeratosis induced by benzalkonium chloride exposure from laundry rinse aids. Australas J Dermatol. 2017 Aug;58(3):e138-e140. doi: 10.1111/ajd.12551. Epub 2016 Sep 19. PMID: 27641714.

6. Tartari F, Vincenzi C, Di Altobrando A, et al. Allergic contact dermatitis to benzalkonium chloride with erythema multiforme-like reaction in a child. Contact Dermatitis. 2020 Jun;82(6):397-399. doi: 10.1111/cod.13481. Epub 2020 Apr 3. PMID: 32112429.

7. Basketter DA, Marriott M, Gilmour NJ, et al. Strong irritants masquerading as skin allergens: the case of benzalkonium chloride. Contact Dermatitis. 2004 Apr;50(4):213-7. doi: 10.1111/j.0105-1873.2004.00331.x. PMID: 15186375.

8. Wentworth AB, Yiannias JA, Davis MD, et al. Benzalkonium Chloride: A Known Irritant and Novel Allergen. Dermatitis. 2016 Jan-Feb;27(1):14-20. doi: 10.1097/DER.0000000000000160. PMID: 26756511.

9. Wallace CA, Pichardo RO, Yosipovitch G, et al. Granular parakeratosis: a case report and literature review. J Cutan Pathol. 2003 May;30(5):332-5. doi: 10.1034/j.1600-0560.2003.00066.x. PMID: 12753175.

10. Braun-Falco M, Laaff H. Granular parakeratosis--a clinical-pathological correlation of 10 cases. J Dtsch Dermatol Ges. 2009 Apr;7(4):340-4. English, German. doi: 10.1111/j.1610-0387.2008.06964.x. Epub 2008 Dec 3. PMID: 19054421.

11. Scheinfeld NS, Mones J. Granular parakeratosis: pathologic and clinical correlation of 18 cases of granular parakeratosis. J Am Acad Dermatol. 2005 May;52(5):863-7. doi: 10.1016/j.jaad.2004.12.031. PMID: 15858479.

12. Pimentel DR, Michalany N, Morgado de Abreu MA, et al. Granular parakeratosis in children: case report and review of the literature. Pediatr Dermatol. 2003 May-Jun;20(3):215-20. doi: 10.1046/j.1525-1470.2003.20306.x. PMID: 12787269.

13. Patrizi A, Neri I, Misciali C, et al. Granular parakeratosis: four paediatric cases. Br J Dermatol. 2002 Nov;147(5):1003-6. doi: 10.1046/j.1365-2133.2002.04953.x. PMID: 12410715.

14. Giraldi, S, Abagge, KT, Carvalho, VOd, et al. Paraqueratose granular: relato de seis casos em crianças. Anais Brasileiros de Dermatologia, 81(1), 59-64. https://doi.org/10.1590/S0365-05962006000100008

15. Borok J, Matiz C, Goldenberg A, et al. Contact Dermatitis in Atopic Dermatitis Children-Past, Present, and Future. Clin Rev Allergy Immunol. 2019 Feb;56(1):86-98. doi: 10.1007/s12016-018-8711-2. PMID: 30225535.

16. Sanmiguel, Adam, Elizabeth A. Grice. Interactions between Host Factors and the Skin Microbiome. Cellular and Molecular Life Sciences 72, no. 8. 2014: 1499-515. doi:10.1007/s00018-014-1812-z.

17. Weyrich LS, Dixit S, Farrer AG et al. The skin microbiome: associations between altered microbial communities and disease. Australas. J. Dermatol. 2015; 56: 268–74.

18. Kong HH, Oh J, Deming C et al. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012; 22: 850–9.

19. Kumarasinghe SPW, Chandran V, Raby E, et al. Hyperkeratotic flexural erythema responding to amoxicillin-clavulanic acid therapy: Report of four cases. Australas J Dermatol. 2019 Nov;60(4):311-314. doi: 10.1111/ajd.13069. Epub 2019 May 2. PMID: 31049927.

20. Jaconelli L, Doebelin B, Kanitakis J, et al. Granular parakeratosis in a patient treated with liposomal doxorubicin for ovarian carcinoma. J Am Acad Dermatol. 2008 May;58(5 Suppl 1):S84-7. doi: 10.1016/j.jaad.2007.05.031. PMID: 18489055.

