Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity

<p>Abstract</p> <p>Background</p> <p>Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes.</p> <p>Methods</p> <p>We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802).</p> <p>Results</p> <p>Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids.</p> <p>Conclusion</p> <p>Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution.</p

Case report and summary of literature: giant perineal keloids treated with post-excisional radiotherapy

BACKGROUND: Keloids are common benign tumors of the dermis, typically arising after insult to the skin. While typically only impinging on cosmesis, large or recurrent keloids may require therapeutic intervention. While no single standardized treatment course has been established, several series report excellent outcomes for keloids with post-surgery radiation therapy. CASE PRESENTATION: We present a patient with a history of recurrent keloids arising in the absence of an ascribed trauma and a maternal familial history of keloid formation, whose physical examination several large perineal keloids of 6-20 cm in the largest dimension. The patient was treated with surgical extirpation and adjuvant radiation therapy. Radiotherapy was delivered to the scar bed to a total dose of 22 Gy over 11 daily fractions. Acute radiotherapy toxicity necessitated a treatment break due to RTOG Grade III acute toxicity (moderate ulceration and skin breakdown) which resolved rapidly during a 3-day treatment break. The patient demonstrated local control and has remained free of local recurrence for more than 2 years. CONCLUSION: Radiotherapy for keloids represents a safe and effective option for post-surgical keloid therapy, especially for patients with bulky or recurrent disease

Metastatic breast carcinoma mimicking a sebaceous gland neoplasm: a case report

<p>Abstract</p> <p>Introduction</p> <p>Breast cancer is common in women and its metastases involve the skin in approximately one quarter of patients. Accordingly, metastatic breast cancer shown to be cutaneous through histology must be distinguished from a wide variety of other neoplasms as well as the diverse morphologic variants of breast cancer itself.</p> <p>Case presentation</p> <p>We report the case of a 61-year-old Caucasian woman with cutaneous metastases of a bilateral ductal breast carcinoma that in histopathological examination mimicked an adnexal neoplasm with sebaceous differentiation.</p> <p>Conclusion</p> <p>Against the background of metastatic breast carcinoma, dermatopathological considerations of sebaceous differentiation of skin lesions are presented and discussed focusing on the rare differential diagnosis of sebaceous carcinoma of the breast.</p

Telomere shortening may be associated with human keloids

<p>Abstract</p> <p>Background</p> <p>Keloids are benign skin tumors that are the effect of a dysregulated wound-healing process in genetically predisposed patients. They are inherited with an autosomal dominant mode with incomplete clinical penetrance and variable expression. Keloids are characterized by formation of excess scar tissue beyond the boundaries of the wound. The exact etiology is still unknown and there is currently no appropriate treatment for keloid disease.</p> <p>Methods</p> <p>We analyzed sample tissues were obtained from 20 patients with keloid skin lesions and normal skin was obtained from 20 healthy donors. The telomeres were measured by Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay. Quantitative Real-Time RT-PCR analysis of hTERT gene expression was performed and intracellular ROS generation was measured.</p> <p>Results</p> <p>In this study, we determined whether telomeric shortening and the expression of human telomerase reverse transcriptase (hTERT) occurs in keloid patients. Using Terminal Restriction Fragment (TRF) analysis and Real-Time PCR assay, we detected a significant telomere shortening of 30% in keloid specimens compared to normal skin. Using quantitative Real-Time RT-PCR, telomerase activity was found absent in the keloid tissues. Moreover, an increase in ROS generation was detected in fibroblasts cell cultures from keloid specimens as more time elapsed compared to fibroblasts from normal skin.</p> <p>Conclusion</p> <p>Telomere shortening has been reported in several metabolic and cardiovascular diseases. We found that telomere shortening can also be associated with human keloids. Chronic oxidative stress plays a major role in the pathophysiology of several chronic inflammatory diseases. Here we found increased ROS generation in fibroblasts from keloid fibroblasts cell cultures when compared to normal skin fibroblasts. Hence we conclude that oxidative stress might be an important modulator of telomere loss in keloid because of the absence of active telomerase that counteracts telomere shortening.</p

Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2 alpha (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. the identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.National Institutes of Health National Human Genome Research InstituteLife Sciences Discovery FundWashington Research FoundationMassachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USAUniv Washington, Dept Pediat, Seattle, WA 98195 USAUniv Washington, Dept Genome Sci, Seattle, WA 98195 USAUniv Western Sydney Macarthur, Sch Med, Campbelltown, NSW 2560, AustraliaGenet Learning Disabil Serv, Newcastle, NSW 2298, AustraliaJohns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilPontificia Univ Catolica Parana, Dept Internal Med, BR-1155 Curitiba, Parana, BrazilWestern Gen Hosp, South East Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, ScotlandUniv Florence, Dept Genet & Mol Med, I-50132 Florence, ItalyHop Necker Enfants Malad, Dept Genet, INSERM, U781, F-75015 Paris, FranceUniv Paris Descartes Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, FranceHop Cote Nacre, CHU Caen, Serv Genet, F-14033 Caen 9, FranceUniv Connecticut, Ctr Hlth, Dept Reconstruct Sci, Farmington, CT 06030 USABoston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA 02115 USATreuman Katz Ctr Pediat Bioeth, Seattle Childrens Res Inst, Seattle, WA 98101 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilNational Institutes of Health National Human Genome Research Institute: 1U54HG006493National Institutes of Health National Human Genome Research Institute: 1RC2HG005608National Institutes of Health National Human Genome Research Institute: 5RO1HG004316Life Sciences Discovery Fund: 2065508Life Sciences Discovery Fund: 0905001Web of Scienc

