Continuing Education Activity

Fox-Fordyce disease, or apocrine miliaria, is a rare chronic inflammatory skin disorder affecting the apocrine glands. It presents with a pruritic papular eruption primarily in areas rich in apocrine glands, such as the axillae, areolae, and anogenital region. Initially described in 1902, its exact etiology remains elusive, although obstruction of the apocrine gland duct due to keratin accumulation is believed to play a central role. Fox-Fordyce disease predominantly affects females and is diagnosed primarily through clinical evaluation due to the absence of specific diagnostic tests. Management of Fox-Fordyce disease is challenging, focusing on alleviating symptoms such as pruritus, with treatment options ranging from topical medications to systemic therapy and surgical intervention.

This activity on Fox-Fordyce disease aims to enhance healthcare professionals' understanding and management strategies for this rare dermatological condition. It reviews clinical presentation, diagnosis, and treatment to equip providers with the necessary knowledge for practical patient evaluation and management. Emphasizing interprofessional collaboration, the activity highlights the importance of collaborative care in improving patient outcomes, especially in symptom management and treatment selection. This initiative enhances healthcare professionals' ability to provide optimal care for Fox-Fordyce disease patients, ultimately improving their quality of life.

Objectives:

• Identify the etiology of Fox-Fordyce disease.
• Assess the physical examination findings in Fox-Fordyce disease.
• Compare the treatment options available for Fox-Fordyce disease.
• Strategize with the interprofessional team to enhance care coordination and communication to improve patient outcomes in Fox-Fordyce disease.

Introduction

Fox-Fordyce disease, known as apocrine miliaria, is a rare chronic inflammatory skin disorder affecting apocrine glands, presenting with a pruritic papular eruption in regions like axillae and anogenital areas. Described in 1902 by George Henry Fox and John Addison Fordyce, it primarily affects females.[1] Diagnosis relies on clinical evaluation due to a lack of specific tests. Treatment, challenging due to limited research, often targets symptom relief, with topical medications as the preferred initial option. However, systemic and surgical interventions are also available for management (see Image. Fox-Fordyce Disease).

Etiology

The precise cause of Fox-Fordyce disease remains elusive. However, a critical factor in its etiopathogenesis appears to be the obstruction of the apocrine gland duct due to keratin accumulation in the follicular infundibulum.

Several etiological hypotheses have been proposed for Fox-Fordyce disease. These include genetic factors, hormonal influences, laser hair reduction, and triggers that induce sweating.

• Familial inheritance: While Fox-Fordyce disease typically occurs sporadically, it is uncommon in sisters, monozygotic females, male twins, and daughter-father duos.[2][3][4][5]

• Hormonal involvement: Fox-Fordyce disease commonly manifests in post-pubertal adolescent girls and women, with rarity in prepubertal and postmenopausal women, as well as men. Hormonal involvement is supported by premenstrual flare-ups and improvement during pregnancy, postmenopause, and with oral contraceptive pills.[6] 

• Laser hair reduction: Laser hair reduction has been implicated in developing Fox-Fordyce disease, possibly due to follicular infundibulum damage from laser irradiation leading to keratinocyte dysmaturation and subsequent keratin plugging.[7][8][9][10] The condition may arise after multiple sessions with various lasers, such as diode, alexandrite, and IPL, indicating thermal damage to the hair follicle as a common underlying pathology.[7] While idiopathic and laser-induced Fox-Fordyce disease shares histopathological and clinical similarities, further investigation is needed to determine if they represent distinct entities.  

• Trigger factors for itch: Stress, excitement, sweating resulting from exercise, and hot and humid weatherall triggerr pruritis in Fox-Fordyce disease.[11]

Epidemiology

The precise prevalence and incidence of Fox-Fordyce disease remain uncertain due to its rarity. It typically manifests in postpubertal adolescent girls and women, commonly between the ages of 13 and 35.[11] Occurrence before puberty, after menopause, and in males is uncommon.  

Pathophysiology

The pathogenesis of Fox-Fordyce disease remains incompletely understood. However, it is believed to involve the occlusion of apocrine ducts due to keratin accumulation in the follicular infundibulum.[12] This theory is supported by histological evidence demonstrating hyperkeratotic cores within follicular infundibula in the involved skin.[13] Inflammation occurs following duct rupture.

