Acroqueratoelastoidosis de Costa / Acrokeratoelastoidosis of Costa

La acroqueratoelastoidosis de Costa es una genodermatosisde herencia autosónimica dominante con penetrancia incompleta. Es un trastorno de las fibras elásticas exclusivamente cutáneo y a nivel acral. Se caracteriza por la presencia de pápulas eritematosas, amarillentas o del color de la piel normal en la cara marginal de los dedos de las manos o de los pies, que se agrupan, forman placas con aspecto de empedrado y se extienden de forma simétrica al dorso, las palmas y las plantas. El hallazgo histológico patognomónico es la elastorrexis. Se presenta el caso de un niño de 7 años con una acroqueratoelastoidosis que comprometía las manos y los pies, asociada a prurito.

Acrokeratoelastoidosis of Costa is a genodermatosis of autosomal dominant inheritance with incomplete penetrance.It is a cutaneous disorder of the elastic fibers at the acral level.The clinical feature is the presence of erythematous, yellowish or normal skin-colored papules on the marginal aspect of the fingers and/or toes, which agminate to form cobblestone-like plaques and extend symmetrically to the dorsum and palms and soles. The pathognomonic histologic finding is elastorrhexis. We present a 7-year-old boy with acrokeratoelastoidosis involving hands and feet, associated with pruritus.

Focal linear elastosis in a patient with joint hypermobility syndrome.

Focal linear elastosis (FLE) is a benign skin findingcharacterized by hypertrophic linear plaques withabnormal elastic fibers on histology. We present aunique case in which focal linear elastosis occurredin the setting of joint hypermobility syndrome(JHS). Our patient, a 20-year-old man with a medicalhistory significant for symptoms consistent with JHS,had been followed by the rheumatology clinic formany months. He was referred to the dermatologydepartment for further evaluation of asymptomaticlongitudinal bands on his back that had been presentfor many years. He denied trauma but endorsed ahistory of 'stretch marks.' On examination there werenumerous horizontally oriented, firm, linear, yellowto flesh colored bands, all non-tender to palpation.Punch biopsies were performed of involved anduninvolved skin. Histopathology of normal skinrevealed no significant abnormalities whereasinvolved skin demonstrated broadened collagenbundles in the deep dermis. The elastic fiber stain,Verhoeff-Van Gieson, revealed a gross increase in thenumber of elastic fibers, fragmented fibers, fiberswith "paintbrush" or widened-ends, fibers of varyingthickness, and clumped fibers. This combination ofhistopathologic and clinical features was consistent with FLE.

Fibulin-4 E57K Knock-in Mice Recapitulate Cutaneous, Vascular and Skeletal Defects of Recessive Cutis Laxa 1B with both Elastic Fiber and Collagen Fibril Abnormalities.

Fibulin-4 is an extracellular matrix protein essential for elastic fiber formation. Frameshift and missense mutations in the fibulin-4 gene (EFEMP2/FBLN4) cause autosomal recessive cutis laxa (ARCL) 1B, characterized by loose skin, aortic aneurysm, arterial tortuosity, lung emphysema, and skeletal abnormalities. Homozygous missense mutations in FBLN4 are a prevalent cause of ARCL 1B. Here we generated a knock-in mouse strain bearing a recurrent fibulin-4 E57K homozygous missense mutation. The mutant mice survived into adulthood and displayed abnormalities in multiple organ systems, including loose skin, bent forelimb, aortic aneurysm, tortuous artery, and pulmonary emphysema. Biochemical studies of dermal fibroblasts showed that fibulin-4 E57K mutant protein was produced but was prone to dimer formation and inefficiently secreted, thereby triggering an endoplasmic reticulum stress response. Immunohistochemistry detected a low level of fibulin-4 E57K protein in the knock-in skin along with altered expression of selected elastic fiber components. Processing of a precursor to mature lysyl oxidase, an enzyme involved in cross-linking of elastin and collagen, was compromised. The knock-in skin had a reduced level of desmosine, an elastin-specific cross-link compound, and ultrastructurally abnormal elastic fibers. Surprisingly, structurally aberrant collagen fibrils and altered organization into fibers were characteristics of the knock-in dermis and forelimb tendons. Type I collagen extracted from the knock-in skin had decreased amounts of covalent intermolecular cross-links, which could contribute to the collagen fibril abnormalities. Our studies provide the first evidence that fibulin-4 plays a role in regulating collagen fibril assembly and offer a preclinical platform for developing treatments for ARCL 1B.