21. Resnik KS, DiLeonardo M. Incidental granular parakeratotic cornification in carcinomas. Am J Dermatopathol. 2007 Jun;29(3):264-9. doi: 10.1097/DAD.0b013e3180465860. PMID: 17519624.

22. Roebrock K, Wolf M, Bovens S, et al. Inhibition of benzalkonium chloride-induced skin inflammation in mice by an indol-1-ylpropan-2-one inhibitor of cytosolic phospholipase A2 α. Br J Dermatol. 2012 Feb;166(2):306-16. doi: 10.1111/j.1365-2133.2011.10637.x. Epub 2011 Dec 6. PMID: 21929537.

23. Sadakane K, Ichinose T. Effect of the hand antiseptic agents benzalkonium chloride, povidone-iodine, ethanol, and chlorhexidine gluconate on atopic dermatitis in NC/Nga mice. Int. J. Med. Sci. 2015; 12: 116–25.

24. Isaac J, Scheinman PL. Benzalkonium Chloride: An Irritant and Sensitizer. Dermatitis. 2017 Nov/Dec;28(6):346-352. doi: 10.1097/DER.0000000000000316. PMID: 28885313.

25. Patel U, Patel T, Skinner RB Jr. Resolution of granular parakeratosis with topical calcitriol. Arch Dermatol. 2011 Aug;147(8):997-8. doi: 10.1001/archdermatol.2011.214. PMID: 21844474.

26. Contreras ME, Gottfried LC, Bang RH, et al. Axillary intertriginous granular parakeratosis responsive to topical calcipotriene and ammonium lactate. Int J Dermatol. 2003 May;42(5):382-3. doi: 10.1046/j.1365-4362.2003.01722.x. PMID: 12755978.roebrock

27. Samrao A, Reis M, Niedt G, Rudikoff D. Granular parakeratosis: response to calcipotriene and brief review of current therapeutic options. Skinmed. 2010 Nov-Dec;8(6):357-9. PMID: 21413654.

28. Brown SK, Heilman ER. Granular parakeratosis: resolution with topical tretinoin. J Am Acad Dermatol. 2002 Nov;47(5 Suppl):S279-80. doi: 10.1067/mjd.2002.109252. PMID: 12399751.

29. Ravitskiy L, Heymann WR. Botulinum toxin-induced resolution of axillary granular parakeratosis. Skinmed. 2005 Mar-Apr;4(2):118-20. doi: 10.1111/j.1540-9740.2005.03700.x. PMID: 15785142.

30. Laimer M, Emberger M, Brunasso AM, et al. Laser for the treatment of granular parakeratosis. Dermatol Surg. 2009 Feb;35(2):297-300. doi: 10.1111/j.1524-4725.2008.01052.x. Erratum in: Dermatol Surg. 2009 Mar;35(3):557. PMID: 19215276.

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Granular parakeratosis (GP) is a benign skin condition first described by Northcutt et al in 1991 as pruritic, red or brown, hyperkeratotic papules and plaques confined to one or both axillae of four patients.[[1]] Since the initial description, extra-axillary sites of involvement have also been reported. These include the inter- and infra-mammary areas, inguinal, groin, perianal and genital skin, beneath the abdominal pannus and in non-intertriginous sites such as the lumbosacral area.[[2–4]]

GP is thought to be a consequence of abnormal epidermal differentiation and keratinocyte maturation from the stratum granulosum to the stratum corneum[[1–3]] through a pathogenesis that is not yet fully understood. The process is possibly exacerbated by mechanical and chemical irritation, compounded by occlusive environments.[[2–4]] In recent years, there has been a greater recognition of the association between GP and chemical irritants found in antiseptics, especially laundry rinse aids and detergents containing benzalkonium chloride (BAC).[[5,6]] BAC is a quaternary ammonium cationic compound used as an antimicrobial preservative for a range of applications. It is active against a wide range of bacteria, yeasts and fungi, but it is increasingly being recognised as a skin irritant.[[7–9]] We have noticed a number of cases of GP in adults and children who share a common history of recent exposure to BAC in laundry rinse solutions commonly found on the New Zealand market.

