Medical Journal of Dr. D.Y. Patil Vidyapeeth

: 2015  |  Volume : 8  |  Issue : 1  |  Page : 84--86

Alkaptonuria: Case report

Swapna S Khatu1, Yuvraj E More1, Divyank Vankawala1, Deepali Chavan2, Neeta R Gokhale1,  
1 Department of Dermatology, Smt Kashibai Navale Medical College and Hospital, Pune, Maharashtra, India
2 Senior Resident, Department of Dermatology, Smt Kashibai Navale Medical College and Hospital, Pune, Maharashtra, India

Correspondence Address:
Swapna S Khatu
Smt Kashibai Navale Medical College and Hospital, Narhe, Pune - 411 041, Maharashtra


Alkaptonuria is a rare, autosomal-recessive disorder of phenylalanine/tyrosine metabolism due to congenital deficiency of the enzyme homogentisic acid oxidase. Herein, we are reporting a classical case of alkaptonuria with extensive skin pigmentation and skeletal involvement. Histopathological examination also revealed classical ochre-colored deposits in dermis.

How to cite this article:
Khatu SS, More YE, Vankawala D, Chavan D, Gokhale NR. Alkaptonuria: Case report.Med J DY Patil Univ 2015;8:84-86

How to cite this URL:
Khatu SS, More YE, Vankawala D, Chavan D, Gokhale NR. Alkaptonuria: Case report. Med J DY Patil Univ [serial online] 2015 [cited 2022 Jan 19 ];8:84-86
Available from:

Full Text


Alkaptonuria is a rare, autosomal-recessive disorder of phenylalanine/tyrosine metabolism due to congenital deficiency of the enzyme homogentisic acid oxidase. [1] It is characterized by triad of homogentisic aciduria, ochronosis, and precocious degenerative arthropathy. [1] The worldwide incidence of alkaptonuria is 1:250000 with preponderance in Czechoslovakian and German population. [2] There are very few cases reported from India.

 Case Report

A 55-year-old female, resident of Pune, presented with complaints of severe back ache, pain in the hip joint, and inability to walk without support since last 3 to 4 years in orthopedic department. A dermatological opinion was sought for her cutaneous and ocular pigmentation. History revealed that patient noticed dark-colored pigmentation over face, eyes, and hands since last 8 to 10 years. She had noticed that her urine used to turn dark on standing since childhood. There was no systemic complaint. She was born of third degree consanguineous marriage and was second in birth order. There was no history of any chronic drug intake. Family history was non-contributory.

On examination, bluish-black pigmentation was seen on the sclera bilaterally, between limbus and lateral canthus. Discoloration of pinna and nose was present [Figure 1]a and b. Dark discoloration was observed over both palms, along thenar, hypothenar eminence, and sides of fingers along with pits with relative sparing of center [Figure 2]. Nails and dorsum of hands were also showing bluish-colored discoloration mainly along the extensor tendons [Figure 3]. The oral and genital mucosa was normal. Examination of spine revealed tenderness in lumbar region and restricted movements in all directions. Chest expansion was within normal limits. Systemic examination was normal. Her ECG, 2D echocardiogram, and USG abdomen were normal.{Figure 1}{Figure 2}{Figure 3}

Complete blood count and serum biochemistry were normal. In view of degenerative arthropathy and bluish discoloration, the patient was further investigated for alkaptonuria. Her urine sample turned black on alkalinization with few drops of 10% ammonia and also showed presence of homogentisic acid. Radiological examination of spine showed loss of lumbar lordosis, reduction in all disc spaces, and fusion of vertebral bodies with dense calcification of all intervertebral discs [Figure 4]a and b. And examination of hip joint revealed narrowing of joint space [Figure 5].{Figure 4}{Figure 5}

Biopsy taken from dorsum of hand showed deposition of ochronotic pigment in the dermis, with disruption of collagen fibers [Figure 6].{Figure 6}

A diagnosis of alkaptonuria was made, and patient was started on oral vitamin C 500 mg twice daily and low protein diet.


Alkaptonuria, an autosomal-recessive disorder, is first described by Garrod in 1902. [3] Deficient enzyme was identified by La Du et al. in 1958. Pollak et al. mapped the alkaptonuria gene to the chromosome 3q2. [1]

Alkaptonuria is due to deficiency of homogentisic acid oxidase in kidney and liver. This leads to accumulation of homogentisic acid, an immediate metabolite of phenylalanine, and tyrosine metabolism. [1],[4] As homogentisic acid accumulates both intracellularly and extracellularly, it is oxidized to benzoquinone acetate, which polymerizes to form melanin-like polymer, resulting in deposition of polymer, a dark yellow pigment or 'ochre' occurs in the cartilage and other connective tissue. [1]