Function of latent TGFß binding protein 4 and fibulin 5 in elastogenesis and lung development.

Mice deficient in Latent TGFß Binding Protein 4 (Ltbp4) display a defect in lung septation and elastogenesis. The lung septation defect is normalized by genetically decreasing TGFß2 levels. However, the elastic fiber assembly is not improved in Tgfb2(-/-) ;Ltbp4S(-/-) compared to Ltbp4S(-/-) lungs. We found that decreased levels of TGFß1 or TGFß3 did not improve lung septation indicating that the TGFß isoform elevated in Ltbp4S(-/-) lungs is TGFß2. Expression of a form of Ltbp4 that could not bind latent TGFß did not affect lung phenotype indicating that normal lung development does not require the formation of LTBP4-latent TGFß complexes. Therefore, the change in TGFß-level in the lungs is not directly related to Ltbp4 deficiency but probably is a consequence of changes in the extracellular matrix. Interestingly, combination of the Ltbp4S(-/-) mutation with a fibulin-5 null mutant in Fbln5(-/-) ;Ltbp4S(-/-) mice improves the lung septation compared to Ltbp4S(-/-) lungs. Large globular elastin aggregates characteristic for Ltbp4S(-/-) lungs do not form in Fbln5(-/-) ;Ltbp4S(-/-) lungs and EM studies showed that elastic fibers in Fbln5(-/-) ;Ltbp4S(-/-) lungs resemble those found in Fbln5(-/-) mice. These results are consistent with a role for TGFß2 in lung septation and for Ltbp4 in regulating fibulin-5 dependent elastic fiber assembly.

Estudo comparativo entre pentoxifilina e triancinolona no tratamento das cicatrizes hipertróficas pós-queimadura quanto à remodelação do colágeno e das fibras do sistema elástico / Comparative study of pentoxifylline and triamcinolone in the treatment of post-burn hypertrophic scars on the collagen remodeling and elastic system fibers

Introdução: O tratamento das sequelas cicatriciais permanece um desafio na prática diária. Corticosteroides injetáveis são amplamente utilizados no combate a queloides e cicatrizes hipertróficas, mas substâncias como a pentoxifilina (PTF) também têm demonstrado eficácia clínica na modulação dessas cicatrizes. Objetivos: No presente estudo, propusemos a comparação dos efeitos da PTF e do corticosteroide triancinolona nas cicatrizes hipertróficas de pacientes vítimas de queimaduras por meio de análise histológica da organização das fibras que contêm colágeno e das fibras do sistema elástico. Métodos: Foram estudadas amostras de pele cicatricial de 10 pacientes, entre 20 e 40 anos, com história de queimaduras em tronco, com até 24 meses de evolução, não tratadas cirurgicamente. Cada paciente teve duas áreas cicatriciais tratadas, uma com Hexacetonido de Triancinolona 20 mg/ml e outra com Pentoxifilina 1 mg/ ml; tendo sido realizadas três aplicações intracicatriciais com intervalos mensais. Uma biópsia de cada área tratada foi colhida após 30 dias de cada aplicação. Resultados: Os resultados clínicos foram evidentes e semelhantes para as duas drogas: diminuição da espessura, do prurido, da hiperemia e da consistência da cicatriz. Não se observaram diferenças arquiteturais no tecido conjuntivo subepidérmico quando comparadas a cicatriz original com as cicatrizes após cada tipo de tratamento (grandes feixes de fibras colágenas em todas as direções, com ausência de fibras do sistema elástico). Estudos subsequentes envolvendo a análise da espessura total da cicatriz e o grau de vascularização/ inflamação presentes se fazem necessários na investigação da justificativa da eficácia clínica dos tratamentos. Conclusão: Concluímos que a PTF teve uma resposta clínica e morfológica similar à triancinolona nos casos tratados.