Patients with GP often pose as a diagnostic challenge for clinicians and can have a long period of symptomatology with multiple presentations and investigations prior to correct diagnosis. In the context of increasing use of antiseptics and disinfectants during and beyond the era of the novel coronavirus (SARS-CoV-2) COVID-19 pandemic, we also anticipate the irritant effects of BAC to be heightened and that cases of GP will continue to rise. The aim of this study was to draw attention to the presentations and course of illness of patients with GP and examine the role of BAC as a possible aetiology.

Methods

We identified 13 cases of GP in adult and paediatric patients who presented to public and private Auckland dermatological clinics between 2015 to 2020. All diagnoses were made following specialist dermatologist consultation. Epidemiological data, clinical presentation, investigation results and treatment outcomes were collected from clinical records, and all patient information was de-identified. Skin biopsy findings were recorded for patients where available. Institutional approval for the report was granted by the Auckland District Health Board Research Office.

Results

Thirteen cases of GP (seven adults; six children) are included. Four patients (three adults; one child) were seen at the Auckland District Health Board public dermatology outpatient clinic, and nine patients (four adults; five children) were seen at a private dermatology clinic in Auckland. The duration from rash onset to GP diagnosis by the dermatologist ranged from two weeks to 18 months. All patients reported recent exposure to Dettol laundry additive (Reckett Benckiser, United Kingdom) or Canesten rinse solution (Bayer, New Zealand), both of which are laundry rinse aids that contain BAC (content described in Table 1). One child (patient five) also had further exposure to BAC in QV Flare Up Cream (Douglas Pharmaceuticals Ltd, New Zealand), which was applied topically after his rash had started, and this resulted in further exacerbation of his condition.

Table 1: Benzalkonium chloride concentrations in selected products available in New Zealand.

Clinical details of the 13 patients are summarised in Appendix Table 1. Patient ages ranged from eight months to 72 years (median=31 years). Ten of the 13 patients were of full or partial Asian ethnicity. Six patients had a personal (n=5) or family (n=1) history of atopic or irritant contact dermatitis. One patient also had active psoriasis at the time of diagnosis, which was confirmed histologically. The rashes shared a common theme of erythematous papules and plaques, accompanied by varying degrees of desquamation and scaling (Figures 1 and 2). There was associated lichenification (indicating chronicity) in eight patients. Four patients reported pruritus. The distribution included the axillae, groin, trunk, limbs, anterior neck and natal cleft. Interestingly, in one patient the rash was noticed on the helices of the ears. In two patients, the rash was predominantly in a pattern of distribution reflective of areas of close contact with clothing or fabric (neckline, nappy and waistband).

Figure 1: Granular parakeratosis in an adult. Close up of the back and left axilla, showing an erythematous rash with areas of hyperkeratosis at the peripheries of the eruption (a, b). Hyperkeratosis and fissuring in the left elbow flexure (c). Hyperpigmentation, fissuring and desquamation at the neckline (d).

Figure 2: Granular parakeratosis in a child. Clinical photography showing the morphology and distribution of the erythematous and brownish hyperkeratotic papules and plaques, around the umbilicus (e), in the front of the torso and axilla (f, g).

Blood tests were done on six patients and did not reveal any systemic involvement. Skin scrapings were taken from six patients and all yielded skin flora of insignificant growth. Nine 4mm skin biopsies of the affected areas were taken from four adults: seven of the nine specimens showed typical features of parakeratosis, acanthosis and mixed dermal inflammatory infiltrates. None of the nine biopsy specimens showed evidence of bacterial or fungal infection on serial stains. The most frequent histological diagnoses were dermatitis (eczema) or psoriasis. None of the paediatric patients had skin biopsies performed. Patch testing was completed for two patients and both were negative for a series of allergens including BAC, thereby excluding allergic contact dermatitis.

