Alkaptonuric ochronosis is an autosomal recessive metabolic disorder characterized by deficiency of homogentisic acid oxidase enzyme. It enables homogentisic acid to accumulate, being polymerized & be systemically deposited within various tissues of the body resulting in dark brown/ black pigmentation & dystrophic calcification of connective tissues including cartilage, joint capsule (ochronosis). There is no definitive cure for alkaptonuric ochronosis and treatment is aimed at controlling symptoms. Multiple systemic complications occur as a result of alkaptonuric ochronosis. In skeletal system, there is lumbosacral degenerative disc disease, disc calcification as well as widespread arthritic changes in peripheral & weight bearing joints. In the respiratory system, dyspnoea can develop owing to limited chest expansion due to stiffening of costal cartilages. In the cardiovascular system, coronary & valvular calcification frequently occurs. In the genitourinary system, calculi formation and urine discolouration are chief manifestations. However, bone fractures are unusual. This article describes a fracture neck of femur in an undiagnosed patient of alkaptonuria with all its systemic manifestations managed at a tertiary care centre. We have also reviewed the pathogenesis, clinical features and management of alkaptonuria from the available literature.

A 65 years old male who was a retired govt. employee by profession presented with acute onset pain in left hip & inability to bear weight following history of trivial fall at home. He did not have any complaints of hip pain before this episode but having chronic backache & knee pain (on & off) for last 7 years. He was diabetic and hypertensive on regular medications and also took inhalers for breathlessness. He was somewhat dependent in his activities of personal care & hygiene on his family members due to poor health.

On examination, he was alert, conscious, co-operative and oriented to time, place & person. His vitals were stable. His left lower limb was shortened & externally rotated. Range of movement of hip was painfully restricted. He had no distal neurovascular deficit. Careful re-examination revealed dark brown pigmentation of sclera, lips, hand and nails.

He had a past history of right sided nephrectomy for renal stone in 2004 but no documents were available with the patient party. USG whole abdomen showed an empty renal fossa on right side.

 A plain radiograph of pelvis showed a displaced fracture of neck of right femur. Radiograph of knee & spine showed severe arthritic changes & generalized osteopenia.

He was offered total hip arthroplasty but his activity level & financial constraints made him to allow hemi-replacement arthroplasty; and the same was performed through a modified Hardinge approach in lateral position under spinal anaesthesia. Exposure during surgery was difficult due to hard & stiff fascia and joint capsule. Intra-operatively, his soft tissues including joint capsule found to be thickened & had dark brown pigmentation. After exposure of hip joint, femoral head was extracted and the acetabulum was inspected. It was found that femoral head & acetabular cartilage had dark brown pigmentation but there were no defects in cartilage cap. Right hip hemiarthroplasty was completed as planned. Hip was stable post-reduction.

He was offered total hip arthroplasty but his activity level & financial constraints made him to allow hemi-replacement arthroplasty; and the same was performed through a modified Hardinge approach in lateral position under spinal anaesthesia. Exposure during surgery was difficult due to hard & stiff fascia and joint capsule. Intra-operatively, his soft tissues including joint capsule found to be thickened & had dark brown pigmentation. After exposure of hip joint, femoral head was extracted and the acetabulum was inspected. It was found that femoral head & acetabular cartilage had dark brown pigmentation but there were no defects in cartilage cap. Right hip hemiarthroplasty was completed as planned. Hip was stable post-reduction

In the post-operative period, clinical diagnosis of alkaptonuria was made. His urine was tested which turned black on exposure to air. We screened his immediate family members with their urine test (after informed consent) which revealed a positive test in two of them. The confirmatory urine for homogentisic acid test could not be done due to lack of access to the same.

His post-operative period was uneventful.  Post-operative radiograph showed satisfactory implant position.

 He was started full weight bearing on third post-operative day. He had a painless, mobile & stable hip on further follow-ups. His latest follow-up was 6 months post-surgery. He was able to stand & walk without support. He was not on any medications for pain except his routine medications for diabetes & hypertension.

