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Surg. cosmet. dermatol. (Impr.) ; 13: e20210002, jan.-dez. 2021.
Article in Portuguese | LILACS-Express | LILACS | ID: biblio-1368584


A ocronose exógena é um quadro de hiperpigmentação cutânea por acúmulo de substâncias derivadas de fenol na pele ou mucosas, sem acometimento de outros tecidos. Ocorre, principalmente, por uso de clareadores, sendo mais frequente a hidroquinona como despigmentante. As lesões apresentam difícil tratamento, sendo resistentes a diversas abordagens. Por vezes, é necessário utilizar tecnologias com laser ou luz intensa pulsada para atingir algum grau de melhora. O presente trabalho realizou revisão de literatura entre janeiro de 1990 e julho de 2020, organizando publicações acerca do uso destas tecnologias na ocronose exógena

Exogenous ochronosis is a cutaneous hyperpigmentation condition caused by the accumulation of substances derived from phenol on the skin or mucous membranes without affecting other tissues. It occurs mainly due to the use of bleaching agents, most frequently hydroquinone. The lesions are difficult to treat, being resistant to several approaches. Sometimes it's necessary to use laser technologies or intense pulsed light to achieve some degree of improvement. The present work consists of a literature review of publications on these technologies in exogenous ochronosis from January 1990 to July 2020.

Article | IMSEAR | ID: sea-194595


Exogenous ochronosis is an infrequent skin disorder characterised by bluish-black or grayish brown pigmentation on dermis. It is the most common condition caused due to long term application of Hydroquinone skin preparations for melasma, skin brightening, cholasma, acne induced pigmentation etc. This report refers to a case of 39-year-old female patient who presented to the hospital with chief complaints of progressive formation of dark lesions over face, neck since one and half-year. She had history of usage of hydroquinone (4%) cream for skin brightening for a period of three months. Based on clinical findings and history she was diagnosed to have acquired exogenous ochronosis and was treated with microdermabrasion, cosmelan peel, yellow peel, glutathione tablets, topical sunscreen and kojic acid cream. Patient noted 50% improvement in her condition after 4 months of treatment. It is believed that application of high concentrations of hydroquinone for a prolonged period causes exogenous ochronosis. This case report suggests that exogenous ochronosis can occur after three months of application.

Autops. Case Rep ; 10(4): e2020197, 2020. tab, graf
Article in English | LILACS | ID: biblio-1131843


Ochronosis is a cutaneous disorder caused by the accumulation of phenols, either endogenously as homogentisic acid in patients with alkaptonuria (autosomal recessive disorder with deficiency of the enzyme homogentisic acid oxidase), or exogenously in patients using phenol products such as topical creams containing hydroquinone or the intramuscular application of antimalarial drugs. Exogenous ochronosis (EO) typically affects the face and was reported in patients with dark skin such as Black South Africans or Hispanics who use skin-lightening products containing hydroquinone for extended periods. Recently more cases have been reported worldwide even in patients with lighter skin tones, to include Eastern Indians, Asians, and Europeans. However, just 39 cases of EO have been reported in the US literature from 1983 to 2020. Here we present two cases; a 69 and a 45-year-old female who were seen for melasma, given hydroquinone 4% cream daily and tretinoin 0.05%. Both patients noticed brown spots on their cheeks, which progressively enlarged and darkened in color. The diagnosis of ochronosis was confirmed by characteristic histopathological features on the punch biopsy. Unfortunately, neither patient responded to multiple treatments (to include, tazarotene 0.1% gel and pimecrolimus ointment, topical corticosteroids, and avoidance of hydroquinone containing products). We also present a case of classic (endogenous) ochronosis in a patient with alkaptonuria to picture the histological similarities of these two entities. EO is an important clinical consideration because early diagnosis and treatment may offer the best outcome for this notoriously refractory clinical diagnosis.

