Introduction

Definition and overview of fox-fordyce disease

Fox-Fordyce disease, also known as apocrine miliaria, is a rare chronic inflammatory disorder of the skin affecting the apocrine sweat glands.¹ Apocrine sweat glands play a pheromonic role in animals and humans. These glands respond to stimuli such as stress and sexual activity. They typically become especially active during puberty. Apocrine sweat glands are found in the armpits, breast, and anogenital regions. The sweat produced in these areas is typically more odoured and thicker than the sweat produced by eccrine glands. This thicker sweat obstructs the apocrine glands because of an accumulation of keratin - though this aetiology has not exactly been defined yet. It typically affects individuals assigned female at birth (AFAB) after adolescence,  has no specific diagnostic tests,  and is diagnosed through clinical evaluation. Managing Fox-Fordyce disease can be challenging as the condition is chronic and recurrent. Management and treatment are often focused on alleviating the symptoms the patient presents, with various treatment options being available. ¹

Understanding the pathophysiology of fox-fordyce disease

Aetiology

This condition was first described in 1902 by George Henry Fox and John Addison Fordyce as an uncommon eruption that affects sites on the skin that bear apocrine sweat glands. The exact aetiology is not yet known but is hypothesised to be due to the keratinous obstruction of intraepidermal apocrine gland ducts. This obstruction causes the blocked ducts to rupture which leads to sweat seeping from the ducts causing inflammation around the hair follicles.^2,3

It is also speculated that genetics plays a role in disease development because it has been described in identical twins and familial history has occasionally been reported by those with this condition. Another hypothesis is that there is a hormonal influence in the development of the disease as it is often described in young people AFAB (commonly aged 13 to 35)  - over 90% of those affected are people AFAB. Symptoms associated with the disease often present after puberty, but resolve during pregnancy when using oral contraceptive pills and after menopause. The disease also flares around the time of menstruation. No ethnic or racial predilections are thought to be factors that lead to the development of the disease.^1,3

There have also been reports of the development of Fox-Fordyce disease after undergoing laser hair removal. This is thought to be because of heat injury to the hair follicles by the procedure using specific lasers such as diode, alexandrite, and IPL.^4,5

Another factor that contributes to the development of the disease is increased sweating (triggered by exercise, humid climate, sexual activity, emotional stress, and even tight clothing).

Symptomatology

Symptoms of Fox-Fordyce disease can appear suddenly, especially after exposure to environmental or physical factors such as humid weather, heat, and friction.¹ You will notice an eruption of multiple, small, smooth, dome-shaped, uniform, skin-coloured raised bumps on your skin. Sometimes these bumps may present as slightly yellow. Diagnosis of the disease is mainly based on the typical distribution accompanied by characteristic pruritus - it’s paroxysmal to the condition. 

As a result of the pruritus, you may notice excoriations (a loss of a portion of the epidermis and dermis) and lichenification (thickening and hyperpigmentation of the skin with exaggerated skin lines) in the affected areas. Furthermore, hair may become sparse in the affected areas. This can eventually progress to apocrine anhidrosis (the inability to effectively sweat when presented with suitable stimuli such as exercise or heat).^3,6

While there is potential for scarring, and pruritus makes this condition an uncomfortable one to have when it manifests, there are various treatment and management approaches available to people with Fox-Fordyce disease.

Conventional treatment approaches

Fox-Fordyce disease treatment can be challenging due to the lack of research into the condition, however, the target is often symptom relief. Conventional interventions include strategies that can alleviate inflammation of the hair follicles, prevent further obstruction of the ducts or decrease sweating. Some options aim to remove or destroy sweat glands in the impacted area.¹ Consultations with a dermatologist are recommended to get professional advice on the best treatment path for you.

Topical therapies

These are the preferred initial options because they are readily available, easy to administer and have low risk for serious adverse side effects. The treatment regimen is entirely dependent on the individual’s tolerance to the topical therapy and personal circumstances make one option more suitable than the others. There are several topical therapy options: ¹

1. Corticosteroids

These are the preferred first-line treatments as they are least likely to cause skin atrophy, fissuring, or striae (stretch marks). Usually, you are instructed to apply these twice daily until you notice an improvement in symptoms. Thereafter, there will be a subsequent reduction to applying the creams once a day or 2-3 times a week.⁷

2. Retinoids

Topical retinoids (tretinoin and adapalene) are available to alleviate symptoms of Fox-Fordyce disease as they are believed to be able to reduce occlusion of both hair follicles and ducts. They’re less commonly prescribed than corticosteroids as they are more likely to cause skin irritation hence patients may be instructed to apply every other day when beginning treatment with topical retinoids until a tolerance is developed.^8,9

3. Topical clindamycin

This is often used to help control acne however it can also be used for other skin conditions such as Fox-Fordyce. Clindamycin is an antibiotic whose exact mechanism of action remains unclear but it works to stop the growth of bacteria. After a few weeks of use, patients may see improvement in the lesions at the site of concern.¹⁰

