Download Alkaptonuric Ochronosis

n Case Report
Alkaptonuric Ochronosis
Mukand Lal, MBBS, MS; Manoj Thakur, MBBS, MS, DNB; Sandeep Kashyap, MBBS, MS
abstract
Full article available online at Healio.com/Orthopedics
Alkaptonuria, with its sequel, ochronosis, is a rare disease, with an incidence of
1:125,000 to 1:1 million worldwide. Reported cases of ochronotic arthropathy and
other orthopedic manifestations are mostly limited to a single family tree, and few
cases have been reported. This study highlights 9 previously unreported patients with
sporadic presentation and varied orthopedic manifestations of alkaptonuria. Patient
age ranged from 34 to 50 years. One patient who had severe arthropathy of the right
hip joint along with subcutaneous nodules over both knees and Achilles tendons
underwent total hip replacement. Another patient had intramedullary calcification
of the femur. An additional patient had associated caries of the spine at L3, L4, and
L5, with resolution of symptoms after antitubercular chemotherapy. Another patient
had associated features of hyperthyroidism, which was an incidental finding. A further patient had nonunion fracture of the neck of the femur and underwent total hip
replacement. The remaining 4 patients had typical features of low backache and
arthritis of the large joints. The parents were nonconsanguineous, and only 2 patients
had affected siblings. The remaining 7 patients had sporadic nonfamilial presentation. Diagnosis was established by typical clinical and radiologic findings and biochemical analysis. At 2 years of follow-up, both patients who underwent total hip
replacement were normal, with no radiologic signs of loosening or lysis. Clinicians
need a high index of suspicion and awareness to make the diagnosis of ochronosis.
The current study is unique because of presentation with subcutaneous nodules in
1 patient and associated caries of the spine in another patient. [Orthopedics. 2014;
37(12):e1141-e1149.]
Figure: Anteroposterior radiograph showing fracture nonunion of the neck of the femur 1 year postoperatively.
The authors are from the Department of Orthopaedics, Indira Gandhi Medical College, Shimla,
India.
The authors have no relevant financial relationships to disclose.
Correspondence should be addressed to: Sandeep Kashyap, MBBS, MS, Department of Orthopaedics, Indira Gandhi Medical College, Prakash Niwas, Near Chitkara Park, Shimla 171003, India
([email protected]).
Received: May 23, 2013; Accepted: April 9, 2014; Posted: December 10, 2014.
doi: 10.3928/01477447-20141123-94
DECEMBER 2014 | Volume 37 • Number 12
e1141
n Case Report
A
lkaptonuria is a rare inherited
autosomal recessive metabolic
disorder caused by deficiency of
homogentisic acid oxidase (homogentisic
acid 1, 2 dioxygenase) enzyme.1 The enzyme homogentisic acid oxidase is absent
in the liver and kidneys. Consequently, homogentisic acid is excreted in urine and the
urine turns dark brown or black on oxygenation and alkalinization.2 This condition is
characterized by a triad of manifestations,
including homogentisic acid in the urine
(alkaptonuria), ochronosis characterized
by deposition of homogentisic acid in connective tissue and cartilage, and spondyloarthropathy involving the axial and appendicular skeleton (ie, arthritis of the spine
and large joints).1 Less common manifestations include renal, urethral, and prostatic
calculi; cardiovascular abnormalities; and
valvular disease.3-5
Alkaptonuria was one of the first conditions in which the law of mendelian recessive inheritance was proposed as well as 1
of the conditions in the charter of the group
of inborn errors of metabolism. The term
ochronosis was first coined by Virchow6 in
1866, when he found pigmentation of tissues that appeared ochre, meaning yellow,
when examined microscopically.7 This disorder is rare, with an incidence of 1:125,000
to 1:1 million worldwide.1,4,8,9 However, in
certain areas of eastern Europe, chiefly Slovakia, and the Dominican Republic, the incidence is as high as 1:19,000.10
The authors report 9 cases of patients
who had alkaptonuria with ochronosis.
Most previous studies of alkaptonuria
were limited to patients from a single family tree or a few case reports. This study
highlights nonfamilial, sporadic presentation and atypical manifestations of alkaptonuria that were not reported before. Patients were informed that data about their
cases would be submitted for publication,
and they consented.
Cases
All patients were 34 to 50 years old.
Eight patients had a history since child-
e1142
B
Figure 1: Preoperative anterior photograph showing subcutaneous nodules over the Achilles tendon
(A). Preoperative lateral photograph showing subcutaneous nodules over the knees (B).