Humans , Female , Middle Aged , Aged , Skin Pigmentation , Skin Cream/adverse effects , Ochronosis/diagnosis , Phenols , Skin , Skin Diseases , Cheek , Alkaptonuria , Homogentisic Acid
Article in Chinese | WPRIM | ID: wpr-744486


Objective To summarize the clinical manifestation,diagnosis and treatment methods of ochronotic joint disease,thus to improve grassroots medical workers awareness of ochronotic arthritis.Methods The clinical data of 1 case of ochronotic arthritis in the Second Municipal Hospital of Weihai Affiliated to Qingdao University and literature data were analyzed. Results The male patient,65 years old,because the right femoral neck fracture admitted to accidentally falls in patients with bilateral antihelix ear cartilage and local black pigmentation,resection of the femoral head cartilage surface,black,dark color round ligament,partial hip joint capsule was dark,multi segmental lumbar vertebral intervertebral space narrowing disc hardening,laboratory urine silver nitrate and ammonium hydroxide exami-nation appear dark brown discoloration, confirmed the diagnosis of patients with ochronotic joint disease. Conclusion We should improve cognition of ochronotic joint disease,examination by medical history,clinical mani-festations,laboratory and imaging,diagnosis of ochronotic arthritis,thus to reduce the rate of misdiagnosis.

Article in Japanese | WPRIM | ID: wpr-738363


Alkaptonuria is a rare genetic disease, in which amino acids and tyrosine cannot be processed. A 72-year-old man with a history of aortic valve stenosis presented with coronary 3-vessel disease. Intraoperative findings included ochronosis, which is pigmentation caused by the accumulation of homogentistic acids in connective tissues, or on the severely calcified aortic valve, the intima of the aorta, and the coronary arteries. The pigmented region of the coronary arteries had significant stenosis. Aortic valve replacement and coronary artery bypass were performed. From these findings and his past history of arthritis, we diagnosed alkaptonuria. The patient had an uneventful recovery.

Rev. bras. anestesiol ; 68(3): 307-310, May-June 2018. graf
Article in English | LILACS-Express | LILACS | ID: biblio-958296


Abstract The current case report describes two cases of alkaptonuric ochronosis for anesthetic management. Alkaptonuria is a rare genetic orphan disease of tyrosine metabolism characterized by an accumulation of homogentisic acid in cartilage and connective tissues. Patients present most commonly for orthopedic joint surgery due to progressive arthropathy that can be misdiagnosed many a times. However respiratory, airway, cardiovascular and genitourinary systems complications can occur with age progressing. Restricted range of motion of cervical spine may lead to difficulty with airway management. In addition, degenerative changes and stiffness of lumbar spine due to ochronosis would make neuraxial blockade challenging. Although this inherited condition is extremely rare, anesthesiologists should be aware of its existence and prepare for management of potential challenging problems. This report highlights special care and precautions that need to be taken during anesthetic management.

Resumo Este relato descreve o manejo anestésico em dois casos de ocronose alcaptonúrica. Alcaptonúria é uma doença genética rara do metabolismo de tirosina caracterizada por acúmulo de ácido homogentísico em cartilagem e tecidos conjuntivos. Os pacientes geralmente recorrem à cirurgia ortopédica devido à artropatia progressiva, que, muitas vezes, pode ser diagnosticada incorretamente. No entanto, complicações das vias respiratórias, cardiovasculares e geniturinárias podem ocorrer com o avanço da idade. A restrição de mobilidade da coluna cervical pode levar ao manejo difícil das vias aéreas. Além disso, as alterações degenerativas e a rigidez da coluna lombar devido à ocronose podem tornar o bloqueio neuroaxial um desafio. Embora essa condição hereditária seja extremamente rara, os anestesiologistas devem estar cientes de sua existência e se preparar para o manejo de potenciais problemas desafiadores. Este relato destaca os cuidados e as precauções especiais que devem ser tomadas durante o manejo anestésico.

Article in English | WPRIM | ID: wpr-715206


Alkaptonuria (AKU, OMIM: 203500) is a rare autosomal recessive disorder of tyrosine metabolism due to a defect of enzyme activity, homogentisate 1,2-dioxygenase (HGD). The patients with AKU initially presented with dark urine discoloration, and ochronosis and arthritis develop after third decades of life. With advances of Internet resources, web-based health seekers for rare disease are increasing. Here, we report the case of an 18-year-old boy with AKU who visited our center due to dark black urine based on self-diagnosis via web searching of this rare condition. Compound heterozygous mutations in HGD gene, IVS5+3A>C and IVS12+6T>C were identified and both of mutations were detected in his parents. Our case illustrates the utility of publicly available Internet resources for diagnosis of rare disease.