Introduction: The treatment of scarring sequelae remains challenge in daily practice. Injecting corticosteroids are widely used to combat keloids and hypertrophic scars, but substances such as pentoxifylline (PTF) have also demonstrated clinical efficacy in modulating these scars. Objectives: This study set out to compare the effects of TFP and corticosteroid triamcinolone in hypertrophic scars of burn victims by histological analysis of the organization of the fibers containing collagen and elastic system fibers. Methods: Scar skin samples from 10patients were studied between 20 and 40 years, with a history of burns on the trunk, up to 24 months of evolution, not surgically treated. Each patient had two treated scar areas, one with triamcinolone hexacetonide 20 mg/ml and the other with pentoxifylline 1 mg/ml; having been held three intracicatriciais applications at monthly intervals. A biopsy of each treated area was harvested after 30 days of each application. Results: The clinical results were evident and similar for the two drugs: thinning, itching, hyperemia and scar consistency. There were no differences in architectural subepidermal connective tissue when compared with the original scar scars after each treatment (large bundles of collagen fibers in all directions with no elastic system fibers). Subsequent studies involving the analysis of the total thickness of the scar and the extent of vascularization/inflammation gifts are needed to investigate the reasons of clinical efficacy of treatments. Conclusion: We conclude that TFP had a clinical and morphological response similar to triamcinolone in treated cases.

Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4.

Autosomal recessive cutis laxa (ARCL) is a clinically and genetically heterogeneous group of disorders characterized by loose, inelastic skin and variable systemic involvement and severity. Mutations in the FBLN4 gene are associated with ARCL1B. Fibulin-4 is important in elastic fiber formation and smooth muscle cell differentiation. We describe herein an 8-year-old boy who presented with severe aortic root dilatation and arterial tortuosity at 1 year of age which required surgical repair. His parents were consanguineous and there was a family history of three brothers who died early in life with an unknown type of connective tissue disorder in the 1960s. Both parents of the patient reported here were related to these three boys. We used a homozygosity mapping strategy with a 900K SNP array and identified FBLN4 as a candidate gene in an extended region of homozygosity. We sequenced this gene in the patient and identified a homozygous non-synonymous mutation at c.376G>A (p.Glu126Lys) in exon 5 that was predicted to be damaging. ARCL1B has most typically been associated with early demise but our report suggests that long-term survival is possible. With this longer term survival we are learning more about the natural history of this disorder, which includes baroreceptor reflex failure and low bone mineral density in this patient.

Absence of TGFbeta signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm.

To address the requirement for TGFbeta signaling in the formation and maintenance of the vascular matrix, we employed lineage-specific mutation of the type II TGFbeta receptor gene (Tgfbr2) in vascular smooth muscle precursors in mice. In both neural crest- and mesoderm-derived smooth muscle, absence of TGFbeta receptor function resulted in a poorly organized vascular elastic matrix in late-stage embryos which was prone to dilation and aneurysm. This defect represents a failure to initiate formation of the elastic matrix, rather than a failure to maintain a preexisting matrix. In mutant tissue, lysyl oxidase expression was substantially reduced, which may contribute to the observed pathology.

Restrictive dermopathy--a lethal congenital laminopathy. Case report and review of the literature.

Restrictive dermopathy (RD) is a rare, fatal, and genetically heterogeneous laminopathy with a predominant autosomal recessive heredity pattern. The phenotype can be caused by mutations in either LMNA (primary laminopathy) or ZMPSTE24 (secondary laminopathy) genes but mostly by homozygous or compound heterozygous ZMPSTE24 mutations. Clinicopathologic findings are unique, allowing a specific diagnosis in most cases. We describe a premature newborn girl of non-consanguineous parents who presented a rigid, translucent and tightly adherent skin, dysmorphic facies, multiple joint contractures and radiological abnormalities. The overall clinical, radiological, histological, and ultrastructural features were typical of restrictive dermopathy. Molecular genetic analysis revealed a homozygous ZMPSTE24 mutation (c.1085_1086insT). Parents and sister were heterozygous asymptomatic carriers. We conclude that RD is a relatively easy and consistent clinical and pathological diagnosis. Despite recent advances in our understanding of RD, the pathogenetic mechanisms of the disease are not entirely clarified. Recognition of RD and molecular genetic diagnosis are important to define the prognosis of an affected child and for recommending genetic counseling to affected families. However, the outcome for a live born patient in the neonatal period is always fatal.

