A 69-year-old man reports that he began to develop bluish discoloration over his ears in his early 30s. In his late 30s, he started developing deposits of a dark pigment in his sclera.
The patient subsequently developed severe arthritis and tendonitis requiring extensive surgical interventions, including spinal laminectomies; bilateral knee, hip and shoulder replacement; and tendon repairs and debridements.
The patient was recently diagnosed with a mitral valvulopathy secondary to his underlying condition. His family history is noncontributory. He takes ibuprofen and occasionally codeine, as needed, for pain.
Physical exam reveals blue-black scleral deposits and blue-grey pigmentation of the patient’s hands and ears. A urine organic acid analysis reveals elevated levels of homogentisic acid. Additionally, you note that his urine turns black upon standing, as well as with the addition of sodium hydroxide (lye).
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Alkaptonuria is a rare autosomal recessive disorder in which deficient activity of homogentisic acid dioxygenase leads to the accumulation of homogentisic acid in connective tissues. Incidence is estimated to be between 1:250,000 to 1:1,000,000.
Patients initially develop symptoms between 30 and 40 years of age as homogentisic acid accumulates in connective tissue, polymerizes and is oxidized to benzoquinone acetate, a dark pigment. The affected tissues become weakened and brittle, leading to chronic inflammation and degeneration.
The most common presentations include:
- Urine darkening on standing or with the addition of a strong base (such as sodium hydroxide)
- Dark pigmentation of the pinna, sclera and/or nasal ala
- Degenerative arthritis/arthropathy of the spine (low back pain and kyphosis) and large joints (knees, shoulder, hips)
- Cardiac valve calcification/stenosis
- Renal and prostatic stones
Alkaptonuria diagnosis is made based on elevated urinary homogentisic acid. The other answer choices were a bit of a trick, as none of the features in this case are consistent with a porphyria.
Treatment and prognosis
Alkaptonuria treatment consists of pain management, joint replacement, cardiac valve replacement and other supportive measures.
There has been little proven benefit with dietary restriction of tyrosine or phenylalanine (precursors to homogentisic acid) or with vitamin C supplementation (ascorbic acid inhibits the oxidation of homogentisic acid).
Experimental therapy with nitisinone, a drug that blocks the accumulation of homogentisic acid, has not led to clinically significant improvement.
Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine in Houston.
- Keller JM, Macaulay W, Nercessian OA et al. “New developments in ochronosis: review of the literature.” Rheumatology Int. 2005; 25(2): 81-85.
- Phornphutkul C, Introne J, Perry MB et al. “Natural history of alkaptonuria.” N Engl J Med. 2002. 2002; 347(26): 2111-2121.
- Yancovitz M, Anolik R, Pomeranz MK. “Alkaptonuria.” Dermatol Online J. 2010;16(11):6.