Clinics in Dermatology (2015) 33, 483–491

Hyperhidrosis, bromhidrosis, and chromhidrosis: Fold (intertriginous) dermatoses Kristina Semkova, MD a,⁎, Malena Gergovska, MD b , Jana Kazandjieva, MD, PhD a , Nikolai Tsankov, MD, PhD c a

St. John's Institute of Dermatology, London, Westminster Bridge Road, SE1 7EH, United Kingdom Euro Derma Clinic, Sofia, Bulgaria c Tokuda Hospital, Sofia, Bulgaria b

Abstract Human sweat glands disorders are common and can have a significant impact on the quality of life and on professional, social, and emotional burdens. It is of paramount importance to diagnose and treat them properly to ensure optimal patient care. Hyperhidrosis is characterized by increased sweat secretion, which can be idiopathic or secondary to other systemic conditions. Numerous therapeutic options have been introduced with variable success. Novel methods with microwave-based and ultrasound devices have been developed and are currently tested in comparison to the conventional approaches. All treatment options for hyperhidrosis require frequent monitoring by a dermatologist for evaluation of the therapeutic progress. Bromhidrosis and chromhidrosis are rare disorders but are still equally disabling as hyperhidrosis. Bromhidrosis occurs secondary to excessive secretion from either apocrine or eccrine glands that become malodorous on bacterial breakdown. The condition is further aggravated by poor hygiene or underlying disorders promoting bacterial overgrowth, including diabetes, intertrigo, erythrasma, and obesity. Chromhidrosis is a rare dermatologic disorder characterized by secretion of colored sweat with a predilection for the axillary area and the face. Treatment is challenging in that the condition usually recurs after discontinuation of therapy and persists until the age-related regression of the sweat glands. © 2015 Elsevier Inc. All rights reserved.

Human sweat glands (sudoriferous or sudoriparous glands) are subdivided into three main types—eccrine, apocrine, and apoeccrine—based on their different structure, anatomic distribution, function, secretory products, and mechanism of excretion.

Eccrine glands Eccrine glands are distributed with varying density over the entire skin surface with the exception of the lips, ear canal, ⁎ Corresponding author. E-mail address: [email protected] (K. Semkova). http://dx.doi.org/10.1016/j.clindermatol.2015.04.013 0738-081X/© 2015 Elsevier Inc. All rights reserved.

prepuce, glans penis, labia minora, and clitoris. The glands are 10 times smaller than apocrine glands and open with a duct directly onto the skin surface. Eccrine sweat is a dilute salt solution that contains mostly water and electrolytes. The total volume of eccrine sweat depends on the number of functional glands in the respective area and the size of the surface opening. The degree of secretory activity is regulated by neural and hormonal mechanisms. At their maximum capacity, eccrine glands can produce more than three liters of secretions per hour.1 Eccrine sweat has three primary functions: thermoregulation, excretion of electrolytes and exogenous substances, and protection as an important part of the skin barrier.

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Apocrine glands Apocrine glands are found in limited areas over the body, mostly in the axillary region, perineum, around the nipples, in the ears, and on the eyelids. They secrete small amounts of oily fluid that is excreted into the pilary canal of the hair follicle and not directly onto the skin surface. Apocrine sweat is initially odorless when excreted onto the skin but is soon degraded by the resident bacteria. Its breakdown products are responsible for the individual pheromonal body odor.2–4

Apoeccrine glands Apoeccrine glands are a mixed type of sweat glands, as they simultaneously show features of the other two wellstudied types.2 They presumably develop during puberty from eccrine glands and can represent up to 50% of all axillary glands. Apoeccrine glands continuously secrete a thin, watery sweat with similar sodium and potassium concentrations as eccrine sweat. These glands show a greater responsiveness to cholinergic and adrenergic stimuli than eccrine glands, and their overall sweat secretion rate is higher than that of other types of sweat glands. Due to this and to their abundance in the axillary region, it is believed that apoeccrine glands are of paramount significance for axillary sweating.

