Are You Confident of the Diagnosis?
What you should be alert for in the history
Characteristic findings on physical examination
Fox-Fordyce disease (FFD) commonly presents with follicular papules around the breast, perineal region, axillae, external genitalia, and/or periareolar region. The papules are discrete, multiple, smooth, dome- or pinhead-shaped, shiny, and firm. Papules can be flesh colored, pink, or sometimes darker. They tend to appear in a linear arrangement, which can alternate with normal skin. Individual papules can range from 1 to 3mm in diameter. Serous or milky fluid appears upon pricking the papule (Figure 1, Figure 2).
Hair is sparse or absent in the affected regions. Chronic pruritus is a cardinal symptom of FFD. Pruritus tends to be worse at night and may precede the papular eruption. Emotional states such as excitement and nervousness can worsen FFD symptoms. Perspiration, exercise, warm weather, and sexual activity can also exacerbate FFD.
Expected results of diagnostic studies
Histology of FFD reveals hyperkeratosis at the site where the apocrine duct opens into the hair follicle. Follicular plugging, spongiotic vesicles (containing inflammatory cells and keratinocytes), and acanthosis of infundibular epithelium may be seen. Rupture of the apocrine gland ducts may lead to chronic inflammatory changes in the dermis. Degenerated ducts contain basophilic material, foreign body giant cells, and monocytes. Lymphocytic inflammatory infiltrate, polymorphonuclear infiltrate, and foamy macrophages surround the infundibula and apocrine ducts. Mucin may be found primarily in follicles and lumina of apocrine glands.
FFD can be identified by specific localization, uniform appearance, and symptomatology. The major clinical signs of FFD include chronic pruritus and numerous small papules around the axillae, genitalia, and/or periareolar region. In cases where clinical diagnosis is unclear, the histologic hallmarks of FFD include hyperkeratosis of the epidermis with follicular plugging and intermittent spongiosis (characteristic of FFD), rupture of the apocrine gland, and chronic peri-infundibular or periductal lymphocytic or neutrophilic inflammation. The presence of mucin in the glands and tissue involved help signify FFD. Transverse sections are superior to vertical sections when diagnosing FFD via histopathology. FFD illustrates dilated ducts with surrounding “dark zones” on high-definition optical coherence tomography imaging, which may be used if FFD is suspected but not confirmed by histopathology.
There is a long differential for FFD. Various xanthomas can be confused with FFD, but in xanthomas, foamy cells are not restricted to a peri-infundibular and periductal distribution. The differential diagnosis may also include perifollicular granulomatous lesions. FFD has foamy histiocytes, while granulomatous infiltrate has epithelioid histiocytes. FFD can be confused with perifollicular xanthomatosis, which has a perifollicular adventitial sheath packed with xanthoma cells and vacuolated keratinocytes in the infundibular region. Perifollicular xanthomatosis may be a xanthomatous variant of FFD.
Other considerations in the differential diagnosis include Fordyce spots (yellow papules on mucosal surfaces correlating with ectopic sebaceous glands), lichen planus (pruritic flat-topped, violaceous, polygonal papules), acanthosis nigricans (velvety papillomatous hyperpigmented plaques usually on axilla and neck), folliculitis (erythematous papulopustular eruption of hair-bearing areas like scalp, legs, and trunk), leiomyoma (benign or solitary erythematous painful nodules on upper extremity), lichen nitidus (eruption of very tiny skin-colored papules on trunk or penis), syringoma (small skin-colored or yellowish papules typically on eyelids but can be on other sites such as the trunk or genitalia.)
Other possibilities include lichen amyloidosis (pebbly lichenified papules or plaques usually on shin), Darier’s disease (brown, scaly, verrucous papules predominantly on the trunk), contact dermatitis (various presentations depending on allergen/irritant and severity), axillary papular mucinosis (multiple white, tiny papules in axillae), and verruca plana (flat-topped verrucous papules).
Who is at Risk for Developing this Disease?
Ninety percent of FFD cases are females in the age range of 14 to 35 years (21 on average). There are reported cases of postmenopausal women and prepubertal girls with FFD. Males and females have the same clinical manifestations of FFD. There are three cases that suggest that FFD has a hereditary component (FFD occurring in a father and daughter, two sisters, and identical male twins). FFD may also be more common in the Jewish population. Genetic impact on FFD remains to be elucidated.
What is the Cause of the Disease?
There is still no definitive explanation of the pathophysiology of FFD since it was first described by Fox and Fordyce in 1902. A common explanation is that obstruction of the excretory duct of the apocrine gland by a keratin plug provokes dilatation of the sweat gland. The pressure increases and induces rupture of apocrine glands, resulting in formation of spongiotic vesicles. The extravasated apocrine sweat within the vesicles stimulates pruritus. Extravasated apocrine secretions in the dermis and infundibular epidermis can also attract macrophages that ingest lipid secretions and become foamy macrophages.
