Targeting TGF-ß signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica.

GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF-ß signaling. In this study, we investigated the role of TGF-ß-signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of GorabPrx1 conditional knockouts with the TGF-ß neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF-ß overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF-ß dysregulation was not a cell-intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF-ß signaling caused elevated Nox4 expression in GorabPrx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN-mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating GorabPrx1 mutants with the antioxidant N-acetylcysteine ameliorated the osteoporosis phenotype. TGF-ß induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the GorabPrx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF-ß-Nox4-senescence axis and therapeutic strategies for GO.

Erythrokeratodermia variabilis treated with isotretinoin. A clinical, histologic, and ultrastructural study.

A 30-year-old woman with erythrokeratodermia variabilis was treated with oral isotretinoin for four months. Clinical and light and electron microscopic observations were made before and after treatment. A characteristic electron microscopic feature was subnormal numbers of keratinosomes within the stratum granulosum of hyperkeratotic plaques. Isotretinoin therapy resulted in almost complete clinical clearing of these plaques and restoration of normal numbers of epidermal keratinosomes. In addition, distinctive dyskeratotic cells containing clumped tonofilaments were observed within the stratum granulosum by electron microscopy. These cells persisted after retinoid treatment.

Epidermodysplasia verruciformis in a setting of common variable immunodeficiency.

A 14-year-old native American female with common variable immunodeficiency was admitted for bone marrow transplantation. Preoperative evaluation showed a generalized lichenoid papular eruption present for several years. Light microscopy revealed expansion of the epidermis by atypical keratinocytes; electron microscopy showed intranuclear papillomavirus inclusions within the granular keratinocytes; DNA hybridization revealed a type 5-related human papilloma virus homology. Four days after bone marrow transplantation the lichenoid papules blackened and began to disappear. Within 30 days after bone marrow transplantation the distribution and appearance of the papules was similar to that of the pretransplantation evaluation. One year after transplantation the patient showed evidence of a successful T lymphocyte graft. No transformation to squamous cell carcinoma had occurred. Epidermodysplasia verruciformis has been associated with deficient cell-mediated immunity, the varying severity of which does not predict the tendency to neoplasm formation (2, 5). Several distinct human papillomavirus genomes have been recovered with DNA hybridization techniques in these patients. It is hoped that the bone marrow transplantation might be associated with diminished transformation to squamous cell carcinoma.

Melanoma masquerading as Spitz nevus following acute lymphoblastic leukemia.

A malignant melanoma originally diagnosed as a Spitz nevus led to the death of a 10-year-old boy. The melanoma developed four years after therapy was begun for acute lymphoblastic leukemia. Melanomas in children are rare. Melanomas histologically resembling Spitz nevi have been reported. Deep contiguous growth and melanization are suspicious features. Lymphoproliferative malignancies are most commonly reported to occur in patients surviving treatment for acute lymphoblastic leukemia. Melanoma following acute lymphoblastic leukemia has not been described previously.

Glycosaminoglycans of pleural mesothelioma: a possible biochemical variant containing chondroitin sulfate.

Glycosaminoglycans of a malignant pleural mesothelioma have been characterized histochemically and biochemically and compared with those of normal lung, pleural plaque, lung carcinoma, and other connective tissue neoplasms. Chondroitin sulfate constituted the major glycosaminoglycan (approximately 80% of total) present in the pleural mesothelioma while hyaluronic acid was present in only trace amounts (approximately 3% of total). In particular chondroitin 6-sulfate was the predominant isomer, constituting 80% of the total chondroitin sulfate. Control tissue exhibited different proportions of glycosaminoglycans and none of them contained as high an absolute concentration of chondroitin sulfate as the mesothelioma. These findings differ from previous reports demonstrating increased concentration of hyaluronic acid in mesothelioma and suggest the possible existence of a biochemically different form of this neoplasm.