4. Topical calcineurin inhibitors (TCIs)

These work by blocking calcineurin, a protein that leads to skin inflammation. There are two kinds of TCIs (pimecrolimus and tacrolimus) that are prescribed based on the severity of skin inflammation. However, using both has resulted in moderate to almost complete clearance of the small bumps that are characteristic of Fox-Fordyce disease. In this way, they are similar to corticosteroids however they do not run the risk of causing cutaneous atrophy.^11,12,13

Systemic therapies

1. Oral Contraceptives

The use of oral contraceptives to treat Fox-Fordyce symptoms supports the hypothesis that hormonal imbalance is a factor in the aetiology of this disease. It’s not completely curative, however, treatment using norethynodrel with mestranol proved to be effective at controlling pruritus and resolving the presence of the small bumps that appear as a result of the condition.¹⁴

2. Oral Retinoids

In anecdotal reports, there has been success reported when treating symptoms with oral retinoids in a male patient. However, whether that relief was long-lasting was not mentioned, meaning this is not a curative treatment option.¹⁵

If there is a secondary infection shown or suspected, systemic antibiotics will likely be prescribed.¹ 

With the above-mentioned treatment and management options, disease symptoms may recur once the cessation of treatment happens, however, there are other treatment options that may be more invasive but can confer longer-lasting effects.

Emerging and alternative therapies

A low incidence rate and lack of understanding of the pathophysiology of Fox-Fordyce disease means there is limited evidence-based research being performed, meaning that innovative treatments are few and far between. However, there is evidence of successful alternative therapies that have longer-lasting effects than what is currently used as first-line therapies.

Laser therapy

Though laser hair removal procedures have been indicated to precede the development of Fox-Fordyce disease, there is use for other types of lasers such as the CO2 laser for the management of the disease lesions. Anecdotal reports show that after 3 fractional CO2 laser treatments during a 5 month period, a Fox-Fordyce patient showed significant improvements with no complications throughout treatment. Furthermore, these results were maintained for 1 year after commencement of therapy.¹⁶

Combined laser therapy and surgical intervention

Surgical intervention is used in severe cases of this disease where lesions are large and are an aesthetic issue for the patient. However, this is not a favourable treatment option as there is a risk of hypertrophic scarring that may continue to pose aesthetic challenges for the patient.  

A combination with laser therapy has been indicated as an alternative to minimise scarring and prevent the recurrence of lesions. One such combination treatment was done with a 1500 nm infrared erbium glass laser (usually used to treat active acne vulgaris) to treat a case of remnant lesions after surgical excision of prominent, severe lesions on the areola. The 1500 nm infrared erbium glass laser is used as it can effectively penetrate the deep skin layer where the apocrine glands exist, causing thermal injury to the glands. 14 months post-treatment, the patient was recurrent and free of lesions.¹⁷ Pulsed dye lasers have also been indicated as effective treatment options for Fox-Fordyce patients.¹⁸

Botulinum toxin

Botulinum toxin (botox) injections have been indicated as a suitable and effective treatment option for Fox-Fordyce patients. 3 months following 1 round of treatment, the patient reported that their pruritus was almost completely gone, there was a visible reduction in the number of papules from the baseline presentation that left some post-inflammatory hyperpigmentation and a couple of scars. There were also no adverse side effects reported. These results were maintained after a 6 month follow-up period.¹⁹ 

Other alternative therapies that have shown promising results are phototherapy, microwave technology, electrocoagulation, liposuction-assisted curettage, and copper vapour.^1,20,21,22

Summary

Fox-Fordyce is an uncommon chronic skin condition mostly observed in people AFAB of childbearing age (13-35 years old). Individuals often present with multiple, small, skin-coloured, uniform bumps in the armpits, breasts, and anogenital region as this is where apocrine sweat glands are present. Though the exact aetiology is not yet understood, it is hypothesised that due to the “thicker” sweat produced in these areas, there is a higher chance of keratin accumulation that causes blockages to the sweat glands and ducts leading to their rupture and subsequent seepage of sweat into hair follicles, The occlusion of these follicles then leads to the flesh coloured bumps earlier described, coupled with pruritus. Symptoms of this condition are exacerbated by heat, humid weather, and friction. 

There are no specific tests available for diagnosis of this disease thus diagnosis is entirely reliant on clinical evaluation. A lack of understanding of the aetiology of this disease coupled with the non-specific symptoms also makes treatment a challenge; most treatment options are therefore focused on the alleviation of symptoms. 

There are several treatment options available: first-line therapies include topical therapies such as corticosteroids, antibiotic creams and topical retinoids. However, some alternative therapies have been indicated as being more effective, less likely to cause adverse effects, and overall greater at preventing the recurrence of the lesions characteristic of this condition. These alternative therapies include using fractional lasers, botox injections, microwave technology, and liposuction-assisted curettage.