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Background: Cutaneous exogenous ochronosis (EO) is frequently graded and staged according to the Dogliotti or Phillips classification system, both in research studies and in clinical practice. There are no data to support the use of these systems in either of these settings. These systems additionally purport that the clinical and histopathological findings of EO are concordant; however, anecdotal evidence suggests otherwise. We aimed to determine the clinical‐histopathological concordance rates in EO and to assess the suitability of the Dogliotti and Phillips classification systems for the grading and staging of EO lesions. Methods: Five cutaneous EO cases diagnosed at our institution were studied. Clinical and histopathological data were obtained by medical record and histopathology slide review. Each case was assigned a clinical and histopathological grade according to both the Dogliotti and Phillips classifications. Clinical‐histopathological concordance rates were determined for each classification. Results: Clinical‐histopathological concordance was seen in 80% and 60% of EO lesions when graded according to the Dogliotti and Phillips classifications, respectively. Conclusions: Cutaneous EO lesions do not consistently show clinical‐histopathological concordance. Although the Dogliotti and Phillips classifications may have clinical utility, they are not suitable to grade EO histopathologically. [ABSTRACT FROM AUTHOR]

Blue discoloration of the skin and cartilage, or ochronosis, is a rare physical examination finding. We present two cases of childhood onset ochronosis, one exogenous and one endogenous in etiology. The first was caused by minocycline use for severe acne, and the second was caused by congenital alkaptonuria. [ABSTRACT FROM AUTHOR]

Interestingly, comparison of the histopathologic findings of the annular EO lesions in patients with and without systemic sarcoidosis showed only minor differences.5 In patients with systemic sarcoidosis, the zonal pattern on histopathology was less defined. Only 1 patient had skin lesions outside of the area of EO, but it was not reported whether this patient had systemic sarcoidosis or cutaneous lesions only. Keywords: ochronosis; exogenous; exogenous ochronosis; perforating; granulomatous EN ochronosis exogenous exogenous ochronosis perforating granulomatous 1219 1222 4 09/21/21 20211001 NES 211001 Introduction Exogenous ochronosis (EO) is a cutaneous disorder induced by cosmetic application of skin lightening agents, most commonly hydroquinone.1 The pathogenesis is secondary to inhibition of local activity of homogentisic acid oxidase by hydroquinone, leading to accumulation of homogentisic acid that polymerizes to form ochronotic pigment in the skin. AG-like change in EO has been reported in a patient who presented with annular lesions on a background of severe EO.7 Of note, in AG, elastophagocytosis is a prominent feature, which is absent in actinic granuloma-like EO. [Extracted from the article]

A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty‐seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty‐seven attended more than once and received nitisinone 2 mg daily. Twenty‐three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18FPositron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; ochronosis associated closely with spondyloarthropathy scores (R =.65; P <.0001). Nitisinone reversed ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy. [ABSTRACT FROM AUTHOR]

Arthroplasty in the spondyloarthropathy (SPOND) of alkaptonuria (AKU) in incompletely characterised. The aim was to improve the understanding of arthroplasty in AKU through a study of patients attending the National Alkaptonuria Centre (NAC). Eighty‐seven patients attended the NAC between 2007 and 2020. Seven only attended once. Fifty‐seven attended more than once and received nitisinone 2 mg daily. Twenty‐three attended at least twice without receiving nitisinone. Assessments including questionnaire analysis eliciting details of arthroplasty and other surgical treatments for SPOND, 18FPETCT and CT densitometry at the neck of hip and lumbar spine, as well as photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Photographs were scored to derive ochronosis scores. Blood and urine samples were collected for chemical analyses. The prevalence of arthroplasty was 36.8%, similar in males and females, occurring especially in the knees, hips and shoulders. Multiple arthroplasties were found in 29 patients (33.3%) in this cohort. Incident arthroplasty was 6.5% in the nitisinone group and 7.1% in the no‐nitisinone group. Incident arthroplasty was 11.3% in the group with baseline arthroplasty and 3.51% in the group without. A strong association of arthroplasty with SPOND (R = 0.5; P <<.0001) and ochronosis (R = 0.54; P <.0001) was seen. Nitisinone had no significant effect on incident arthroplasty. Arthroplasty due to ochronosis and SPOND is common in AKU. Nitisinone decreased ochronosis but had no effect on arthroplasty in this cohort. [ABSTRACT FROM AUTHOR]

Summary: Exogenous ochronosis is a cutaneous condition characterized by blue‐black pigmentation resulting as a complication of long‐term application of skin‐lightening creams containing hydroquinone and other substances such as quinine, phenol and mercury derivatives. We report a case of a 55‐year‐old woman who developed exogenous ochronosis as a result of prolonged use of topical hydroquinone for 5 years, characterized by greyish hyperpigmented patches on the nose and cheeks. The diagnosis was confirmed histologically. Treatment with picosecond laser resulted in marked clinical improvement together with improvement in overall texture and quality of the skin. [ABSTRACT FROM AUTHOR]

