Heterocromia de íris: uma revisão das condições que podem afetar a pigmentação iridiana / Heterochromia: a review of conditions that may affect iris pigmentation

RESUMO A íris é responsável pela cor dos olhos. Ela ainda realiza o controle da quantidade de luz que penetra no olho pela pupila. Variações nos genes de cada indivíduo, além da quantidade e da qualidade de melanina na íris, determinam a cor dos olhos. A heterocromia é caracterizada por diferenças na coloração da íris de um mesmo indivíduo, sendo, na maioria das vezes, benigna. Existem basicamente três tipos de heterocromia de íris: central, setorial e completa. A heterocromia de íris pode ter como causa alterações genéticas e congênitas, relacionadas ou não a síndromes específicas, como a de Sturge-Weber, a de Waardenburg, a de Parry-Romberg e a de Horner congênita. Há também causas adquiridas, como doenças ou lesões, trauma ocular e corpos estranhos intraoculares, uso de certas medicações tópicas, siderose ocular, irites ou uveítes como a síndrome uveítica de Fuchs, dentre outras. Diante de um paciente com heterocromia de íris, deve-se entender o contexto e o curso clínico desse sinal, pois pode se tratar de uma alteração de pigmentação benigna ou existir uma doença base em curso, que requer terapêutica específica. Este artigo de revisão de literatura visa abordar as principais etiologias relacionadas à heterocromia de íris, além de discorrer sobre a anatomia e a fisiologia da coloração iridiana e sobre a fisiopatologia de suas possíveis alterações.

ABSTRACT The iris is responsible for eye color and controls the amount of light that enters the eye through the pupil. Variation in each individual's genes, besides the quantity and quality of melanin in the iris, determine eye color. Heterochromia is characterized by different colors of irises in the same individual, and it is benign in most cases. There are basically three types of heterochromia: central, partial and complete. Heterochromia can be caused by genetic and congenital alterations, which may or may not be related to specific conditions, such as Sturge-Weber syndrome, Waardenburg syndrome, Parry-Romberg syndrome and congenital Horner syndrome. It may be associated to acquired causes like diseases or injuries, such as eye trauma and intraocular foreign bodies, use of some topical medications, ocular siderosis, iritis or uveitis, such as Fuchs´ uveitis, among others. When assessing a patient with heterochromia, one must understand the context and clinical course of this signal, since it may be a benign pigmentation disorder or there may be an underlying disease, which requires specific therapy. This literature review article was set out to address the main etiologies related to heterochromia, in addition to describing the anatomy and physiology of the iris color and the pathophysiology of possible alterations.

Presentación clínica de pigmentación melánica fisiológica / Clinical presentation of physiologic melanin pigmentation

Las pigmentaciones de la cavidad oral son comunes, éstas pueden representar diversas entidades clínicas, desde cambios fisiológicos hasta cambios malignos. Las pigmentaciones en la encía se conocen como pigmentaciones melánicas o melanosis gingival; en la encía se observan como tinciones oscuras ocasionadas por la acumulación de melanina en la zona. Éstas se consideran comunes, pueden representar variación normal en la pigmentación de melanina de la mucosa oral, hasta representar procesos malignos. En general, las personas de piel más oscura presentan frecuentemente mayor pigmentación de melanina oral que las personas de piel clara. Las variaciones en la pigmentación fisiológica oral están determinadas genéticamente a menos que estén asociadas con alguna enfermedad subyacente (AU)

Pigmentation of the oral cavity is common, it can represent diverse clinical entities, from physiological changes to malignant changes. Gum pigmentations are known as melanic pigmentations or gingival melanosis, and are observed as dark stains caused by the accumulation of melanin in the localized area. These are considered common, they can represent normal variation in melanin pigmentation of the oral mucosa, or malignant processes. In general, people with darker skin often exhibit greater pigmentation of oral melanin than people with fair skin. Variations in oral physiological pigmentation are genetically determined unless they are associated with some underlying disease (AU)

