Discussion
Multiple causes of pigmented bone and cartilage exist, including
ochronisis, metabolic bone diseases, metal deposits, sequestrum, and
metastatic disease. Ochronosis as described here, can be exogenous or
endogenous.
Exogenous ochronosis results from prolonged exposure to certain
chemicals. Patient 1 took Minocycline for severe acne for 8 years.
Minocycline, a yellow-colored, semi-synthetic tetracycline antibiotic
turns black when oxidized, causing disfiguring discoloration of the
skin, lips, nails, oral mucous, ear cartilage, conjunctiva, teeth,
bones, thyroid gland, and pigmentation of heart valves in a
dose-dependent manner. The incidence ranges between 3 and
15%7. Used for the treatment of a wide range of gram
positive and negative infections, onchronisis is most often seen in
patients receiving a dose of 100-200mg/day for as little as one year.
Minocycline-induced hyperpigmentation can be severely disfiguring and is
more likely to occur in certain populations of patients (eg: those with
phemphigus, pemphigoid, atopic dermatitis, or cystic acne). Pigmentation
is a commonly recognized adverse reaction associated with most of the
drugs in the tetracycline family, affecting the skin, nails, teeth, oral
mucosa, bone in the oral cavity, ocular structures, cartilage, thyroid,
and other visceral structures. Minocycline-induced hyperpigmentation
should be considered in the differential diagnosis of ochronosis. Other
medications that may cause changes in skin pigmentation include
anti-malarias, amiodarone, bleomycin and
chlorpromazine8. Suwannarat et al. in 2004 published a
case series of 5 patients who presented with findings consistent with
ochronosis, including pigmentary changes of the ear and mild
degenerative changes of the spine and large joints. These patients were
clinically diagnosed 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withdrawn based on normal urine HGA levels.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 periods7.
Endogenous ochronosis results from alkaptonuria (AKU), an autosomal
recessive mutation in the HGD gene resulting in a disorder of tyrosine
metabolism due to deficiency of homogentisate 1,2 dioxygenase (HGD)
activity. This causes an accumulation of homogentisic acid (HGA),
ochronosis, and destruction of connective tissue resulting in joint
disease. AKU, the working diagnosis for patient 2, is progressive, with
dark urine, onchronsis of eyes and ears, and severe ochronotic
arthropathy. It is diagnosed near birth with lifelong implications.
Ocular pigmentation is especially prominent and appears in 70% of ACU
patients. Referred to as the Osler sign, ochronotic pigment deposition
becomes evident in the third decade of life. There is no literature to
suggest that scleral pigment deposition is associated with any effects
on visual function. If urine of an alkaptonuric patient is alkalinized
or allowed to stand, the homogentisic acid metabolizes to a melanin-like
substance, and the urine appears brown to black9.
Aciduria causing darkly stained diapers in infancy is one method of
diagnosis. Ochronotic pigment appears in cartilage, intervertebral
disks, skin, and sclera10. Currently, no available
treatment has been conclusively shown to prevent complications of
alkaptonuria. Restriction of dietary protein in pediatric patients has
been advocated, with the aim of reducing HGA excretion. Treatment is
currently based on symptomatology.
The differential diagnosis for blue discoloration of the skin and
cartilage is broad, these two patients presented with blue ears and
sclera of two different pediatric onset etiologies. While they have
different etiologies for their ochronosis both patients demonstrate the
adulthood implications of conditions with childhood onset.