A
hood of brownish-black stains of the undergarments and a change in urine color
to black when it was left standing for few
hours. One patient had a varied presentation that included a history of brownishblack discoloration of the initial 2 to 3
drops of urine for the past 3 years. This
manifestation occurred at 47 years of age,
which is unusual, and the patient had fracture nonunion of the neck of the femur
at 50 years of age, although he underwent closed reduction and internal fixation within 48 hours of injury. He subsequently underwent total hip replacement.
Another patient had collapse of the head
of the femur with osteoarthritis of the hip
joint along with subcutaneous nodules.
This patient also underwent total hip replacement. One patient had intramedullary calcification of the femur. Associated
caries of the spine was found in 1 patient
at L4 and L5 and was managed conservatively with rest and antituberculous chemotherapy. One woman had an incidental
finding of associated features of hyperthyroidism. Seven patients initially presented
with backache. This group of patients included a brother and sister, although their
parents and siblings were normal. Findings on systemic examination of the cardiovascular system, respiratory system,
and abdomen were normal in all patients.
Findings on neurologic examination were
normal, except for 1 patient who had caries of the spine. On local examination,
results of Schober’s test were positive in
all patients. Initial screening was done by
adding alkali (sodium hydroxide) to the
urine sample: the color changed to reddish-brown (Figure 1). Similarly, addition of ferric chloride and silver nitrate to
the urine sample gave the urine a transient
green and black color, respectively, in
all 9 patients. Confirmation was done by
liquid gas chromatography, and findings
were positive in all patients. Findings of
other studies, such as electrocardiogram,
chest radiograph, and echocardiogram,
were normal in all patients. Similarly, results of tests for C-reactive protein, rheumatoid factor, and HLA-B27 were negative. Serum levels of magnesium, calcium,
parathyroid hormone, 25-OH vitamin D,
vitamin B12, folic acid, and ferritin were
within normal levels. Results of all other
routine studies were within normal limits.
The presenting features, symptoms, and
clinical profiles of all of these patients are
shown in Table 1. Table 2 shows the test
results, radiologic findings, and treatment.
Discussion
Alkaptonuria, along with its sequela,
ochronosis, is a rare disease of aromatic
amino acid metabolism. The earliest case
was described in an Egyptian mummy,
ORTHOPEDICS | Healio.com/Orthopedics
n Case Report
Harwa dating from 1500 b.c.11,12 The term
alkapton was first used by Boedeker13 in
1859 to describe urine discoloration caused
by a reducing compound that was identified as homogentisic acid by Wolkow and
Baumann14 1891. In his Croonian lectures
of 1908, Garrod15 coined the term inborn
error of metabolism and proposed that alkaptonuria results from a deficiency of an
enzyme that normally splits the aromatic
ring of homogentisic acid. The deficient
enzyme was identified by La Du16 in 1958.
Pollak et al17 located the alkaptonuric gene
to 3q2 in a 16-cM region. Joint disease
in alkaptonuria was initially reported by
Albrecht,18 and later Osler19 clinically diagnosed ochronosis for the first time in 2
brothers with alkaptonuria. A worldwide
review showed that approximately 600
cases have been reported since 1962.20
Accumulation of homogentisic acid in
various tissues leads to polymerization to
an oxidized product, benzoquinone, that
causes tissue injury that leads to melaninlike polymers.21 Several theories exist
as to how alkaptonuria results in ochronosis, including acting as a chemical irritant that causes inflammation and rapid
degeneration of the joints and physically
binding to connective tissue and altering
the structure and interactions of the macromolecules.3
In most pediatric patients, darkening
of the urine is the only feature that suggests alkaptonuria. This reaction is pH-dependent and never occurs in acidic urine.
In the current series, 8 of 9 patients had
a history of urine discoloration in childhood. One patient who was 47 years old
had minimal urine discoloration, although
urine pH was normal on examination. The
diagnosis in this patient was made intraoperatively during total hip replacement
for fracture nonunion of the neck of the
femur when the femoral head was found
to have black discoloration along with
bluish-black discoloration of the soft tissue around the hip. Patients are usually
asymptomatic until the third or fourth decade and usually do not seek medical at-
DECEMBER 2014 | Volume 37 • Number 12
tention at an early age. The probable reason cited is the decrease in renal clearance
with age.22 In the current series, 6 of 9 previously asymptomatic patients presented
with low backache in the third to fourth
decade. They did not seek medical attention for skin or urine discoloration, and all
had a history of urine discoloration since
childhood. Results of renal function tests
and creatinine clearance were normal.
