[Show abstract][Hide abstract] ABSTRACT: Background:
Oral mechanistic target of rapamycin inhibitors have been shown to reduce visceral tumor volume in patients with tuberous sclerosis complex (TSC).
We sought to evaluate the cutaneous response to oral sirolimus in patients with TSC and an indication for systemic treatment, including long-term effects.
A retrospective analysis of 14 adult patients with TSC prescribed sirolimus to treat lymphangioleiomyomatosis was performed. Serial photographs of angiofibromas, shagreen patches, and ungual fibromas taken before, during, and after the treatment period were blinded, then assessed using the Physician Global Assessment of Clinical Condition (PGA). Microscopic and molecular studies were performed on skin tumors harvested before and during treatment.
Sirolimus significantly improved angiofibromas (median treatment duration 12 months; median PGA score 4.5 [range 1.5-5]; Wilcoxon signed rank test, P = .018) and shagreen patches (median treatment duration 10 months; median PGA score 4.5 [range 3.5-5]; Wilcoxon signed rank test, P = .039), whereas ungual fibromas improved in some patients (median treatment duration 6.5 months; median PGA score 4.66 [range 2.75-5]; Wilcoxon signed rank test, P = .109). Clinical, immunohistochemical, or molecular evidence of resistance was not observed (range 5-64 months of treatment).
This was a retrospective analysis limited to adult women with lymphangioleiomyomatosis.
Oral sirolimus is an effective long-term therapy for TSC skin tumors, particularly angiofibromas, in patients for whom systemic treatment is indicated.
No preview · Article · Sep 2015 · Journal of the American Academy of Dermatology
[Show abstract][Hide abstract] ABSTRACT: Importance
The 2012 International Tuberous Sclerosis Complex Clinical Consensus Conference was convened to update the last consensus statement in 1998. Skin and dental lesions are common in tuberous sclerosis complex (TSC) and are a frequent concern for patients. Recognition of these lesions is imperative for early diagnosis, given the treatment advances that may improve patient outcomes. Objective
To detail recommendations for the diagnosis, surveillance, and management of skin and dental lesions in TSC. Evidence Review
The TSC Dermatology and Dentistry Subcommittee, 1 of 12 subcommittees, reviewed the relevant literature from 1997 to 2012.Findings
A consensus on skin and dental issues was achieved within the Dermatology and Dentistry Subcommittee before recommendations were presented, discussed, and agreed on in a group meeting of all subcommittees from June 14 to 15, 2012.Conclusions and Relevance
Skin and dental findings comprise 4 of 11 major features and 3 of 6 minor features in the diagnostic criteria. A definite diagnosis of TSC is defined as the presence of at least 2 major features or 1 major and 2 or more minor features; in addition, a pathological mutation in TSC1 or TSC2 is diagnostic. Skin and oral examinations should be performed annually and every 3 to 6 months, respectively. Intervention may be indicated for TSC skin or oral lesions that are bleeding, symptomatic, disfiguring, or negatively affecting function. Options presented include surgical excision, laser(s), or use of a mammalian target of rapamycin inhibitor.
No preview · Article · Jul 2014 · JAMA Dermatology
[Show abstract][Hide abstract] ABSTRACT: Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue. They are primarily responsible for synthesizing collagen and glycosaminoglycans; components of extracellular matrix supporting the structural integrity of the skin. Dermal fibroblasts play a pivotal role in cutaneous wound healing and skin repair. Preclinical studies suggest wider applications of dermal fibroblasts ranging from skin based indications to non-skin tissue regeneration in tendon repair. One clinical application for autologous dermal fibroblasts has been approved by the Food and Drug Administration (FDA) while others are in preclinical development or various stages of regulatory approval. In this context, we outline the role of fibroblasts in wound healing and discuss recent advances and the current development pipeline for cellular therapies using autologous dermal fibroblasts. The microanatomic and phenotypic differences of fibroblasts occupying particular locations within the skin are reviewed, emphasizing the therapeutic relevance of attributes exhibited by subpopulations of fibroblasts. Special focus is provided to fibroblast characteristics that define regional differences in skin, including the thick and hairless skin of the palms and soles as compared to hair-bearing skin. This regional specificity and functional identity of fibroblasts provides another platform for developing regional skin applications such as the induction of hair follicles in bald scalp or alteration of the phenotype of stump skin in amputees to better support their prosthetic devices.
Full-text · Article · May 2014 · International Journal of Molecular Sciences
[Show abstract][Hide abstract] ABSTRACT: Earlier studies showed that dermal cells lose trichogenic capacity with passage, but studies on the effect of keratinocyte passage on human hair follicle neogenesis and graft quality has been hampered by the lack of a suitable model system. We recently documented human hair follicle neogenesis in grafted dermal-epidermal composites and in the present study we determined the effects of keratinocyte passage on hair follicle neogenesis. Dermal equivalents were made with cultured human dermal papilla cells and were overlaid with either primary or passaged human keratinocytes to form dermal-epidermal composites; these were then grafted onto immunodeficient mice. Superior hair follicle neogenesis was observed using early keratinocyte cultures. Characteristics such as formation of hair shafts and sebaceous glands, presence of hair follicles with features of anagen or telogen follicles, and reproducible hair and skin function parameters make this model a tool to study human hair follicle neogenesis and development.This article is protected by copyright. All rights reserved.