Adolescent , Alkaptonuria , Arthritis , Databases, Genetic , Diagnosis , Homogentisate 1,2-Dioxygenase , Humans , Internet , Male , Metabolism , Ochronosis , Parents , Rare Diseases , Tyrosine
Surg. cosmet. dermatol. (Impr.) ; 8(4): 370-372, out.-dez. 2016. ilus
Article in English, Portuguese | LILACS-Express | LILACS | ID: biblio-877372


Ocronose exógena é doença cutânea rara, geralmente associada ao uso tópico de hidroquinona. Leva à hiperpigmentação acinzentada ou preto-azulada, devido à deposição dérmica de pigmento ocre. Não existe tratamento padronizado, e as opções terapêuticas são em geral frustrantes. Relatamos o caso de uma paciente com ocronose exógena após uso de hidroquinona, tratada com laser fracionado de CO2 e apresentando resultado bastante satisfatório.

Exogenous Ochronosis is a rare skin disease. It is usually associated with the topical use of hydroquinone, resulting in a grayish or bluish black hyperpigmentation due to dermal deposition of ocher pigment. There is no gold standard treatment and the therapeutic options are generally not effective. We report a case of a patient with exogenous achronosis after use of Hydroquinone, treated with CO2 Laser and showing very good results.

Rev. AMRIGS ; 60(4): 374-376, out.-dez. 2016. ilus
Article in Portuguese | LILACS | ID: biblio-847864


A Alcaptonúria é uma doença autossômica recessiva rara caracterizada pelo acúmulo de ácido homogentísico. Denomina-se também ocronose e manifesta-se por pigmentação azulada de tecidos orgânicos e urina enegrecida, além de artropatia. A seguir, será relatado o caso de irmãos portadores de artropatia ocronótica e a conduta ortopédica (AU)

Alkaptonuria is a rare autosomal recessive disease characterized by the accumulation of homogentisic acid. It is also called ochronosis and is manifested by bluish pigmentation of organic tissues and blackened urine, besides arthropathy. Here the authors report the case of siblings with ochronotic arthropathy and the orthopedic management (AU)

Humans , Male , Female , Middle Aged , Alkaptonuria/diagnosis , Alkaptonuria/genetics , Ochronosis/diagnosis , Ochronosis/genetics , Joint Diseases/diagnosis , Joint Diseases/therapy , Siblings
Article in English | WPRIM | ID: wpr-28316


Ochronosis is a musculoskeletal manifestation of alkaptonuria, a rare hereditary metabolic disorder occurs due to the absence of homogentisic acid oxidase and leading to various systemic abnormalities related to deposition of homogentisic acid pigmentation (ochronotic pigmentation). The present case reports the clinical features, radiographic findings, treatments and results of a cervical spondylotic myelopathy woman patient due to the ochronotic arthropathy of the cervical spine. The patient aged 62 years was presented with gait disturbance and hand clumsiness. Physical examination, X-rays, computed tomography and lab results of the urine sample confirmed the presence of ochronosis with the involvement of the cervical spine. The patient underwent a modified cervical laminoplasty due to multi-segment spinal cord compression. The postoperative follow-up showed a good functional outcome with patient satisfaction. The present study concludes the conditions and important diagnostic and surgical aspects of a patient. It is necessary to identify the condition clinically and if cord compression is observed, appropriate surgical interventions needs to be instituted.

Alkaptonuria , Female , Follow-Up Studies , Gait , Hand , Homogentisate 1,2-Dioxygenase , Homogentisic Acid , Humans , Ochronosis , Patient Satisfaction , Physical Examination , Pigmentation , Spinal Cord Compression , Spinal Cord Diseases , Spine
Rev. bras. ortop ; 49(6): 675-680, Nov-Dec/2014. graf
Article in English | LILACS | ID: lil-732901


Alkaptonuria is a rare metabolic disease in which a deficiency of the enzyme homogentisate dioxygenase causes an accumulation of homogentisic acid. Ochronosis consists of excessive deposition of homogentisic acid in the connective tissue and presents as a chestnut brown or black pigmentation. With aging, the accumulation of pigments from homogentisic acid in the joints causes osteoarthrosis. There is no specific treatment for the disease and the approach is symptomatic. Arthroplasty is the solution for severe cases of osteoarthrosis caused by this pathological condition and presents results comparable to those from patients with primary osteoarthrosis. Here, the case of a 67-year-old patient who underwent several arthroplasty procedures because of osteoarthrosis caused by this rare pathological condition is presented. The last surgical intervention consisted of total right knee arthroplasty...

