Forty-year-old male, farmer, with history of mild obstructive sleep apnoea, bilateral carpal tunnel syndrome, and ex-smoker as of four years ago (11 pack-years). Referred to Internal Medicine out-patient services for mechanical back pain and bilateral knee pain of five years since onset. The medical history reported very dark-coloured urine during work activity over the past 10 years. During the physical examination, the presence of blue-grey pigmentation of the sclera and ear helix was noted. No signs of inflammation or swelling of the joints was noted. Amino acid fractionation in blood and urine was measured, in addition to organic acids in the urine, with the results showing notable elevation in urine homogentisic acid levels (12200 mg/24 h; NR < 10 mg/24 h). A transthoracic echocardiogram (no changes) and x-rays of the spine, hip, and knees were performed. These showed no signs of osteoarthritis. Genetic testing confirmed the presence in homozygosis of the pathogenic variant c.1102A > G p.(Met368Val) in gene HGD.

Forty-five-year-old female who is a first-degree relative of the patient described above. History of Scheuermann’s disease and iron deficiency anaemia secondary to uterine fibroids. Referred to Internal Medicine out-patient services for a two-year history of generalised back pain with no improvement with analgesics. The medical history noted dark-coloured urine since adolescence. The physical examination noted ochronosis of the outer ear with ochronosis of the macula in the left eye. Urine HGA levels were measured (13276 mg/24 h) and genetic testing was performed, confirming the same pathogenic variant described above (c.1102A > G p.[Met368Val] in gene HGD). The transthoracic echocardiogram showed no changes, and the x-ray of the right knee revealed notable joint space narrowing. Bone densitometry presented normal results.

As described above, alkaptonuria is secondary to homogentisate-dioxygenase (HGD) deficiency, leading to its accumulation and resulting tissue damage, which is caused by deposits of a melanin-like pigment, the polymerized form of benzoquinone acetic acid (BQA), which has a high affinity for connective tissue. The pigment also deposits in large joints and the spine, particularly in the lumbosacral region (ochronotic arthropathy). This entity frequently causes urine to change colour to dark brown or black when exposed to air. It can also be associated with genitourinary and cardiac complications, the latter characterised by valve involvement and early calcification of the coronary arteries.2 Diagnosis is confirmed via quantitative HGA measurement in urine analysis and mutations in the HGD gene. As for treatment, other than protein-restriction based dietary measures, nitisinone is an approved therapy, which is a competitive inhibitor of 4-hydroxyphenylpyruvate dioxygenase (second enzyme in the tyrosine catabolic pathway), and presents reduced urinary and blood HGA levels of over 95%.3 The SONIA-2 study demonstrated the efficacy of nitisinone at a dose of 10 mg per day,4 though it was later shown that lower doses (2 mg per day) provide similar efficacy with a lower incidence of side effects.5 This drug reduces the alkaptonuria severity score index (AKUSSI) and seems to partially reverse eye and ear ochronosis.

In conclusion, though alkaptonuria is a rare entity, it should be considered in young patients with chronic joint pain and/or early osteoarthritis. A targeted examination and medical history should be performed to detect urinary changes or typical findings in the sclera and ear helix.

Obtained.