Analysis of ADAR1 gene variants in two pedigrees affected with dyschromatosis symmetrica hereditaria / 中华医学遗传学杂志

OBJECTIVE@#To detect variants of ADAR1 gene in two Chinese pedigrees affected with dyschromatosis symmetrica hereditaria (DSH).@*METHODS@#Clinical data and peripheral blood samples of the pedigrees were collected. All exons of the ADAR1 gene were amplified by PCR and subjected to Sanger sequencing. Suspected pathogenic variants were validated among other members of the pedigrees and 100 unrelated healthy controls.@*RESULTS@#For pedigree 1, Sanger sequencing has identified a heterozygous missense variant c.3002G>C (p.Asp968His) in exon 11 of the ADAR1 gene in the proband and his father. For pedigree 2, a novel nonsense variant c.3145C>T (p.Gln1049Ter) was identified in exon 12 of the ADAR1 gene in the proband and his son, which were previously unreported and absent among the healthy controls.@*CONCLUSION@#The c.3002G>C (p.Asp968His) and c.3145C>T (p.Gln1049Ter)variants of the ADAR1 gene probably underlay the DSH in the two pedigrees.

Dyschromatosis universalis hereditaria: Infrequent genodermatoses in India.

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis reported initially and mainly in Japan. However, subsequent cases have been reported from other countries. We report a case of DUH in a south Indian woman with a positive family history with cosmetic disfigurement and severe psychological impairment.

Cutaneous mosaicisms: concepts, patterns and classifications / Mosaicismos cutaneos: conceitos, padroes e classificacoes

A mosaic is an organism composed of two or more genetically distinct cell populations derived from a genetically homogeneous zygote. Cutaneous mosaicisms are the clinical expressions of these disorders. The main event which allows the existence of mosaicism is a genetic mutation, either structural or functional. Cutaneous mosaicisms usually manifest by specific patterns on the skin and the archetypic pattern is the system of Blaschko lines, but others include checkerboard, phylloid, large patches without midline separation and lateralization. Since 1901, when Blaschko lines were first described, the study of mosasicism has helped to elucidate the behavior of numerous genetic diseases, generating therapeutic perspectives for these pathologies, including the promising gene therapy.

Um mosaico é um organismo formado por duas ou mais populações de células geneticamente distintas originadas a partir de um mesmo zigoto geneticamente homogêneo. Os mosaicismos são as expressões clínicas dessa desordem, e a mutação gênica seu evento determinante, que pode ser tanto estrutural quanto funcional. Os mosaicismos cutâneos costumam se expressar em padrões específicos, dentre os quais podem ser mencionados as prevalentes linhas de Blaschko, o padrão "checkerboard", o padrão filóide, o padrão em placa sem separação na linha média e o padrão de lateralização, que serão abordados neste artigo. Desde 1901, momento da primeira descrição das linhas de Blaschko, o estudo dos mosaicismos tem contribuído para a elucidação do comportamento de numerosas desordens genéticas, de forma a criar perspectivas terapêuticas para essas doenças, incluindo a promissora terapia gênica.

Mechanisms regulating melanogenesis* / Mecanismos reguladores da melanogênese

Skin pigmentation is an important human phenotypic trait whose regulation, in spite of recent advances, has not yet been fully understood. The pigment melanin is produced in melanosomes by melanocytes in a complex process called melanogenesis. The melanocyte interacts with endocrine, immune, inflammatory and central nervous systems, and its activity is also regulated by extrinsic factors such as ultraviolet radiation and drugs. We have carried out a review of the current understanding of intrinsic and extrinsic factors regulating skin pigmentation, the melanogenesis stages and related gene defects. We focused on melanocyte-keratinocyte interaction, activation of melanocortin type 1 receptor (MC1-R) by peptides (melanocyte-stimulating hormone and adrenocorticotropic hormone) resulting from proopiomelanocortin (POMC) cleavage, and mechanisms of ultraviolet-induced skin pigmentation. The identification and comprehension of the melanogenesis mechanism facilitate the understanding of the pathogenesis of pigmentation disorders and the development of potential therapeutic options.