A alcaptonúria é uma doença metabólica rara em que a deficiência da enzima ácido homogentísico-oxidase provoca uma acumulação de ácido homogentísico. A ocronose consiste na deposição excessiva de ácido homogentísico no tecido conjuntivo e apresenta-se como uma pigmentação acastanhada ou preta. Com o envelhecimento, a acumulação de pigmentos de ácido homogentísico nas articulações provoca osteoartrose. Não existe um tratamento específico para a doença e a abordagem é sintomática. A artroplastia é a solução para casos graves de osteoartrose causada poressa patologia e apresenta resultados compa-ráveis aos doentes com osteoartrose primária. Os autores apresentam o caso de um doente de 67 anos submetido a várias artroplastias, em virtude da osteoartrose causada por essa rara patologia. A última intervenção cirúrgica foi uma artroplastia total do joelho direito...

Humans , Male , Aged , Alkaptonuria , Arthroplasty, Replacement, Knee , Knee , Osteoarthritis
An. bras. dermatol ; 89(5): 799-801, Sep-Oct/2014. tab, graf
Article in English | LILACS | ID: lil-720794


Alkaptonuria, also called endogenous ochronosis, is a rare metabolic autosomal recessive disorder. It occurs by complete inhibition of homogentisic acid oxidase enzyme having its deposition in various tissues. Male patient, 52 years old, sought medical help complaining about progressive appearance of hyperchromic papules on the lateral edge of the second finger of both hands for 02 years. He also complained about darkening of urine, sperm and underwear. Incisional biopsy of second hand finger and test for homogentisic acid in the urine results were positive. The findings are compatible with the diagnosis of alkaptonuria. Given these findings, treatment was initiated, followed-up by other specialties and he was advised to avoid certain foods.

Humans , Male , Middle Aged , Alkaptonuria/pathology , Ochronosis/pathology , Sclera/pathology , Skin/pathology , Biopsy
Article in Korean | WPRIM | ID: wpr-656418


In this report, a case of a black meniscus with underlying ochronosis is described. Further analysis by laboratory findings showed that the patient had underlying alkaptonuria, which was previously undiagnosed. The patient's symptoms showed improvement after arthroscopic treatment.

Alkaptonuria , Arthroscopy , Humans , Knee , Ochronosis
Indian J Biochem Biophys ; 2013 Oct; 50(5): 339-344
Article in English | IMSEAR | ID: sea-150243


Alkaptonuria (AKU) is a very rare autosomal recessive disorder of tyrosine metabolism in the liver due to deficiency of homogentisate 1,2 dioxygenase (HGD) activity, resulting in the accumulation of homogentisic acid (HGA). Circulating HGA pass into various tissues through-out the body, mainly in cartilage and connective tissues, where its oxidation products polymerize and deposit as a melanin-like pigment. Gram quantities of HGA are excreted in the urine. AKU is a progressive disease and the three main features, according the chronology of appearance, are: darkening of the urine at birth, then ochronosis (blue-dark pigmentation of the connective tissue) clinically visible at around 30 yrs in the ear and eye, and finally a severe ochronotic arthropathy at around 50 yrs with spine and large joints involvements. Cardiovascular and renal complications have been described in numerous case report studies. A treatment now is available in the form of a drug nitisinone, which decreases the production of HGA. The enzymatic defect in AKU is caused by the homozygous or compound heterozygous mutations within the HGD gene. This disease has a very low prevalence (1:100,000-250,000) in most of the ethnic groups, except Slovakia and Dominican Republic, where the incidence has shown increase up to 1:19,000. This review highlights classical and recent findings on this very rare disease.

