Fox-Fordyce disease (apocrine miliaria)

INTRODUCTION — Apocrine miliaria, more commonly referred to as Fox-Fordyce disease (FFD), is an uncommon, usually chronic, pruritic skin condition that is postulated to occur when apocrine or apoeccrine sweat ducts become occluded and inflamed (picture 1A-E). George Henry Fox and John Addison Fordyce originally described FFD in 1902 as pruritic papules in the axillae [1]. Since then, FFD has been recognized in other body sites containing apocrine glands, including the areolae, anogenital skin, and other areas.

Treatment of FFD can be difficult, but often necessary, because of associated pruritus. Local therapies, such as topical corticosteroids, topical clindamycin, and topical calcineurin inhibitors, are typically used as initial treatments, with oral and procedural therapies primarily reserved for refractory disease. Limited data prevents conclusions on the relative efficacy of interventions. Recurrence is common after discontinuation of treatment.

The clinical features, diagnosis, and management of FFD will be reviewed here. Eccrine miliaria are reviewed separately. (See "Miliaria".)

EPIDEMIOLOGY — The majority of cases of FFD occur in young women. The female to male ratio is 9:1 and the disease most often begins between the ages of 13 and 35 years [2]. There are occasional reports of the development of FFD in prepubertal children and postmenopausal women [3-5].

PATHOGENESIS — The pathogenesis of FFD is not fully understood but appears to involve occlusion of sweat glands. There are three types of sweat glands in humans: apocrine, apoeccrine, and eccrine glands [6]. Apocrine glands are the largest sweat glands and are found on the axillae, eyelids, areola, nipple, external auditory meatus, and periumbilical and anogenital skin. The secretory ducts of apocrine glands open onto the infundibulum of hair follicles. Apoeccrine glands are of intermediate size, are primarily found in the axillae, and have secretory ducts that open directly onto the skin surface. Eccrine glands, the smallest and most widely distributed sweat glands, do not play a role in FFD.

Two forms of FFD have been described: follicular and nonfollicular.

●Follicular Fox-Fordyce disease – In most cases, the cause of FFD appears to be occlusion of the apocrine duct, resulting from the accumulation of keratin in the follicular infundibulum. This theory is supported by the histopathologic finding of hyperkeratotic cores within follicular infundibula in involved skin [6].

Subsequent rupture of the apocrine duct causes inflammation within the surrounding tissue. The multiple reports of the development of FFD or FFD-like eruptions following laser hair removal, a procedure that can damage the follicular infundibulum, also suggest occlusion and disruption of the sweat duct as contributors to FFD [7-9].

●Nonfollicular Fox-Fordyce disease – Nonfollicular FFD involves obstruction of apoeccrine ducts, which open directly onto the skin surface rather than into hair follicles. The accumulation of detached apoeccrine secretory cells within the sweat duct may cause the obstruction [6].

Other proposed contributors to FFD include environmental, physical, and hormonal factors, although the role of these is not entirely clear. Conditions that induce sweating seem to aggravate FFD, particularly hot and humid environments, occlusive clothing, and exercise. Emotional stress and sexual activity have also been associated with exacerbations of the disease.

The marked female predominance observed in FFD and the rarity of the disease prior to puberty suggest a role for hormones in the pathogenesis. FFD may flare before or during menses, may improve or flare with pregnancy [10], and may remit with menopause. Hormones, particularly androgens, can influence keratinocyte adhesion, composition of sweat, and other factors that may affect the apocrine gland [11].

CLINICAL FEATURES — The primary lesions of FFD are 2 to 3 mm papules that may be yellow, skin-colored, reddish, or violaceous. They appear in crops and are limited to the distribution of apocrine glands (picture 1A-E). Most papules are perifollicular. A linear pattern is often evident when the skin is stretched.

FFD most often occurs in areas with many apocrine glands, such as the axillary, areolar, perianal, and genital areas. Other potential locations include the external auditory canal, periumbilical area, chest, medial thighs, and eyelids. Skin involvement is usually bilateral.

FFD is typically extremely pruritic. Longstanding cases may exhibit lichenification in the involved area secondary to chronic scratching, which manifests as coarse, thickened, hyperpigmented or violaceous skin.

Severe cases may cause destruction of the gland and the associated hair follicle, resulting in anhidrosis within the affected area. Hair within affected areas may be dry, brittle, sparse, or absent.

HISTOPATHOLOGY — Histopathologic examination of FFD usually shows hyperkeratosis and plugging of the follicular infundibulum and excretory duct of the apocrine gland, usually at the site of insertion into the hair follicle. The duct becomes dilated proximal to the plug, where apocrine secretions accumulate and a spongiotic vesicle may be seen. This may cause the duct to rupture. Inflammatory cells, usually lymphocytes, are in the surrounding tissues and within the ductal epithelium. In patients with apoeccrine gland involvement, ductal obstruction may be detected in the intraepidermal portion of the apoeccrine sweat duct [6].

