Elaine Siegfried, MD

A 17-year-old girl with mild acne, anxiety, and depression presented for evaluation of a persistent left ankle “bruise.” The lesion had appeared almost 2 years earlier following an injury. Plain films and MRI obtained at that time were normal; the patient had made 3 orthopedic visits for splinting, with follow-up. Although her symptoms resolved after 6 weeks, the discoloration persisted.

Primary care evaluation at that time revealed a history of menorrhagia and frequent nosebleeds (once weekly for a month) but no other bruising. Findings from the physical examination were remarkable only for a non-tender “ecchymosis” on the left ankle. Results of laboratory tests-including CBC count, coagulation studies, and Von Willebrand factor-were unremarkable. A hematologist curbside consultation recommended no further workup.

The discoloration had not faded 2 months later, when the patient sustained a repeated injury to the left ankle after stumbling. She experienced pain and swelling, and was unable to bear weight. A sprain was diagnosed, and the ankle was splinted. Again, the ecchymosis persisted after the pain and swelling resolved.

Sixteen months later, the family sought a hematology evaluation for the persistent discoloration. The patient’s current medications were escitalopram (Lexapro), olanzapine (Zyprexa), and minocycline. A comprehensive history confirmed that 2 previous surgeries were not complicated by bleeding problems. Results of an extensive laboratory evaluation were unremarkable (tests was done for factors VIII, XI, and Von Willebrand; fibrinogen; thrombin time; alpha-2 antiplasmin activity; and tissue plasminogen activator antigen). The hematologist assumed that the reinjury was the most likely cause of the bruising and recommended repair of ankle ligaments to decrease laxity.

Six months later, our dermatology evaluation verified that the patient had been taking minocycline, 100 mg twice daily for 5 years, missing doses infrequently. The blue-gray discoloration was noted to involve not only the dorsal aspect of her left foot and ankle (

) but also 2 common sites of trauma-below the left knee (smaller patch in 

) and similar, more subtle discoloration over both shins. Examination of her maxillary/mandibular mucosal sulci revealed similar pigmentation 

 that extension of discoloration into the interdigital spaces supports an endogenous source of pigment. The patient’s face, back, and chest were free of acne. These characteristic features supported a diagnosis of minocycline hyperpigmentation.

The patient refused confirmatory skin biopsy. Minocycline was discontinued, with the expectation that the discoloration would spontaneously improve within 1 year.


Bluish hyperpigmentation is a well-documented side effect of long-term treatment with minocycline.

 The risk has been estimated at 2.4% to 14.8%; the hyperpigmentation is most often seen during chronic treatment for acne and rosacea, but the problem has also been noted in up to 41% of patients with rheumatoid arthritis who take minocycline for its anti-inflammatory effects.

Hyperpigmentation is most often noted to occur in the skin but may also involve sclera, teeth, and nails.

 Median time to pigmentation changes in patients taking 100 to 200 mg/d has been estimated at 12 months, with a range of 3 months to 6 years.

 To minimize the risk, it is optimal to limit long-term therapy to no more than 12 months. The new extended-release formulation is associated with a lower incidence of dose-related adverse events (ie, nausea, vomiting, dizziness). The adverse events related to duration, such as hyperpigmentation, autoimmune hepatitis, and hypersensitivity reactions, are less clearly affected by the extended-release formulation.

Three patterns of minocycline hyperpigmentation have been described

 hyperpigmentation is characterized by a blue-black color that occurs in sites of previous inflammation or scarring, typically within facial acne scars. Biopsy shows iron deposition in the dermis.
• 

 features blue-gray discoloration that affects otherwise normal skin, often on lower extremities. Biopsy specimens exhibit melanin and iron deposits in the deeper dermis and fat.
• 

 is described as diffuse, muddy brown discoloration accentuated in sun-exposed areas reflecting superficial melanin deposition in epidermis or dermis.

The hyperpigmentation in our patient’s case did not fit any of these categories. The most obvious lesion was localized to a previous trauma site, typical for type I, but the blue-gray discoloration suggested deep dermal, fat, or even muscle pigment deposition, rather than the characteristic cutaneous scar. Our patient also had gingival margin hyperpigmentation. This is possibly the most common site of involvement, but it can be easily overlooked. Gingival melanin hyperpigmentation is a normal variant in darker-skinned people, but in light-skinned individuals, monitoring for minocycline discoloration at the gingival margin may help detect early changes and avoid progression.