The relatively recent reports of Fox-Fordyce disease or Fox-Fordyce disease-like eruptions after laser hair reduction also support the theory of gland occlusion or disruption and follicular infundibulum damage. Laser hair reduction procedures have been documented to cause follicular damage, aligning with the pathogenesis hypothesis.[9][10][14]

Other potential factors contributing to Fox-Fordyce disease include obstruction of apocrine ducts supported by histological evidence of intraepidermal sweat duct occlusion by detached apocrine secretory cells. Additionally, hormonal, physical, and environmental factors may play a role.[13] Increased sweating, triggered by exercise, humid climates, tight clothing, sexual activity, and emotional stress, correlates with disease exacerbation.

Female predominance in Fox-Fordyce disease suggests a hormonal influence, as symptoms rarely appear before puberty, may worsen around menses, worsen or improve during pregnancy, and go into remission during menopause.[15] Androgen hormones, in particular, can alter keratinocyte adhesion and sweat composition, leading to secretion retention, glandular rupture, and dermal inflammation.[2][3][16] Extravasation of glandular content is hypothesized to cause pruritus, with itching preceding the clinical appearance of papules in Fox-Fordyce disease.[14]

Histopathology

Histological examination typically reveals hyperkeratosis and plugging of the apocrine gland's follicular infundibulum and excretory duct. A spongiotic vesicle may form where apocrine secretions accumulate proximal to the plug within the dilated duct, potentially leading to duct rupture. Fox-Fordyce disease is further characterized by perifollicular infiltration of lymphocytes and foamy histiocytes, often resulting in hair loss. Lymphocytes typically surround the ductal epithelium and adjacent tissue. In cases involving apocrine gland participation, obstruction of the intraepidermal portion of the apocrine sweat duct may be observable.[13]

The periductal lymphohistiocytic infiltrate frequently includes mast cells. Additionally, some cases exhibit perifollicular fibrosis and dyskeratotic cells within the follicular infundibulum. Perifollicular foam cells or xanthomatosis are recognized as a histopathological hallmark of Fox-Fordyce disease. Periodic Acid-Schiff (PAS) staining indicates that these foam cells' cytoplasm may resemble the content of apocrine gland secretions.[17][18][19] Immunohistochemistry of biopsy sections from Fox-Fordyce disease typically demonstrates intense CD68 positivity in peripheral xanthomatous histiocytes.

History and Physical

Fox-Fordyce disease commonly impacts apocrine gland-rich regions like the axillae, areolae, and anogenital area, with lesser occurrences on the umbilicus, perineum, and medial upper thigh.[11] Less frequently affected sites include the lips, thorax, abdomen, and legs.[17] Bilateral involvement is typical in affected areas.

Primary lesions in Fox-Fordyce disease are typically 2 to 3 mm dome-shaped follicular or perifollicular papules, varying in color from skin-colored to yellow, reddish, or violaceous. They exhibit a characteristic distribution around apocrine gland-dense areas such as the axillae, areolae, perianal, and genital regions, often appearing linear when the skin is stretched. Associated features include hypotrichosis, hyperkeratosis, and excoriation marks due to scratching from pruritus.[20]

The characteristic skin eruption of Fox-Fordyce disease is frequently accompanied by severe pruritus, exacerbated by hyperhidrosis, sweating, stress, and anxiety. This intense itching can significantly impact patients' quality of life, leading to discomfort and distress.

Chronic Fox-Fordyce disease can manifest as lichenified, thickened, coarse, hyperpigmented skin secondary to damage caused by persistent scratching. Localized anhidrosis and brittle, sparse, or absent hair may occur due to gland and hair follicle destruction in severe cases. 

Fox-Fordyce disease follows a chronic, relapsing-remitting course that can persist for years. Improvement may occur as affected glands become damaged, leading to local anhidrosis. Additionally, symptoms typically ease during pregnancy and after menopause.

Evaluation

The diagnosis of Fox-Fordyce disease is primarily clinical. However, additional evaluation methods may include:

• Dermoscopy: Revealing hair follicle-centered papules, traumatized terminal hairs, and blackheads.[21]

• Histopathology: Biopsy showing characteristic changes, including perifollicular foam cells.

