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Apocrine Miliaria

Editor: Sidharth Sonthalia Updated: 5/22/2023 9:40:10 PM

Introduction

Fox-Fordyce disease (FFD), an eponym for apocrine miliaria, is a rare chronic inflammatory skin disorder of the apocrine glands characterized by a pruritic papular eruption in the apocrine gland-rich parts of the body, including the axillae, areolae, anogenital region, among others. This disorder was first described in 1902 by George Henry Fox and John Addison Fordyce as pruritic papules in the axillae.[1] Since then, it has been seen in the other aforementioned apocrine gland containing regions. FFD has a female predominance, and the mainstay of diagnosis is clinical evaluation. Treatment is challenging, as there is a paucity of research in this area, but it is often necessary secondary to prominent pruritus. There are multiple treatment options, including topical, systemic, and surgical, although topical medicines remain the initial treatment of choice.

Etiology

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Etiology

The exact cause of Fox-Fordyce disease remains unknown. Obstruction of the apocrine gland duct resulting from keratin accumulation in the follicular infundibulum seems to be central to its etiopathogenesis.

The following are etiological factor hypotheses:

Familial Inheritance

Although FFD is typically a sporadic condition, there are rare instances of it occurring in sisters, monozygotic females, male twins, and daughter-father duo.[2][3][4][5]

Hormonal

FFD typically presents in post-pubertal adolescent girls and women. It is rare in prepubertal and post-menopausal women and men. Further credence to the hormonal involvement comes from premenstrual flare-ups and improvement with pregnancy, post-menopause, and oral contraceptive pills.[6] 

Laser Hair Reduction (LHR)

FFD has been described to result from different kinds of lasers used for LHR.[7][8][9][10] There are speculations that the laser irradiation results in damage sustained by the follicular infundibulum, followed by subsequent keratinocyte dysmaturation and resultant keratin plugging.[9] The fact that FFD may result from multiple sessions of different lasers and light devices, including diode, alexandrite, and IPL, strongly suggests the role of thermal damage to the hair follicle as the underlying pathology independent of the laser wavelength.[7] Although idiopathic FFD and LHR-induced FFD share histopathology and clinical features, whether they represent the same or different entities requires further exploration.

Trigger factors for Itch

Stress, excitement, sweating resulting from exercise, and hot and humid weather are all triggers.[11]

Epidemiology

The exact prevalence and incidence are unknown, as it is a rare disorder.

A mentioned before, Fox-Fordyce disease typically presents in post-pubertal adolescent girls and women, reportedly between 13 and 35 years of age.[11] Its occurrence is rare before puberty, after menopause, and in males.  

Pathophysiology

Pathogenesis is not entirely defined. Putative root cause points to the occlusion of apocrine ducts by the accumulation of keratin in the follicular infundibulum. This theory is supported by histology demonstrating hyperkeratotic cores within follicular infundibula in involved skin.[12] Inflammation results from rupture of the duct.

The relatively recent reports of FFD or FFD-like eruptions after LHR also support the theory mentioned above of gland occlusion/disruption and damage to the follicular infundibulum, as this procedure has been shown to cause follicular damage.[10][13][9]

Other possible contributions to Fox-Fordyce disease include obstruction of apocrine ducts based on histological evidence of intraepidermal sweat duct occlusion by detached apocrine secretory cells [12]; and hormonal, physical, and environmental factors. Increased sweating, e.g., caused by exercise, humid climate, occlusive clothing, sexual activity, and emotional stress, also correlates with disease exacerbation.

Female predominance further suggests a hormonal component, especially because symptoms rarely present before puberty, flares may worsen around menses or worsen/improve during pregnancy,[14] and go into remission during menopause. It is important to note that hormones androgens, in particular, have been shown to alter keratinocyte adhesion, sweat composition, and other elements.[15]

This situation causes secretion retention with consequent rupture of the glandular structure and secondary inflammation of the dermis.[2][3] The extravasation of the glandular content has been suggested to be the cause of pruritus. Itching, which may be secondary to the inflammation caused by the spewed sweat, usually precedes the clinical appearance of the papules of FFD.[13]

Histopathology

As mentioned previously, hyperkeratosis and plugging of the apocrine gland’s follicular infundibulum and the excretory duct are typically visible upon histologic examination. A spongiotic vesicle may appear where apocrine secretions have accumulated proximal to the plug within the dilated duct, which may cause rupture of the duct. Fox-Fordyce disease is also characterized by perifollicular infiltration of lymphocytes and foamy histiocytes, leading to hair loss. Lymphocytes are usually within the ductal epithelium and surrounding ductal tissue. In patients with apocrine gland involvement, a ductal obstruction may be detectable in the intraepidermal portion of the apocrine sweat duct.[12]

The periductal lymphohistiocytic infiltrate often shows the presence of mast cells. There have also been cases of perifollicular fibrosis and dyskeratotic cells in the follicular infundibulum.