A pigmentação da pele é um importante traço fenotípico do ser humano mas apesar dos recentes avanços a sua regulação não está ainda totalmente esclarecida. O pigmento melanina é produzido nos melanossomas pelos melanócitos, num processo complexo designado por melanogénese. O melanócito interatua com os sistemas endócrino, imunitário, inflamatório e nervoso central e a sua atividade é também regulada por fatores extrínsecos como a radiação ultravioleta e fármacos. Fizemos uma revisão do conhecimento atual sobre os fatores intrínsecos e extrínsecos reguladores da pigmentação cutânea, etapas da melanogénese e defeitos genéticos relacionados. Fizemos enfoque na interação melanócito-keratinócito, na ativação do receptor da melanocortina tipo 1 (MC1-R) pelos péptidos (hormona estimuladora do melanócito e hormona adrenocorticotrófica) resultantes da clivagem da proopiomelanocortina (POMC) e mecanismos da pigmentação induzida pela radiação ultravioleta. A identificação e compreensão dos mecanismos reguladores da pigmentação cutânea facilitam o conhecimento dos mecanismos patogénicos dos distúrbios da pigmentação e o desenvolvimento de potenciais opções terapêuticas.

Reticulate pigmentary disorders.

Reticulate pigmentary disorders is a term that is loosely defined to include a spectrum of acquired and congenital conditions with different morphologies. The presentations vary from the reticular or net like pattern to the" freckle like" hyper and hypopigmented macules that are usually restricted to the true genetic "reticulate" pigmentary disorders. There is little clarity on this topic and related terms, in major dermatology textbooks. Hence, to harmonize the different entities we feel that the term "mottled pigmentation" could be used to include reticulate pigmentary disorders (acquired and congenital), dyschromasias and the disorders with a reticular pattern. The genetic reticulate pigmentary disorders can also be classified according to the gene loci which in the majority of cases are localized to keratin 5/14. A more useful clinical method of classification is based on the regional distribution, which includes facial, truncal, acral or flexural types. In this review we will largely focus on the inherited reticulate pigmentary disorders.

Doença de Dowling-Degos: apresentação clínica e histopatológica clássica / Dowling-Degos disease: classic clinical and histopathological presentation

A doença de Dowling-Degos é uma genodermatose rara que consiste numa desordem pigmentar reticulada. Caracteriza-se pela presença de máculas hiperpigmentadas nas regiões flexurais com distribuição em rede; lesões tipo comedão no dorso e na região cervical; e cicatrizes cribriformes na face, particularmente periorais. Apresentamos um caso de um paciente de 51 anos, masculino, com lesões tipo macrocomedões, cicatrizes cribriformes, cistos e máculas hipercrômicas no dorso, tórax anterior, axilas, pescoço, região genital e face. Relatava ter dois filhos, três irmãos e o pai com quadro semelhante. As biópsias de pele foram características da doença de Dowling-Degos, mostrando dilatação folicular, epiderme digitiforme, com áreas de aspecto de "chifre de veado" e focos de hiperpigmentação da camada basal.

Dowling-Degos disease (DDD) is a rare genetic disease of the skin (reticulate pigmented anomaly), clinically characterized by flexural brown pigmented reticulate macules, comedo-like papules on the back, neck and pitted perioral or facial scars. We present the case of a 51 year-old man with macrocomedo-like lesions, pitted scars, cysts, hyperpigmented macules in his back, chest, axillae, neck, groin and face. The patient reported having two children, three brothers and a father with a similar condition. The histopathology of the skin biopsies was very characteristic of Dowling-Degos disease, showing dilated follicular, fingerlike projections called rete ridges (dermal pegs), with thinning of the suprapapillary plates, resulting in an "antler-like" pattern and increased pigmentation of the basal layer.