Hyperhidrosis Hyperhidrosis (also polyhidrosis or sudorrhea) is a common medical condition characterized by abnormally increased sweating, defined as sweat secretion that largely exceeds the quantity required for normal body thermoregulation. In patients with hyperhidrosis, sweat secretion may occur at low temperatures or at rest. The disorder is associated with a significant quality of life burden from a psychological, emotional, and social perspective. Studies on quality of life reveal that the negative effects of hyperhidrosis are comparable to those of conditions such as severe psoriasis, end-stage renal failure, rheumatoid arthritis, and multiple sclerosis.5 Hyperhidrosis is primary (idiopathic) or secondary to other diseases. It is generalized (involving the whole body) or focal (involving specific body sites, most commonly the axillae, palms, soles, and face).6 Hyperhidrosis can be further distinguished by anatomic distribution of affected regions and by laterality: unilateral versus bilateral and symmetric.7 Primary hyperhidrosis is idiopathic and focal.6 It affects about 2.8% of the U.S. population.8 It shows no sexual predilection and most commonly affects people between 25 and 64 years of age. Rarely, patients may be affected in early childhood.8 Japanese individuals are reportedly affected by

K. Semkova et al. hyperhidrosis more than 20 times more frequently than other ethnic groups;9–11 however, all races can be affected. Genetic predisposition is seen in about 30% to 50% of people with an autosomal dominant mode of transmission, incomplete penetrance, and variable phenotype.11 Only one primary focal hyperhidrosis locus was mapped to chromosome 14q11.2-q13, but no disease-causing gene has been identified.12 Secondary hyperhidrosis can be either generalized or focal and results from an underlying condition such as endocrine, neurologic, or infectious disorders.

Pathophysiology Hyperhidrosis is observed in the areas with the highest density of eccrine and apoeccrine sweat glands. Apocrine glands have not been shown to contribute to excessive sweat production.13 Axillary hyperhidrosis is the most common, followed by palmar and plantar hyperhidrosis. In the localized form, hyperhidrosis is due to an abnormal regeneration of sympathetic nerves or a localized abnormality in the number or distribution of the eccrine glands. Essential hyperhidrosis, which is a disorder of the eccrine sweat glands, is usually associated with sympathetic overactivity.14 Generalized hyperhidrosis may be a result of autonomic dysregulation, or it may be a consequence of a systemic disease, febrile illness, and adverse effects of medications or malignancy. Hyperhidrosis beginning later in life requires investigations for endocrine disorders (diabetes mellitus, hyperthyroidism, and hyperpituitarism) or neurologic conditions (including peripheral nerve injury, Parkinson’s disease, reflex sympathetic dystrophy, spinal injury, and Arnold-Chiari malformation). Asymmetric hyperhidrosis may also be a sign of neurologic disease.15 Additional causes include pheochromocytoma, carcinoid syndrome, respiratory disease, and psychiatric disease. Hyperhidrosis may accompany hot flashes during menopause. Medications associated with excessive sweating include propranolol, physostigmine, pilocarpine, tricyclic antidepressants, and serotonin reuptake inhibitors. It has been reported that the temperament and character profile of patients with essential hyperhidrosis 16 is not related to social phobia or personality disorder.

Clinical presentation Primary hyperhidrosis usually involves the hands, axillae, feet, and the craniofacial region. The diagnostic criteria include excessive sweating for at least 6 months with 4 or more of the following present: • primary involvement of eccrine-dense (axillae/palms/ soles/craniofacial) sites

Hyperhidrosis, bromhidrosis, and chromhidrosis: Fold (intertriginous) dermatoses • • • • • •

bilateral and symmetric distribution absence of signs at night episodes at least weekly onset at 25 years of age or younger positive family history impairment of daily activities.17