Topical preparations (most commonly emollients and mild to moderate potency topical corticosteroids) had commonly been trialled prior to presentation to the dermatologist’s clinic, and systemic therapies, such as broad-spectrum antibiotics or anti-fungals, had also been prescribed in some cases. These yielded variable responses. At the time of diagnosis, patients were advised to avoid further contact with BAC and rewash clothing without the BAC-containing laundry rinses. Follow-up data were available for five cases, all of which reported improvement or resolution of skin rash following cessation of BAC exposure.

Discussion

The clinical features in our 13 patients fit well with the characteristic appearance of GP described in published literature.[[1,3,9–12]] Hyperkeratotic papules on an erythematous or brown base, often coalescing into plaques in a predominantly flexural distribution, are characteristic. Non-intertriginous involvement of the lumbosacral area, abdomen, limbs, face and neck was also noted in our cases. Involvement of the helices of the ears has not previously been reported and we postulate that this may be related to site of contact with traces of BAC on bedding.

GP has been described in all ages and both sexes, although it is more commonly reported in females.[[9–11]] In our series, the age of our patients at time of rash onset ranged widely from eight months to 72 years and just over half of cases were in females (7/13, 54%). Interestingly, 10/13 (77%) of our cohort were of full or partial Asian ethnicity. To the best of our knowledge, the occurrence of GP has not previously been described to have a particular geographical or racial predilection. Our finding may reflect local cultural practices related to laundry and hygiene.

There are many histopathologic variants of GP,[[11]] with the most common findings being hyperkeratosis, parakeratosis, epidermal acanthosis and hypergranulosis.[[2,3]] Mild to moderate capillary dilatation, proliferation of the upper papillary dermis and scattered perivascular inflammatory lymphohistiocytic infiltrate are also described.[[3,10,11]] Some histological features may overlap with psoriasis, and many of our cases also had spongiosis in the epidermis, which is classically seen in dermatitis (eczema). Of note, eczema and psoriasis were common histological misdiagnoses in our series. We propose that GP is unlikely to be diagnosed on histopathology alone; in most cases, GP should be a clinical diagnosis.

The precise aetiology and triggers of GP remain uncertain at present. Microscopic studies showing decreased cytoplasmic expression of filaggrin during cornification suggests that the primary underlying cause may be abnormal processing of profilaggrin to filaggrin (structures that maintain the keratohyalin granules in the stratum corneum during cornification).[[1–3]] Physical factors such as hyperhidrosis, obesity and friction are also thought to contribute to the evolvement of GP via chemical and or mechanical irritation, resulting in compromised epidermal maturation and barrier function.[[2,5,10]] A humid and occlusive environment, commonly found in cutaneous folds, may exacerbate penetration of irritants into the skin, which possibly explains the predominantly intertriginous distribution.[[2,4,13,14]] Five of our patients also had atopic dermatitis, which is a speculated risk factor for GP, as epidermal barrier dysfunction in atopic dermatitis may also facilitate increased penetration of irritants.[[13,15]] The skin microbiome is also important in mediating various processes involving immune responses and epidermal development and differentiation.[[16]] Previous studies have commented on how, in response to internal or external factors, altered skin microbial communities contribute to the disease pathology of a number of cutaneous conditions including acne, atopic dermatitis and psoriasis.[[17]]  Perhaps akin to the hypothesis of atopic dermatitis being associated with a loss of microbiome diversity secondary to overabundance of cutaneous Staphylococcus aureus,[[18]] Kumarasinghe et al postulate that flexural hyperkeratotic lesions such as GP could be triggered by an overgrowth of flora with a predominance of anaerobes.[[19]] In recent years GP has also been reported in association with chemotherapy for ovarian and breast carcinoma, as well as several keratinocytic neoplasms.[[9,20,21]]

Of the contact irritants that may contribute to development of GP, BAC is most widely reported.[[5,7–9,22,23]] BAC, an ammonium compound commercialised for more than 50 years, is used as an antiseptic and preservative[[7,23]] across a wide range of applications commonly found on the New Zealand market, including but not limited to eye drops, bath oils, skin cleansers, sanitisers and laundry rinse aids. These are alternative names for BAC:

  • N-Alkyl-N-benzyl-N
  • N-dimethylammonium chloride
  • Alkyldimethylbenzylammonium chloride
  • ADBAC
  • BC50
  • BC80
  • Alklbenzyldimethyl
  • Alkyl benzyldimethyl ammonium chloride
  • Ammonyx
  • Barquat MB-50
  • Barquat MB080
  • Benirol
  • Bradophen
  • BTC
  • Cequartyl
  • Drapolene
  • Dropolex
  • Enuclene
  • Germitol
  • Gesminol
  • Osuan
  • Paralkan
  • Parasterol
  • Quaternary ammonium compounds rodalon
  • Zephiran
  • Zephiran chloride
  • Zilkonium chloride

Robinson et al described GP in a susceptible subset of patients following exposure to laundry wash containing BAC;[[ 5]] and a paediatric case study in Brazil reported six cases of GP following exposure to commonly used infant skincare products containing BAC.[[14]] In our series, all patients reported use of a laundry rinse containing BAC prior to development of the rash. BAC is thought to irritate the skin by disrupting cellular epidermal lipid bilayers and promoting inflammatory cell infiltration, leading to activation of leucocytes, granulocytes, inflammatory proteins and cytokines (tumour necrosis factor-alpha, prostaglandin E2, interleukins-1a, -1b, -6, and -8).[[7,8,22]] As an antiseptic, BAC may also contribute to disease pathology by means of inducing changes to resident microbiome populations and disrupting skin homeostasis. Although less frequently reported as a sensitiser, BAC is also listed as a contact allergen on the Australian Baseline Series (ABS). Prolonged exposure to BAC can potentially predispose individuals to sensitisation and induce allergic contact dermatitis.[[5,7,10,24]]

The Environmental Protection Authority (EPA), a Crown Agent established in 2011, regulates BAC in New Zealand. The EPA categorises BAC of different concentrations (>33%; >5–25%; >1–5%) into classification codes as per the Hazardous Substances and New Organisms Act 1996. All businesses selling goods containing chemicals must apply for hazardous-substances approval from the EPA, provide an accessible chemical-safety data sheet and comply with labelling in accordance with the hazards of the particular chemical concentration. As per the EPA’s most recent reassessment of BAC in June 2020, BAC at all concentrations is not classified as a skin sensitiser. This means that in New Zealand there is no mandatory requirement for goods containing BAC to display any labelling to warn consumers of potential irritant or sensitisation effects. There is currently no limit on BAC concentration in cleaning products, although for products directly in contact with skin, the EPA limits BAC content to 3% in hair products and 0.1% in other cosmetics, such as hand-sanitisers. In light of an increasing awareness of BAC’s irritant properties and association with GP, we hence propose closer surveillance and an updated review of BAC at its various commercially available concentrations, with a particular focus on cleaning products and other common household solutions and their potential role in dermal irritation or sensitisation.  

There is currently no optimal or standardised approach to treatment for GP. There is also a paucity of high-quality evidence and controlled trials. According to our experience and other reports, treatment in the form of topical and systemic corticosteroids, retinoids, vitamin D analogues (eg, calcipotriene), keratolytics (such as salicyclic acid and ammonium lactate), antifungals and antimycotics are all of variable efficacy.[[15,25–27]] Recently, the use of broad-spectrum oral antibiotic therapy has been reported, with the proposed mechanism being modification and correction of the skin microbiome.[[19]] However, this therapy was trialled in two of our cases without noticeable improvement. The use of neurotoxin Clostridium botulinum type A has been described in patients who also suffer from hyperhidrosis;[[29]] and destructive procedural treatments such as cryotherapy, YAG and carbon dioxide lasers are also reported.[[30]] Many patients demonstrate spontaneous improvement, although the course of the eruption varies from several weeks to years.[[3,4]] In general, we consider general skin cares, withdrawal of BAC-containing laundry rinses, and avoidance of irritants to be the mainstay of treatment.