No preview · Article · Apr 2014 · Experimental Dermatology
[Show abstract][Hide abstract] ABSTRACT: We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) vs 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) vs 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62) and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus the clinical and histological appearances and the molecular pathology of these UV related XP nevi and melanomas were different from nevi and melanomas in the general population. This article is protected by copyright. All rights reserved.
Full-text · Article · Jan 2014 · Pigment Cell & Melanoma Research
[Show abstract][Hide abstract] ABSTRACT: Tuberous Sclerosis Complex (TSC) is characterized by the formation of tumors in multiple organs and is due to germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects, and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from 4 patients, and in each case second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet "signature" mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas, and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions.
Full-text · Article · Nov 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (e.g., chylous pleural effusions, lymphangioleiomyomas) and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) in the tumor suppressor genes, TSC1 or TSC2, which leads to hyper-activation of the mammalian target of rapamycin (mTOR). Sirolimus slows the decline of lung function, reduces chylous effusions and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells.
Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation. Cells from blood were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-Phycoerythrin (PE) antibodies, and urine and chylous effusion cells with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH.
LAM cells with TSC2 LOH were identified, in this cohort, in 100% of blood specimens and 75% of urine samples from patients before therapy; over a mean duration of 2.2 ± 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood (P < 0.001) and 8% in urine (P = 0.003). Following therapy, greater loss of circulating LAM cells was seen in post-menopausal patients (p = 0.025).
Patients receiving sirolimus had a progressive loss of circulating LAM cells, which was dependent on time of treatment and menopausal status.
[Show abstract][Hide abstract] ABSTRACT: Sex prevalence in lung disease suggests that sex-specific hormones may contribute to the pathogenesis and/or progression of at least some lung diseases, such as lung adenocarcinoma, lymphangioleiomyomatosis (LAM) and benign metastasising leiomyoma (BML). Oestrogen is an important hormone in normal lung development and in the pathogenesis of female predominant pulmonary diseases. In vivo and in vitro studies have facilitated our understanding of disease pathogenesis and discovery of potential therapeutic targets. Oestrogen promoted disease progression in cell and animal models of lung adenocarcinoma, LAM and BML. Specifically, oestrogen enhanced tumour growth and metastasis in animal models of these diseases. Furthermore, 17β-estradiol (E2), the most abundant form of oestrogen in humans, increased the size and proliferation of cultured cells of lung adenocarcinoma and LAM. Coupled with the known mechanisms of oestrogen metabolism and signalling, these model systems may provide insights into the diverse effects of oestrogen and other hormones on lung diseases. Anti-oestrogen treatments that target key events of oestrogen synthesis or signalling, such as aromatase activity, oestrogen receptors and signalling pathways, may offer additional opportunities for clinical trials.
Preview · Article · Sep 2013 · European Respiratory Review
[Show abstract][Hide abstract] ABSTRACT: Purpose: Some forms of genetic skin disease are highly prevalent and others are exceedingly rare, but collectively, genetic skin disorders (or genodermatoses) are often poorly understood. The purpose of this article, therefore, is to increase nurses’ awareness and understanding of some of the physical, psychological, social, and ethical issues facing patients with inherited skin disorders.
Organizing Construct: This article offers an overview of genetic skin diseases; highlights the complexity and prevalence of the genodermatoses; describes inheritance patterns, genetics, and treatment for six genodermatoses; and reviews some of the ethical, privacy, technological, and resource issues nurses should consider when caring for patients with genetic skin disorders.
Conclusions: Because genodermatoses are found in all age groups, across all populations, and within all healthcare settings, nurses are uniquely positioned to address the educational and healthcare needs of patients and families with inherited skin disorders.
Clinical Relevance: Over the past two decades, genetics has evolved from a niche specialty into general practice. To ensure that patients and their families receive appropriate services and resources, nurses must have a working knowledge of genetic concepts. This article reinforces key genetic concepts while discussing many of the issues and concerns important to caring for patients with genetic skin disease.
Full-text · Article · Jan 2013 · Journal of Nursing Scholarship
[Show abstract][Hide abstract] ABSTRACT: Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues. Surprisingly, we found that downregulation of FLCN leads to increased cell-cell adhesion in functional cell-based assays and disruption of cell polarity in a three-dimensional lumen-forming assay, both of which are phenocopied by downregulation of p0071. These data indicate that the FLCN-p0071 protein complex is a negative regulator of cell-cell adhesion. We also found that FLCN positively regulates RhoA activity and Rho-associated kinase activity, consistent with the only known function of p0071. Finally, to examine the role of Flcn loss on cell-cell adhesion in vivo, we utilized keratin-14 cre-recombinase (K14-cre) to inactivate Flcn in the mouse epidermis. The K14-Cre-Bhd(flox/flox) mice have striking delays in eyelid opening, wavy fur, hair loss, and epidermal hyperplasia with increased levels of mammalian target of rapamycin complex 1 (mTORC1) activity. These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling, with broad implications for the role of cell-cell adhesion molecules in the pathogenesis of human disease, including emphysema and renal cell carcinoma.
[Show abstract][Hide abstract] ABSTRACT: The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.