One of the first symptoms of alkaptonuria is darkening of the urine upon standing (Due to the oxidation and polymerization of homogentisic acid). Dark urine stains on the diaper are sometimes the first telltale sign of the disease in infants. Darkening of urine is the only feature suggestive of alkaptonuria in the pediatric age group in most patients. [5]

Apart from the above phenomenon, the patient usually remains asymptomatic until third or fourth decade. [5] The earliest sign is pigmentation of sclera, especially at the insertion of lateral rectus muscle (Osler's sign) usually starts around third decade. [1],[5] Skin pigmentation becomes more obvious in 4 th decade. One of the first sites to be affected is the ear cartilage involving concha, antihelix, and tragus in that order (ochronosis). [6] The discoloration tends to be most pronounced on sun-exposed sites, cartilage of the ears and nose, areas of high eccrine sweat gland density, such as axillae, palms soles, and genitalia. [1] The bluish discoloration of mucosae tendons, especially dorsum of hands, nail bed and crown half of the teeth may be seen. Tendons show similar discoloration and it is demonstrated by making a fist, upon which, there is discoloration of the extensor tendons over the knuckles. [5] A heavy deposition in the larynx, tracheobronchial tree, esophagus may result in hoarseness and dysphagia, [7] involvement of tympanic membrane and ossicles may cause tinnitus and deafness. [1],[6] Abnormal pigmentation of kidneys and prostate, heart valves, endocardium, aortic intima, coronaries, and rarely, aortic calcification and pigmented prostatic calculi have been observed on surgical procedures. [8]

Ochronotic arthropathy is a particularly troublesome feature and appears around the 4 th decade. There is involvement of weight-bearing joints like spine and knees as well as shoulders, with narrowing of joint spaces and calcifications. Arthritis is the only disabling effect of this condition and occurs in almost all patients as age advances. [1],[5],[6]

The diagnosis is confirmed by the identification and quantification of homogentisic acid in urine using gas liquid chromatography. The levels of homogentisic acid are increased in the blood, urine, and tissues. Screening for mutations is done after extracting the genomic DNA from whole blood and subjecting it to PCR. [1],[2],[9]

Active surveillance for cardiac, renal, and prostate complications should be done after the 4 th decade. [1] No effective therapy is available for the treatment of alkaptonuria at present. Dietary restriction of phenylalanine and tyrosine play a limited role in reducing the excretion of homogentisic acid. Foods to be avoided include milk, meat, poultry, egg, cheese, and nuts. Diet may prevent further progression of arthropathy. Vitamin C (ascorbic acid), an antioxidant given in the dose of 500 mg twice daily, inhibits the polymerization of homogentisic acid and can reduce the tissue damage, but its efficacy has not been proven. [1],[5]

Nitisinone, a triketone herbicide, has shown to significantly reduce the excretion of homogentisic acid by inhibiting the enzyme 4-hydroxy phenylpyruvate dioxygenase that is responsible for the synthesis of homogentisic acid. [1],[5],[10] Long term studies are needed regarding its safety and efficacy. Supportive therapy like NSAIDs and physical therapy is used for arthropathy.


Dr. Shridhar Babangiri, Associate Professor of Department of Pathology, Smt Kashibai Navale Medical College, for providing us histopathological images.


1Tharini G, Ravindran V, Hema N, Prabhavathy D, Parveen B. Alkaptonuria. Indian J Dermatol 2011;56:194-6.
2Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, et al. Natural history of alkaptonuria. N Engl J Med 2002;347:2111-21.
3Garrod AE. The incidence of alkaptonuria: A study of chemical individuality. Lancet 1902;2:1616-20.
4Dogra A, Bajwa GS, Bajwa N, Khurana S. Alkaptonuria. Indian J Dermatol Venereol Leprol 2001;67:271-2.
5Verma SB. Early detection of alkaptonuria. Indian J Dermatol Venereol Leprol 2005;71:189-91.
6Mahajan VK, Sharma NL, Yadav RS. Precocious degenerative arthropathy and bluish patches on ears: Ochronosis and alkaptonuria. Indian J Dermatol 2004;49:149-53.
7O'Brien WM, La Du BN, Bunim JJ. Biochemical, pathologic and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy. Am J Med 1963;34:813-38.
8Albers SE, Brozena SJ, Glass LF, Fenske NA. Alkaptonuria and ochronosis: Case report and review. J Am Acad Dermatol 1992;27:609-14.
9Hill A, Hoag GN, Zaleski WA. The investigation of aromatic acids in phenylketonuria, alkaptonuria and tyrosinosis using gas-liquid chromatography. Clin Chim Acta 1972;37:455-62.
10Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, et al. Use of nitisinone in patients with alkaptonuria. Metabolism 2005;54:719-28.