The variability in time from rash onset to diagnosis of GP in our cases (two weeks to 18 months) may be reflective of the lack of familiarity with this condition among clinicians locally and perhaps even internationally. Of the 363,343 skin biopsies from flexural dermatoses submitted by dermatologists at a large institute of dermatopathology in New York, the frequency of GP on histology was 0.005% (18 of 363,343), with only one correct clinical diagnosis in the 18 histologically confirmed cases of GP.[[11]] Similarly, Braun Falco and colleagues found histopathological features of GP in ten of 250,000 skin biopsies (0.004%), but GP had not been considered as a clinical diagnosis in any of the ten cases.[[10]] Our cases demonstrated that histopathology is rarely definitive in GP, which may lead to alternative diagnoses being sought, contributing to further diagnostic delay.

The differential diagnoses of intertriginous rashes are broad and include seborrhoeic dermatitis, irritant or allergic contact dermatitis, acanthosis nigricans, Hailey–Hailey disease, Darier’s disease, pemphigus vegetans, candidiasis, dermatophytosis, flexural drug eruptions and Dowling–Degos disease.[[3,9–11]] In the paediatric population, differentials also include napkin dermatitis, acrodermatitis enteropathica, or Letterer–Siwe disease.[[12,13]] Clinical and investigative findings, histopathological subtleties, as well as limited or no response to targeted treatment(s) will help differentiate these from GP.

This report is a retrospective case series, which makes it difficult to prove causality. Only two of our patients received formal skin patch testing to exclude an allergic contact dermatitis; however, we consider patch testing to be unnecessary in most cases where the clinical presentation is classical as GP arises from irritant rather than allergic mechanisms. Patch testing should be reserved for patients who do not respond to avoidance of BAC and other irritants.

Conclusion

Our case series describes the development of GP in a cohort of patients exposed to BAC via laundry rinses and provides further evidence for the hypothesis that GP is an irritant contact reaction pattern with BAC as a likely culprit. Our experience is that patients often have delayed diagnosis. We advocate that healthcare professionals maintain clinical suspicion for GP when encountering patients presenting with flexural dermatoses, and a history of recent exposure to BAC should be specifically sought. We anticipate this to be particularly relevant in the context of the COVID-19 pandemic and an anticipatory increased use of antiseptics. Heightened awareness of GP results in a more-timely diagnosis with reduced medical visits, investigations and unnecessary therapies. Clinical diagnosis is usually possible, and biopsy should only be considered to exclude differential diagnoses in selected cases. We propose that the mainstay of treatment remains as identification and removal of skin irritants including BAC, in combination with emollients.

Table 2: Characteristics of patients presenting with granular parakeratosis.

Summary

Abstract

AIM: Granular parakeratosis (GP) is a benign dermatosis characterised by a rash at intertriginous sites. The pathogenesis is uncertain although it is proposed to be an irritant contact reaction with cases related to benzalkonium chloride (BAC) reported. Our experience is that patients often have delayed diagnosis. This study aims to review the clinical presentation and histopathological features of GP. METHODS: This study is a retrospective case series of adult and paediatric patients seen at dermatology clinics in Auckland, New Zealand. Information was collected on patient demographics, presentation, investigations and management. RESULTS: Thirteen cases (seven adults; six children) are included. The typical presentation of GP was erythematous or brown, scaly papules and plaques with desquamation in a predominantly flexural distribution. All patients reported recent exposure to BAC in laundry rinse solution. Nine biopsies were taken from four patients. Psoriasiform and eczematous findings were common on histopathology. The mainstay of treatment was cessation of BAC exposure. CONCLUSION: GP has a distinct clinical pattern although histopathological findings are varied. Clinicians should have a high index of suspicion for GP in patients presenting with erythematous flexural eruptions and seek a history of BAC exposure, especially in the context of the COVID-19 pandemic and increased antiseptic use.

Aim

Method

Results

Conclusion

Author Information

Dr Catherine JL Tian: House Officer (Doctor), Auckland District Health Board, Auckland, New Zealand. Dr Diana Purvis: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand. Dr Harriet S Cheng: Dermatologist, Department of Dermatology, Auckland District Health Board and University of Auckland, Auckland, New Zealand.

Acknowledgements

Correspondence

Dr Harriet S Cheng, Department of Dermatology, Auckland District Health Board, Private bag 92189, Auckland Mail Centre, Auckland 1142, (09) 367 0000

Correspondence Email

harrietc@adhb.govt.nz

Competing Interests

Nil.

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