(with permission of Archives of Dermatology 1979;115;461-463)
Alkaptonuria hyperpigmentation

Alkaptonuria, also known as hereditary ochronosis, is a rare, autosomal recessively inherited disorder characterized by mutations in the homogentisate 1,2-dioxygenase gene that codes for homogentisic acid dioxygenase--an enzyme that plays a part in the degradation of phenylalanine and tyrosine. Massive accumulation of homogentisic acid (HGA) and its (pigmented) oxidative products occurs. Diagnosis is made by finding elevated levels of HGA in a 24-hour urine. The urine may turn dark when left at room temperature and exposed to air. Alternatively, the urine may be turned dark immediately by adding a few drops of sodium hydroxide. Teeth may stain. Patients may complain of a "sweat that stains clothing." The highest incidence is in Slovakia (1 in 19,000).


The skin overlying cartilaginous structures may take on a blue/gray appearance--usually sometime after the age of 30. This may be most noticeable on the ear or nose. The tympanic membrane and even the cerumen may be bluish/black. A pigmented spot between the corneal margin and the inner canthus anterior to the tendinous insertion of the horizontal rectus muscle characteristically occurs in alkaptonuria (Osler's sign). Erroneous enucleation of the eye has been performed. Pigmentation may also occur on the cornea, conjunctiva, tarsal plates, and eyelids. There may be a brown discoloration of the axillae and groin. This is thought to be related to chronic exposure to pigmented sweat. There may also be papules and blackened blue vesicles in the palms and soles, perhaps brought on by friction.


The alkaptonuria-associated arthritis typically begins in the third decade of life and has a predilection for large joints and spine; however, it tends to spare the sacroiliac region. There ay be spinal stenosis with cord compression as well as fractures of the vertebrae and long bones.


There is no cure. The arthropathy and any valvular disease should be treated appropriately. Joint replacement is common. Low-protein diets and vitamin C have been investigated with unclear results.


Nitisinone is licensed for the treatment of tyrosinemia, and has been studied for use in alkaptonuria. A 3-year trial showed that nitisinone reduced urine and plasma HGA by 98% and 95% respectively, but clinical parameters did not improve. More studies are needed to see if starting the medication earlier can provide clinical benefit.

Additional Pictures

Alkaptonuria of the eye Alkaptonuria of the ear


Alkaptonuria of the hands resembling Acrokeratoelastoidosis. JAAD 2011;65, Issue 2, Pages e45–e46

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