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Author: Ali Alikhan, BS, University of California, Davis School of Medicine

Ali Alikhan is a member of the following medical societies: American Medical Student Association/Foundation, Islamic Medical Association of North America, and Student National Medical Association

Coauthor(s): Ai-Lean Chew, MBChB, Specialist Registrar, Department of Dermatology, St John's Institute of Dermatology, UK; Howard I Maibach, MD, Professor and Vice Chairperson, Department of Dermatology, University of California School of Medicine at San Francisco; Consulting Staff, University of California Hospitals

Editors: Marjan Garmyn, MD, PhD, Professor, Faculty of Medicine, Katholieke Universiteit Leuven, Belgium; Chair and Adjunct Head, Department of Dermatology, University of Leuven, Belgium; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

Author and Editor Disclosure

Synonyms and related keywords: berlock dermatitis, perfume phototoxicity, perfume photoirritation, bergapten phototoxicity, bergapten photoirritation, bergamot phototoxicity, bergamot photoirritation, photodermatitis pigmentaria, dermite pigmentée en forme de coulée, 5-Methoxypsoralens photoirritation

Background

Berloque dermatitis obtains its name from the German word berlock or the French berloque, meaning trinket or charm. Rosenthal1 coined the term in 1925 to describe pendantlike streaks of pigmentation on the neck, face, arms, or trunk. He suspected they were due to fluid droplets, unaware that Freund2 in 1916 had described hyperpigmented macules due to sun exposure after the application of eau de cologne. The phototoxic ingredient causing the pigmentation proved to be bergapten, a component of oil of bergamot, derived from the rind of Citrus bergamia, the bergamot lime. Several cases were reported in the 1950s and 1960s following increased use of perfumes containing oil of bergamot and the passion for sunbathing. Since the introduction of artificial oil of bergamot and the reduced use of the natural product in perfumes, berloque dermatitis has become rare.

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Pathophysiology

Phototoxicity or photoirritation is a chemically induced nonimmunologic acute skin irritation requiring light (usually within the UVA spectrum, ie, 320-400 nm). The skin response resembles exaggerated sunburn and does not require prior sensitization; it can be caused by a single simultaneous exposure to the chemical and light source. The photoactive chemical may enter the skin via topical administration, or via ingestion, inhalation, or parenteral administration. The reaction can be evoked in all subjects as long as the concentration of the chemical and the dose of light are sufficient.

In the case of berloque dermatitis, the phototoxic reaction is induced by the effect of long-wave ultraviolet (UVA) radiation on bergapten, or 5-methoxypsoralens, a furocoumarin now known to be the only photoactive component of bergamot oil (see Media File 2). The bergapten-UVA radiation combination induces an intensification of melanogenesis and a corresponding increase in the number of functional melanocytes, which are more dendritic and dopa-positive. The distribution of melanosomes in keratinocyte changes from the aggregate to nonaggregate form.

Frequency

United States

The exact incidence of berloque dermatitis is unknown. In the Untied States, berloque dermatitis now is exceedingly rare due to the use of bergapten-free fragrance formulations. The US Hazardous Substances Act issued regulations stating that products containing oil of bergamot must not exceed 62 ppm bergapten, 2% bergamot oil. Following work performed by Marzulli and Maibach3 and reported in 1970, even lower concentrations than this have been recommended (<0.3% bergamot oil, equivalent to 0.001% bergapten), and bergapten-free bergamot oil is used almost always now in the Untied States. However, in some countries where bergamot oil continues to be used, berloque dermatitis remains a problem. Even in the Untied States, milder forms still are being observed. Recently, a patient was reported to have severe berloque dermatitis due to using a suntan booth immediately after applying some 40-year-old Shalimar perfume, which contained bergamot oil.

Apart from the bergamot lime, bergapten also is a component in other substances, inducing bergapten phototoxicity without the typical pendantlike appearance of berloque dermatitis. For instance, in Norway, bergapten phototoxicity has been reported due to Heracleum laciniatum and in Denmark due to Heracleum mantegazzianum (giant hogweed).4, 5

Mortality/Morbidity

Phototoxic reactions currently are the most frequently recognized form of photosensitivity reactions. Berloque dermatitis, however, is far more uncommon due to the reasons described above.

Race

Precise information about racial predilection is not available.

Sex

Berloque dermatitis usually occurs in females who wear fragrances containing oil of bergamot, but males who wear fragrances or fragrance-containing products, such as aftershave lotion, also may develop berloque dermatitis.

Age

Berloque dermatitis usually occurs in women, although it can occur in persons of any age who apply fragrances containing oil of bergamot.



History

The clinical presentation of berloque dermatitis may be classically divided into 2 phases. The initial acute inflammatory phase consists of erythema, edema, pain, pruritus, and increase in skin temperature around the area of contact with the phototoxic agent. The second stage is hyperpigmentation of the lesion. Patients usually present with small areas of redness or pigmentation of the skin, usually on sun-exposed areas, such as the neck. Pain and, sometimes, pruritus may be felt during the acute erythematous phase before the lesions become hyperpigmented. However, hyperpigmentation is the chief complaint; sometimes patients may not even recall the inflammatory phase. A careful history may reveal use of a perfume or fragrance-containing product on the skin prior to a period of sun exposure, such as sunbathing or a picnic. If untreated, the natural history of the disease also is biphasic; the inflammatory lesions resolve in days to weeks, but the pigmentation may last months or even years.

