History
Alkaptonuria is often recognized at birth when parents note discoloration of the urine.
Nevertheless, many patients with this metabolic disorder are symptomless until ochronotic changes occur with bluish-black pigmented patches in the sclera developing in patients aged 30-39 years. [16] These ocular discolorations are located between the corneal margin and the inner canthus. One case involved a 64-year-old male patient first diagnosed with ochronosis from a knee arthroscopy 30 years prior. He was asymptomatic except for brown-colored deposits in the sclera, episclera, cornea, conjunctiva, and limbus. Fundoscopy was normal, and no treatment was required. [17]
The fourth decade often marks the onset of thickening and blue-black or gray-blue discoloration of the ear cartilage.
Other body locations that frequently display the alteration in skin hue are the eyelids, the forehead, the cheeks, the axillae, the genital region, the nail beds, the buccal mucosa, the larynx, the tympanic eardrum, and the tendons (most easily demonstrated by the patient making a fist).
AbdulKarim et al present the interesting case of a 66-year-old woman with known alkaptonuria who presented with ochronosis of the bilateral breasts and chest wall. The patient had concomitant tender lumps and dense breast tissue with coarse calcifications. [18]
Ochronotic arthropathy develops later with arthritic symptoms. [19]
Lee et al relate an interesting case of exogenous ochronosis in a 66-year-old woman with discolored patches in the perioral area and bilateral sclerae. Over-the-counter skin bleaching cream and unspecified supplements were the suspected culprits. [20]
Physical Examination
Dark urine noted in diapers is usually the presenting manifestation of this entity.
For those cases of alkaptonuria not diagnosed in infancy, black cerumen and axillary pigmentation may be noted before age 10 years.
Gray-black scleral pigmentation in the configuration of small, dark rings is noted in the third decade.
Ear cartilage alterations in the fourth decade include discoloration with a grayish blue hue, followed by structural changes with stiffness, contour irregularities, and calcification.
(See the images below.)
Ochronosis revealing a perioral bluish black macular eruption after hydroquinone use.
Periorbital discoloration due to excessive use of topical bleaching preparations containing hydroquinone.
Ochronotic discoloration can also be detected on the nasal tip, the costochondral junctions, the extensor tendons of the hands, the cheeks, the fingernails, and the buccal mucosa.
Arthritic signs of ochronotic arthropathy develop in the third and fourth decades. Narrowing of the joint spaces and disk calcifications occur. [21] Lower back, hip, and knee pain and stiffness are not uncommon. Inflammation, calcification, and rupture of tendons and ligaments may also occur. [22]
The clinical discoloration of the skin is a result of the formation of ochronotic pigment granules in the dermis and in the apocrine glands. Thus, the ochronotic changes of cartilaginous and tendinous structures are best appreciated in regions in which the overlying skin is of minimal thickness, such as the ears, the nasal tip, and the extensor tendons of the hands.
Accumulation of this pigment in cardiac tissue can lead to an inflammatory reaction and progressive heart valve dysfunction, with aortic stenosis being the most common, but in rare cases aortic regurgitation may also be observed. [23, 24] There is also a single reported case of high-grade internal carotid artery stenosis secondary to ochronosis. The carotid plaque found in this case was noted to be heavily brown-black pigmented. [25]
Causes
Alkaptonuria is a genetic disorder related to a deficiency of homogentisic acid oxidase. [26]
Ochronotic pigmentation can develop from medications. Similar skin and cartilage alterations can be induced by quinacrine administration and at sites of quinine injections. [27] Quinines directly inhibit homogentisic acid oxidase. Carbolic acid topical applications to cutaneous ulcers have also induced ochronotic skin alterations.
Exogenous ochronosis has been reported with topical applications of phenol and hydroquinones to the skin. [28, 29, 30, 31] In the case of hydroquinone, it is reported that 35% of black Africans exhibit ochronotic skin changes when using a 6-8% hydroquinone preparation over a prolonged period. Indeed, the prevalence among users of these skin lighteners has been stated to be 69% in a South African study. In African Americans, this cutaneous adverse effect of hydroquinones has also been reported, even when using 2% hydroquinone products. With exogenous ochronosis, the arthropathy seen with alkaptonuria does not occur.
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Ochronosis revealing a perioral bluish black macular eruption after hydroquinone use.
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Periorbital discoloration due to excessive use of topical bleaching preparations containing hydroquinone.
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Upon microscopic examination, amber-colored, oval structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).
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Upon higher magnification (of Image 3), ochronosis reveals homogenization and swelling of collagen bundles (hematoxylin and eosin, original magnification X100).
