[Alkaptonuria: evolution and course of the disease towards ochronotic arthropathy. Series of cases managed with joint replacement]. / Alcaptonuria: evolución y curso de la enfermedad hacia artropatía ocronótica. Serie de casos manejados con reemplazo articular.

INTRODUCTION: alkaptonuria is a very rare metabolic disease with autosomal recessive inheritance due to HGA oxidase deficiency. Classically described and diagnosed in the third to fourth decade of life, affecting both men and women; Its diagnostic impression is clinical based on the blue/black coloration of the conjunctivae, however it is confirmed by the specific analysis of the enzyme in the urine, to date there is no cure and its treatment is palliative and symptomatic. MATERIAL AND METHODS: descriptive, observational, case series study, the primary objective of which is to describe the progression of the disease and its involvement in the musculoskeletal system. RESULTS: two clinical cases are presented in women and men in which the broad clinic is illustrated, its progressive advance and the different alterations that it can generate in the musculoskeletal system. CONCLUSIONS: alkaptonuria is a rare disease which leads to a severe secondary arthropathy, currently without a specific management which is based on treating the symptoms, in its final stages joint replacements are a management option with satisfactory results for the relief of pain.

INTRODUCCIÓN: la alcaptonuria es una enfermedad metabólica inusual, de herencia autosómica recesiva dada por la deficiencia de la oxidasa de HGA. Clásicamente descrita y diagnosticada sobre la tercera a cuarta década de la vida, la cual tiene afectación en ambos sexos, su impresión diagnóstica es clínica, basándose en la coloración azul/negro de las conjuntivas; sin embargo, se confirma mediante el análisis específico de la enzima en la orina, actualmente no existe un tratamiento definitivo, sólo alternativas en cuanto a lo paliativo y sintomático. MATERIAL Y MÉTODOS: estudio descriptivo, observacional, de tipo serie de casos, como objetivo primario se describe la progresión de la enfermedad y su compromiso en el sistema musculoesquelético. RESULTADOS: se presentan dos casos clínicos en mujer y hombre, los cuales ilustran: variedad clínica, avance progresivo y las alteraciones que puede generar en el sistema musculoesquelético. CONCLUSIONES: la alcaptonuria es una enfermedad rara, la cual conlleva una artropatía secundaria severa, sin un tratamiento definitivo dirigido a tratar los síntomas, incluso en sus estadios finales los reemplazos articulares son una opción para proporcionar manejo del dolor obteniendo resultados satisfactorios.

Más de 100 años de evolución en el estudio de los errores innatos del metabolismo / Over 100 years of evolution in the field of inborn errors of metabolism

Durante la primera década del pasado siglo, Archibal Garrold definía el concepto de individualidad química al referirse a los Errores Innatos del Metabolismo (EIM), y en particular a la alcaptonuria.Con la identificación del trastorno metabólico que conduce a la fenilcetonuria (PKU) en 1934, y el impacto del tratamiento nutricional en los pacientes afectados, quedaba demostrado la importancia del diagnóstico temprano de esta enfermedad para el éxito desde el punto de vista terapéutico. Después del desarrollo de los métodos de inhibición enzimática de Guthrie para el tamiz neonatal masivo, implementados en la década del 60 del pasado siglo, los programas para el tamizaje neonatal de la PKU se hicieron obligatorios en los EE. UU y en la mayoría de los países europeos. La PKU ha devenido modelo dentro...(AU)

Menisco negro: ocronosis como hallazgo durante procedimiento artroscópico / Black meniscus. Ochronosis as a finding during arthroscopic procedure

La ocronosis es un signo causado por la acumulación de ácido homogentísico en los tejidos conectivos ricos en colágeno. La enfermedad que subyace a dicho trastorno es la alcaptonuria, un raro trastorno metabólico en el catabolismo de la tirosina y la fenilalanina.Se presentan los casos de dos pacientes con lesiones meniscales, cuyo diagnóstico de alcaptonuria fue constatado tras el hallazgo, en el procedimiento artroscópico, de pigmentación negra en los tejidos de la rodilla. Tipo de estudio: Reporte de casos. Nivel de evidencia: IV

Ochronosis is a sign caused by the accumulation of homogentisic acid in collagen-rich connective tissues. The disease underlying this disorder is alkaptonuria, a rare metabolic disorder in the catabolism of tyrosine and phenylalanine.We present the cases of two patients with meniscal tears whose diagnosis of alkaptonuria was verified after the arthroscopic finding of black pigmentation in the tissues of the knee. Type of study: Case reports. Level of evidence: IV

Exogenous Ochronosis (EO): Skin lightening cream causing rare caviar-like lesion with banana-like pigments; review of literature and histological comparison with endogenous counterpart

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.

Ochronosis Presenting as Methemoglobinemia.

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.

Anesthetic management of two patients with alkaptonuric ochronosis for total knee arthroplasty / Manejo anestésico de dois pacientes com ocronose alcaptonúrica para artroplastia total do joelho

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.

Alcaptonúria (ocronose): relato de caso de irmãos / Alkaptonuria (ochronosis): a case report of siblings

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)

Ochronotic arthropathy as a paradigm of metabolically induced degenerative joint disease. A case-based review.

