Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain

Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of alkaptonuria.