The pathogenesis of keratin plug formation is unknown, but damage to keratinocytes within the follicular infundibulum may stimulate abnormal maturation and keratin production. Depilatory lasers may damage keratinocytes and initiate disease in predisposed patients, as there are cases reporting the onset of lesions within months of laser hair removal.
Electron microscopy has not conclusively implicated apocrine sweat glands in the generation of FFD. Alternatively, it has been suggested that apoeccrine glands are involved in FFD. Obstruction of the intraepidermal apocrine sweat ducts by apoeccrine detached secretory epithelial cells may also lead to FFD.
Hormonal imbalances may play a role in FFD. FFD is related to the menstrual cycle, lactation, and gestation. Pruritus is more intense during menstruation, when estrogen levels are lower. Estrogenic compounds (mestranol and norethynodrel, diethylstilbestrol, and ovarian tablets) have been shown to alleviate FFD. Patients with FFD have been shown to have high follicle stimulating hormone (FSH) levels by several authors. Some clinicians have reported success in diminishing FFD by using estrogenic compounds that inhibit FSH. The possible interplay of these hormones and FFD is still unclear. There is conflicting evidence as to whether FFD is attenuated during pregnancy. Hyperthyroidism may be associated with FFD as well.
Systemic Implications and Complications
There are no reported systemic effects or complications due to FFD. FFD is a rare disease, and its mechanism has still not been elucidated.
Table I. Treatments that showed improvement in pruritis or papular lesions
|(Numbers, dosages, and regimens are based on case reports and don’t serve as conclusive treatments)|
|Clindamycin (twice daily for 4 weeks)|
|Benzoyl peroxide 5% topically (daily for 8 weeks) plus loratadine 10mg by mouth (daily for 4 weeks)|
|Pimecrolimus 1% cream (twice daily for 8 weeks and maintenance dose needed twice a week)|
|1:1 mixture of tretinoin 0.05% cream and hydrocortisone 1% cream (every other night for 6 weeks, then 3 nights a week of only tretinoin for maintenance therapy)|
|Tretinoin 0.1% cream (every other night for 4 weeks; relapse after treatment discontinuation)|
|Intralesional triamcinolone acetonide: 1% lidocaine with triamcinolone (9 treatments over 11 weeks, 4 injections of 0.5cc of mixture was given at each treatment; Triamcinolone concentration was 5mg per cc)|
|Enovid (norethnodrel with mestranol) (several months, relapse after treatment discontinuation)|
|Testosterone propionate 25mg (3 times weekly for 3 to 4 months; relapse after treatment discontinuation)|
|Oral conjugated estrogens 5mg (daily for 3 to 4 months; relapse after dosage reduction)|
|Diethylstilbestrol 1mg (daily for 6 months)|
|Isotretinoin 30mg (daily for 8 weeks, then 15 mg daily maintenance dose over 2 months; relapse after treatment discontinuation )|
|Ultraviolet exfoliation (4-6 treatments)|
|Electrocoagulation to 3 to 4mm depth (each lesion once)|
|Liposuction-assisted curettage (once)|
|Surgical excision (done once; excision closed with advancement flaps)|
Optimal Therapeutic Approach for this Disease
No rigorous clinical trials have been performed on the efficacy of treatments for FFD. From case reports, topical clindamycin solution (twice daily for 4 weeks), benzoyl peroxide 5% plus oral loratadine (daily for 8 weeks), tacrolimus 0.1% ointment (twice daily for 3 months), and pimecrolimus 1% topical cream (twice daily for 8-12 weeks) provide safe initial treatment options for FFD. These topical applications have been reported to resolve pruritus and papular lesions with minimal signs of relapse. However, these treatments are ineffective or inadequate in some patients.
Topical tretinoin or oral isotretinoin have also presented a reasonably effective way to control FFD. Unfortunately, these treatments require maintenance doses to prevent relapse, may cause significant irritation, and do not work in all patients. Isotretinoin also involves regular blood tests and pregnancy tests, as well as concomitant oral contraception. Adapalene may be less irritating while still decreasing pruritus intensity and number of lesions. Topical corticosteroids and antihistamines inconsistently alleviate pruritus. Hormonal treatments (i.e., testosterone or estrogen) have been inconsistent and possess less potent effects on resolving pruritus and papular lesions in FFD. None of these hormones have been tested for long-term efficacy.
Additionally, there are surgical techniques that have shown great success in permanently resolving FFD. These techniques include electrocoagulation, surgical excision, dermabrasion, and liposuction-assisted curettage. These choices should not be pursued in this benign disease until other methods are exhausted, or presentation is severe. None of the surgical methods have reported any major adverse effects. Fractional CO2 laser and botulinum toxin injections have been used in the axilla with reduction in the number of lesions and in the intensity of pruritus. When discussing treatment options with patients, it is important to mention the lack of data on treatment of FFD, as well as the various treatment options and associated tolerability/side effect profile.