Ochronosis presents as bluish-black
or grayish-blue pigmentation of the pinna and outer ocular tissues such as the
sclera, cornea, and conjunctiva. Scleral
pigmentation (Osler’s sign) starts around
the third decade. This sign was found in
2 patients. The effects are most noticeable in areas where the body is exposed
to the sun and where sweat glands are located and are best appreciated in regions
with thin overlying skin. All patients in
the series had bluish-black pigmentation
of the pinna. In addition, patients may
have widespread dusky discoloration of
the cheeks, forehead, axilla, and genitals.
Nails may be stained brown.5 Brown nail
color was found in only 2 patients in the
authors’ series.
Initial screening can be done with a
simple biochemical test on a urine sample.
With this testing, urine color changes to
black with the addition of sodium hydroxide and a transient green color appears with
the addition of ferric chloride. Other tests
include the ammoniacal silver nitrate test,
Benedict’s test, and the N-butanol test.23
The diagnosis is usually confirmed by
detecting and measuring the amount of
homogentisic acid in urine with gas liquid
chromatography, thin-layer chromatography, or enzymatic spectrophotometry. In
the current series, all patients were initially screened with 2 of the previously
mentioned biochemical tests, mainly the
addition of sodium hydroxide and ferric
chloride. In all patients, the diagnosis was
confirmed by thin-layer chromatography.
Magnetic resonance imaging was used to
establish the diagnosis in the patient with
caries of the spine.
In ochronosis, radiographs of the
lumbar spine show gross calcification,
vacuum phenomenon, and loss of height
of the intervertebral disks accompanied
by fusion (pseudo-block) vertebrae formation, predominantly in the dorsolumbar region.24 This typical presentation
of reduced intervertebral disk space,
vacuum phenomenon, and wafer calcification of the intervertebral disks on
radiographs of the dorsolumbar region
was seen in all patients. Although calcification has been seen in the menisci,
symphysis pubis, pinnae, nasal cartilage,
tendons, kidneys, heart walls, and great
vessels,25 1 patient in the authors’ series
had unusual intramedullary calcification
of the femur.
Grossly, the involved tissue usually
shows pigmentation that varies from brown
to black. Microscopically, the hyaline cartilage shows deposition of ochre-colored
granules that is more marked in the deeper
layers.4 Brownish-black pigmentation of
the femur head, known as black hip, along
with degenerate pigmented articular cartilage was found in 2 of the patients during
hip replacement (Figure 9).
Ochronotic arthropathy is a particularly troublesome feature. Premature arthritis in the large joints develops after
the third decade and usually affects the
weight-bearing joints, mainly the spine,
hips, knees, and later the shoulders. Musculoskeletal manifestations are first noted
in the spine. Typically, involvement of
the large peripheral joints occurs several
years after spinal involvement.20 Usually,
involvement of these joints is severe and
often requires joint replacement.4,24,26,27
In the authors’ series, 1 patient had severe
arthropathy of 1 hip and underwent hip
joint replacement. After 4 years of follow-up, he had a good Harris Hip Score
of 86 and could perform normal routine
activities. In contrast to rheumatoid arthritis, the smaller joints of the hand and
feet are unaffected. The sacroiliac joint is
also spared, thereby distinguishing this
condition from ankylosing spondylitis. In
e1143
n Case Report
Table 1
Patient Profiles
Case No./
Age, y/Sex
Presenting Symptoms
Family History
Local Examination
1/47/M
Pain in right groin for 3 y
Limping more on right side
Pain in left knee
Generalized body aches
Difficulty in ambulation
Parents nonconsanguineous
Siblings normal
Stooping posture
Restricted dorsolumbar spine movements
Restricted movements of right hip joint
and left knee
Scleral pigmentation (Osler’s sign), with
slate blue discoloration of skin over dorsum of hands, pinna, and nail bed
Subcutaneous nodules over Achilles
tendons and both knees (Figure 1)
Patchy alopecia
Limp with antalgic gait
2/49/M
Progressive low backache for 15 y
History of discoloration of both eyes
for 4 y
Pain in both knee, hip, shoulder, and
elbow joints for last 12 y
Unable to walk without support on
admission
Parents nonconsanguineous