Other histologic changes may include vacuolar changes and dyskeratotic cells within the duct and surrounding tissues [12]. Perifollicular foam cells, or "foamy macrophages," are found in most specimens of FFD [13]. Epidermal hypertrophy and acanthosis may be present in longstanding disease.

DIAGNOSIS — In most patients, a diagnosis of FFD can be made based upon the presence of a bilateral eruption consisting of multiple, uniform, follicular or perifollicular, skin-colored, reddish, or violaceous papules limited to the axillae or other apocrine gland-rich areas (eg, areola, anogenital skin).

The typical patient is a female in her teens to thirties, and intense pruritus is characteristic. Pustules, vesicles, cysts, and abscesses are typically absent. In chronic cases, scratching can lead to cutaneous lichenification, which may conceal the classic clinical findings. (See 'Clinical features' above.)

Reported dermoscopic findings include light brown to dark brown, structureless areas usually around hair follicles [14]. Hyperkeratotic, follicular plugging and traumatized terminal hairs have also been described [14,15]. (See "Overview of dermoscopy".)

In patients with atypical clinical findings, a biopsy may be necessary to confirm the diagnosis. A 4 mm punch biopsy of a papule is usually sufficient. Transverse sectioning of the specimen may best show the diagnostic features [16]. (See "Skin biopsy techniques".)

DIFFERENTIAL DIAGNOSIS — FFD should be distinguished from other papular eruptions that may occur in axillary or anogenital skin. Attention to the clinical features is often sufficient for distinguishing these disorders from FFD. Examples include:

●Folliculitis – Follicular erythematous papules and/or pustules are characteristic features of infectious folliculitis (picture 2). Pustules are not a feature of FFD. (See "Infectious folliculitis".)

●Pseudofolliculitis – Pseudofolliculitis, also known as "ingrown hairs," may manifest as multiple follicular papules (picture 3). The beard area of the face is the most common site (pseudofolliculitis); however, the condition may also occur in axillary or pubic areas. Pseudofolliculitis usually follows hair removal, particularly with shaving. Trapped loops of hair may be visible. (See "Pseudofolliculitis barbae".)

●Miliaria rubra and miliaria profunda – Eccrine miliaria are vesicular or papular eruptions that result from occlusion of eccrine sweat glands. Miliaria rubra is characterized by erythematous 2 to 4 mm papules (picture 4). Miliaria profunda presents with multiple skin-colored papules (picture 5). Unlike FFD, miliaria rubra and miliaria profunda may occur in any site with eccrine glands. (See "Miliaria".)

●Colloid milia – Colloid milium is an uncommon, cutaneous deposition disorder that results from degenerative changes in the skin. Colloid milia present as yellowish or brown, translucent papules, often in sun-exposed areas, such as the face, neck, dorsal hands, or back (picture 6). A skin biopsy reveals accumulations of homogenous, amorphous, eosinophilic material in the dermis [17].

●Granular parakeratosis – Granular parakeratosis is an uncommon cutaneous disorder characterized by the development of hyperkeratotic brown-red papules that coalesce to form plaques in intertriginous areas (picture 7). The axilla is the most frequent site of involvement. Pruritus is common. (See "Granular parakeratosis".)

●Syringomas – Syringomas present as multiple 2 to 4 mm skin-colored, brown, or pink papules (picture 8). Syringomas most frequently occur on periorbital skin but may also occur in intertriginous sites or other areas [18]. A biopsy may be necessary to distinguish syringomas from FFD. Histologic examination of syringomas reveals small collections of epithelial cells with central ducts in the superficial dermis. (See "Cutaneous adnexal tumors", section on 'Syringoma'.)

●Acanthosis nigricans – Acanthosis nigricans presents as hyperpigmented velvety plaques that may have a somewhat papular appearance (picture 9). This disorder usually appears on intertriginous sites or skin-folds, such as in the axillae or on the posterior neck. Less frequently, acanthosis nigricans appears on the dorsal hands or in other areas. (See "Acanthosis nigricans".)

●Hailey-Hailey disease – Hailey-Hailey disease (benign familial pemphigus) is a genetic disorder that causes loss of keratinocyte adhesion (acantholysis). The disorder primarily affects intertriginous skin. Common findings include flaccid vesicles, superficial erosions, macerated plaques, and vegetative plaques (picture 10A-B). A skin biopsy can confirm the diagnosis. (See "Hailey-Hailey disease (benign familial pemphigus)".)