Perifollicular foam cells or xanthomatosis is considered a histopathological hallmark of FFD. The periodic acid-Schiff (PAS) staining has suggested that the nature of the cytoplasm of these foam cells might be similar to the content of the apocrine gland secretions.[16][17][18] Immunohistochemistry of a biopsy section of FFD shows intense CD68 positivity in peripheral xanthomatous histiocytes.

History and Physical

Location

Fox-Fordyce disease typically affects apocrine gland-rich areas of the body such as axillae, areolae, anogenital area, and to a lesser extent, the umbilicus, perineum, and medial aspect of the upper thigh.[11] Less frequently affected locations include the lips, thorax, abdomen, and legs.[16] Bilateral skin involvement is typical.

Lesional Morphology

Primary lesions are 2 to 3 mm dome-shaped follicular or perifollicular papules that are typically characterized by distribution, although they can vary in color (skin-colored, yellow, reddish, violaceous). Their distribution is in crops around apocrine-gland dense areas (axillary, areolar, perianal, genital) that may appear linear when the skin becomes stretched. Associated features include hypotrichosis and hyperkeratosis, and excoriation marks secondary to scratching.

Chief Symptoms

FFD’s characteristic skin eruption is often associated with extreme pruritus, which worsens with hyperhidrosis, sweating, stress, and anxiety.

Chronic FFD may present as lichenified, thickened, coarse, hyperpigmented skin secondary to damage caused by scratching. Severe FFD may also demonstrate localized anhidrosis and brittle, sparse, or absent hair due to the subsequent destruction of the gland and associated hair follicle.

Clinical Course

The course of FFD is chronic relapsing and remitting, which may continue for years. The disease may improve as the affected glands become damaged, often with resulting local anhidrosis. FFD usually improves during pregnancy and after menopause.

Evaluation

The diagnosis of Fox-Fordyce disease is by and large clinical. However, evaluation with the following methods is possible:

(1) Dermoscopy reveals hair follicle-centered papules, traumatized terminal hairs, and blackheads.[19]

(2) Histopathology - Biopsy from the papules reveals the changes detailed above (vide supra), with perifollicular foam cells pathognomonic of the condition.

(3) In vivo High-definition optical coherence tomography (HD-OCT) -  Axial/slice images showed distinct epidermal lesions in the epidermis extending into the upper dermis. Intralesional dilated ductal structures surrounded by a dark rim indicative of fluid were visible in the en face images. Hyperrefractile (bright) lesions appeared on the skin surface on 3-dimensional reconstruction.[20][21] HD-OCT remains an experimental imaging technique for FFD.

Treatment / Management

Data is limited to case reports and small case series, precluding definitive recommendations on the best approach. 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

First-line treatments include topical and oral retinoids, topical benzoyl peroxide, topical clindamycin, intralesional or topical corticosteroids (TCS), topical calcineurin inhibitors (CNIs), and oral contraceptives.[16] These are the initial choices because of availability, easy administration, and low risk for serious side effects. There has been no establishment of optimal regimens. Recurrence is possible after discontinuing treatment.(B3)

  • Low potency topical corticosteroids (TCS) are best (less risk of skin atrophy, striae, fissuring), usually twice daily until symptoms improve and then may decrease to daily use two to three times per week.
  • Topical clindamycin twice daily. Patients may see improvement in the first few weeks. The mechanism is unclear.[22]
  • Topical CNIs reduce inflammation akin to TCS without the risk of cutaneous atrophy. Both pimecrolimus and tacrolimus use have resulted in moderate to near-complete clearance.[23][24][25]
  • Topical retinoids - Both tretinoin and adapalene are options. These are thought to reduce follicular occlusion and secondary ductal occlusion. Skin irritation is an issue. Patients may tolerate application every other day instead of daily may be better tolerated.[26][27]
  • Oral isotretinoin has shown decent results in anecdotal reports.[28]
  • (B3)

Second Line and Novel Treatments

These are better for cases that are severe and/or refractory to the first-line therapies. These include:

Surgical excision, fractional lasers including 1550 nm erbium glass, pulsed dye laser, botulinum toxin, phototherapy, electrocoagulation, copper vapor, and CO laser, liposuction-assisted-curettage, and microwave technology.[29][30][31][32][33][34](B3)