Localized unilateral or segmental hyperhidrosis is rare and of unknown etiology. It usually occurs on the forearm or forehead in otherwise healthy individuals with no evidence of the typical triggering factors found in essential hyperhidrosis. Hyperhidrosis affecting relatively small areas (less than 100 cm2)11 includes idiopathic unilateral circumscribed hyperhydrosis, gustatory sweating, lacrimal sweating, Harlequin syndrome, and emotional hyperhidrosis. There are reported associations of unilateral circumscribed hyperhydrosis with blue rubber bleb nevus, glomus tumor, POEMS syndrome, burning feet (Gopalan’s) syndrome, trench foot, causalgia, pachydermoperiostosis, and pretibial myxedema. Gustatory sweating is associated with encephalitis, syringomyelia, diabetic neuropathies, herpes zoster, parotitis, and auriculotemporal (Frey’s) syndrome. Lacrimal sweating is due to postganglionic sympathetic deficit, often seen in Raeder’s syndrome. Harlequin syndrome is described as a unilateral hyperhidrosis and flushing that are predominantly induced by exercise or heat.18 The sympathetic deficits are usually limited to the face. Unilateral hyperhidrosis has been described on the right sides of the forehead, the nose, and the palmar surface of the right hand with anhidrosis on the left hand.19 Hyperhidrosis affecting relatively large areas (generalized; covering over 100 cm2)11 occurs in people with a past history of spinal cord injuries, orthostatic hypotension, posttraumatic syringomyelia and in association with peripheral neuropathies, familial dysautonomia (Riley-Day syndrome), congenital autonomic dysfunction with universal pain loss, and exposure to cold, notably associated with cold-induced sweating syndrome. It could also be associated with brain lesions, episodic with hypothermia (Hines-Bannick syndrome) or without hypothermia, olfactory conditions, or systemic medical problems, such as pheochromocytoma, Parkinson’s disease, thyrotoxicosis, diabetes mellitus, fibromyalgia, or congestive heart failure.

Laboratory investigations The iodine starch test may be used if direct visualization of the areas affected by hyperhidrosis is desired. This test requires spraying the affected area with a mixture of 0.5 to 1 g of iodine crystals and 500 g of soluble starch. Areas with increased sweat secretion turn black. There are many other test methods, including the Minor’s starch-iodine test with gravimetric analysis,20 dynamic sudorometry,21 thermoregulatory sweat test,17 and skin conductance.22

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Additional tests to clarify a possible underlying pathology include thyroid function, blood glucose, urinary catecholamines, uric acid, and purified protein derivative. Chest radiography may be used to rule out tuberculosis or a neoplastic condition. In patients with hyperhidrosis, the eccrine glands have normal morphologic structure and functions. In patients with localized hyperhidrosis, an abnormal number and/or distribution of otherwise normal eccrine glands may be found.

Treatment Various therapeutic options can be used to treat axillary hyperhidrosis: topical medications, systemic medications, iontophoresis, botulinum toxin, and surgical procedures. Each case must be evaluated separately, considering the severity and extent of the clinical condition, as well as the advantages and disadvantages of each method. The treatment of axillary hyperhidrosis should follow a step-by-step strategy, always beginning with conservative methods. All treatment options for hyperhidrosis require frequent monitoring by a dermatologist for evaluation of the therapeutic progress.

Topical treatments Topical treatments include boric acid, topical anticholinergics, 2% to 5% tannic acid solutions, resorcinol, potassium permanganate, formaldehyde,23 glutaraldehyde, and methenamine. All of these agents have limited effectiveness or are restricted due to side effects such as staining, contact sensitization, and irritation. Aluminum salt solutions are the most common antiperspirants in use.24 Aluminum chloride works by blocking the openings of the sweat ducts. It is believed that the metal ions precipitate with mucopolysaccharides, damaging the epithelial cells along the lumen of the duct and forming a plug that blocks sweat secretion. Sweat is still produced, as evidenced by the appearance of miliaria during heat stress, with sweat building up behind the obstruction created by the metallic salt25; however, normal sweat gland function returns with epidermal renewal, necessitating retreatment once or twice a week. Aluminum chloride tends to work best in the axillae. Products containing 10% to 20% aluminum chloride hexahydrate are the first line of treatment for underarm sweating. Some patients may be prescribed a product containing a higher dose of aluminum chloride, which is applied nightly onto the affected areas; this approach may also work for sweating of the palms and soles. Caution is advised when the face is treated as aluminum chloride may cause severe eye irritation.