Siblings normal
Stooping posture
Scleral pigmentation
Restricted dorsolumbar spine movements
Tenderness in dorsolumbar region
Painful and restricted range of motion of
both knee joints, both hip joints (right
more than left), and bilateral shoulder
and elbow joints
Scleral pigmentation (Osler’s sign),
ochronotic pigmentation of skin over
pinna, earlobes, and nail beds
3/34/M
Laborer
Low backache with radiation to back
of thigh
Stiffness and difficulty bending
forward and doing hard work for last
4-5 y
Increased pain intensity for last 6 mo
and pain at night
History of evening increase in temperature and loss of appetite for last
4-5 mo
Severe limitation of activity and difficulty in performing work for gainful
employment
Brown-black discoloration of both
ears for last 5-6 y
Parents nonconsanguineous
Siblings normal
Brown pigmentation of both ears (more
marked in right ear)
Restricted movements in dorsolumbar
region
Tenderness in dorsal and lumbosacral
spine
Tenderness more marked at L3, L4,
and L5, with marked tenderness on application of twisting force along base of
spinous process; twist tenderness
Neurologic examination:
Brisk knee and ankle reflexes on presentation with ill-sustained ankle clonus
Babinski: Extensor response
Normal after 18 mo of antitubercular
therapy
4/38/F
Housewife
Pain in lower back, difficulty bending forward and performing routine
household activities for last 10 y
Bluish-black discoloration of both
ears for last 6-7 y
Hyperthyroidism for last 5-6 y, with
use of antithyroid drugs for same
duration
Parents nonconsanguineous
Siblings normal
Exophthalmos and brownish-black discoloration of cartilage of both pinnae
Mild dorsolumbar kyphosis with tenderness and loss of lumbar lordosis
5/42/M
Postman
Low backache for last 6 y
Bluish-black discoloration of both
ears for last 5 y
Parents nonconsanguineous
Siblings normal
Restricted movements at dorsolumbar
spine, mainly flexion
e1144
ORTHOPEDICS | Healio.com/Orthopedics
n Case Report
Table 1 (cont’d)
Patient Profiles
Case No./
Age, y/Sex
Presenting Symptoms
Family History
Local Examination
6/38/M
Farmer
Low backache for last 9 y, initially
when rising from sitting position, now
constant
Difficulty walking and doing moderate to heavy work
Pain in both shoulders, knees, and
hips for last 1.5 y
Bluish-black discoloration of both
ears for last 5 y
Parents nonconsanguineous
Siblings: Sister 4 y younger had similar
problems for last 4 y (Case 7)
Terminal restriction of internal and
external rotation of both hips
Restricted movements at dorsolumbar
spine
7/34/F
Housewife
Low backache for last 4 y
Pain while doing routine household
work
Parents nonconsanguineous
Siblings: Brother 4 y older had similar
problems for last 4 y (Case 6)
Bluish-black discoloration of external
ears and gums (Figure 2)
Painful movements at dorsolumbar
spine, mainly flexion
8/36/M
Police constable
Parents nonconsanguineous
Siblings normal
Painful movements at dorsolumbar
spine, mainly flexion
9/50/M
Farmer
Presented with fracture
Nonunion of neck of femur after primary fixation with partially threaded
cancellous screws (Figure 3)
Bluish-black discoloration of initial
2-3 drops of urine for last 3 y
Pain in both knees for 3 y
Parents nonconsanguineous
Siblings normal
Bluish-black discoloration of external
ears
Movements of knee joints terminally
painful
Abbreviations: F, female; M, male.
the authors’ series, 7 of 9 patients had low
backache primarily as the initial presentation. Associated involvement of the hips
and knees occurred in 2 patients in the
fifth decade, and the rest of the patients
were in the third and fourth decades at the
time of the study.
Heart problems often start after 50 years
of age.2 Patients may have signs of aortic
or mitral valvulitis. Pigment deposits that
lead to the formation of atherosclerotic
plaques and calcification of the coronary
arteries may be seen.28,29 Fisher et al20 reported a 69-year-old (seventh decade) patient with cardiovascular involvement who
had severe aortic stenosis, calcified valves,
and gross aortic pigmentation. The mean
age of patients in the authors’ series was
39.7 years. None of the patients had cardiovascular involvement, possibly because
they were relatively young. However, all
DECEMBER 2014 | Volume 37 • Number 12
of the current patients underwent electrocardiography and echocardiography to
rule out cardiovascular complications.
