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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 59  |  Issue : 4  |  Page : 390-393

Pursuit of Osler's sign


Department of Ophthalmology, Pondicherry Institute of Medical Sciences, Puducherry, India

Date of Submission29-Mar-2021
Date of Decision03-Jul-2021
Date of Acceptance10-Jul-2021
Date of Web Publication21-Dec-2021

Correspondence Address:
Dr. Suriya Djeamourthy
Department of ophthalmology, Pondicherry Institute of Medical Sciences, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_30_21

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  Abstract 


A 58-year-old male came to the ophthalmology outpatient department with complaints of blackish discoloration in both eyes, which he noticed 6 months back. He had a history of bilateral knee pain and stiffness for 6 months, for which he was admitted in the orthopedics ward and planned for total knee replacement, since he was diagnosed to have bilateral OA knee. On examination, his BCVA was 6/9 in both eyes. In the interpalpebral area, there was a grayish conjunctival and scleral pigmentation seen in both the eyes in the perilimbal area at the lateral rectus insertion, which showed typical Osler's sign suggestive of alkaptonuria. Cornea was clear with a quiet anterior chamber. The pupil was round and reacting to both direct and indirect light reflexes, and there were early cataractous changes in the lens. Fundus examination with an indirect ophthalmoscope showed normal optic disc and vessels in both eyes. This is a classic case of alkaptonuria having typical signs. Many cases of alkaptonuria were diagnosed only after the development of symptoms. Scleral pigmentation usually starts during the mid-twenties; hence, being aware of this, ocular sign in alkaptonuria can lead to an early diagnosis and better outcome.

Keywords: Alkaptonuria, homogentisic acid oxidase, Osler's sign


How to cite this article:
Djeamourthy S, Sankar S, Sigamani VP, Srinivasan R. Pursuit of Osler's sign. TNOA J Ophthalmic Sci Res 2021;59:390-3

How to cite this URL:
Djeamourthy S, Sankar S, Sigamani VP, Srinivasan R. Pursuit of Osler's sign. TNOA J Ophthalmic Sci Res [serial online] 2021 [cited 2022 Sep 29];59:390-3. Available from: https://www.tnoajosr.com/text.asp?2021/59/4/390/333166




  Introduction Top


Alkaptonuria is a rare, autosomal recessive inborn error in the metabolism of phenylalanine and tyrosine, leading to accumulation of homogentisic acid (HGA) in the connective tissues, due to deficiency of HGA.[1],[2] Alkaptonuria is also referred to as hereditary ochronosis/HGA oxidase deficiency/ORPHA56/black bone disease/black urine disease.[3],[4] Ochronosis usually develops in the fourth decade of life with equal male and female preponderance.[2] Birth prevalence is estimated at around 1/250,000–1/1,000,000 in most ethnic groups.[5] It is more common in Slovakia and the Dominican[6] Presence of HGA in the urine, ochronosis (bluish-black pigmentation in connective tissue such as sclera, cartilage, and heart valves), and arthritis of larger joints and spine are the major clinical features in alkaptonuria.[3] The most common ocular manifestations include bluish-black discoloration (ochronotic pigments) of the conjunctiva, cornea, and sclera. Since it is a multiorgan presentation involving the bones, cartilage, heart, and eyes, multiple specialties are involved. We as ophthalmologists have a key role in the diagnosis of the alkaptonuria.


  Case Report Top


A 58-year-old male was referred to the ophthalmology outpatient department for ocular examination. He presented with complaints of blackish discoloration of both eyes for 6 months. He gave a history of bilateral knee pain and stiffness for 6 months, for which he was admitted under the orthopedics department. On general examination, there was blackish discoloration of both ear lobes and nail and teeth [Figure 1] and [Figure 2]. On systemic examinations, the cardiovascular, respiratory, gastrointestinal, and central nervous systems were found to be within normal limits. Ocular examination revealed that visual acuity in both eyes was 6/9. In the interpalpebral area, there was a grayish conjunctival and scleral pigmentation, which was pinguecula-like pigmentation seen in both the eyes in the perilimbal area at the lateral rectus insertion [Figure 3] and [Figure 4]. Cornea was clear with a quiet anterior chamber. The pupil was round and reacting to both direct and indirect light reflexes, and there were early cataractous changes in the lens. Fundus examination with an indirect ophthalmoscope showed normal optic disc and vessels in both eyes. Optical coherence tomography was normal. On investigating further, complete blood picture was within normal limits. Erythrocyte sedimentation rate was 16 mm/1st h, complete urine examination was normal, but the color of the urine turned dark on exposure to atmosphere [Figure 5]. Ultrasound abdomen was normal. Electrocardiography was normal. Echocardiography revealed no valvular disease. Rheumatoid arthritis factor was negative. C-reactive protein was negative. X-ray of both knees showed Grade 4 osteoarthritis due to ochronotic arthropathy. The patient was advised bilateral total knee replacement (TKR) surgery from orthopedics department and was proceeded During TKR surgery, orthopedicians noted blackish tissue over femur, tibia, and the patella which was removed [Figure 6]. The biopsy was sent to histopathology which showed brown-black discoloration of the cartilage [Figure 7].
Figure 1: Teeth showing blackish discoloration

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Figure 2: Blacking discoloration of pinna

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Figure 3: Right eye showing slate gray scleral pigmentation

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Figure 4: Left eye showing slate gray scleral pigmentation

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Figure 5: Color of the urine turned dark on exposure to atmosphere

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Figure 6: Blackish tissues on knees in arthroscopy

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Figure 7: Cartilage showing brown-black discoloration (H and E, ×100)

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  Discussion Top


Alkaptonuria is a rare disease with a very incidence of one in 100,000–250,000 in most countries, with the notable exception in Slovakia, where the disease appears in 1 in 19,000 people.[1] In 20% of cases, alkaptonuria is diagnosed before 1 year of age, while in 80%, the mean age at the time of diagnosis is 29. AKU is an autosomal recessive genetic disease which was first described by Garrod as an “inborn error of metabolism” in 1901 in London.[2] The defects have been mapped to chromosome 3, between regions 3q21 and q23.