Caso para diagnóstico / Case for diagnosis

A discromatose simétrica hereditária (acropigmentação de Dohi) é alteração pigmentar rara, genética, com padrão de herança autossômica dominante. Caracteriza-se por máculas hiper e hipocrômicas com padrão mosqueado e distribuição acral. Apresenta-se paciente masculino, 13 anos, com máculas hiper e hipocrômicas disseminadas no dorso das mãos e pés, além de efélides na face e lesões atróficas lineares periorbitárias. É necessário o diagnóstico diferencial com as outras pigmentações reticuladas.

Dyschromatosis symetrica hereditaria (reticulate acropigmentation of Dohi) is a rare autosomal dominant disease. It starts as hyperpigmented and hypopigmented macules in reticular pattern on the extremities. We present a case of a 13-year old boy that showed hyper and hypopigmented macules distributed on the dorsal aspects of the extremities, freckle-like pigmented macules on the face and periorbital atrophic linear lesions. Differentiation with others reticulate pigmentation manifestations is necessary.

Caso para diagnóstico / Case for diagnosis

O piloleiomioma é uma neoplasia benigna originada do músculo eretor do pelo. Atinge adultos jovens, sem predileção por sexo. As lesões podem ser solitárias ou múltiplas, acometem mais frequentemente as extremidades e costumam apresentar dor espontânea ou após estímulos físicos. Descreve-se um caso de piloleiomioma múltiplo unilateral em paciente jovem do sexo feminino, com queixa de prurido nas lesões.

Piloleiomyoma is a benign neoplasm arising from the erector pilorum muscle in the skin. It occurs in young adults of both genders. Lesions can be single or multiple and more frequently involve extremities. Pain may occur spontaneously or after physical stimulation. We describe a case of unilateral multiple piloleiomyoma in a young woman, complaining of itching lesions.

Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.

Primary pigmented nodular adrenocortical disease and Cushing's syndrome

Primary pigmented nodular adrenocortical disease (PPNAD) is a form of bilateral adrenocortical hyperplasia that is often associated with corticotrophin (ACTH)-independent Cushing's syndrome (CS) and is characterized by small to normal-sized adrenal glands containing multiple small cortical pigmented nodules (1,2). PPNAD may occur in an isolated form or associated with a multiple neoplasia syndrome, the complex of spotty skin pigmentation, myxomas, and endocrine overactivity, or Carney complex, in which Cushing's syndrome is the most common endocrine manifestation (3). Molecular studies have led to the identification of several genes, defects in which may predispose PPNAD formation; all of these molecules play important role for the cAMP signaling pathway. This review intends to present the most recent knowledge of the pathology and molecular genetics of the benign bilateral adrenocortical lesions, as well as to discuss the modern tools for diagnostics and treatment of this condition.

A doença adrenocortical nodular pigmentada primária (PPNAD) é uma forma de hiperplasia adrenocortical bilateral que está freqüentemente associada com a síndrome de Cushing (SC) ACTH-independente, sendo caracterizada por glândulas adrenais de tamanho pequeno ou normal contendo múltiplos nódulos corticais pigmentados pequenos. PPNAD pode ocorrer de forma isolada ou associada com uma síndrome de neoplasia múltipla, o complexo de manchas pigmentadas na pele (lentigíneas), mixomas e hiperatividade endócrina, ou complexo de Carney, no qual a SC é a manifestação endócrina mais comum. Estudos moleculares levaram à identificação de vários genes que, quando mutados, podem predispor à formação da PPNAD; todas essas moléculas têm um papel importante na via de sinalização do AMPc. Esta revisão pretende apresentar os conhecimentos mais recentes sobre a patologia e a genética molecular das lesões adrenocorticais benignas bilaterais e discutir os modernos instrumentos para diagnóstico e tratamento dessa condição.

Acropigmentación reticulada de Kitamura / Kitamura's reticulated acropigmentation

Se presentan tres casos de acropigmentación reticulada de Kitamura y se especifican sus caracteres clínicos e histopatológicos, marcando similitudes y diferencias con comunicaciones anteriores de otros autores. Se incluye el diagnóstico diferencial con otras afecciones hiperpigmentadas, de patrón reticulada acral y general