The differential diagnosis includes osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, and calcium pyrophosphate arthropathy. Disk calcification in the
spine can also mimic hyperparathyroidism,
hemochromatosis, amyloidosis, diffuse
idiopathic skeletal hyperostosis, or surgical spinal fusion. All patients in this study
had normal serum calcium, phosphate, and
parathyroid hormone levels; therefore, hyperparathyroidism was excluded from the
differential diagnosis. Similarly, in the absence of symmetrical polyarthritis, ruled
out by relevant tests and investigations,
there was no history of early morning stiffness, the rheumatoid factor finding was
negative in all patients, and the erythrocyte
sedimentation rate was normal in 7 patients
except 1 who had caries of the spine. Rheumatoid arthritis was also ruled out because
none of the patients had symmetrical polyarthritis or morning stiffness; rheumatoid
factor was negative in all 9 patients; and
the erythrocyte sedimentation rate was
raised only in 1 patient with caries of the
spine and normal in the other 8 patients.
The HLA-B27 finding was negative in all
patients, excluding ankylosing spondylitis.
Serum ferritin levels were normal in all patients; this finding, associated with normal
liver and renal profiles in all patients, excluded hemochromatosis.
Genetically, alkaptonuria is inherited
as an autosomal recessive trait. All of the
close and remote relatives of all patients
in the current study underwent screening,
and there was no familial presentation
in 7 patients. Only 2 patients, who were
brother and sister, were affected, but their
e1145
n Case Report
Table 2
Investigations and Treatment
Case No.
Analyses
Radiologic Findings
Treatment
1
Normal
Calcification of intervertebral disks with vacuum phenomenon
at lumbar spine and narrowing of intervertebral disk space
Radiographs of right hip showed degenerative changes and collapse of head of femur (Figure 5)
Total hip replacement
(Figure 4)
Vitamin C
2
Normal
Dorsolumbar spine radiograph showed wafer-like calcification
of intervertebral disks, mainly in lumbar spine, and gas vacuum
phenomenon with markedly decreased intervertebral disk space
(Figure 6)
Radiograph of knee joints showed features of arthritis with
degenerative changes
Radiograph of pelvis and hip joints showed decreased joint
space bilaterally
Computed tomography of dorsolumbar spine showed degenerative changes with vacuum phenomenon
Radiograph of lower end of left femur showed intramedullary
calcification (Figure 7)
Vitamin C
3
Erythrocyte sedimentation
rate 62 mm first h
Radiologic examination of dorsolumbar spine
Characteristic pathogenic changes of ochronosis, as in Case 2
At L3-L4, radiographs showed loss of disk space with anterior
erosion over L4
Magnetic resonance imaging showed decreased intervertebral
disk space, end-plate erosions, and abscess formation anteriorly
(Figure 8)
Antitubercular
chemotherapy for 18 mo
Vitamin C
4
Increased triiodothyronine
and tetraiodothyronine and
decreased thyroidstimulating hormone levels
Radiograph showed decreased intervertebral disk space and
calcification with osteoporosis
Skeletal survey normal
Antithyroid drugs
Analgesics
Symptomatic treatment
Physical therapy
5
Normal
Radiologic examination of dorsolumbar spine showed waferlike calcification of intervertebral disks, mainly in lumbar spine,
and gas vacuum phenomenon with degenerative changes in
dorsolumbar spine
Vitamin C
Analgesics
Symptomatic treatment
6
Normal
Characteristic wafer-like calcification of intervertebral disks,
mainly in lumbar spine, and gas vacuum phenomenon with
degenerative changes in dorsolumbar spine
Radiograph of both hips showed early degenerative changes
Vitamin C
Analgesics
Symptomatic treatment
7
Normal
Characteristic wafer-like calcification of intervertebral disks,
mainly in lumbar spine, and gas vacuum phenomenon with
degenerative changes in dorsolumbar spine
Vitamin C
Analgesics
Symptomatic treatment
8
Normal
Wafer-like calcification of intervertebral disks, mainly in lumbar
spine, and gas vacuum phenomenon with degenerative changes
in dorsolumbar spine
Vitamin C
Analgesics
Symptomatic treatment
9
Normal
Fracture nonunion of neck of femur after fixation with partially
threaded cancellous screws at 1 y
Dorsolumbar spine radiograph showed wafer-like calcification
of intervertebral disks, mainly in lumbar spine, and gas vacuum
phenomenon with markedly decreased intervertebral disk space
Radiograph of knee joints showed features of arthritis with
degenerative changes
Total hip replacement
Vitamin C
Analgesics
Symptomatic treatment
parents and grandparents had no symptoms.
e1146
Compression of the cervical cord as
a result of alkaptonuric arthropathy of
the atlantoaxial joint has been reported.30
In the current series, 8 of 9 patients had
ORTHOPEDICS | Healio.com/Orthopedics
n Case Report
Figure 3: Anteroposterior radiograph showing
fracture nonunion of the neck of the femur 1 year
postoperatively.