There are a good number of publications on alkaptonuria presenting with arthritis but there are only a handful of case reports in the context of fractures. Ranganath et al [1] described two cases of advanced alkaptonuria with coexisting osteoporosis. One patient developed multiple non-vertebral fragility fractures and the other developed vertebral fragility fractures while in nitisinone therapy and bisphosphonate therapy. Both were managed conservatively with teriparatide injections for 2 years. Zacharia et al [2] reported a patient with alkaptonuric ochronosis and scoliosis who suffered a fracture neck of femur. The patient was planned for hip arthroplasty but due to operative difficulties, underwent hip excision arthroplasty. She was followed up for 3 years and was ambulant with a painless limp. Fisher et al [3] reported a 69 years old lady with alkaptonuria presenting with a distal femur fracture following a low energy trauma despite 2 years of alendronate therapy. She also had a history of severe arthritis requiring joint replacement surgeries in her right hip and both knees and aortic valve replacement surgeries for severe aortic stenosis. She underwent a retrograde femoral nailing following which she recovered well. Collins et al [4] reported a 63 years old man with alkaptonuric ochronosis who sustained a stress fracture of neck of left femur which necessitated a surgical repair and recovered without any complications. Similarly, a stress fracture of right femoral neck was described by Park et al [5]. She recovered well after a total hip arthroplasty and her right hip was pain-free at 1 year follow-up.

Alkaptonuria results from the deficiency of the enzyme Homogentisic acid 1,2 dioxygenase (HGD). This enzyme is found in the kidney, liver, colon, small intestine, and prostate [10] and plays an important role in tyrosine metabolism. In its absence, homogentisic acid (HGA) is produced in excess by the liver, which in turn is oxidized into an ochronotic pigment polymer that accumulates in the tissue causing ochronosis.

 The triad of alkaptonuria includes homogentisic aciduria, ochronosis, and ochronotic osteoarthropathy. The clinical features of alkaptonuria are secondary to ochronosis [3, 7, 8, 9, 10, 11]. It causes grey pigmentation of the sclera, ear cartilage, and skin. The respiratory reserve is decreased leading to restrictive lung disease. It affects the cardiovascular system causing arrythmias and an increase in the risk of coronary artery disease and valvular heart diseases including aortic stenosis and aortic regurgitation. It causes peripheral neuropathy, diplopia, and cerebrovascular accident. There is an increased incidence of gall bladder, renal, and prostatic stones.

 Our patient was neither diagnosed nor evaluated for alkaptonuria before. His history of intake of medications for breathlessness could be suggestive of restrictive lung disease or heart disease secondary to alkaptonuria. His echocardiography revealed aortic stenosis with valvular calcification. He also had a history of nephrectomy due to renal stone secondary to alkaptonuria. He had arthritic changes in multiple peripheral & weight bearing joints along with lumbosacral degenerative disc diseases as evident from his plain radiographs.

At present, there is no cure for alkaptonuria. Treatment is mainly symptomatic and palliative like pain control, physiotherapy and joint replacement surgeries. Vitamin C is usually prescribed due to its ability to decrease the oxidation of HGA. A low protein diet can reduce the severity of disease by reducing the tyrosine load. Nitisinone, a triketone herbicide has been shown to have a significant impact on alkaptonuria treatment. It inhibits the conversion of tyrosine to homogentisic acid resulting in reduced HGA level in plasma & urine. But it causes increased level of tyrosine in the body.this can lead to leukopenia, thrombocytopenia, porphyria, corneal irritation [6,7,12]. The life expectancy of patients with alkaptonuria is usually normal; however, they have a significant decrease in the quality of life from as early as fourth decade onwards, with symptoms such as pain, dyspnoea, insomnia [6]. Hence, patient education & awareness are very crucial in this disease.

Here, we report a rare & unique case of neck of femur fracture in a patient of alkaptonuria treated with hemi-replacement arthroplasty of hip in a tertiary care centre. So, it is essential to consider the possibility of this condition when we come across a patient with similar clinical findings. This article describes an overview of alkaptonuria with a discussion on etiopathogenesis, clinical features, diagnosis, treatment & anticipated complications during surgery.

ACKNOWLEDGEMENT

Dr. Masum Abdullah Barbhuiya (Asst. Prof.), Dept. of Orthopaedics, AMCH, Dibrugarh.

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