Systemic agents Systemic agents, including anticholinergic medications such as propantheline bromide, glycopyrrolate, oxybutynin, and benztropine, are effective as they inhibit acetylcholine, the

486 preglandular neurotransmitter for sweat secretion.26,27 Oxybutynin is an antimuscarinic drug that was first associated with the resolution of hyperhidrosis in 1988.28 Oxybutynin has provided good results and is an alternative for treating hyperhidrosis at both common and uncommon sites.29 According to one study,30 the dosing schedule is started at 2.5 mg daily for the first week, then 2.5 mg twice daily from days 8 to 21, and 5 mg twice daily starting at day 22. More than 70% of patients in the oxybutynin group treated for palmar or axillary hyperhidrosis noted significant improvement, whereas only 27.3% of patients in the corresponding placebo group had moderate improvement (P 0.001). Other systemic medications, such as sedatives and tranquilizers, indomethacin, and calcium channel blockers, have been reported effective in the treatment of palmoplantar hyperhidrosis.

Iontophoresis Iontophoresis was first introduced in 1952. The procedure consists of passing a galvanic current across the skin.31–33 The mechanism of action remains unclear. Iontophoresis of tap water and normal saline solution in idiopathic hyperhidrosis is a relatively common treatment and is most effective for sweating of the hands and feet. Multiple agents have been used; however, treatment with anticholinergic iontophoresis is more effective than tap water iontophoresis.34 According to one study, iontophoresis or phonophoresis could be used to facilitate percutaneous delivery of botulinum toxin A. Improvement of hyperhidrosis lasted for 16 weeks after treatment.35

Botulinum toxin Botulinum toxin (BTX) injections are an effective treatment approach for hyperhidrosis due to their anticholinergic effects at the neuromuscular junction and in the postganglionic sympathetic cholinergic nerves in the sweat glands.36–39 Botulinum neurotoxin-type A (BTX-A) is a useful and safe treatment option for most areas of the body. The application of 1 U/cm2 of BTX-A (50 to 100 U per axilla) is recommended.40 The therapeutic effect lasts for 6 to 8 months. Injections of BTX must be repeated at varying intervals to maintain long-term results. Side effects include injection-site pain and flulike symptoms. Botox used for sweating of the palms can cause mild, temporary weakness. In addition to pharmacologic therapy, other treatments include surgical sympathectomy, radiofrequency ablation,41 surgical excision of the affected areas, and subcutaneous liposuction.

Sympathectomy Sympathectomy has been used as a permanent effective treatment since 1920, and it is usually reserved as a last

K. Semkova et al. treatment option.42 In an endoscopic thoracic sympathectomy, cuts, burns, or clamps interrupt the thoracic ganglion on the main sympathetic chain that runs alongside the spine. Endoscopic thoracic sympathectomy is generally considered a “safe, reproducible, and effective procedure and most patients are satisfied with the results of the surgery.”42 Compensatory sweating is a severe and undesirable side effect of this procedure.

Suction-curettage Suction-curettage of sweat glands is a minimally invasive surgical technique that is easy to perform and safe, with high rates of success and relatively few side effects. It is generally well tolerated by patients and requires shorter time away from daily activities compared with other surgical modalities. Considering the less serious complications (and lower associated costs), better cosmetic outcome, and resolution of symptoms, liposuction-curettage provides a promising option for axillary hyperhidrosis.43

Laser technology Laser technology has also been used externally for glandular disruption in the treatment of hyperhidrosis. The 1064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was used for axillary hyperhidrosis in 17 patients and was determined to be safe and effective by subjective and objective measures.44 Novel methods of microwave-based and ultrasound devices have been developed. Microwave-based devices45 have recently been used to treat hyperhidrosis. Investigators found that 94% of patients experienced at least a 1-point decrease on the Hyperhidrosis Disease Severity Scale, whereas 55% reported a 2-point or greater decrease. Ultrasound technology has also been introduced as a new method in the treatment of hyperhidrosis.46

Prognosis Hyperhidrosis has physiologic and psychological consequences, such as cold and clammy hands, dehydration, and skin infections secondary to maceration of the skin. 47 Severe cases of hyperhidrosis significantly affect the patient’s quality of life and can be disabling in professional, academic, and social aspects, causing embarrassment and work-related disability and depressive symptoms. 33 Hyperhidrosis is difficult to treat, but the now available newer treatment options offer a better prognosis for patients.