Differential Diagnosis

Although Fox-Fordyce disease is easily diagnosable by its typical clinical presentation and characteristic histopathology, certain conditions must be considerations in differential diagnoses:

  • Folliculitis – erythematous papules and/or pustules; FFD does not have pustules
  • Pseudofolliculitis – “ingrown hairs” - typically involving the lower shave-area of the neck in men and repeatedly waxed areas in women.
  • Miliaria rubra or profunda – eccrine miliaria are vesicular or popular eruptions with occlusion of eccrine sweat glands. Unlike FFD, the above may occur in any site with eccrine glands.
  • Milia – 1 to 2 mm epidermal inclusion cysts, usually on the face, usually white or yellow (used to distinguish from FFD papules)
  • Granular parakeratosis – uncommon, hyperkeratotic brown-red papules that coalesce into plaques in intertriginous areas (axilla is most common). Pruritus is common.
  • Syringomas – multiple 2 to 4 mm skin-colored, brown, or pink papules. Most common on periorbital skin but may occur in intertriginous areas or other areas. It may need a biopsy to distinguish it from FFD. Histology reveals small collections of epithelial cells with central ducts in the superficial dermis.[35][36]
  • Acanthosis nigricans – hyperpigmented velvety plaques that may have a papular appearance; occurs in intertriginous sites or skin folds, e.g., axillae or posterior neck.
  • Graham-Little-Piccardi-Lasseur syndrome - characterized by lichen planopilaris and non-scarring alopecia of other parts of the body, typically axillae
  • Darier's disease & Hailey-Hailey disease [37]
  • A pruritic generalized variant of Trichostasis spinulosa - It presents with typical involvement of the face, trunk (interscapular area), and the differential is the dermoscopic finding of multiple vellus hairs bundled in a funnel-like structure.[38]

Pertinent Studies and Ongoing Trials

Although, at present, there is no published report, there is a hypothesis that fractionated microneedle radiofrequency may be an effective therapeutic option in Fox-Fordyce disease.[39] This concept has been extrapolated from the proven histopathological evidence of the efficacy of microneedle radiofrequency for the treatment of axillary hyperhidrosis.[40] Moreover, there are reports that micro-needling promotes the migration and proliferation of epidermal and dermal cells, especially keratinocytes and fibroblasts, that release several growth factors that might result in a favorable transformation of the perifollicular cellular milieu and reduce pruritus.[41]

Prognosis

There is no definitive cure for Fox-Fordyce disease, but the symptomatic improvement to complete resolution has been reported with the treatment modalities mentioned before (vide supra).[22] Thus, the overall prognosis is not bad.

Complications

Chronic Fox-Fordyce disease may present as lichenified, thickened, coarse, hyperpigmented skin secondary to damage caused by scratching. Severe FFD may also demonstrate localized anhidrosis and brittle, sparse, or absent hair due to the subsequent destruction of the gland and associated hair follicle.

Deterrence and Patient Education

Data on Fox-Fordyce disease is limited to case reports and small case series, precluding definitive recommendations on the best approach to management. 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. The patient may also be instructed to try reducing stress, avoiding humid climates, and avoiding occlusive clothing to offset the pruritus. 

Pearls and Other Issues

Physicians often confuse Fordyce spots (FS) with Fox-Fordyce disease.

Fordyce spots are tiny (1 to 5 mm), slightly elevated yellowish or white papules which represent a variant of sebaceous glands that are visible without hair follicles and typically involve the vermilion border of the lips, buccal mucosa, glans, or shaft of the penis, and the vulva in females. They are of no consequence, but patients often seek consultation owing to their concern about the lesions and for cosmetic purposes.

Enhancing Healthcare Team Outcomes

Fox-Fordyce disease is a rare skin disorder and often gets misdiagnosed. Most skin disorders initially present to the primary care provider or nurse practitioner. 

Coordinated care between primary care providers and those who specialize in dermatology will best serve the patient, as this is a difficult diagnosis to make if the practitioner is unfamiliar with the disease process and presentation. 

Moreover, since plastic surgeons, as well as practitioners of other specialties, perform LHR, their recognition of the development of pruritic papules representing FFD following multiple sessions of LHR requires reinforcement. 

After the clinician makes the diagnosis, the pharmacist should educate the patient on the different drug therapies available and their potential adverse effects. If untoward side effects arise, the pharmacist should report their concerns to the clinician. The nurse should provide patient education regarding the various cosmetic procedures available and the need to avoid stress, intense exposure to light and sunlight. Clinicians should obtain informed consent before any treatment and not offer unrealistic patient expectations. Only through such an interprofessional team approach can outcomes be improved. [Level 5]

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