Alkaptonuria/complications , Alkaptonuria/genetics , Alkaptonuria/metabolism , Alkaptonuria/therapy , Homogentisic Acid/metabolism , Humans , Melanins/biosynthesis , Ochronosis/complications
An. bras. dermatol ; 87(4): 633-636, July-Aug. 2012. ilus
Article in English | LILACS | ID: lil-645338


Exogenous ochronosis is a rare, cosmetically disfiguring condition, resulting from the longterm use of topical hydroquinone in treatment of melasma. It manifests as gray-brown or blue-black macules in hydroquinone-exposed regions. The exact incidence of ochronosis is unknown. High rates have been reported in the South African population, and it is rare in the United States. We report the case of a patient who developed exogenous ochronosis while using topical hydroquinone. It is necessary to recognize this disorder at the earliest stage and discontinue hydroquinone immediately, as its treatment is difficult. Sun exposure facilitates the formation of exogenous ochronosis and must be strictly avoided, although it is a practical problem in the tropical climate of Brazil, particularly for those who work outdoors.

Ocronose exógena é uma condição rara, cosmeticamente desfigurante, devido ao uso tópico indiscriminado de hidroquinona para tratamento do melasma. Manifesta-se como máculas marrom-acinzentadas ou preto-azuladas em áreas cutâneas do uso de hidroquinona. A exata incidência de ocronose Exógena é desconhecida. Altos índices têm sido relatados em populações sul-africanas, sendo rara nos Estados Unidos. Relatamos um caso de uma paciente que desenvolveu ocronose Exógena durante uso de hidroquinona para tratamento do melasma. É necessário o reconhecimento dessa patologia no seu estágio precoce e imediata descontinuação da droga, pois seu tratamento é difícil. A exposição solar é um fator precipitante e deve ser estritamente evitada, embora isso seja difícil no clima tropical do Brasil, especialmente para aqueles que trabalham ao ar livre.

Female , Humans , Middle Aged , Dermatologic Agents/adverse effects , Hydroquinones/adverse effects , Melanosis/drug therapy , Ochronosis/chemically induced , Ochronosis/pathology
Rev. colomb. reumatol ; 18(4): 304-310, oct.-dic. 2011. ilus
Article in Spanish | LILACS | ID: lil-636875


La ocronosis es la manifestación de la alcaptonuria en el tejido conjuntivo, se origina por la alteración en el metabolismo del ácido homogentísico, producto de la mutación autosómica recesiva del gen HGO, en el brazo largo del cromosoma 3 (3q21-23). Es una patología infrecuente, que se caracteriza por la presencia de calcificaciones de los discos intervertebrales y depósito de ácido homogentísico en el tejido conjuntivo y los tendones. Se presentan dos casos compatibles con las características clínicas y radiológicas de ocronosis.

Ochronosis is the manifestation of alkaptonuria in the connective tissue. It is originated by the alteration in the metabolism of homogentisic acid, a product of autosomal recessive mutation of HGO, gene in the long arm of chromosome 3 (3q21-23). It is a rare disease, characterized by the presence of calcifications in the intervertebral discs and deposit of homogentisic acid in connective tissue and tendons. We present two compatibles cases with the clinical and radiological features of ochronosis.

Humans , Female , Middle Aged , Ochronosis , Connective Tissue , Alkaptonuria , Homogentisic Acid , Mutation
An. bras. dermatol ; 86(4,supl.1): 31-34, jul,-ago. 2011. ilus
Article in Portuguese | LILACS | ID: lil-604114


A ocronose exógena consiste em hiperpigmentação crônica de áreas previamente tratadas com agentes tópicos como: a hidroquinona, a resorcina, os antimaláricos e o fenol. O diagnóstico precoce permite suspender prontamente o agente causador, uma vez que as opções terapêuticas disponíveis são escassas e com resultados insatisfatórios. Reportam-se três casos de ocronose exógena na face, diagnosticados pela dermatoscopia. O estudo dermatoscópico evidenciou estruturas amorfas de coloração cinza-enegrecido, algumas obliterando as aberturas foliculares. O exame histopatológico corroborou o diagnóstico.

Exogenous ochronosis consists of chronic hyperpigmentation of areas previously treated with topical agents such as hydroquinone, resorcinol, antimalarials and phenol. Early diagnosis allows to promptly suspend the causative agent and it is imperative since the available therapeutic options are scarce and have presented so far unsatisfactory results. Three cases of exogenous ochronosis on the face which were diagnosed with the use of dermoscopy are presented. Dermatoscopy showed blackish-gray amorphous structures, some obliterating the follicular openings. Histopathological examination confirmed the diagnosis.