Hyperhidrosis, bromhidrosis, and chromhidrosis: Fold (intertriginous) dermatoses

Bromhidrosis Bromhidrosis (from Greek: bromos [stench] and hidros [sweat]) is a chronic condition that presents clinically with an abnormal and excessively unpleasant body odor. It is also known as osmidrosis, bromidrosis, ozochrotia, and malodorous sweating or body odor. All sweat gland types could be involved in bromhidrosis. Bromhidrosis shows no racial predilection but is more common in men. Apocrine bromhidrosis occurs after puberty, reflecting the time of maturation of apocrine glands. Eccrine bromhidrosis may develop at any age, including childhood.

Pathophysiology Bromhidrosis occurs secondary to excessive secretion from either apocrine or eccrine glands that becomes malodorous on bacterial breakdown. The condition is further aggravated by poor hygiene or underlying disorders promoting bacterial overgrowth, including diabetes, intertrigo, erythrasma, and obesity.

Apocrine bromhidrosis Apocrine bromhidrosis is the most common form of bromhidrosis. Its pathogenesis is multifactorial. Studies have shown that compared with control subjects, individuals with bromhidrosis have more numerous and larger apocrine glands.48 Apocrine secretions are decomposed by skin surface bacteria into ammonia and short-chain fatty acids, with their characteristic strong odors. The most abundant of these acids is (E)-3-methyl-2-hexenoic acid (E3M2H).49,50 In the axillary region, bacterial flora have been shown to transform non-odoriferous precursors in sweat to more odoriferous volatile acids, thus creating the specific body odor. A specific zinc-dependent N-α-acyl-glutamine aminoacylase (N-AGA) from Corynebacterium species releases these acids (primarily E-3 M2 H and (RS)-3-hydroxy-3methylhexanoic acid [HMHA]) and other odoriferous substances from glutamine conjugates in sweat and thus creates the specific individual body odor.51 Various factors can affect eccrine sweat and cause eccrine bromhidrosis. Bacterial degradation of sweat-softened keratin; ingestion of some foods, including garlic, onion, curry, and alcohol; ingestion of certain medications (eg, penicillin, bromides) and toxins; underlying metabolic (disturbances in amino acid metabolism; sweaty feet syndrome; cat odor syndrome, isovaleric acidemia, and hypermethioninemia) or endogenous causes and hyperhidrosis have all been associated with bromhidrosis. The mechanism of hyperhidrosis-induced bromhidrosis is unclear, but excessive apocrine secretion may create a favorable environment for

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bacterial overgrowth, thus contributing to further keratin degradation and odor enhancement.52,53 A foreign body in the nasal cavity is a reported cause of generalized bromhidrosis in the pediatric population.19,54 Bromhidrosis may affect more than one member of a given family, and recent studies have proposed an autosomal dominant pattern of inheritance, particularly in Asian patients. A strong relationship between bromhidrosis and wet earwax type associated with the single-nucleotide polymorphism rs17822931 of the ABCC11 gene has been found.55,56

Clinical presentation Patients present with excessively strong and offensive body odor, emanating primarily from the axillary region but also from the genitals or feet. Physical examination in apocrine bromhidrosis is usually unremarkable, as it is a functional and not a morphologic disorder. In eccrine bromhidrosis, bacterial degradation of keratin may result in maceration and wet keratin accumulation, especially on the plantar and intertriginous surfaces. In cases involving an underlying disease, the examination may reveal its relevant signs. Nasal passages should be examined in children with generalized eccrine bromhidrosis, as a nasal foreign body is a recognized and underlying cause for this condition.35,36

Laboratory investigations Bromhidrosis is primarily a clinical diagnosis. Laboratory investigations are needed only to elucidate a suspected underlying cause or for academic purposes. The odor-producing chemicals may be found by chromatography or spectroscopy, but this does not affect the therapeutic approach. Metabolic amino acid disorders should be diagnosed by specific testing of the urine or sweat for the aberrant amino acid product. Histologic examination of hematoxylin-eosin–stained specimens may show an increased number and size of apocrine glands, but this finding is not invariable.29

Treatment Improved hygiene, antibacterial agents, antiperspirant agents, lasers, BTXs, and, ultimately, surgery can be tried, taking into account the patient’s quality of life and expectations. Mild cases can be treated conservatively, but laser or surgical treatment is needed for a definitive cure. Treatment of the concomitant underlying skin or systemic conditions should be considered as well. Improved hygiene and topical antiseptics and antibacterial agents reduce bacterial overgrowth and the malodorous products from the breakdown of bacterial fatty acids. Hair removal may show an additional benefit by preventing sweat