Physical

Erythema, edema, vesiculation, hyperpigmentation, and desquamation are typical phototoxic skin effects. In classic berloque dermatitis, brown hyperpigmentation with or without preceding erythema is seen in a droplike or pendantlike configuration. It usually is distributed over the sides of the neck in adult females, although it may be seen in any part of the body where perfume was applied followed by sun-exposure.

Some less typical presentations of berloque dermatitis are, for example, symmetrical facial pigmentation on a man, caused by aftershave lotion containing bergapten, and an infant who developed pigmentation on her body and arms where her mother applied eau de toilette prior to taking her to the beach.

Causes

Bergapten, or 5-methoxypsoralen, is the photoactive component of bergamot oil from the bergamot lime (C bergamia), which is a popular ingredient in perfumes and fragrances. Apart from their obvious existence in cosmetics and toiletries (such as toilet water, aftershave lotions, colognes, sunscreen lotions, moisturizers), perfumes also are found in soap, household cleaners, detergents, air fresheners, and a myriad of other everyday items.

Besides the bergamot lime, bergapten is a naturally occurring component of various other fruits and plants (see Media File 3). Examples of these are figs (Ficus carica), celery (Apium graveolens), lemon oil, Tromso palm (H laciniatum), Queen Anne's lace (Ammi majus), and giant Russian hogweed (H mantegazzianum). All these are capable of inducing bergapten phototoxicity, although they are not perfume-related and, therefore, classified as phytophotodermatitis rather than berloque dermatitis.



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Lab Studies

  • Predictive testing: Phototoxicity testing is not carried out diagnostically, but rather for predictive purposes. It routinely is included in the safety evaluation of raw materials by the Research Institute for Fragrance Materials and several methods for identifying phototoxic compounds have been reported. Both in vitro and in vivo methods are used currently. Generally, for in vivo testing, measured amounts of fragrance material are tested, either in laboratory animals (eg, mouse, rabbit, guinea pig models), or ultimately in humans, with an artificial light source. This identifies potential phototoxic substances before they are marketed.
  • In an attempt to decrease animal use in predictive dermatology, the European Union, in cooperation with the European Centre for the Validation of Alternative Methods (ECVAM) and the Interagency Coordinating Committee for the Validation of Alternative Methods (ICVAM), has supported the development of in vitro alternatives.6, 7 Initial trials revealed reasonable sensitivity and specificity8, 9, 10, 11; false-positive results and false-negative results have already been documented.12, 13, 14 Thus far, several cosmetic products have been examined in vitro for phototoxicity.15

Other Tests

  • Clinical diagnosis and the role of photopatch testing: Clinical identification of phototoxicity largely resides in morphology and a high index of clinical suspicion. Photopatch testing may be performed if photoallergy is strongly suspected. This consists of occlusive application of the test chemical(s) to the back, followed by irradiation with an UV light source. The results are evaluated at several time intervals, according to an established score based on the skin reaction pattern. Adequate controls are imperative to differentiate phototoxicity from photoallergy. In phototoxicity, all controls will have a positive response, whereas in photoallergy, controls should be negative.

Histologic Findings

The histopathological findings in berloque dermatitis are identical to other phototoxic reactions, an irritant cutaneous response. The epidermal changes consist of keratinocyte necrosis, intercellular and intracellular edema, and intraepidermal blisters. In severe cases, these blisters may rupture, resulting in subepidermal bullae. Neutrophils enter the epidermis at an early stage. In contrast to the extensive epidermal damage, only a mild perivascular infiltrate is present. Changes associated with berloque pigmentation are an increased number and size of melanosomes, melanocyte hypertrophy with increased arborization of dendrites, increased transfer of melanosomes to keratinocytes, and increased tyrosinase activity within the proliferating melanocytes.



Medical Care

The primary aim of the therapeutic regime is discontinuation of the offending substance. If berloque dermatitis is the putative diagnosis, all bergamot oil-containing perfumes should be avoided. Any perfumes that are worn should be worn on covered-up areas, not on areas of sun exposure.

If the patient presents in the acute phase and is in considerable discomfort, wet compresses may be helpful in relieving the discomfort. Simple analgesia may be given if the patient is in pain.

For secondary hyperpigmentation, the natural course of the dermatitis is spontaneous resolution after several months, but some lesions may persist much longer. The most important step is to minimize exposure to the sun. This may be done by avoiding strong sunlight whenever possible, avoiding the use of sunbeds and using a strong sunscreen (SPF 30 or higher) with activity in both the UVA and UVB spectra. Camouflage also may be used on exposed hyperpigmented areas, for cosmetic reasons. Dermablend and Covermark are preparations combining a water-resistant opaque base with a broad-spectrum sunscreen.