Figure 4: Postoperative anteroposterior radiograph of total hip replacement.
A
B
Figure 2: Photographs showing bluish-black discoloration of the external ears (A) and the gums (B).
no neurologic deficit or gait disturbance.
Findings on cervical spine examination
were normal in all 9 patients. One patient
with caries of the spine had exaggerated
deep tendon reflexes of the lower limb
along with an extensor Babinski response
that resolved after 3 months of antitubercular therapy.
Osteoporosis associated with alkaptonuria was reported in previous studies.31,32
Fisher et al20 reported low-energy trauma
of the distal radius and femoral fracture
despite 2 years of alendronate therapy. In
the authors’ patients, although none presented with a fracture, 1 patient showed
evidence of osteoporosis on radiographs
of the lumbosacral spine. This finding
was confirmed by bone mineral density
analysis (T-score, 1.3). This patient had
no risk factors for osteoporosis, such as
malnutrition, immobility, smoking, medication (corticosteroids, anticonvulsants),
or family history of osteoporotic fractures,
although she had thyrotoxicosis.
DECEMBER 2014 | Volume 37 • Number 12
A
Figure 5: Preoperative anteroposterior radiograph
of the right hip showing degenerative changes and
collapse of the head of the femur.
Tendon ruptures, chiefly of the Achilles tendon, have occurred and have been
treated successfully with primary repair.
One patient in this series also had subcutaneous nodules around the knees and
Achilles tendons that were mobile and
were not fixed to underlying structures.
He also had patchy alopecia over the
scalp. This presentation of ochronosis has
not been reported before.
Pseudo-ochronosis has been described
as a result of argyria,33 which is a localized collection of silver granules in the
glands, in the walls of blood vessels, and
among elastic fibers. Pseudo-ochronosis
is also found after long-term use of L-dopa, methyldopa,34 antimalarial agents, or
products containing hydroxychloroquine,
phenol, resorcinol, and mercury or picric
acid.35 No patient in this study had a history of use of these drugs.
It is necessary to obtain a history of
drug intake in all patients because mi-
B
Figure 6: Anteroposterior radiograph of the dorsolumbar spine showing wafer-like calcification of
the intervertebral disks, mainly in the lumbar spine,
and gas vacuum phenomenon with markedly decreased intervertebral disk space (A). Lateral radiograph of the dorsolumbar spine showing wafer-like
calcification of the intervertebral disks, mainly in
the lumbar spine, and gas vacuum phenomenon
with markedly decreased intervertebral disk space
(B).
e1147
n Case Report
Figure 7: Radiograph of the lower end of the left
femur showing intramedullary calcification.
B
A
Figure 8: Coronal magnetic resonance imaging scan showing a patient with caries of the lumbar spine
with decreased intervertebral disk space and end-plate erosions at L3, L4, and L5 (A). Sagittal magnetic
resonance imaging scan showing a patient with caries of the lumbar spine with decreased intervertebral
disk space and end-plate erosions at L3, L4, and L5 (B).
A
B
Figure 9: Intraoperative photographs showing inferior (A) and superior (B) views of black pigmentation of the femur head.
nocycline-induced pigmentation36 or intramuscular injection of quinine, leading
to bluish-black pigmentation in the buttocks,37 resembles exogenous alkaptonuria. The authors found no such history
among their patients.
Currently, only symptomatic treatment of complications of alkaptonuria is
available, and there is no specific or effective treatment of alkaptonuria. There
are anecdotal reports that a diet low in
e1148
protein, especially containing tyrosine
and phenylalanine, can help to delay or
partially reverse late manifestations.38
Vitamin C partially ameliorates the condition by impairing the polymerization
of homogentisic acid21 and preventing
homogentisic acid oxidase from binding
to connective tissue. Wolff et al39 treated
2 adults with a high dose of ascorbic
acid. They found that its derivative, benzoquinone, completely disappeared from
urine. In the authors’ study, all patients
were given vitamin C 500 mg 3 times a
day. Six showed some clinical improvement, as assessed by a subjective pain
rating score, on subsequent follow-up.