488 and bacteria accumulation on the hair shaft; however, other methods excluding laser surgery should be preferred, as bromhidrosis has been reported as a potential adverse effect of laser hair removal.57 Topical antibiotics for bromhidrosis include clindamycin and erythromycin, but antiseptics should be tried first to limit the risk of bacterial resistance. Antiperspirants containing aluminum salts enhance drying, limit maceration, and may improve both apocrine and eccrine bromhidrosis, particularly when these occur in association with hyperhidrosis.58 Laser treatment has been effective in a number of patients. A frequency-doubled, Q-switched Nd:YAG laser (1064 nm) has been used in axillary bromhidrosis.59 Several studies have shown the beneficial effect for a long-term cure with the 1444-nm Nd:YAG laser that destroys the apocrine glands by subdermal coagulation.58,60 Transient pain and limitation of mobility persisting for 1 to 4 weeks postoperatively are the main side effects. Another successful treatment modality BTX-A, which denervates eccrine sweat glands and temporarily decreases sweat production. BTX-A has been used effectively in axillary61,62 and genital bromhidrosis.63 In a cohort study of 67 patients with axillary bromhidrosis, BTX-A inhibited eccrine and apoeccrine sweating but no apocrine sweating, demonstrating that a close positive correlation between malodor and sweating is the indication for BTX-A treatment.64 Different surgical methods have been tried with consistent success.65–69 Three main approaches are possible: removing only subcutaneous tissue without removing skin and with or without axillary superficial fascia removal70 ; removing skin and subcutaneous tissue en bloc68 ; and removing skin and subcutaneous tissue en bloc with removing of the adjacent subcutaneous tissue.51,71 Regeneration of gland function over a period of years may be observed, and this depends mainly on the depth and extension of surgical excision. A novel surgical approach has combined surgical intervention with additional carbon dioxide laser vaporization for the residual apocrine glands.72 Advantages of this combined approach include a high success rate, low complication rate, no admission treatment, less scarring, and rapid recovery. Superficial liposuction curettage is a minimally invasive technique for outpatient treatment that is less traumatic than open surgery. Suction is used to remove the subcutaneous tissue through small incisions in the axilla. The advantages of this technique are smaller scars, lower complication rates, and minimal postoperative care.73,74 The disadvantage of this method is the higher rate of recurrence. Ultrasound-assisted suction aspiration is an alternative option with better long-term results and similar cosmetic benefits. 75,76 Its main mechanism is liquefaction of fat and sweat glands. Upper thoracic sympathectomy has been used in some patients with a reported satisfaction rate of about 71%77; however, this method is usually reserved for hyperhidrosis.

K. Semkova et al.

Chromhidrosis Chromhidrosis (from Greek: chroma [color] and hidros [sweat]) is a rare dermatologic disorder, characterized by secretion of colored sweat with a predilection for the axillary area and the face. The condition was first described by Yonge in 1709, and the pathophysiology was elucidated in 1954 by Walter B. Shelley (1917-2009) and Harry J. Hurley (1927-2009), who attributed the coloration to lipofuscin granules in the apocrine glands.78 Lipofuscin is a yellowish brown pigment that is not specific to the apocrine glands and is usually found in the cytoplasm of cells that do not normally divide (eg, neurons). In apocrine chromhidrosis, lipofuscin pigment granules in apocrine glands occur in a higher-than-normal concentration or a higher-than-normal state of oxidation. This leads to blue, yellow, green, or black discoloration of the apocrine secretions. Even though the pathophysiology is clear, the etiology of and predisposing factors for accumulation of lipofuscin granules accumulation is as of yet unknown.79 Substance P also plays a role in the pathogenesis, which is evidenced by the efficacy of treatment with topical capsaicin.80

