Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Electron microscopy description | Electron microscopy images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Collie CJ, Ho JD. Ochronosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/skinnontumorochronosis.html. Accessed April 15th, 2021.
Definition / general
- Disorders characterized by blue-gray to black pigmentation due to deposition of ochre colored pigment in connective tissues
- 2 main forms: alkaptonuria / endogenous ochronosis (homogentisate 1,2 dioxygenase deficiency) and exogenous ochronosis (overuse of topical hydroquinone and other medicaments)
Essential features
- Deposition disorder characterized by deposition of homogentisic acid in connective tissue
- May result from an inborn error of metabolism (alkaptonuria) or from overuse of topical hydroquinone or other phenol containing medications (exogenous ochronosis)
- Alkaptonuria presents with hyperpigmentation, arthropathies, kidney disease and heart disease
- Exogenous ochronosis patients primarily present with hyperpigmentation involving the face, neck or upper limbs
- Classical histologic findings in the skin include formation of banana shaped, yellow-brown deposits and heavy elastosis in the superficial dermis
ICD coding
Epidemiology
- Alkaptonuria
- Very rare; prevalence 1:100,000 - 250,000 (J Med Genet 2002;39:E40)
- Exogenous ochronosis
- Little data available
- F > M
- Variable prevalence among ethnicities with dark skinned individuals thought to be the most affected (Indian J Dermatol 2015;60:537)
- U.S. data: 22 cases in 50 years (J Am Acad Dermatol 2007;57:854)
Sites
- Alkaptonuria: skin (ear, face, acral surfaces and axillae), sclera, bone cartilage, kidney and cardiac valves
- Exogenous ochronosis: skin of the malar areas, temples, lower cheeks, neck, forearms and hands
Pathophysiology
- Alkaptonuria
- Inborn error of tyrosine metabolism secondary to autosomal recessive loss of function mutations in HGD / HGO (Nat Genet 1996;14:19)
- Resultant deficiency of homogentisate 1,2 dioxygenase leads to accumulation of homogentisic acid and eventual deposition in collagen rich tissue (Calcif Tissue Int 2017;101:50)
- Long term deposition leads to degenerative arthritis, cardiac valvulopathy, renal disease and oculocutaneous pigmentation (N Engl J Med 2002;347:2111)
- Exogenous ochronosis
- Localized inhibition of homogentisate 1,2 dioxygenase primarily by topical application of phenol containing compounds, particularly hydroquinone (Arch Dermatol 1985;121:1239)
- Deposition and polymerization of homogentisic acid on collagen and elastic fibers (Am J Dermatopathol 2014;36:989, Am J Dermatopathol 2020;42:571)
Etiology
- Alkaptonuria
- Autosomal recessive loss of function mutations in HGD / HGO
- Exogenous ochronosis
- Prolonged use of topical hydroquinone (Dermatol Online J 2019;25:13030/qt5vd7h6xc)
- Less common associations include antimalarials, phenol, resorcinol, quinine injections, mercury and picric acid (Am J Clin Dermatol 2001;2:213, J Am Acad Dermatol 1986;15:357)
Clinical features
- Alkaptonuria
- Blue-gray to black macules and papules on sclera, cheeks, cartilaginous portions of the ear and acral surfaces (N Engl J Med 2002;347:2111)
- Brown discoloration of the axillae (Int J Rheum Dis 2014;17:327)
- Black discoloration of urine if left to stand
- Renal disease, including calculi, tubulointerstitial disease and renal tubular acidosis (Clin Nephrol 2015;84:339, Mod Pathol 1992;5:464, Saudi J Kidney Dis Transpl 2018;29:997)
- Arthritis (N Engl J Med 2002;347:2111)
- Cardiac valvulopathy (J Heart Valve Dis 2006;15:730)
- Exogenous ochronosis
- Speckled blue-gray or brown-black macules on head, neck, upper limbs and hands; more severe on malar areas and other sun exposed skin (Am J Dermatopathol 2019;41:e47)
- Occasional caviar-like papules (Int J Dermatol 2013;52:413)
- Areas of admixed hypopigmentation or erythema occasionally noted
- Dematoscopic examination reveals dark amorphous structures in involved skin with obliteration of follicular ostia (Indian J Dermatol Venereol Leprol 2013;79:819)
Diagnosis
- Alkaptonuria
- Urine gas chromatography mass spectrometry analysis for homogentisic acid (J Chromatogr B Analyt Technol Biomed Life Sci 2014;963:106)
- PCR evaluating for HGD mutations (Clin Genet 2003;63:145)
- Skin biopsy
- Exogenous ochronosis
- High index of suspicion in the correct clinical context
- Thorough medication history
- Examination of cosmetic cream ingredients for hydroquinone
- Skin biopsy
Laboratory
- Increased urinary levels of homogentisic acid on gas chromatography mass spectrometry analysis in alkaptonuria (J Chromatogr B Analyt Technol Biomed Life Sci 2014;963:106)
- Pathogenic biallelic mutations of HGD on molecular testing with PCR (JIMD Rep 2015;24:3)
Radiology description
