The Laryngoscope C 2015 The American Laryngological, V

Rhinological and Otological Society, Inc.

Case Report

Minocycline-Induced Hyperpigmentation of Tympanic Membrane, Sclera, Teeth, and Pinna Stephen Reese, BA; Kenneth Grundfast, MD A 40-year-old woman was referred by her primary care physician for evaluation after a routine physical exam revealed bilateral brownish pigmentation of the tympanic membrane. Head and neck examination in the otolaryngology clinic revealed bluish hue of both sclera, teeth, and portions of her pinnae. A hearing test revealed bilateral mild sensorineural hearing loss. The patient had a history of taking minocycline for 14 years, and the hyperpigmentation that she had is known to be a rare complication of prolonged minocycline use. However, to our knowledge, this is the first case showing photographic evidence of minocycline-induced tympanic membrane hyperpigmentation. Minocycline-induced hyperpigmentation should be considered when a patient presents with brown or blue discoloration of the tympanic membrane. Key Words: Minocycline, hyperpigmentation, adverse effects, tympanic membrane, otology. Laryngoscope, 125:2601–2603, 2015

INTRODUCTION Minocycline-induced hyperpigmentation is a rare side effect of prolonged use of minocycline.1 Common sites affected in the head and neck include the skin, teeth, sclera, and oral mucosa, although a number of corporeal sites have been noted.2 We present a case of minocycline-induced hyperpigmentation of the tympanic membrane, sclera, teeth, and pinnae. A similar hyperpigmentation can be seen in patients with alkaptonuria, a genetic disorder in which the body cannot convert homogentisic acid to maleylacetoacetic acid, a step in the normal phenylalanine and tyrosine degradation pathway.3 Alkaptonuria was ruled out in our patient, but she does have eardrum abnormalities not previously depicted with photographs in the medical literature. Knowledge of this eardrum abnormality, easily detectable with otoscopy, may be useful to all who examine the eardrums of patients.

CASE REPORT A 40-year-old woman was referred by her primary care physician for the incidental finding of speckled brownish pigmentation surrounding the umbo in both

From the Boston University School of Medicine (S.R.), Boston, Massachusetts; the Department of Otolaryngology (K.G.), Boston Medical Center, Boston, Massachusetts, U.S.A. Editor’s Note: This Manuscript was accepted for publication April 9, 2015. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Stephen Reese, 26 River Street, Apt. 3, Cambridge, MA 021319. E-mail: [email protected] DOI: 10.1002/lary.25365

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eardrums. Complete examination of the head and neck revealed a bluish hue of the sclera, teeth, and pinnae. The patient reported being aware of color changes to her teeth and pinnae for 5 years, but was not bothered by these cosmetic changes or curious enough to seek a formal evaluation. She had been taking oral minocycline daily for 14 years as treatment for acne vulgaris and was still taking minocycline at the time of presentation. Past medical history was negative, and she was taking no other medications. Physical examination revealed a faint bluish color of the skin of the pinnae, sclera, and teeth (Figs. 1 and 2) and bilateral brownish spots (Fig. 3) surrounding the umbo of both tympanic membranes. Audiological evaluation revealed hearing within normal limits in the speech range, but bilateral sensorineural high-frequency hearing loss along with low-frequency hearing loss in the left ear was noted. No imbalance, plugged sensation, or tinnitus was noted. Subjectively, she reported difficulty discerning speech in the setting of high background noise. Patient did not report any abnormal urine color and no joint pain was noted. The patient was informed that a side effect of minocycline can be the kind of hyperpigmentation that she had noticed and she was advised to stop taking the medication. She complied with the recommendation to discontinue taking minocycline, and subsequent evaluation 9 months later revealed slight diminution in the blue color of the pinnae (Fig. 2).

DISCUSSION To our knowledge, this is the first report appearing in an otolaryngology publication of minocycline-induced hyperpigmentation of the tympanic membrane. Minocycline is a semisynthetic antibacterial compound in the Reese and Grundfast: Minocycline-Induced Hyperpigmentation

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Fig. 1. Blue-gray hue of sclera (A) and teeth (B). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

tetracycline class used to treat moderate to severe inflammatory acne vulgaris. There have been reports of minocycline-induced hyperpigmentation as a consequence of prolonged minocycline use involving an array of anatomical locations including the oral mucosa, sclera of eyes, aortic valves, teeth, nails, skin, and bone.1,4,5 Hyperpigmentation of the tympanic membrane due to minocycline use was previously reported in a series of two out of five patients describing situations where patients were incorrectly misdiagnosed as having alkaptonuria but actually had minocycline hyperpigmentation.6 However, no photographic evidence demonstrating the hyperpigmentation of the tympanic membrane was provided, and the audience was directed toward rheumatologists, not otolaryngologists. There are four types of minocycline hyperpigmentation,7,8 and a combination of patterns has been described. Type I hyperpigmentation is characterized by a circumscribed blue-black discoloration in areas of scarred tissue primarily localized to the facial dermis.7 Type II hyperpigmentation is characterized by circumscribed blue-gray pigmentation of previously normal skin primarily occurring in the dermis/subcutaneous fat of the forearm and legs.7 Type III hyperpigmentation presents diffusely in normal epidermal, and dermal tissue and is accentuated in sun-exposed areas.7 Type IV hyperpigmentation is characterized by circumscribed