Alkaptonuria is a rare, hereditary metabolic disorder in which a deficiency in the homogentisate 1,2-dioxygenase enzyme results in an accumulation of homogentisic acid. Deposition of excess homogentisic acid in different intra- and extra-articular structures with high content of connective tissue causes brownish-black pigmentation and weakening, ultimately resulting in tissue degeneration and finally osteoarthritis. Ochronotic arthropathy is considered a rapidly progressive, disabling condition in which weight-bearing joints and the thoracolumbar spine are predominantly affected. Patients often require multiple joint replacements, such as in the case of the patient presented here. At present, there is no definitive cure for ochronosis, and management is predominantly symptomatic.

Instituto de Radium de Minas Gerais: vanguarda da radioterapia no Brasil, 1923-1935 / Minas Gerais Radium Institute: at the forefront of radiotherapy in Brazil, 1923-1935

Este artigo propõe estudar os primeiros 12 anos de existência do Instituto de Radium de Minas Gerais, fundado em 1922. Sua atuação na luta contra o câncer no Brasil, ainda pouco conhecida, começa a ser esboçada pelo estudo de documentação institucional inédita. Através de um banco de dados elaborado com informações constantes em seu livro de registro de pacientes, foram feitos levantamentos estatísticos dos tipos de câncer e das formas de tratamento existentes entre 1923 e 1935. Esse livro faz parte de um conjunto de outros cinco recentemente descobertos no Centro de Memória da Medicina/UFMG. A documentação permite resgatar os primórdios das intervenções de radioterapia no país e acompanhar seu desenvolvimento e a influência exercida por esse hospital modelo.

This article proposes to study the first 12 years of the Minas Gerais Radium Institute, founded in 1922. Its work in the fight against cancer in Brazil, albeit still little known, is coming to light as its institutional documents are studied. A database has been prepared using information from its patient register, based on which statistical analyses have been done to identify the types of cancer and treatments available there between 1923 and 1935. This register is one of five recently unearthed at the Medicine Memory Center of the Universidade Federal de Minas Gerais. Through them, the earliest experiments in radiotherapy in Brazil can be reconstituted, and its development and the influence of this model hospital can be mapped out.

Knee osteoarthrosis secondary to ochronosis -clinical case / Osteoartrose do joelho secundária a ocronose -Caso clínico

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...

Primer reporte de alcaptonuria en el Perú / First report of alkaptonuria in Peru

La alcaptonuria es un error innato del metabolismo causado por la deficiencia de la homogentisiato 1,2 dioxidasa (HGD), produciéndose un exceso de ácido homogentísico (HGA). Se presenta el caso de una mujer de 57 años quien, desde que nació, su orina se tornaba de color negro; desde hacía 9 años presentaba una pigmentación verdosa en los lechos ungueales que no mejoró con tratamientos antifúngicos y en los últimos 9 meses presentó artrosis de articulaciones grandes que fue empeorando, forzándola a usar una silla de ruedas por el intenso dolor generado por la artrosis de caderas y columna lumbar. Por la descripción de los síntomas se le solicitó la medición de HGA en orina lo que confirmó el diagnóstico de alcaptonuria. Se sugirieron analgésicos, dieta sin productos que contuvieran tirosina y fue referida para cirugía de reemplazo de cadera. Se trata del primer reporte de caso de alcaptonuria en el Perú.

Alkaptonuria is an inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD) which produces an excess of homogentisic acid (HGA). A case is presented of a 57 year old woman whose urine has turned black since birth. For 9 years she presented a greenish pigmentation in her nail beds that did not improve with antifungal treatments, and in the last 9 months she showed worsening large joint osteoarthritis. This situation forced her to use a wheelchair due to the intense pain caused by osteoarthritis in her hips and lumbar spine. From the description of symptoms, her urinary HGA was measured which confirmed the diagnosis of alkaptonuria. Analgesics and a diet without tyrosine-containing products were suggested. The patient was also referred for hip replacement surgery. This is the first reported case of alkaptonuria in Peru.

Alkaptonuria--case report.

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.

Alkaptonuria - Case report

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.

[First report of alkaptonuria in Peru]. / Primer reporte de alcaptonuria en el Perú

Alkaptonuria is an inborn error of metabolism caused by deficiency of homogentisate 1,2-dioxygenase (HGD) which produces an excess of homogentisic acid (HGA). A case is presented of a 57 year old woman whose urine has turned black since birth. For 9 years she presented a greenish pigmentation in her nail beds that did not improve with antifungal treatments, and in the last 9 months she showed worsening large joint osteoarthritis. This situation forced her to use a wheelchair due to the intense pain caused by osteoarthritis in her hips and lumbar spine. From the description of symptoms, her urinary HGA was measured which confirmed the diagnosis of alkaptonuria. Analgesics and a diet without tyrosine-containing products were suggested. The patient was also referred for hip replacement surgery. This is the first reported case of alkaptonuria in Peru.

Ocronosis: descripción de dos casos familiares, reseña histórica y revisión de la literatura / Ochronosis: report of two familial cases, historical overview and review of the literature

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.