Chloracne

Etiology

Chloracnegens are fat-soluble and persist in the body fat and skin for a long period after exposure. Routes of exposure include direct skin contact, ingestion, and inhalation. Most cases are related to occupational[5] or accidental exposure; however, the poisoning of Ukrainian President Victor Yushchenko is a notable case involving purposeful poisoning using dioxin. 

Chloracne is caused by exposure to halogenated aromatic hydrocarbons found in:

• Fungicides
• Herbicides
• Insecticides
• Wood preservatives

Chemicals responsible for inducing chloracne include:

• Chlornaphthalene
• Chlorobenzene
• PCBs
• Polychlorinated dibenzo-p-dioxins (PCDDs)
• Polychlorinated dibenzofurans (PCDFs)
• Pyrazole derivatives
• Chlorophenol contaminants
• Trifluoromethyl

Epidemiology

Chloracne is a rare skin condition that is most often reported as a hazard of occupational exposure and may be seen in chemical production workers and those who handled, applied, or were exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD)-contaminated pesticides.[5] Outbreaks have occurred with accidental mass exposures, and at least 1 well-known individual has been targeted by poisoning. The first documented human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD)-contaminated chemicals was reported in 1949 after a trichlorophenol reactor exploded in Nitro, West Virginia, communities have been affected by contaminated oil in Missouri and industrial waste in Seveso, Italy.[6] The largest reported incident occurred in Japan in 1968, involving approximately 1600 victims.[2] During the Vietnam War, Agent Orange was used widely, but the true prevalence of chloracne in Vietnam veterans is not known. Today, the use of polyhydrocarbons containing dioxin is restricted.[7]

Pathophysiology

Chloracne is an acne-like condition due to the persistence of toxic chemicals and their metabolites. Toxins accumulate within the sebaceous glands and alter their normal physiology from oil-producing glands into chloracne's cyst-like structures (hamartomas).[8] These changes occur through activating the aryl hydrocarbon receptor (AHR), expressed in keratinocytes and sebocytes, accelerating epidermal terminal differentiation (keratinization), and converting sebocytes toward keratinocyte differentiation.[9][10] Specimens from the epidermis and cyst epithelium of MADISH patients demonstrate a strong expression of small proline-rich protein 2 (SPRR2), secretory leukocyte peptidase inhibitor (SLPI), epigen (EPGN), and the nuclear factor erythroid-derived 2 like 2 (NRF2) target NAD(P)H dehydrogenase, quinone 1 (NQO1).[11]

Systemically, chloracnegens can act as EDCs, in which they behave like other endogenous hormones such as estrogens, progesterone, and androgens. They can also manipulate numerous receptors, like those related to retinoids or aryl hydrocarbons, resulting in overactivation and perturbations of the normal metabolic pathways. As a result, EDCs can lead to thyroid dysfunction, reproductive issues (cryptorchidism, hypospadias, testicular cancer, and female precocious puberty), leukemia, brain tumors, neurobehavioral disorders, type 2 diabetes, and obesity.[3]

Histopathology

The glaring lack of sebaceous glands is the most distinguishing histopathologic feature of chloracne.[4] There are often epidermal cysts that may be superficial with an open punctum or dermal cysts.

History and Physical

The course of systemic symptoms and skin changes varies based on the duration and level of toxic exposure. If massive exposure occurs, symptoms may appear within days. Chloracne lesions may not appear for weeks to months after exposure.

Acute, high-level exposure to halogenated aromatic compounds may cause the following systemic symptoms:

• Gastrointestinal distress (nausea, vomiting, diarrhea)
• Liver dysfunction
• Pancreatitis
• Neuropathy
• Joint pain

Skin lesions appear on the cheeks and postauricular skin and may progress into the axillae and groin. They may also involve the shoulders, chest, back, and abdomen or, in very advanced cases, extend to the extremities. The skin may first appear excessively oily before the typical lesions of chloracne arise, including:

• Open and closed comedones (blackheads and whiteheads)
• Nodules and cysts
• Pustules

Other cutaneous and mucosal problems seen with chloracne include:

• Palmar or plantar hyperhidrosis (excessive sweating of the palms and/or soles)
• Porphyria cutanea tarda (pigmentation, increased hair growth, and blisters on exposed skin) 
• Hypertrichosis of body hair
• Hyperpigmentation of skin, hair, or nails
• Conjunctivitis, hyperpigmentation of the conjunctival mucosa, and enlargement of meibomian glands [2][12][2]

Evaluation

A targeted history and physical exam are vital for a correct diagnosis. Toxicologic screenings for halogenated aromatic hydrocarbons may be performed, but there is conflicting evidence regarding their reliability. In the past, polyhydrocarbons were routinely measured in the blood and urine. In a group of individuals exposed to 2,3,7,8-TCDD, chloracne, gamma-glutamyl transferase elevations, and triglycerides, alterations in follicular stimulating hormone and luteinizing hormone correlated to serum 2,3,7,8-TCDD levels.[6] However, due to differences in individual sensitivities to dioxin and its related chemicals, and because these substances can be concentrated within adipose and skin structures, it is challenging to diagnose chloracne solely based on serum toxic equivalent values.[4]

Biopsies of affected skin may show a reduction of the normal sebaceous gland density and skin hamartomas. Immunohistochemistry can be carried out on biopsy specimens to assess the gene expression (ie, CYP1A1).[13]

Treatment / Management

Once chloracne is diagnosed, the primary action is to prevent further exposure to the chemical source, which, in many cases, improves the lesions. If lesions persist for a long time despite eliminating further toxin exposure, treatments for acne vulgaris, such as topical retinoids, oral antibiotics, or isotretinoin, may be considered. Comedones may be expressed, and cysts may be excised. Recently, a small cohort of Japanese patients with dioxin-related sequelae for 30 to 40 years was treated orally with a cinnamaldehyde-containing antioxidant called Keishibukuryogan. Treatment with this herbal medicine, which exhibits aryl hydrocarbon receptor (AHR)–cytochrome P450 family 1 subfamily A member 1 (CYP1A1) inhibition and nuclear factor erythroid 2 p45-related factor 2 (NRF2) activation, improved the patient's chloracne and associated systemic symptoms.[14] Patients with chloracnegen exposure history must be followed longitudinally because the toxic exposure may also impact other organs than the skin and may be linked to various malignancies.

Differential Diagnosis

The differential diagnoses for chloracne include the following:

• Acne vulgaris
• Favre-Racouchot syndrome (also known as solar or senile comedones and nodular elastosis with cysts and comedones)
• Folliculitis
• Dilated pore of Winer
• Epidermal inclusion cyst
• Milia
• Folliculotropic mycosis fungoides
• Nevus comedonicus

Prognosis

The severity and duration of chloracne lesions correlate to toxin exposure time and levels. Once the exposure has been isolated and removed, lesions generally improve without further intervention, although this may take years.

Complications

Chloracne is associated with a variable amount of permanent scarring. Lesions on the malar cheeks and postauricular skin tend to persist longer than those localized elsewhere on the body.[2] 

Immunotoxicity, namely immunosuppression[15], and developmental effects may occur over long periods of exposure to dioxin and dioxin-like compounds.[16] Malignancies linked to chloracnegen exposure include non-Hodgkin lymphoma, soft-tissue sarcomas (such as dermatofibrosarcoma protuberans, and leiomyosarcomas)[17], and nonmelanoma skin cancer.[18]