If the pigmentation is persistent, hydroquinone constitutes the mainstay of medical therapy. It usually is given twice a day, at a concentration of about 2%, for several months. At higher concentrations, the patient would be at risk of irritation. Hydroquinone sometimes is administered in conjunction with topical tretinoin (Retin-A). Kligman and Willis16 devised a concoction known as Kligman's formula, consisting of hydroquinone, tretinoin, dexamethasone, ethanol, and propylene glycol, which they found effective in treating hyperpigmentation.

A novel therapy for pigmentary disorders is ellagic acid, now commercialized in Japan. Ellagic acid is a naturally existing polyphenol that inhibits tyrosinase activity by chelation of the copper ion(s) at the active center of the enzyme. The efficacy in a placebo-controlled trial for preventing UV-induced pigmentation has been shown to be 86%, and no side effects have been reported.



Medical therapy is largely unnecessary for the treatment of berloque dermatitis, except in cases with persistent hyperpigmentation. In these cases, skin-bleaching agents (eg, hydroquinone) are the mainstays of therapy.

Drug Category: Depigmenting agents

Skin bleaching agents are indicated for the gradual depigmentation of hyperpigmented skin conditions.

Drug NameHydroquinone USP 4% (Claripel cream with sunscreens)
DescriptionProduces reversible depigmentation of skin by inhibiting enzymatic oxidation of tyrosine to 3-(3,4-dihydroxyphenyl-alanine (dopa)) and suppression of other melanocyte metabolic processes. Exposure to sunlight or ultraviolet light will cause repigmentation, which may be prevented by the broad-spectrum sunscreen agents contained in this product.
Adult DoseApply to affected areas bid
Pediatric Dose<12 years: Not established
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity to drug or related products
InteractionsNone reported
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsMay produce unwanted cosmetic effects if not used as directed; physician should be familiar with contents of prescribing insert before prescribing or dispensing medication; test for skin sensitivity before using product by applying to small area of unbroken skin (minor redness is not a contraindication, but discontinue use if there is itching, vesicle formation, or excessive inflammatory response); avoid contact with eyes; do not use for prevention of sunburn; discontinue use if no lightening effect is noted after two mo of treatment; on rare occasions, a gradual blue-black darkening of the skin may occur (discontinue use if it occurs)

Drug NameHydroquinone (Eldopaque-Forte, Solaquin Forte, Lustra)
DescriptionIndicated for the gradual bleaching of hyperpigmented skin conditions such as chloasma, melasma, freckles, senile lentigines, and other unwanted areas of melanin hyperpigmentation. Also is used to reduce hyperpigmentation caused by photosensitization associated with inflammation or with the use of certain perfumes (berloque dermatitis).
Topical application of hydroquinone produces a reversible depigmentation of the skin by inhibition of the enzymatic oxidation of tyrosine to 3, 4-dihydroxyphenylalanine (dopa) and suppression of other melanocyte metabolic processes. Depigmentation may take 1-4 mo to occur while existing melanin is sloughed off and excretion of new melanin is increased by hydroquinone. Exposure to sunlight or ultraviolet light will cause repigmentation, which may be prevented by broad-spectrum sunscreen agents.
Available topically, in strengths of 2-4%, in the form of a cream, lotion, solution, powder, or gel.
Adult DoseApply uniformly to affected areas and rub-in bid; use until desired degree of pigmentation obtained; frequency can be tapered down to a maintenance regime
Pediatric Dose<12 years: Not established
>12 years: Administer as in adults
ContraindicationsDocumented hypersensitivity; sunburn
InteractionsNone reported
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
PrecautionsAnimal reproduction studies have not been conducted; not known whether hydroquinone can affect reproductive capacity or cause fetal harm when used topically on a pregnant woman (only use in pregnant women when clearly indicated)
Mild skin irritation and sensitization have occurred following topical application and occur more frequently with higher concentration; dryness and fissuring of paranasal and infraorbital areas have been reported; chronic use (up to 8 y) has been reported to produce ochronosis and colloid milium; some formulations contain sodium metabisulfite, a sulfite that may cause serious allergic type reactions (eg, hives, itching, wheezing, anaphylaxis) in certain susceptible persons (test for skin sensitivity before using any hydroquinone preparation by applying a small amount to a normal patch of skin and checking it after 24 h); minor redness is not a contraindication, but patient should refrain from using if itching, vesiculation, or excessive inflammatory response is observed
Sunscreen use is essential because even minimal sunlight sustains melanocytic activity; do not apply near eyes, to cut, abraded, or sunburned skin, after shaving, or over miliaria rubra (prickly heat)



Media file 1:  Hyperpigmented streaks on the dorsa of hands of a patient with bergapten phototoxicity
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Media type:  Photo

Media file 2:  Molecular structure of 5-methoxypsoralen (bergapten)
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Media type:  Graph

Media file 3:  Bergapten-containing plants
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Media type:  Graph



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Berloque Dermatitis excerpt

Article Last Updated: Jun 2, 2008