Although nitisinone has been approved
by the US Food and Drug Administration for the treatment of tyrosinemia type
115, its safety profile and outcome have
not been established in alkaptonuria.4
Because alkaptonuria is rare, there
is a high likelihood that it will be unnoticed, especially in areas where the incidence is low. Therefore, clinicians need a
high index of suspicion and awareness to
make the diagnosis of ochronosis. Low
backache is common in the general popu-
lation and is also the presenting symptom
in the third to fourth decade in patients
with ochronosis. There is a high probability that ochronosis in a patient who
presents with low backache will be diagnosed as a simple case of dorsolumbar
spondylosis unless the typical clinical
features of urine discoloration and specific radiologic findings are correlated
with backache. In developing and tropical countries, a high incidence of bone
and joint tuberculosis exists, but its association in a patient with ochronosis
confounded the diagnosis.
Conclusion
The current study is unique because of
the presentation of 1 patient with subcutaneous nodules and 1 patient with associated caries of the spine. One patient had
nonunion fracture of the neck of the femur
and underwent total hip replacement. Although nonunion has not been described
in ochronosis, it could be the cause in this
case because the patient had no other risk
factor for nonunion and underwent closed
reduction and internal fixation with minimal manipulation after 48 hours of injury.
ORTHOPEDICS | Healio.com/Orthopedics
n Case Report
At follow-up of 3 years, both patients with
total hip replacement are normal. In these
patients, morbidity and complications are
significantly decreased by early diagnosis
and management. Enzyme replacement
with recombinant homogentisic acid oxidase enzyme could be a promising future
therapy. The association of hyperthyroidism in 1 patient was an incidental finding.
References
1. Stanbury JB, Wyngaarden JB, Fredrickson
DS: Alkaptonuria. In: The Metabolic Basis
of Inherited Disease. 4th ed. New York, NY:
McGraw Hill; 1978:268-280.
2.Smith R. Disorders of the skeleton. In:
Weatherall D, Ledingham J, Warrell D, eds.
The Oxford Textbook of Medicine. Oxford
University Press; 1996:3085-3086.
3. Keller JM, Macaulay W, Nercessian OA,
Jaffe IA. New developments in ochronosis:
review of the literature. Rheumatol Int. 2005;
25:81-85.
4. Phornphutkul C, Introne WJ, Perry MB, et
al. Natural history of alkaptonuria. N Engl J
Med. 2002; 347:2111-2121.
5. Parikh A, Khubchandani RP, Bharucha BA,
Kumta NB, Pandya MB, Naik G. Alkaptonuria: a series of seven cases. J Assoc Physicians India. 1988; 36:565-566.
6. Virchow R. Em Fall von allgemeiner Ochronose der Knorpel und knorpelahnlichen
Theile. Archiv fur Pathologische Anatomie
und Physiologie und fur klinische Medizin.
1866; 37:212.
7.Vijaikumar M, Thappa DM, Srikanth S,
Sethuraman G, Nadarajan S. Alkaptonuric
ochronosis presenting as palmoplantar pigmentation. Clin Exp Dermatol. 2000; 25:305307.
8. Konttinen YT, Hoikka V, Landtman M, et al.
Ochronosis: a report of a case and a review of
literature. Clin Exp Rheumatol. 1989; 7:435444.
9. Janocha S, Wolz W, Srsen S, et al. The human
gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics. 1994; 19:5-8.
10. Zatkova A, Chmelikova A, Polakova H, Ferakova E, Kadasi L. Rapid detection methods
for five HGO gene mutations causing alkap-
DECEMBER 2014 | Volume 37 • Number 12
tonuria. Clin Genet. 2003; 63:145-149.
11. Stenn FF, Milgram JW, Lee SL, Weigand RJ,
Veis A. Biochemical identification of homogentisic acid pigment in an ochronotic Egyptian mummy. Science. 1977; 197:566-568.
12. Lee SL, Stenn FF. Characterization of mummy bone ochronotic pigment. JAMA. 1978;
240:136-138.
13. Boedeker C. Ueber das Alcapton; ein neurer
Beitrag zur Frage. Welche Stoffe des Harnes
konnen Kupferreduction bewirken? Zeitschrift
fur rationelle Medizin. 1859; 3(7): 130.
14. Wolkow M, Baumann E. Homogentisic acid.
Zeitschrift fur Physiologische Chemie. 1891;
15:288.
ochronotic arthropathy. Orthop Rev. 1990;
19:1005-1009.