The clinical potential of antiangiogenic fragments of extracellular matrix proteins

Neovasculature development is a crucial step in the natural history of a cancer. While much emphasis has been placed on proangiogenic growth factors such as VEGF, it is clear that endogenous angiogenesis inhibitors also have critical roles in the regulation of this process. Recent research has identified several cryptic fragments of extracellular matrix/vascular basement membrane proteins that have potent antiangiogenic properties in vivo. It has become apparent that many of these fragments signal via interactions with endothelial integrins, although multiple downstream effector pathways have been implicated and endostatin, the first non-collagenous domain of collagen XVIII, influences an intricate signalling network. The activity of these molecules in animal models suggests that they may have significant clinical activity; however, results of phase I/II trials with endostatin were disappointing. Many possible reasons can be found for the failure of these studies. Weaknesses in trial design, endostatin administration regimen and patient selection are identifiable, and importantly the lack of a clearly defined antiangiogenic mechanism for endostatin hindered assessment of biologically effective dose. Additionally, in vivo immunological and proteolytic function-neutralising mechanisms may have negated endostatin's actions. Lessons learned from these studies will aid the future clinical development of other antiangiogenic extracellular matrix protein fragments

Utilizing Targeted Gene Therapy with Nanoparticles Binding Alpha v Beta 3 for Imaging and Treating Choroidal Neovascularization

Purpose: The integrin αvβ3 is differentially expressed on neovascular endothelial cells. We investigated whether a novel intravenously injectable αvβ3 integrin-ligand coupled nanoparticle (NP) can target choroidal neovascular membranes (CNV) for imaging and targeted gene therapy. Methods: CNV lesions were induced in rats using laser photocoagulation. The utility of NP for in vivo imaging and gene delivery was evaluated by coupling the NP with a green fluorescing protein plasmid (NP-GFPg). Rhodamine labeling (Rd-NP) was used to localize NP in choroidal flatmounts. Rd-NP-GFPg particles were injected intravenously on weeks 1, 2, or 3. In the treatment arm, rats received NP containing a dominant negative Raf mutant gene (NP-ATPμ-Raf) on days 1, 3, and 5. The change in CNV size and leakage, and TUNEL positive cells were quantified. Results: GFP plasmid expression was seen in vivo up to 3 days after injection of Rd-NP-GFPg. Choroidal flatmounts confirmed the localization of the NP and the expression of GFP plasmid in the CNV. Treating the CNV with NP-ATPμ-Raf decreased the CNV size by 42% (P<0.001). OCT analysis revealed that the reduction of CNV size started on day 5 and reached statistical significance by day 7. Fluorescein angiography grading showed significantly less leakage in the treated CNV (P<0.001). There were significantly more apoptotic (TUNEL-positive) nuclei in the treated CNV. Conclusion: Systemic administration of αvβ3 targeted NP can be used to label the abnormal blood vessels of CNV for imaging. Targeted gene delivery with NP-ATPμ-Raf leads to a reduction in size and leakage of the CNV by induction of apoptosis in the CNV

Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors

Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentally as well as in the adult. In light of the widespread use of systemic and intraocular anti-VEGF therapies for the treatment of angiogenesis associated with tumor growth and wet macular degeneration, systematic investigation of the role of VEGF in the adult retina is critical.Using immunohistochemistry and Lac-Z reporter mouse lines, we report that VEGF is produced by various cells in the adult mouse retina and that VEGFR2, the primary signaling receptor, is also widely expressed, with strong expression by Müller cells and photoreceptors. Systemic neutralization of VEGF was accomplished in mice by adenoviral expression of sFlt1. After 14 days of VEGF neutralization, there was no effect on the inner and outer retina vasculature, but a significant increase in apoptosis of cells in the inner and outer nuclear layers. By four weeks, the increase in neural cell death was associated with reduced thickness of the inner and outer nuclear layers and a decline in retinal function as measured by electroretinograms. siRNA-based suppression of VEGF expression in a Müller cell line in vitro supports the existence of an autocrine role for VEGF in Müller cell survival. Similarly, the addition of exogenous VEGF to freshly isolated photoreceptor cells and outer-nuclear-layer explants demonstrated VEGF to be highly neuroprotective.These results indicate an important role for endogenous VEGF in the maintenance and function of adult retina neuronal cells and indicate that anti-VEGF therapies should be administered with caution

The Extracellular Matrix and Blood Vessel Formation: Not Just a Scaffold

The extracellular matrix plays a number of important roles, among them providing structural support and information to cellular structures such as blood vessels imbedded within it. As more complex organisms have evolved, the matrix ability to direct signalling towards the vasculature and remodel in response to signalling from the vasculature has assumed progressively greater importance. This review will focus on the molecules of the extracellular matrix, specifically relating to vessel formation and their ability to signal to the surrounding cells to initiate or terminate processes involved in blood vessel formation