●Darier disease – Darier disease is a genetic disorder characterized by acantholysis and persistent, skin-colored or red-brown, keratotic, greasy papules in a seborrheic distribution (picture 11A-B). Intertriginous involvement can present as warty, vegetative papules or plaques in the axillae, groin, or perineum. Associated skin maceration and malodor is common. Most patients exhibit nail dystrophy (picture 12A-B). A skin biopsy can confirm the diagnosis. (See "Darier disease".)

CLINICAL COURSE — FFD tends to follow a chronic relapsing and remitting course for years. The disease may improve as the affected glands become damaged, often with resultant anhidrosis in the areas. It usually improves after menopause in females.

TREATMENT — Data on treatment options for FFD are primarily limited to case reports and small case series, precluding definitive recommendations on the best approach to treatment. Examples of interventions that may be effective include methods to reduce inflammation, inhibit ductal occlusion, or reduce sweating as well as procedures that remove or destroy sweat glands.

First-line therapy — Topical corticosteroids, topical clindamycin, and topical calcineurin inhibitors are frequently used as first-line therapies because of wide availability, ease of administration, and low risk for serious adverse effects. Optimal regimens for these treatments and comparative efficacy have not been established. The higher cost of topical calcineurin inhibitors may be a limiting factor for some patients. Recurrence is possible after the discontinuation of topical treatments.

In the author's experience, adjunctive gentle exfoliation with a coarse cloth or loofah has also seemed useful.

Topical corticosteroids — Topical corticosteroid therapy may reduce signs and symptoms of FFD by reducing inflammation.

It is well known that treatment of skin that is thin and/or easily occluded (such as intertriginous areas in the axillae, inguinal or genital areas) with topical corticosteroids may result in thinning of the skin; atrophy, striae and fissuring may occur. Thus, it is important to use the least potent topical corticosteroid that is effective. Low-potency topical corticosteroids (eg, groups 5 to 7) are preferred (table 1).

Topical corticosteroids are usually applied twice per day; once the symptoms and/or appearance of FFD improve, treatment may be decreased to once per day and, eventually, to two to three days per week. Patients should be counseled about the risk of striae distensae (stretch marks) and examined periodically for the development of skin atrophy. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Topical clindamycin — Several case reports document improvement in signs and symptoms of FFD with topical clindamycin solution applied twice daily [19-21]. Signs of improvement may be evident as early as the first few weeks of treatment. The mechanism through which topical clindamycin solution may improve FFD is unclear.

Topical calcineurin inhibitors — Like topical corticosteroids, topical calcineurin inhibitors may reduce inflammation in FFD. A few case reports and small series describe benefit of topical pimecrolimus or topical tacrolimus [22,23]. In one series of three patients, twice-daily application of pimecrolimus 1% cream for eight weeks was associated with marked improvement in signs or symptoms of FFD [22]. Improvement was evident as early as the first one to two weeks of treatment. In a separate series of two patients treated with tacrolimus 0.1% ointment twice daily for three months, one patient had marked improvement in FFD and associated pruritus [24]. The second patient did not respond. Unlike topical corticosteroids, topical calcineurin inhibitors do not induce skin atrophy.

Second-line therapy — Topical retinoids are additional topical treatments that may improve FFD. However, local skin irritation is a common side effect that can limit the use of this therapy. Intralesional corticosteroid injection may also improve FFD; patient discomfort and the potential for cutaneous atrophy are disadvantages of this treatment.

Topical retinoids — Topical retinoids are postulated to help FFD through reducing follicular occlusion and secondary ductal occlusion [25]. Application every other day or a few times a week may be better tolerated than daily therapy.

A mixture of tretinoin 0.05% cream and hydrocortisone 1% cream applied every other night led to resolution of FFD within six weeks in a patient with axillary involvement [26]. In another patient, application of tretinoin 0.1% cream every other night to the axilla was associated with reduced pruritus and mild regression of the papular eruption after four weeks [27]. Partial responses to adapalene 0.1% gel have also been reported [3,25].

Intralesional corticosteroids — Similar to topical corticosteroid therapy, clinical experience suggests that injection of diluted concentrations of corticosteroids may improve FFD through reducing inflammation. Triamcinolone acetonide is most commonly used in concentrations of 2.5 mg/mL. General wisdom dictates that no more than 10 mg should be given at a particular site at one time.

Concerns regarding this intervention include patient discomfort during injection and risk for cutaneous atrophy. To minimize risk for cutaneous atrophy, injections should not be performed more frequently than every eight weeks and a careful physical examination to look for evidence of local atrophy should be undertaken prior to subsequent treatments. It is also important to remember that some systemic absorption occurs with intralesional therapy; total dose of triamcinolone acetonide should probably not exceed 40 mg per patient visit and less if the patient is diabetic or has uncontrolled hypertension or narrow angle glaucoma. (See "Intralesional corticosteroid injection".)