Monitoring of patients should be done on a patient-by-patient basis. There is no conclusive way to treat FFD. Signs and symptoms may be treated with the therapies suggested above. Follow-up visits after treatment initiation is necessary to assess efficacy of the treatment regimen chosen. Adjustment or alteration of treatment may be necessary to manage the lesions or pruritus appropriately.
Unusual Clinical Scenarios to Consider in Patient Management
Very little is known about this disorder, except that pruritus and papules typically develop in postpubertal females. FFD has no known systemic effects, and it is considered a benign disease; it can be confused with other more common pathologies. The psychosocial impact of FFD should also be considered in patient care, as it affects sensitive sexual/intimate areas of the body.
A recent report (2011) described a case of Fox-Fordyce disease occurring after axillary laser hair removal.
What is the Evidence?
Although below are the most used references, a survey of most of the previous literature on all known aspects of FFD was done. These aspects include symptoms, signs, histology, possible etiology, hormonal influences, common indications of FFD, other disease in the differential diagnosis, gender differences, age, and most effective treatments of FFD.
Alikhan, A, Gorouhi, F, Zargari, O. “Fox-Fordyce disease exacerbated by hyperhidrosis”. Pediatr Dermatol. vol. 27. 2010. pp. 162-5. (This report includes a good discussion and a brief review of literature on FFD. It provides information about surgical, topical, and oral therapies for FFD. It also gives an insight into presentation, histology, and possible etiology of FFD.)
Boer, A. “Histopathologic patterns of Fox-Fordyce disease”. Am J Dermatopathol. vol. 26. 2004. pp. 482-92. (This article researched much of the literature on the histopathology of FFD. It discusses the common histologic presentation of FFD and discusses possible etiology theories of FFD. In addition, the author discusses common clinical findings of FFD.)
Burgess, N. “Fox-Fordyce disease”. Proc R Soc Med. vol. 26. 1933. pp. 1556-7. (The author provides detailed information about the physical findings upon examination of patients with FFD. Information about demographics [age, gender, and race] of FFD patients is also provided. Common histologic hallmarks of FFD are also discusses by the author.)
Helfman, RJ. “A new treatment of Fox-Fordyce disease”. South Med J. vol. 55. 1962. pp. 681-4. (The description of FFD findings: pruritus, papule, etc., are noted in this work. Demographics and possible treatment via intralesional triamcinolone acetonide is also discussed.)
Helou, J, Maatouk, I, Moutran, R, Obeid, G. “Fox-Fordyce-like disease following laser hair removal appearing on all treated areas”. Lasers Med Sci. vol. 28. 2013. pp. 1205-1207. (Case report describing occurrence of Fox-Fordyce-like disease in axillae, umbilicus and pubis following laser hair removal.)
Kao, PH, Hsu, CK, Lee, JY. “Clinicopathological study of Fox-Fordyce disease”. J Dermatol. vol. 36. 2009. pp. 485-90. (Describes the appearance [papule size, color, etc.] and symptoms of FFD. There is a description of common histology of FFD [ducts, lymphocytes, etc.] and differential diagnosis of FFD.)
Kronthal, HL, Pomeranz, JR, Sitomer, G. “Fox-Fordyce disease: treatment with an oral contraceptive”. Arch Dermatol. vol. 91. 1965. pp. 243-5. (Characteristics to confirm diagnosis of FFD histologically [spongiosis, hyperkeratosis, etc.] are presented. This article also provides information on the demographics of the disease, hormonal interplay of FFD, and possible estrogenic therapy.)
Montes, LF, Cortes, A, Baker, BL, Curtis, AC. “Fox-Fordyce disease”. Arch Dermatol. vol. 80. 1959. pp. 549-53. (This case report discusses possible estrogenic therapy for FFD. Clinical and histologic findings of FFD are also provided. It also discusses the relationship of hormones in FFD [estrogen and FSH].)
Shelley, WB, Levy, EJ. “Apocrine sweat retention in man. II. Fox-Fordyce disease (Apocrine miliaria)”. AMA Arch Derm. vol. 73. 1956. pp. 38-49. (This is a well-researched article with over 15 case reports. It has much of the information about the findings of FFD upon physical examination. It has descriptions of the histopathology: including duct closure and rupture, inflammatory infiltrate, etc. It also has pathologies that are included in the differential diagnosis of FFD, possible pathophysiology, and etiology behind FFD.)
Tetzlaff, MT, Evans, K, DeHoratius, D. “Fox-Fordyce disease following axillary laser hair removal”. Arch Dermatol. vol. 147. 2011. pp. 573-6. (First report of Fox-Fordyce disease as a complication after laser axillary hair removal. They discuss possible etiologic mechanisms and describe the clinical and histologic findings.)
Winkelman, RK, Montgomery, H. “Fox-Fordyce disease”. AMA Arch Derm. vol. 74. 1956. pp. 63-8. (Winkelman and Montgomery describe histopathology; including presentation of follicles, ducts, etc. as well as diagnosis confirmation. There is also detailed information about the findings of FFD upon physical examination.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?