• In vivo high-definition optical coherence tomography: Offering axial/slice images depicting distinct epidermal lesions extending into the upper dermis, with visible intralesional dilated ductal structures surrounded by a dark rim indicative of fluid. Hyperrefractile (bright) lesions may appear in 3-dimensional reconstruction.[22][23] High-definition optical coherence tomography (HD-OCT) remains an experimental imaging technique for Fox-Fordyce disease.

Treatment / Management

Treatment data for Fox-Fordyce disease is primarily limited to case reports and small case series, which hinders the establishment of definitive recommendations for optimal management. However, potential interventions may include strategies to alleviate inflammation, prevent ductal occlusion, or decrease sweating, along with procedures aimed at removing or destroying sweat glands.

First-Line Treatment

First-line treatments include topical and oral retinoids, benzoyl peroxide, clindamycin, intralesional or topical corticosteroids, calcineurin inhibitors, and oral contraceptives.[17] These are initially selected due to their availability, ease of administration, and low risk for serious adverse effects. However, there is no established optimal treatment regimen. Recurrence may occur upon cessation of treatment discontinuation.

• Low-potency topical corticosteroids are preferred due to their low risk of inducing skin atrophy, striae, and fissuring. They are applied twice daily until symptoms improve, with subsequent reduction to daily use 2 to 3 times per week.

• Topical clindamycin applied twice daily. Patients may see improvement in the first few weeks. However, the exact mechanism of action remains unclear.[24]

• Topical calcineurin inhibitors reduce inflammation akin to topical corticosteroids without the risk of cutaneous atrophy. Using both pimecrolimus and tacrolimus has resulted in moderate to near-complete clearance.[25][26][27]

• Both tretinoin and adapalene, topical retinoids, are viable options for Fox-Fordyce disease. They are believed to decrease follicular and secondary ductal occlusion. However, skin irritation may arise. Patients may find application every other day more tolerable than daily use.[28][29]

• Oral isotretinoin has demonstrated promising results in anecdotal reports.[30]

Second-Line and Novel Treatments

These are better for severe and refractory cases unresponsive to first-line therapy. Options include surgical excision, fractional lasers including 1550 nm erbium-glass, pulsed dye laser,[31] botulinum toxin injections, phototherapy, electrocoagulation, copper vapor, CO laser, liposuction-assisted curettage, and microwave technology.[32][33][34][35][36][37][38][39] 

Differential Diagnosis

While Fox-Fordyce disease is typically identifiable through its characteristic clinical presentation and histopathological features, several differential diagnoses should be considered, including:

• Folliculitis: Typically presents with erythematous papules or pustules, whereas Fox-Fordyce disease lacks pustules.

• Pseudofolliculitis: Known as ingrown hairs, it commonly affects the lower shave area of the neck in men and regions that are frequently waxed in women.

• Miliaria rubra or profunda eccrine: Presents as vesicular or papular eruptions resulting from occluded eccrine sweat glands. Unlike Fox-Fordyce disease, miliaria can occur in any area with eccrine glands.

• Milia: 1 to 2 mm epidermal inclusion cysts, usually found on the face and appearing white or yellow. This characteristic helps differentiate them from papules seen in Fox-Fordyce disease.

• Granular parakeratosis: Presents as uncommon hyperkeratotic brown-red papules that often merge into plaques, typically occurring in intertriginous areas, with the axilla being the most common. Pruritus is a common feature of this condition.

• Syringomas: Characterized by multiple 2 to 4 mm skin-colored, brown, or pink papules, typically found on periorbital skin but may also occur in intertriginous areas or other regions. Distinguishing them from Fox-Fordyce disease may require a biopsy. Histologically, syringomas exhibit small collections of epithelial cells with central ducts in the superficial dermis.[40][41]

• Acanthosis nigricans: Characterized by hyperpigmented velvety plaques that may appear papular, typically found in intertriginous sites or skin folds such as the axillae or posterior neck.

• Graham-Little-Piccardi-Lasseur syndrome: Defined by lichen planopilaris and nonscarring alopecia affecting other body areas, particularly the axillae.