27.Demir S. Alkaptonuric ochronosis: a case
with multiple joint replacement arthroplasties. Clin Rheumatol. 2003; 22:437-439.
28.Dereymaeker L, Van Parijs G, Bayart M,
Daenen W, Lauwerijns J, De Geest H. Ochronosis and alkaptonuria: report of a new case
with calcified aortic valve stenosis. Acta Cardiol. 1990; 45:87-92.
29. Kragel AH, Lapa JA, Roberts WC. Cardiovascular findings in alkaptonuric ochronosis.
Am Heart J. 1990; 120(6 pt 1):1460-1463.
15. Garrod AE. The Croonian lectures on inborn
errors of metabolism: Lecture II. Alkaptonuria. Lancet. 1908; 2:73-75.
30. Kusakabe N, Tsuzuki N, Sonada M. Compression of the cervical cord due to alcaptonuric arthropathy of the atlanto-axial joint:
a case report. J Bone Joint Surg Am. 1995;
77:274-277.
16. La Du BN. Alcaptonuria. In: Stanbury JB,
Wyngaarden JB, Fredrickson DS. The Metabolic Basis of Inherited Disease. 4th ed. New
York, NY: McGraw-Hill; 1978:268-282.
31.Savastano AA, Quigley DG, Scala ME.
Spontaneous fractures associated with cortisone therapy in a patient with ochronosis. Am
J Orthop Surg. 1969; 11:116-120.
17. Pollak MR, Chou Y-H, Cerda JJ, et al. Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nature Genet.
1993; 5:201-204.
32. Millea TP, Segal LS, Liss RG, Stauffer ES.
Spine fracture in ochronosis: report of a case.
Clin Orthop Relat Res. 1992; 208-211.
18. Albrecht H. Ueber Ochronose. Zeitschrift fur
Heilkunde. 1902; 23:366.
19. Osler W. Ochronosis. Lancet. 1904; I:10.
20. Fisher AA, Davis MW. Alkaptonuric ochronosis with aortic valve and joint replacements and
femoral fracture: a case report and literature review. Clin Med Res. 2004; 2(4):209-215.
21. Singh R, Mahadevan S, Bhadada S, Bhansali
A. Lady with melanuria and arthralgias. J Assoc Physicians India. 2005; 53:1051.
22. Hamdi N, Cooke TD, Hassan B. Ochronotic
arthropathy: case report and review of the literature. Int Orthop. 1999; 23:122-125.
23. Pratibha K, Seenappaand T, Ranganath K.
Alkaptonuric ochronosis: report of a case and
brief review. Indian J Clin Biochem. 2007;
22:158-161.
24.Spencer JMF, Gibbons C-LM, Sharp RJ,
Andrew J, Athanasou NA. Arthroplasty for
ochronotic arthritis. Acta Orthop Scand.
2004; 75(3):355-358.
25. Justesen P, Andersen P. Radiological manifestations in alkaptonuria. Skeletal Radiol.
1984; 11:204-208.
26. Carrier DA, Harris CM. Bilateral hip and
bilateral knee arthroplasties in a patient with
33. Robinson-Bostom L, Pomerantz D, Wilkel C,
et al. Localized argyria with pseudo-ochronosis. J Am Acad Dermatol. 2002; 46:222-227.
34. Rausing A, Rosen U. Black cartilage after
therapy with levodopa and methyldopa. Arch
Pathol Lab Med. 1994; 118:531-535.
35. Levin CY, Maibach H. Exogenous ochronosis: an update on clinical features, causative
agents and treatment options. Am J Clin Dermatol. 2001; 2:213-217.
36. Suwannarat P, Phornphutkul C, Bernardini I,
Turner M, Gahl WA. Minocycline-induced
hyperpigmentation masquerading as alkaptonuria in individuals with joint pain. Arthritis Rheum. 2004; 50:3698-3701.
37. Bruce S, Tschen JA, Chow D. Exogenous
ochronosis resulting from quinine injections.
J Am Acad Dermatol. 1986; 15:357-361.
38.Morava E, Kosztolanyi G, Engelke UF,
Wevers RA. Reversal of clinical symptoms
and radiographic abnormalities with protein
restriction and ascorbic acid in alkaptonuria.
Ann Clin Biochem. 2003; 40:108-111.
39. Wolff JA, Barshop B, Nyhan WL, et al. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res. 1989;
26:140-144.
e1149