Light microscopy evaluation of a biopsy specimen is the best way to confirm diagnosis and assess for epidermal or dermal involvement, but this is often not necessary to establish the diagnosis.

Initial therapy of minocycline hyperpigmentation involves discontinuing the medication. Localized pigmentation often fades within several months. Diffuse minocycline hyperpigmentation can take years to fade, or it may persist indefinitely.

 In such cases, lesion ablation with Q-switched Alexandrite laser therapy has been used with success.


•  Bluish hyperpigmentation is a well-documented side effect of long-term treatment with minocycline.
• Hyperpigmentation is most often noted to occur in the skin and gingival margin, but it may also involve sclera, teeth, and nails.
• Biopsy is the best way to confirm diagnosis, but this is often not necessary to establish the diagnosis.
• The condition usually resolves spontaneously within months to years after discontinuing the minocycline.


1. Mouton RW, Jordaan H F, Schneider JW. A new type of minocycline-induces cutaneous hyperpigmentation. Clin Exp Dermatol. 2004;29:8-14.
2. Roberts G, Capell HA. The frequency and distribution of minocycline induced hyperpigmentation in a rheumatoid arthritis population. J Rheumatol. 2006;33:1254-1257.
3. Dwyer C M, Cuddihy AM, Kerr RI, et al. Skin pigmentation due to minocycline treatment of facial dermatoses. Br J Dermatol. 1993;129:158-162.
4. Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol. 1996;134:693-695.
5. Maffeis L, Veraldi S. Minocyline in the treatment of acne: latest findings. G Ital Dermatol Venereol. 2010;145:425-429.
6. Alster TS, Gupta SN. Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched Alexandrite Laser. Am Soc Dermatologic Surg. 2004;30:1201-1204.

Articles

A 17-year-old girl being treated for mild acne, anxiety, and depression, presented with an ankle “bruise” related to an injury sustained 2 years earlier.  Symptoms resolved with treatment, but the hyperpigmentation persisted.

Minocycline Hyperpigmentation


A 4-year-old, previously healthy girl presented to a tertiary care children’s hospital emergency department (ED) with large, tense bullae involving up to 40% of her body surface area. The patient’s parents described a 12-day history of itchy, papulovesicular lesions that had progressed into large blisters

The rash began as pruritic pink bumps around the child’s umbilicus that spread over several days to her abdomen and extremities. She was evaluated by her pediatrician 4 days after the initial eruption; an empiric diagnosis of varicella was made although the patient’s temperature was normal and she had no constitutional symptoms. Calamine lotion was recommended to treat the pruritis.

Over the next 3 days, the lesions spread and enlarged, progressing from vesicles to bullae. The child was taken to the ED for re-evaluation. There, therapy with amoxicillin, mupirocin, and oral diphenhydramine was initiated for presumed bullous impetigo.

At home, over the next 5 days, the lesions continued to enlarge and spread, causing significant discomfort, and limiting ambulation. The parents brought the child back to the ED. She was evaluated and transferred for admission to the children’s hospital. The patient had no history of illness, medication use, or known allergy to medications and her immunizations were up-to-date. There was no personal or family history of similar skin lesions, abscesses, or cellulitis. The family had not traveled recently; they were not aware of exposure to ticks or other disease-carrying insects.


The patient’s vital signs were stable and temperature normal on admission. Her height and weight were at the 97th and 89th percentiles, respectively. The physical examination found an otherwise healthy child with a uniform bullous eruption covering most of her body. The presentation was worst on her legs 

 and her arms and trunk were also affected. There were a few smaller lesions on palms, soles, neck, and ears, but her face, scalp, and anogenital mucosa were spared.


The lesions were pink-to-red, discoid, sharply-circumscribed discreet and coalesced, 1- to 3-cm bullae and erosions. Many had central hemorrhagic crusting 

. Intact bullae were filled with straw-colored fluid. A few lesions had a raised border, suggestive of a “rosette” configuration 

Two 3-millimeter punch biopsy skin specimens were submitted on hospital day 1 for light and immunofluorescent microscopy. Histopathologic findings included a linear band of IgA at the basement membrane zone and a subepidermal split with a dense neutrophilic infiltrate. Additional investigation revealed a normal titer for glucose-6-phosphate dehydrogenase (G6PD).


