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Picture of the Month
Mara Nitu, MD;
Keith Ancona, MD;
Cathy Coleman, MD;
Walter W. Tunnessen, Jr, MD
From the Department of Pediatrics, University Hospital at Stony Brook,
Stony Brook, NY (Drs Nitu, Ancona, and Coleman), and the American Board of
Pediatrics, Chapel Hill, NC (Dr Tunnessen).
Arch Pediatr Adolesc Med. 2001;155:1063-1064.
THE PARENTS of a 3-year-old boy sought consultation regarding a brownish
discoloration of their son's clothing and bed sheets noted after episodes
of enuresis. The parents report that the discoloration became more intense
over time. Their son had been healthy and without other complaints. There
was no history of illness or trauma. There were no urinary tract symptoms.
The medical history was unremarkable as was the family history.
There were no abnormal findings noted on the physical examination. Urine
was obtained for examination. The urine was clear and yellow in color with
a specific gravity of 1.010, pH of 6.5, and without evidence of hemoglobin,
myoglobin, red or white blood cells, or protein. A sample of the urine was
observed at room temperature for 48 hours with the color changes shown in
Figure 1.
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Figure 1.
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Denouement and Discussion: Alkaptonuria
Figure 1. A, Appearance of
the urine at the time of the initial void; B, at 24 hours postvoid; C, at
48 hours postvoid.
Alkaptonuria is a rare disorder of tyrosine metabolism inherited as
an autosomal recessive trait, with an incidence of 1 in 200 000.1 A deficiency of homogentisic acid oxidase, the
cause of this disorder, leads to the accumulation of large amounts of homogentisic
acid in the body with subsequent excretion of the acid in the urine. The gene
responsible for alkaptonuria has been mapped to the long arm of chromosome
3, 3q2.2
CLINICAL FEATURES
The only clinical sign of this disorder in the pediatric age group is
the darkening of urine to an almost black color on standing. The change in
coloration, the result of oxidation and polymerization of homogentisic acid,
is enhanced in an alkaline urine. An acid urine may not become darkened after
standing many hours.
The major clinical features of alkaptonuria are not evident until mid
adulthood and are the result of deposition of a blue-black pigment, derived
from oxidation of homogentisic acid, in cartilage and connective tissue. The
pigment results in degeneration of cartilage, particularly that of the spine
and large joints (hips and knees). The arthritis, known as ochronotic arthritis because of the color of the pigment in cartilage,
has clinical characteristics of rheumatoid arthritis, but radiologic findings
are typical of osteoarthritis.2 Stiffness
and discomfort of the back are usually the initial symptoms of the arthritis.
The first evidence of pigment deposition in cartilage and connective
tissue is noted in adults in the third and fourth decades of life. A faint
slate-gray coloration may be perceived through the skin overlaying the cartilage
of the nose and ears.3 Discoloration of
the sclera of the eyes may also be noted. Patients with homogentisic acid
oxidase deficiency have a higher incidence of heart disease, particularly
calcification of the mitral and aortic valves and myocardial infarctions.3
DIAGNOSIS
A presumptive diagnosis of alkaptonuria may be made by demonstrating
the change in color of standing urine over time. Confirmation is made by measuring
the excretion of homogentisic acid in the urine. The addition of oxidizing
agents such as silver nitrate, ferric chloride, or Benedict reagent to the
urine will enhance the color change to brown-black in less than 48 hours.1 Since homogentisic acid is a strong reducing agent,
it will cause a positive reaction with Fehling or Benedict reagent, whereas
it will not result in a positive reaction with glucose oxidase. Phenol poisoning
and malignant melanoma may result in the passage of dark-colored urine, which
is present at the time of voiding rather than developing on standing.
TREATMENT
There is no specific treatment for alkaptonuria. Theoretically, the
deposition of pigment could be prevented by dietary restriction of phenylalanine
and tyrosine to minimal daily requirements. Large doses of ascorbic acid could
possibly impede oxidation and polymerization of homogentisic acid. To date,
these treatments have not proven efficacious.1
AUTHOR INFORMATION
Accepted for publication May 5, 2000.
Reprints: Keith Ancona, MD, Department of Pediatrics, HSC 11 Room
040, SUNY Stony Brook, Stony Brook, NY 11794-8111.
REFERENCES
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1. La Du B Jr. Are we ready to try to cure alkaptonuria? Am J Hum Genet. 1998;62:765-767.
FULL TEXT
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2. Bearn AG. Inborn errors of metabolism: Garrod's legacy. Mol Med. 1996;2:271-273.
PUBMED
3. Rezvani I. Defects in metabolism of amino acids: tyrosine. In: Behrman RE, Kliegman RM, Arvin AM, eds. Nelson
Textbook of Pediatrics. Philadelphia, Pa: WB Saunders Co; 1996:333-335.
SECTION EDITOR: WALTER W. TUNNESSEN, JR, MD
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