- Xray findings in alkaptonuric arthropathy include joint space narrowing, osteophyte formation, joint space calcification and reactive sclerosis of articular surfaces (Radiol Med 2005;110:349)
Prognostic factors
- Alkaptonuria
- Normal life expectancy (Rare Dis 2013;1:e27475)
- Arthropathy increases morbidity
- Exogenous ochronosis
- Late diagnosis and extensive hyperpigmentation at time of diagnosis connote poor prognosis
Case reports
- 53 year old man with knee pain (Medicine (Baltimore) 2019;98:e16837)
- 53 year old man with progressively spreading papules on hands, nose and ears (J Dermatol Case Rep 2015;9:42)
- 56 year old man with blue-gray pigmentation of external ear (ScientificWorldJournal 2010;10:1530)
- 60 year old man with rheumatoid arthritis and new onset facial pigmentation with use of hydroxychloroquine (Eur J Rheumatol 2018;5:206)
- 63 year old woman with ochronosis; reflectance confocal microscopic, dermoscopic and electron microscopic features (Arch Dermatol 2010;146:1021)
Treatment
- Alkaptonuria
- Dietary reduction of phenylalanine and tyrosine
- Cardiac valve replacement
- Arthroplasty
- Oral nitisinone (Metabolism 2005;54:719)
- Oral ascorbic acid (Ann Clin Biochem 2003;40:108)
- Exogenous ochronosis
- Discontinuation of causative agent
- Sunscreen
- Q switch alexandrite laser (Dermatol Surg 2004;30:555)
Clinical images
Microscopic (histologic) description
- Features of ochronosis are similar in both alkaptonuria and exogenous ochronosis
- Early changes include homogenization of collagen and degenerating elastotic fibers (Am J Dermatopathol 2014;36:989, Am J Dermatopathol 2019 Nov 12 [Epub ahead of print])
- Yellow-brown, banana shaped, sickled or round ochronotic bodies deposit in the connective tissue
- Occasional bodies may be seen in direct continuity with collagen or elastic fibers (Am J Dermatopathol 2019 Nov 12 [Epub ahead of print])
- Exogenous ochronosis
- Extensive solar elastosis-like change is noted in an interfollicular distribution
- Decreased basal keratinocyte pigmentation
- Occasionally, ochronotic bodies are seen in association with colloid milium and are designated pigmented colloid milium (J Dermatol Case Rep 2015;9:42)
- Granulomatous reaction has also been reported (J Cutan Pathol 1990;17:236)
- Similar ochronotic bodies are seen in the connective tissues of cardiac, scleral and bony tissue when involved
Microscopic (histologic) images
Positive stains
- Methylene blue (Indian J Dermatol Venereol Leprol 2015;81:623)
- Variable Verhoeff van Gieson (Am J Dermatopathol 2019 Nov 12 [Epub ahead of print])
Negative stains
Electron microscopy description
- Electron dense material within elastic fibers
- Degeneration of elastic fibers with fragmentation, clearing and a moth eaten appearance
- Reference: Arch Dermatol 2010;146:1021
Molecular / cytogenetics description
- Numerous HGD mutations reported in alkaptonuria
- Reference: JIMD Rep 2012;4:55
Sample pathology report
- Right cheek, punch biopsy:
- Ochronosis (see comment)
- Comment: The specimen exhibits extensive elastosis in an interfollicular distribution and scattered yellow-brown, banana shaped deposits in the superficial dermis in keeping with exogenous ochronosis.
Differential diagnosis
- Melasma:
- Increased keratinocyte melanization, which may involve all layers of the epidermis
- Variable papillary dermal melanophages
- Solar elastosis
- Telangiectasia
- Increased mast cells
- Acquired bilateral nevus of Ota-like macules (Hori nevus):
- Scattered dendritic melanocytes in the superficial dermis
- Cells typically heavily pigmented and express melanocyte markers
- Argyria:
- Fine, black granules deposited on the basement membrane of blood vessels and skin adnexa
- Lichen planus pigmentosus:
- Subtle interface dermatitis (active lesion)
- Focal band-like lymphocytic infiltrate (active lesion)
- Band-like or perivascular heavily pigmented melanophages (active and burnt out lesions)
- Facial acanthosis nigricans:
- Hyperkeratosis
- Papillomatosis
- Only subtle increase in basal keratinocyte pigmentation
Additional references
Board review style question #1
A 40 year old Afro-Caribbean woman with a history of long term use of skin lightening products presents with an asymptomatic hyperpigmented eruption involving the face. A punch biopsy reveals yellow-brown, banana shaped deposits in the superficial dermis. What is the most likely diagnosis?
- Acanthosis nigricans
- Argyria
- Exogenous ochronosis
- Lichen planus pigmentosus
- Melasma
Board review style answer #1
Board review style question #2
A 60 year old man presents for hip replacement. On preoperative evaluation, black discoloration of the sclera and ear cartilage are noted and a diagnosis of alkaptonuria is entertained. What enzyme is deficient in patients with alkaptonuria?
- Fumarylacetoacetate hydrolase
- Homogentisate 1,2 dioxygenase
- Tyrosinase
- Tyrosine aminotransferase
- 4-hydroxyphenylpyruvate dioxygenase
Board review style answer #2