The skin-care regimen during the patient’s 4-day hospitalization included a daily whirlpool with ½ cup added bleach followed by application of petroleum jelly and this was to be continued at home until her skin cleared. Oral dicloxacillin, 250 mg (12 mg/kg), was administered twice daily along with prednisolone, 30 mg (1.5 mg/kg) daily. After 1 month, there was significant improvement 

Topical dapsone 5% gel was recommended for application to affected areas but was not authorized by the patient’s insurance plan.


Although rare, chronic bullous disease of childhood (CBDC) is the most common immunobullous disorder seen in children. The acquired condition was initially described in 1970.

 CBDC is immunohistochemically similar to linear IgA bullous disease (LABD) of adults. Both are characterized by a linear pattern of IgA deposition directed against a fragment of collagen XVII known as linear IgA disease antigen (LAD-1), located at the epidermal basement membrane zone.

 Disease expression is similar in the childhood and adult types with minor differences: mean age of onset, distribution and configuration of skin lesions, and risk of recurrence. Our patient presented at the recognized mean age of onset for CBDC, around age 4.5 years.

  LABD presents between 60 to 65 years of age with large bullae on the extremities.

  The classic CBDC skin lesion is a central bulla rimmed by smaller curved or ovoid vesicles-a pattern that has earned them several descriptive names: “rosette”, “string of pearls” and “cluster of jewels”.  The most commonly involved sites in children are the lower trunk, vulvar area and upper thighs. Recurrence rates are higher in children than in adults.

Although not seen in our patient, onset of CBDC lesions is usually insidious. Despite this typical course, however, CBDC is frequently mistaken for acute varicella or bullous impetigo on initial diagnosis. More characteristic lesions generally arise after several weeks. At the peak of a CBDC outbreak, the sheer number of vesicles can be disabling, cosmetically disfiguring, and may interfere with activities of daily living and school attendance.

Our patient’s initial lesions suggested CBCD, but were not classic, so histologic confirmation was required. The differential diagnosis includes bullous impetigo, bullous erythema multiforme, and bullous pemphigoid and pemphigus vulgaris, although all of these were less likely in this case given the patient’s history, demographics, and clinical appearance.

The course of CBDC is marked by intermittent flares and improvement that alternate over a period of months to years before the disease resolves. No prodrome or trigger has been recognized. Bland skin care is recommended for optimal outcome. Where possible, blisters should be left intact to allow the blister roof to serve as a biologic dressing. Daily bathing followed by application of petroleum jelly will help maintain skin integrity.  Lesions generally heal with residual transient dyspigmentation, but without scars.

There is no well-defined standard of care for CBDC. First-line treatment has been with an oral sulfone, dapsone or sulfapyridine, with an oral corticosteroid added as needed. Sulfapyridine, once widely available, is now manufactured by only one company and requires IRB approval for distribution.  Long-term use of either sulfone drug carries the risk of hemolysis. The risk of sulfone-associated severe hemolytic anemia is high in people with inherited G6PD deficiency, so a normal screening G6PD level is required before initiating treatment.

The FDA has recently approved a 5% topical formulation of dapsone for the treatment of acne that may be a safer long-term alternative to oral dapsone for CBDC. Oral corticosteroids offer short term improvement, but chronic use is associated with several adverse reactions, which limit their long-term benefit.

Oral antibiotics, most often dicloxacillin, have been reported as a steroid-sparing alternative for symptom resolution and prevention of future outbreaks.


  • CBDC is the most common autoimmune blistering disease of childhood.
  • The initial pruritic papulovesicular lesions may be misdiagnosed as acute varicella.
  • There is no well-defined treatment for CBDC; referral to a dermatologist is indicated.

1. Siegfried EC, Sirawan S. Chronic bullous disease of childhood: successful treatment with dicloxacillin.

2. Mintz EM, Morel KD. Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood. 

3. Egan, CA, Zone, JJ. Linear IgA bullous dermatosis.

 A 4-year-old, previously healthy girl presented to a tertiary care children’s hospital emergency department (ED) with large, tense bullae involving up to 40% of her body surface area. The patient’s parents described a 12-day history of itchy, papulovesicular lesions that had progressed into large blisters.

Elaine Siegfried, MD

Articles

Minocycline Hyperpigmentation

Chronic Bullous Disease of Childhood