A newly identified splice site mutation in ZMPSTE24 causes restrictive dermopathy in the Middle East.

Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.

Restrictive dermopathy: report and review.

Restrictive dermopathy is a rare autosomal recessive disorder characterized by extreme tautness of the skin causing restricted intrauterine movement and a fetal akinesia deformation sequence. It is uniformly mostly neonatally fatal. The diagnostic findings are skin tautness with near absence of the dermal elastic fibers, usually with no or only minor anomalies of the internal organs. The exact pathogenetic mechanisms are still not known. Fewer than 50 cases have been reported. We report on a case of restrictive dermopathy and discuss the differential diagnoses.

Increased elastic tissue defect formation in the growth restricted Brown Norway rat: a potential link between in utero condition and cardiovascular disease.

Low birth weight for gestational age has been epidemiologically linked to cardiovascular mortality and morbidity in adult life. This study aimed to determine whether in utero growth restriction influences an early feature of atherosclerotic pathology; disruption of the aortic internal elastic lamina (IEL) in the adult Brown Norway (BN) rat. In utero growth restriction was induced by bilateral uterine artery ligation on day 18 of gestation, thereby decreasing newborn BN pup weight by approximately 14%. Restriction surgery significantly increased aortic IEL defect number at 8 wk of age in both sexes compared with no surgery animals (p < 0.002). At 16 wk of age placental restriction surgery significantly increased the number of defects in males compared with both no surgery and sham surgery control groups (p < 0.001). The total number of IEL defects was significantly correlated with several postnatal growth rate parameters, including 72-h postpartum weight. Neither blood pressure was significantly different between treatment groups, nor was it correlated with body weight or IEL defect numbers. The findings of this study seem to support the fetal origins of adult disease hypothesis, by demonstrating that a moderate growth restricting insult dramatically increases aortic elastic tissue defect formation via an apparently blood pressure-independent mechanism.

Elastolisis de la dermis media: a propósito de una caso / Elastolisis half of the dermis: about one case

Describimos al cuadro clínico de una paciente que presenta lesiones circunscriptas con aspecto de piel envejecida, localizadas en tronco. El estudio histopatológico muestra ausencia de fibras elásticas en una banda que compromete la dermis reticular alta. El término elastolisis se utiliza para definir la disminución o ausencia de las fibras elásticas. Las enfermedades elastolíticas pueden ser localizadas o generalizadas, congénitas o adquiridas, con o sin manifestaciones sistémicas. La elastolisis de la dermis media es una afección rara, adquirida, idiopática y sin compromiso extracutáneo. Los hallazgos histológicos son patognomónicos, observándose ausencia de tejido elástico en una banda que compromete la porción media de la dermis.

Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice.

Elastic fibers provide tissues with elasticity which is critical to the function of arteries, lungs, skin, and other dynamic organs. Loss of elasticity is a major contributing factor in aging and diseases. However, the mechanism of elastic fiber development and assembly is poorly understood. Here, we show that lack of fibulin-4, an extracellular matrix molecule, abolishes elastogenesis. fibulin-4-/- mice generated by gene targeting exhibited severe lung and vascular defects including emphysema, artery tortuosity, irregularity, aneurysm, rupture, and resulting hemorrhages. All the homozygous mice died perinatally. The earliest abnormality noted was a uniformly narrowing of the descending aorta in fibulin-4-/- embryos at embryonic day 12.5 (E12.5). Aorta tortuosity and irregularity became noticeable at E15.5. Histological analysis demonstrated that fibulin-4-/- mice do not develop intact elastic fibers but contain irregular elastin aggregates. Electron microscopy revealed that the elastin aggregates are highly unusual in that they contain evenly distributed rod-like filaments, in contrast to the amorphous appearance of normal elastic fibers. Desmosine analysis indicated that elastin cross-links in fibulin-4-/- tissues were largely diminished. However, expression of tropoelastin or lysyl oxidase mRNA was unaffected in fibulin-4-/- mice. In addition, fibulin-4 strongly interacts with tropoelastin and colocalizes with elastic fibers in culture. These results demonstrate that fibulin-4 plays an irreplaceable role in elastogenesis.