Pathophysiology Chromhidrosis is primarily apocrine in origin, but eccrine chromhidrosis may also occur with ingestion of various dyes and drugs (such as quinines81). Pseudochromhidrosis, on the contrary, results from mixing of various compounds with eccrine sweat that is initially secreted as colorless on the skin surface. These compounds include extrinsic dyes, colorants, fungi, or chromogenic bacteria such as Piedraia or Cornynebacterium.82 Chromhidrosis usually develops in puberty with the activation of apocrine secretion. The disease is chronic but follows the natural evolution of apocrine glands and often regresses with age. Although apocrine glands are found in various body areas, including the genital, axillary, areolar skin, and facial regions, chromhidrosis has been reported only on the face,61,63 axillae,83 and the breast areola.84,85 There is no sexual predilection, but this disorder has been reported more commonly in blacks with the exception of facial chromhidrosis, which is exclusive in the white population. In addition to its association with mature apocrine glands, one case of chromhidrosis in an infant has been reported in the literature.86

Clinical presentation The clinical presentation is usually distinctive and does not present a challenge to the dermatologist. Patients report staining of their clothes or underwear in the axillary region and, less commonly, areolar or facial staining. Some people

Hyperhidrosis, bromhidrosis, and chromhidrosis: Fold (intertriginous) dermatoses note an aura of warmth or a prickly sensation provoked by physical or emotional stress preceding the occurrence of colored sweat. The apocrine sweat secretions are odorless, turbid, and of variable color (yellow, green, blue, brown, or black) with follicular accentuation and can be expressed mechanically from the affected glands. Lucent, adherent, colored scales form upon drying of these secretions. Approximately 10% of the population without chromhidrosis may have colored sweat, a physiologic phenomenon that is considered acceptable.

Laboratory investigations Chromhidrosis is a clinical diagnosis, and tests to confirm it are only rarely needed. Wood’s lamp examination is the fastest and easiest confirmatory test for some cases. The yellow, green, and blue apocrine secretions fluoresce in yellow with a Wood’s lamp (ultraviolet wavelength 360 nm), whereas the dark brown and black apocrine secretions usually do not fluoresce. Sweat secretion could be stimulated for the test with intradermal epinephrine or oxytocin. Standard ultraviolet microscopy may show yellow-green fluorescence of the clothes that were in contact with the affected area. On histologic examination the apocrine glands are normal in size and morphology, but the number of glands varies. Increased number of yellow-brown lipofuscin granules is observed in the cytoplasm of secretory cells on standard hematoxylin-eosin staining.87 The granules are positive with periodic acid–Schiff and Oil Red O staining and fluoresce under an ultraviolet microscope with an excitation wavelength of 360 to 395 nm. Additional laboratory tests could be used to differentiate apocrine chromhidrosis from exogenous causes for pigmentation. These include urinary homogentisic acid levels to exclude alkaptonuria, complete blood cell counts to exclude bleeding diathesis, and relevant fungal and bacteriologic cultures to exclude infectious pseudochromhidrosis.

Treatment Treatment is only symptomatic. The condition usually recurs after discontinuation of therapy and persists until the age-related regression of the apocrine glands. Manual or pharmacologically induced expression of the secretions empties the glands, resulting in a symptom-free period of 48 to 72 hours. Successful treatment of chromhidrosis has been reported with capsaicin cream in a few patients.80,88 Capsaicin, an alkaloid found in chili peppers, is commonly used in medicine as a temporary analgesic for the treatment of minor myalgias and arthralgias, rheumatoid arthritis, osteoarthritis, and peripheral neuropathy such as postherpetic neuralgia caused by shingles. Capsaicin depletes neurons of

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substance P, a neurotransmitter and a neuromodulator for pain perception, responsible for the transmission of pain information in the central nervous system. Substance P is also an important factor for apocrine sweat production.71 Capsaicin should be applied once or twice daily for as long as required, but chromhidrosis relapses several days after discontinuation of treatment.62 BTX-A has also been effective for facial and axillary chromhidrosis.89–91 The mechanism by which BTX-A suppresses apocrine chromhidrosis is still unclear. Various mechanisms can be involved, including blockade of cholinergic stimulation and inhibition of substance P release.72,73 Although apocrine glands are less responsive to cholinergic stimulation compared with eccrine glands, cholinergic nerve fibers have been shown around their secretory coils but with a lower density of innervation.74 Treatment results usually persist for 4 to 5 months, and the course of treatment can be continued for as long as needed.

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