Fig. 2. Blue-gray hue of the right pinnae at time of presentation (A) and 9 months after discontinuing minocycline medication (B). [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

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Fig. 3. Brownish spots in a stellate pattern surrounding the umbo in each eardrum (A, B) at the time of presentation. For comparison, diffuse light brown hue to the tympanic membranes as previously reported in a patient with alkaptonuria (C, D). Pictures are reproduced with permission from Sagit et al.11[Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

blue-gray discoloration in the dermis in sites of prior inflammation located in the region of the thorax.7 Depending on the type of hyperpigmentation, pigment may be found within macrophages, fibroblasts, and myoepithelial cells, either freely within the cells or membrane bound.7 In type I and II, discoloration is attributed to minocycline-iron chelation, whereas type III is considered to be caused by minocycline-induced melanization or by a minocycline-melanin complex.7 Type IV discoloration is believed to be either a drug metabolite protein complex or a minocycline-melanin complex.7 Type I and type II pigmentation tend to resolve months to years after cessation of minocycline, whereas type III and IV tend not to dissipate with withdrawal of medication.7 Some evidence suggests that the Q-switched ruby alexandrite lasers may help resolve minocycline-induced hyperpigmentation without adverse consequences.9 Characterization of the particular type of hyperpigmentation in our case was desirable; however, we felt it would be inappropriate to biopsy the lesion given its benign nature and the potential risks of removing tissue from the tympanic membrane. An unusual pigmentation of the tympanic membrane can also be seen in patients who have alkaptonuria, although evidence suggests it may present differently from that of minocycline-induced hyperpigmentation of the tympanic membrane.10,11 In both cases Reese and Grundfast: Minocycline-Induced Hyperpigmentation

of tympanic membrane hyperpigmentation due to alkaptonuria, mixed high-frequency hearing loss was observed. The authors attributed the conductive portion of the hearing loss to deposition of pigmentation that resulted in altered tympanic membrane elasticity and impairment in the function of the ossicular chains.10,11 Because there are so few reports of hyperpigmentation of the tympanic membrane in patients with alkaptonuria or with prolonged administration of minocycline, the relationship between the hyperpigmentation and sensorineural hearing loss remains unknown and may be coincidental. Further, it is not known if there is a causal relationship between hyperpigmentation of the tympanic membrane and any conductive hearing loss that might be manifest in patients with hyperpigmentation of the tympanic membrane. When brown or blue spots are detected in a patient’s eardrum, minocycline-induced hyperpigmentation of the tympanic membrane should be considered as a cause for this unusual finding. Knowledge of how minocycline-induced hyperpigmentation presents in the head and neck region may be helpful in diagnosing this condition and differentiating it from conditions that present in a similar manner, such as alkaptonuria. To our knowledge, this report is the first to present photographic evidence of this extremely rare finding.

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Depending on the type and extent of the pigmentation, disappearance of the discoloration can be expected to occur months to years after cessation of the minocycline therapy.

BIBLIOGRAPHY 1. Gordon G, Sparano BM, Iatropoulos MJ. Hyperpigmentation of the skin associated with minocycline therapy. Arch Dermatol 1985;121:618– 623. 2. Rahman Z, Lazova R, Antaya RJ. Minocycline hyperpigmentation isolated to the subcutaneous fat. J Cutan Pathol 2005;32:516–519. 3. Introne WJ, Gahl WA. Alkaptonuria. 2003 May 9 [Updated 2013 Aug 22]. R In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviewsV [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1454/. 4. Eisen D, Hakim MD. Minocycline-induced pigmentation. Incidence, prevention and management. Drug Saf 1998;18:431–440. 5. Wolfe ID, Reichmister J. Minocycline hyperpigmentation: skin, tooth, nail, and bone involvement. Cutis 1984;33:457–458. 6. Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA. Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain. Arthritis Rheum 2004;50:3698–3701. 7. Mouton RW, Jordaan HF, Schneider JW. A new type of minocyclineinduced cutaneous hyperpigmentation. Clin Exp Dermatol 2004;29:8–14. 8. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980;244:1103–1106. 9. Green D, Friedman KJ. Treatment of minocycline-induced cutaneous pigmentation with the Q-switched Alexandrite laser and a review of the literature. J Am Acad Dermatol 2001;44(2 suppl):342–347. 10. Pau HW. Involvement of the tympanic membrane and ear ossicle system in ochronotic alkaptonuria [in German]. Laryngol Rhinol Otol (Stuttg) 1984;63:541–544. 11. Sagit M, Uludag M, San I. An unusual dark pigmentation on the tympanic membrane. J Laryngol Otol 2011;125:1059–1061.

Reese and Grundfast: Minocycline-Induced Hyperpigmentation

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Minocycline-induced hyperpigmentation of tympanic membrane, sclera, teeth, and pinna.

A 40-year-old woman was referred by her primary care physician for evaluation after a routine physical exam revealed bilateral brownish pigmentation o...
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