Ochronosis is the process in alkaptonuria (AKU) that causes all the debilitating morbidity. The process involves selective deposition of homogentisic acid (HGA)‐derived pigment in tissues altering the properties of these tissues, leading to their failure. Some tissues like cartilage are more easily affected by ochronosis while others such as the liver and brain are unaffected for reasons that are still not understood. In vitro and mouse models of ochronosis have confirmed the dose relationships between HGA and ochronosis and also their modulation by p‐hydroxyphenylpyruvate dioxygenase inhibition. Ochronosis cannot be fully reversed and is a key factor in influencing treatment decisions. Earlier detection of ochronosis preferably by noninvasive means is desirable. A cause‐effect relationship between HGA and ochronosis is discussed. The similarity in AKU and familial hypercholesterolaemia is explored and lessons learnt. More research is needed to more fully understand the crucial nature of ochronosis. [ABSTRACT FROM AUTHOR]

Ochronosis is the blue‐gray discoloration of collagen‐containing tissues due to homogentisic acid (HGA) deposition, secondary to endogenous alkaptonuria or exogenous enzyme inhibition. In renal disease, accumulation of HGA in serum can cause methemoglobinemia. A 60‐year‐old woman with renal disease and anemia presented with 3 days of weakness and months of gray skin discoloration. Her hemoglobin was 8.1g/dl with 24.5% methemoglobin. Despite treatment with methylene blue, exchange transfusion, and continuous renal replacement therapy, the patient died. Autopsy revealed gray discoloration and ochronotic pigment in the ribs and cartilage. Based on these findings, the patient was diagnosed with ochronosis, suggestive of alkaptonuria, complicated by methemoglobinemia. The differential diagnosis for blue‐gray skin discoloration includes argyria, methemoglobinemia, and ochronosis. This patient's clinical and autopsy findings suggested alkaptonuria complicated by methemoglobinemia due to progressive renal dysfunction. Development of methemoglobinemia in the setting of chronic skin discoloration and renal failure should prompt consideration of alkaptonuria. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is a disease caused by a deficient homogentisate 1,2‐dioxygenase activity leading to systemic accumulation of homogentisic acid (HGA), that forms a melanin‐like polymer that progressively deposits onto connective tissues causing a pigmentation called "ochronosis" and tissue degeneration. The effects of AKU and ochronotic pigment on the biomechanical properties of articular cartilage need further investigation. To this aim, AKU cartilage was studied using thermal (thermogravimetry and differential scanning calorimetry) and rheological analysis. We found that AKU cartilage had a doubled mesopore radius compared to healthy cartilage. Since the mesoporous structure is the main responsible for maintaining a correct hydrostatic pressure and tissue homoeostasis, drastic changes of thermal and rheological parameters were found in AKU. In particular, AKU tissue lost its capability to enhance chondrocytes metabolism (decreased heat capacity) and hence the production of proteoglycans. A drastic increase in stiffness and decrease in dissipative and lubricant role ensued in AKU cartilage. Multiphoton and scanning electron microscopies revealed destruction of cell–matrix microstructure and disruption of the superficial layer. Such observations on AKU specimens were confirmed in HGA‐treated healthy cartilage, indicating that HGA is the toxic responsible of morphological and mechanical alterations of cartilage in AKU. Although efforts were made, the exact biochemical mechanism of cartilage degradation in alkaptonuria (AKU) is not clarified in detail yet. Our multidisciplinary study provides novel insights on how homogentisic acid and the ochronotic pigment affect the physico–thermal and mechanical properties of AKU cartilage. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia Hedgehog signaling may also be altered in AKU. Thus, we characterized an AKU cellular model in which healthy chondrocytes were treated withHGA(66 µM) to replicateAKUcartilage pathology. We investigated the degree of activation of the Hedgehog signaling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced Hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the Hedgehog pathway. [ABSTRACT FROM AUTHOR]

Objective Ochronosis is a term used to describe pigment deposition that occurs in the connective tissues of patients with alkaptonuria, an autosomal recessive disorder that results from a deficiency of homogentisic acid oxidase. Brown or blue-gray discoloration of the skin may be seen on the axillary and inguinal areas, face, palms or soles. In addition, blue-black discoloration can be apparent on skin overlying cartilage in which the pigment is deposited, such as the ears. The sclerae are also typically involved. The cheapest screening test to perform prior to expensive lab tests is the urine oxidation test: having it standing in light for a period of 24 h when suspicion has risen. Methods Retrospective analysis of patients with ochronotic arthropathy seen between September 2011 to September 2013 was carried out. Results Seven patients (four male, three female) with ochronotic arthropathy were seen, their mean age was 46.1 years. All patients had bluish-black pigmentations of the ear cartilage and sclera. Spondylosis was seen in all, whereas peripheral arthritis was present in five patients. Moderate aortic insufficiency and calcification of the aortic valve was detected in one male patient. Urine screening for homogentisic acid was positive in all seven patients. Conclusion Alkaptonuria is a rare autosomal recessive disorder of the metabolism caused by deficiency of homogentisic acid oxidase. It is suggested that more widespread screening should be undertaken in order to assess the true incidence of the disorder. [ABSTRACT FROM AUTHOR]