Adult , Female , Humans , Middle Aged , Dermoscopy , Dermatologic Agents/adverse effects , Facial Dermatoses/chemically induced , Hydroquinones/adverse effects , Ochronosis/chemically induced , Facial Dermatoses/diagnosis , Hyperpigmentation/diagnosis , Ochronosis/diagnosis
An. bras. dermatol ; 85(5): 699-703, set.-out. 2010. ilus
Article in Portuguese | LILACS | ID: lil-567834


A ocronose exógena é uma dermatose, aparentemente pouco frequente, caracterizada por hiperpigmentação negro-azulada fuliginosa, localizada na região onde foi aplicado o agente causador. Pode ser causada por uso de medicamentos sistêmicos, os antimaláricos e de uso tópico, como fenol, resorcinol, benzeno, ácido pícrico e a hidroquinona - que é um composto fenólico, com propriedade despigmentante, muito utilizado em formulações dermatológicas para o tratamento de melasma e outras hiperpigmentações. A fisiopatogenia deste processo ainda não está esclarecida e as abordagens terapêuticas são insatisfatórias. Relatam-se quatro casos de pacientes do sexo feminino que, após uso de preparados contendo hidroquinona, desenvolveram hiperpigmentação acentuada na face, caracterizadas no exame dermatológico e histopatológico como ocronose. Enfatiza-se a possibilidade de casos de ocronose exógena estarem sendo diagnosticados erroneamente, como falha de tratamento de melasma, e também para os riscos do uso indiscriminado de formulações, contendo hidroquinona, muitas vezes, sem acompanhamento médico.

Exogenous ochronosis is an infrequent dermatosis characterized as a dark blue hyperpigmentation localized where the causing agent was applied. It may be caused by the use of systemic medication such as antimalarials and by the use of topic substances such as phenol, resorcinol, benzene, or hydroquinone, which is a fenolic compound with depigmentation action, largely used in the treatment of melasma and other hyperpigmentation. The physiopathology of this process is not well clear up to this moment, and the therapeutic measures are not satisfactory either. Here we present four cases of female patients that developed hyperpigmentation on their faces after the use of hydroquinone containing compounds, characterized clinically and histological as ochronosi. We emphasize the possibility of exogenous ochronosis cases being misdiagnosed as a melasma treatment failure. We also emphasize the risks of the indiscriminated use of hydroquinone containing compounds, used, in many instances, without medical prescription.

Adult , Female , Humans , Middle Aged , Dermatologic Agents/adverse effects , Facial Dermatoses/chemically induced , Hydroquinones/adverse effects , Ochronosis/chemically induced , Dermatologic Agents/administration & dosage , Facial Dermatoses/pathology , Hydroquinones/administration & dosage , Melanosis/drug therapy , Ochronosis/diagnosis , Ochronosis/pathology
Surg. cosmet. dermatol. (Impr.) ; 2(4): 319-321, Out.-Dez. 2010. ilus.
Article in English, Portuguese | LILACS-Express | LILACS | ID: biblio-884031


Introdução: A ocronose exógena caracteriza-se por hiperpigmentação assintomática preto-azulada localizada tipicamente na face, no pescoço, no dorso e nas superfícies extensoras das extremidades. Resulta mais comumente do uso de hidroquinona. Objetivo: Enfatizar o uso de várias modalidades terapêuticas para se obter resultado satisfatório no tratamento. Método: O tratamento foi iniciado com laser de Nd:YAG. Sem resposta, foi indicado o laser de CO2 ultrapulsado. Ainda sem resultados satisfatórios, associou-se luz intensa pulsada, microdermoabrasão e peelings químicos. Resultado: resolução completa das lesões. Conclusão: Ocronose exógena é patologia de difícil tratamento, sendo necessária, às vezes, associação de vários métodos para a resolução completa.

Introduction: Exogenous ochronosis is characterized by asymptomatic black-bluish hyperpigmentation, typically located in the face, neck, dorsum and the extensor surfaces of the extremities. It most frequently results from using hydroquinone. Objective:To highlight the use of several therapeutic modalities in order to obtain satisfactory treatment results. Method: The treatment began with the application of Nd:YAG laser. Since there was no response, ultrapulse CO2 laser was indicated. Still without satisfactory results, a combination of intense pulsed light, microdermabrasion and chemical peels was carried out. Results: The total resolution of the lesions was verified. Conclusion: Exogenous ochronosis is difficult to treat, sometimes requiring the combination of several treatment methods.