Aspectos genéticos envolvidos em doenças da aorta / Genetic aspects involved in aortic diseases

Parte dos pacientes com doenças da aorta apresenta algum caráter familiar ou uma síndrome, entre as quais a de Marfan é a mais comum, podendo estar associada a dissecções e aneurismas aórticos. Alterações em genes relacionados ao sistema elástico estão bem determinadas em alguns dos portadores de aortopatias. Mutações da elastina ocorrem na estenose aórtica supravalvar, na qual o lúmen se encontra reduzido, formando-se um gradiente de pressão entre o ventrículo esquerdo e a aorta distal. É transmitida por herança autossômica dominate e é frequentemente associada a lesões em outros territórios vasculares, principalmente a circulação pulmonar periférica. Pode também tomar parte na síndrome de Wiliams, que é mais complexa, com alterações faciais, hipercalcemia infantil e retardo mental, e na qual o gene da elastina está também envolvido, bem como a herança autossômica dominante. Esta última também está presente na síndrome de Marfan, na qual diferentes mutações foram encontradas em outro gene,o da fibrilina, molécula que torna parte no componente microfibrilar do sistema elástico. Por meio de análises de ligação genética de familias com mais de um indivíduo doente da aorta, foram também descritas outras variações cromossomais, inclusive polimorfismo do gene da interleucina-10 em portadores de aneurismas inflamatórios da aorta abdominal. Modelos animais de distúrbios genéticos também contribuiram para o conhecimento das doenças da aorta

EMILIN-1 deficiency induces elastogenesis and vascular cell defects.

EMILINs constitute a family of genes of the extracellular matrix with high structural similarity. Four genes have been identified so far in human and mouse. To gain insight into the function of this gene family, EMILIN-1 has been inactivated in the mouse by gene targeting. The homozygous animals were fertile and did not show obvious abnormalities. However, histological and ultrastructural examination revealed alterations of elastic fibers in aorta and skin. Formation of elastic fibers by mutant embryonic fibroblasts in culture was also abnormal. Additional alterations were observed in cell morphology and anchorage of endothelial and smooth muscle cells to elastic lamellae. Considering that EMILIN-1 is adhesive for cells and that the protein binds to elastin and fibulin-5, EMILIN-1 may regulate elastogenesis and vascular cell maintenance by stabilizing molecular interactions between elastic fiber components and by endowing elastic fibers with specific cell adhesion properties.

Etiology of patent ductus arteriosus in dogs.

Patent ductus arteriosus (PDA) is the most common congenital heart disease in dogs and usually causes heart failure and death unless corrected at a young age. Previous histologic studies in a line of dogs derived from Miniature Poodles with hereditary PDA identified varying degrees of hypoplasia and asymmetry of ductus-specific smooth muscle and the presence of aortalike elastic tissue in the ductus wall sufficient to cause patency. To determine if similar structural abnormalities cause PDA in other dogs, serial-section, 3-dimensional histology of ductal architecture was studied in 8 non-Poodle purebred dogs with PDA with no immediate family history of PDA. Morphologic abnormalities were observed in 7 of 8 dogs with PDA and essentially were the same as those in dogs known to have a hereditary form of PDA. These findings suggest that apparently sporadic PDA in these breeds is caused by a genetic defect in the structure of the ductus arteriosus that is similar or identical to that in the Poodle. The relatives of dogs with PDA, particularly parents, offspring, and siblings, should be screened for evidence of PDA. Dogs with PDA should not be used for breeding, regardless of breed.