Exogenous ochronosis has been reported worldwide following long-term application of skin-lightening creams that contain hydroquinone, phenol or resorcinol. This report documents six patients presenting in Singapore with greatly differing facial dyschromias and discusses the diagnostic difficulties. [ABSTRACT FROM AUTHOR]

Alkaptonuria is a rare, inherited defect of homogentisic acid 1,2-dioxygenase that leads to the widespread deposition of polymeric homogentisic acid, and clinical symptoms from degeneration of joints and the aortic valve. Pathological descriptions are few and mainly those of late-stage changes related to joint or valve failure. In this review, the macroscopic and histopathological changes in the tissues in alkaptonuria are illustrated by the detailed autopsy study of a 74-year-old female who died from disseminated ovarian carcinoma. The pathology is discussed in the context of the literature and in relation to potential pathogenic mechanisms of tissue damage. This review highlights the heterogeneity of some of the manifestations. In symptomatic patients, degenerative changes in synovial and intervertebral joints are usually well advanced, while early changes include diffuse cartilage pigmentation and chondrocyte necrosis. The initial stage of pigment deposition in the cardiovascular system may be influenced by intravascular pressure and flow disturbances, whereas more intense pigmentation affects fibrolipid components of atheromatous plaques. Pigmentation of the aortic and mitral valve cusps and valve rings is a result of intracellular and extracellular pigment deposition and is associated with calcification and clinically significant aortic stenosis. [ABSTRACT FROM AUTHOR]

A 52-year-old Nepali presented with fixed flexion deformity of swollen and painful hips, knees and elbows. He was kyphosed and had bluish black pigmentation in the skin, chonca, sclera and gums. The X-ray of the dorsolumbar spine shown dense calcification and reduced intervertebral disc space. The freshly voided straw-coloured urine turned like darkish brown cola on standing in the laboratory. He was taking lots of analgesics and steroids. He developed chronic renal failure. The electrocardiogram showed prolonged QTc which led to torsades de pointes and ventricular fibrillation. [ABSTRACT FROM AUTHOR]

Abstract. Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E, Proietta M (Università di Roma ‘La Sapienza’, Rome, Italy). Bone metabolism in ochronotic patients (Case report). J Intern Med 2003; 254: 296–300. We investigated skeletal involvement in five male and two female patients with ochronosis, aged 26–82 years. The main parameters of mineral metabolism, together with biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and formation (serum bone isoenzyme of alkaline phosphatase and serum osteocalcin) were evaluated. In the same subjects lumbar spine and femoral bone mineral density (BMD) were also measured by dual energy X-ray absorptiometry. All patients but the younger 26-year-old patient had lower than normal bone mass at femoral neck and total hip, showing marked osteopenia in three cases and osteoporosis in the remaining three cases. However, at lumbar spine BMD measurement provided spuriously overestimated results, because of intervertebral disc calcification and osteophyte formation. As far as biochemical markers of bone turnover are concerned, the most relevant finding was the increased N-telopeptides of type I collagen urinary excretion. Our results suggest that ochronosis may be associated with increased bone resorption rate leading to an accelerated bone loss. A role of the homogentisic acid polymer deposit in bone matrix and cells, possibly with osteocyte damage and interference in collagen metabolism, might be hypothesized. [ABSTRACT FROM AUTHOR]

Ochronosis is a rare disease characterised clinically by bluish-grey skin discolouration and histologically by yellow-brown pigment deposits in the dermis. It occurs in endogenous and exogenous forms. Endogenous ochronosis, also known as alkaptonuria, is an autosomal recessive disease of tyrosine metabolism, resulting in the accumulation and deposition of homogentisic acid in connective tissue. We report a case of facial endogenous ochronosis and coexistent photodamage, which was successfully treated with erbium-doped yttrium aluminium garnet laser resurfacing and deep focal point treatment to remove areas of residual deep pigment. [ABSTRACT FROM AUTHOR]

The article presents a study on alkaptonuria diagnosis through skin biopsy. It mentions the involvement of ochronosis depicting homogentisic acid deposition in the melanocytic nevi of the dermis. An overview of its first occurrence in 1975 through the long-term application of hydroquinone skin-lightening cream is also provided.

ABSTRACT. Purpose: To report a rare case of bilateral asymmetrical melanin-like pigments found in the cornea, conjunctiva and sclera. Methods: Systemic investigation with clinical and laboratory analysis. Results: The case was diagnosed as one of alkaptonuria and ocular ochronosis. [ABSTRACT FROM AUTHOR]

Key Clinical Message A 63-year-old man bearing most signs and symptoms (facial pigmentation, degenerative arthritis, and dark urine) pertinent to his known history of alkaptonuria underwent aortic valve replacement for critical aortic stenosis. Although rare, aortic stenosis is the most common cardiac manifestation of alkaptonuric ochronosis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing ochronosis in black aortic valve.