AKU is considered to be an inborn error of metabolism of phenylalanine and tyrosine, which is characterized by the inability to metabolize HGA. The homogentisate 1,2 dioxygenase (HGD) gene has been mapped to chromosome 3q21–q23 and 14 exons.[7] The functional HGD protein is a hexamer, organized as a dimer of trimers. The HGD mutation database lists 620 variants, out of which almost 80% are missense substitutions. The remaining is deletions, duplications, insertions, or unknown The HGD enzyme catalyzes the conversion of HGA into maleylacetoacetic acid. Therefore, AKU results in the accumulation of HGA at 2000 times the normal rate.[8]

On contact with air, HGA is oxidized to form a pigment-like polymeric material responsible for the black color of standing urine. Over time, HGA is also deposited in cartilage throughout the body and is converted to the pigment-like polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues. The organs involved include cutaneous, cardiovascular, ocular, skeletal, genitourinary, and respiratory. Alkaptonuria is asymptomatic in childhood; hence, diagnosis is usually established at a later age when the patients develop ochronosis, which is the brown-black pigmentation in connective tissues, typically the cartilage, eyes, and skin.

In general, the severity of the disease progresses after the age of 30 and more rapidly in men than in women.[3] Back pain begins from the third decade, and other large joints (knee, shoulder, and hip) are also involved.[4] Tearing of the Achilles tendon is also common seen.[5] Involvement of the aortic leaflets, mitral valve leaflets, and calcifications of the coronary arteries occurs in one-half of all patients.

The common ocular manifestations include slate blue or grayish discoloration found in the sclera and temporal perilimbal near the rectus muscle insertion (Osler's sign).[6] Oil drops like spots in the cornea at the level of Bowman's membrane.[9] Dilated conjunctival vessels can be found supplying the pigmented areas of the conjunctiva.

There are four types of scleral pigmentation patterns:[9]

  • Small “vermiform” or “tube-like” pigment deposits
  • Pinguecula-like pigmentation
  • Laminar structures
  • Dot-like pigmentation.


Other causes of scleral pigmentation include nevus of Ota, melanosis and melanomas, and nevus. In our case, we differentiated from the differential diagnosis with difference in color, the site of pigmentation which was present at the insertion of the recti muscles, and the laterality which was bilateral. The ochronotic pigment can also accumulate at uncommon locations in the eye such as the corneal endothelium, the posterior surface of the lens, the iris, the vitreous, and the optic disc. Other less common ocular manifestations include astigmatism, metabolic keratopathy, primary open angle glaucoma, epiretinal membrane, and central vein occlusion.


  Treatment Top


Vitamin C, as much as 1 g/day, is recommended for older children and adults. The mild antioxidant nature of ascorbic acid helps retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues. Limited use of nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which mediates the formation of HGA, has been reported.[8] Lifestyle changes, counseling, physiotherapy, and palliative care are also advised. Aortic stenosis may necessitate valve replacement and knee replacement surgery may aid in treating ochronotic arthropathy.


  Conclusion Top


Osler's sign is a simple, clinical, and noninvasive sign; being aware of this, simple sign may aid in early diagnosis of alkaptonuria. Early diagnosis and treatment with antioxidants will definitely improve the quality of life and life expectancy.

Declaration of patient's consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guarantee.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Introne WJ, Perry M, Chen M. Alkaptonuria. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2003.  Back to cited text no. 1
    
2.
Garrod AE. The incidence of alkaptonuria: A study in chemical individuality. 1902 [classical article]. Yale J Biol Med 2002;75:221-31.  Back to cited text no. 2
    
3.
Janocha S, Wolz W, Srsen S, Srsnova K, Montagutelli X, Guénet JL, et al. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 1994;19:5-8.  Back to cited text no. 3
    
4.
Introne WJ, Perry M, Chen M. Alkaptonuria. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 2003.  Back to cited text no. 4
    
5.
Alajoulin OA, Alsbou MS, Ja'afreh SO, Kalbouneh HM. Spontaneous Achilles tendon rupture in alkaptonuria. Saudi Med J 2015;36:1486-9.  Back to cited text no. 5
    
6.
Okutucu M, Aslan MG, Findik H, Yavuz G. Glaucoma with alkaptonuria as a result of pigment accumulation. J Glaucoma 2019;28:e112-4.  Back to cited text no. 6
    
7.
Vilboux T, Kayser M, Introne W, Suwannarat P, Bernardini I, Fischer R, et al. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum Mutat. 2009;30:1611-1619. doi:10.1002/humu.21120.  Back to cited text no. 7
    
8.
Aktuglu-Zeybek AC, Zubarioglu T. Nitisinone: A review. ODRR 2017;7:25-35.  Back to cited text no. 8
    
9.
Cheskes J, Buettner H. Ocular manifestations of alkaptonuric ochronosis. Arch Ophthalmol 2000;118:724-5.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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