Refractory disease — Patients who do not achieve satisfactory improvement from topical therapy may benefit from other treatments. Data from case reports suggest that oral contraceptives, botulinum toxin injections, oral isotretinoin, surgical procedures, fractional laser therapy, pulsed dye laser (PDL) therapy, and microwave technology may be effective. Given the limited efficacy data, risks and side effects should be carefully considered prior to proceeding with these interventions:

●Topical calcitriol and betamethasone dipropionate – Use of topical calcitriol 0.005% with betamethasone dipropionate 0.064% was associated with rapid improvement of symptoms in a patient who had failed multiple other topical therapies [28]. High-potency topical corticosteroids, such as betamethasone, must be used with caution and for short durations in intertriginous areas.

●Oral contraceptives – The theory that hormones may contribute to the development of FFD have led to attempts to treat with hormonal therapy. Improvement in FFD with an oral contraceptive containing norethynodrel and mestranol was documented in the 1960s in two patients [29]. A trial of oral contraceptive therapy is reasonable for women with FFD who are also interested in preventing pregnancy. Several months of treatment may be necessary to achieve improvement and disease may recur upon the discontinuation of treatment [29]. (See 'Pathogenesis' above.)

●Botulinum toxin – A patient with intensely pruritic FFD who failed to respond to topical corticosteroid and topical calcineurin inhibitor therapy had resolution of pruritus 15 days after botulinum toxin A injection into the affected areas [30]. A marked reduction in the papular eruption also occurred. The response was maintained for at least eight months after treatment.

●Oral isotretinoin – Oral isotretinoin therapy (30 mg per day for eight weeks, then 15 mg per day) appeared to lead to flattening of papules, reduced symptoms, and eventual almost complete disease clearance in a patient with FFD [31]. However, disease recurred approximately three months after discontinuing isotretinoin. The potential for side effects, such as teratogenicity, can limit long-term use of isotretinoin therapy. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Adverse effects'.)

●Surgical procedures – Physical interventions that have appeared effective in case reports include electrocoagulation of papules [5], liposuction with curettage in the axilla [32], and surgical excision of the affected portion of the axilla [33]. Surgical procedures are generally reserved for patients who cannot be managed with other therapies because of the risk for scarring.

●Laser treatment – The use of lasers to treat FFD is debatable. Improvement with ablative and nonablative fractional lasers or pulsed dye lasers (with or without prior surgical excision) has been documented in case reports [34-36]. However, laser hair removal has also been associated with the development of FFD. (See 'Pathogenesis' above.)

●Microwave technology – Initially developed for treating hyperhidrosis, microwave technology can target and destroy sweat glands (apocrine, apoeccrine, and eccrine) as well as hair follicles. Heating of the dermal-hypodermal junction results in thermolysis. A case report describes the use of microwave technology to treat FFD; two treatments performed nine months apart were associated with resolution of pruritus as well as reduction of axillary hair [37]. The lesions and symptoms had not recurred four months after treatment.

●Other – Dermabrasion and phototherapy have been suggested as additional treatment options; however, data supporting the efficacy of these interventions are lacking. Whether topical glycopyrrolate, a treatment for hyperhidrosis, is effective for FFD is uncertain.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Fox-Fordyce disease (FFD) is an uncommon, pruritic skin disorder that may result from the occlusion of apocrine or apoeccrine sweat ducts and associated inflammation. Most patients with FFD are adolescent or premenopausal adult women. (See 'Epidemiology' above.)

●Clinical features – FFD occurs in apocrine gland-rich sites such as the axilla, areola, and anogenital area. Affected patients develop multiple uniform, perifollicular, skin-colored, reddish, or violaceous papules in a bilateral distribution (picture 1A-E). Pruritus is usually prominent. (See 'Clinical features' above.)

●Diagnosis – A diagnosis of FFD can usually be made based upon the physical examination. Atypical presentations may require a biopsy for diagnosis. (See 'Diagnosis' above.)

●Clinical course – FFD follows a chronic relapsing and remitting course. Improvement may occur after menopause in women. (See 'Clinical course' above.)

●Treatment – The treatment of FFD can be challenging. Data on treatments for FFD are limited to case reports and small series.

•Initial treatment – We suggest topical therapy rather than systemic or surgical therapy as initial treatment (Grade 2C). Our preferred initial treatment options are low-potency topical corticosteroids, topical clindamycin, or topical calcineurin inhibitors. Topical retinoids and intralesional corticosteroid injections are additional local treatment options. (See 'Treatment' above.)

•Refractory disease – Therapeutic options for FFD that cannot be managed with topical treatment include oral contraceptives, botulinum toxin injections, oral isotretinoin, and procedural therapies. Data are limited on the efficacy of these therapies. (See 'Refractory disease' above.)