• Darier's disease & Hailey-Hailey disease.[42]

• A pruritic generalized variant of Trichostasis spinulosa: Manifests with typical involvement of the face and trunk, particularly the interscapular area. Differential diagnosis is distinguished by dermoscopic findings revealing multiple vellus hairs bundled in a funnel-like structure.[43]

Pertinent Studies and Ongoing Trials

Although no published reports currently exist, a hypothesis suggests that fractionated microneedle radiofrequency could be a viable therapeutic option for Fox-Fordyce disease.[44] This idea stems from established histopathological evidence demonstrating the efficacy of microneedle radiofrequency in treating axillary hyperhidrosis.[45] Additionally, reports indicate that microneedling promotes the migration and proliferation of epidermal and dermal cells, including keratinocytes and fibroblasts, which release various growth factors. These factors may lead to a beneficial transformation of the perifollicular cellular environment and potentially alleviate pruritus.[46]

Prognosis

There is currently no definitive cure for Fox-Fordyce disease; however, symptomatic improvement to complete resolution has been reported with the treatment modalities mentioned previously.[24] Thus, the overall prognosis for patients with Fox-Fordyce disease is relatively favorable.

Complications

Chronic Fox-Fordyce disease can manifest as lichenified, thickened, coarse, hyperpigmented skin due to scratching-induced damage. Severe cases may exhibit localized anhidrosis and brittle, sparse, or absent hair resulting from gland and associated hair follicle destruction.

Deterrence and Patient Education

Data on Fox-Fordyce disease are primarily limited to case reports and small case series, which hinders the establishment of definitive management recommendations. However, potential interventions that may prove effective include strategies to reduce inflammation, inhibit ductal occlusion, or decrease sweating, along with procedures to remove or destroy sweat glands. Patients may also be advised to mitigate symptoms by minimizing stress, avoiding humid climates, and refraining from wearing occlusive clothing.

Pearls and Other Issues

Key points to keep in mind about Fox-Fordyce disease include the following:

• Fox-Fordyce disease is a rare chronic inflammatory skin disorder of the apocrine glands, primarily affecting post-pubertal adolescent girls and women.

• Presents with pruritic papular eruptions in apocrine gland-rich areas like the axillae, areolae, and anogenital region.

• The clinical manifestations include dome-shaped papules often distributed linearly around areas rich in apocrine glands. Severe cases may lead to lichenification, hyperpigmentation, and localized anhidrosis.

• Diagnosis is mainly clinical, but additional evaluation methods such as dermoscopy and histopathology can provide supportive evidence.

• Management involves symptomatic relief, typically with topical corticosteroids, clindamycin, retinoids, or other interventions to reduce inflammation and sweating. Severe or refractory cases may require procedures like surgical excision or laser therapy.

• Physicians may confuse Fordyce spots with Fox-Fordyce disease. Fordyce spots are tiny (1 to 5 mm), slightly elevated yellowish or white papules representing a variant of sebaceous glands. They are visible without hair follicles and commonly involve the vermilion border of the lips, buccal mucosa, glans or shaft of the penis, and the vulva in females. While they are of no medical consequence, patients often seek consultation due to cosmetic concerns.

Enhancing Healthcare Team Outcomes

Coordinated care between primary care providers and dermatology specialists is crucial for optimal patient management, especially given the challenging nature of diagnosing Fox-Fordyce disease, particularly for practitioners unfamiliar with its presentation and disease process. Furthermore, it is essential to reinforce the recognition of pruritic papules indicative of Fox-Fordyce disease among plastic surgeons and practitioners of other specialties who perform laser hair reduction. This awareness is crucial, mainly when such papules develop after multiple laser hair reduction sessions.

Once a diagnosis has been established, the pharmacist must educate the patient about the potential adverse effects of the prescribed therapies. If any untoward side effects occur, the pharmacist should promptly communicate their concerns to the clinician. All clinicians, including physicians, advanced practitioners, and nurses, play a vital role in educating patients about available cosmetic procedures and advising them to avoid stress and excessive exposure to light and sunlight. Clinicians must obtain informed consent before initiating treatment and avoid offering unrealistic patient expectations. Only through this collaborative interprofessional approach can patient outcomes be optimized.

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Disclosure: Graham Litchman declares no relevant financial relationships with ineligible companies.

Disclosure: Sidharth Sonthalia declares no relevant financial relationships with ineligible companies.