Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.

Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. PURPOSE: CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. METHODS: Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. RESULTS: Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. CONCLUSION: An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

Occurrence of Anthracnose Caused by Colletotrichum malvarum on Althaea officinalis in Italy.

The cultivation of medicinal plants is increasing in some areas of central Italy where the climate is suitable for organic farming and the production of high-quality plant products. During April and May 2003, plants of Althaea officinalis L. at the seedling stage (two-to-four true leaves) maintained in unheated greenhouses before their transplantation to open fields showed an unusual foliar disease. Necrotic leaf spots of variable shape and size were followed by a rapid wilting of leaves that frequently resulted in a blight of the young plants. Small leaf pieces showing symptoms were sampled, surface treated in 0.1% HgCl2 for 30 s, rinsed twice in sterile water, placed on potato dextrose agar (PDA) (pH 5.5) in petri dishes, and incubated for 7 days at 25 ± 2°C. Colletotrichum malvarum (Braun & Casp.) Southworth (1,2) was consistently recovered from affected tissues. The fungus produced dark colonies with whitish aerial mycelium and acervuli containing hyaline, cylindrical conidia (14 to 25 × 3 to 6 µm) on PDA. The pathogenicity of four fungal isolates was tested by inoculating two, true leaves of 10 plants (A. officinalis) with a conidial suspension (5 × 105 conidia ml-1) from a 10-day-old culture. Plants sprayed with water served as controls. All seedlings were placed in a greenhouse at 24± 2°C under natural light conditions and covered with plastic bags for the first 24 h. Each pathogenicity test was repeated one time. After 5 to 7 days, the inoculated seedlings showed small necrotic leaf spots identical to those observed under natural conditions. Affected leaf areas rapidly enlarged and within a few days, the young plants wilted. No symptoms appeared on the noninoculated controls. C. malvarum was consistently reisolated from the symptomatic test seedlings, whereas the fungus was never isolated from control plants. Standard seed health methods (agar plate and blotter) carried out on samples from the same seed lots used for the unheated greenhouse trials were negative for the presence of the pathogen. The occurrence of anthracnose may be attributed to windborne conidia of C. malvarum coming from infected wild malvaceae species and cultivated hosts grown in open fields in the neighborhood of seedling greenhouses. To our knowledge, this is the first report of C. malvarum on A. officinalis in Italy. References: (1) W. Brandenburger. Page 386 in: Parasitische pilze an gefäbpflanzen in Europa. Fisher Verlag, Stuttgart, Germany, 1985. (2) B. C. Sutton. The genus Glomerella and its anamoroph Colletotrichum. Pages 1-26 in: Colletotrichum, Biology, Pathology and Control. J. A. Bailey and M. J. Jeger eds. CAB International, Wallingford, U.K., 1992.

Three novel type I collagen mutations in osteogenesis imperfecta type IV probands are associated with discrepancies between electrophoretic migration of osteoblast and fibroblast collagen.

In three cases of type IV osteogenesis imperfecta (OI), we identified unique point mutations in type I collagen alpha1(I) cDNA. In two cases, the appearance of dimers indicated the presence of cysteine substitutions in the alpha1(I) protein chain. Cyanogen bromide digestion localized these cross-links to CB8 and 3, respectively. In the third case, the overmodification pattern of the CNBr peptides was compatible with a substitution in the aa 123-402 region of either type I collagen chain. We identified a unique point mutation in each proband, which resulted in substitutions for glycine residues in a 300-aa region of the alpha1(I) helix, specifically, Gly to Ala at codon 220 (GGT-->GCT), Gly to Cys at codon 349 (GGT-->TGT) and Gly to Cys at codon 523 (GGT-->TGT). We compared each proband's fibroblast and osteoblast collagen directly, as well as with fibroblast and osteoblast controls. For all cases, the OI osteoblast collagen was more electrophoretically delayed than OI fibroblast collagen. In the patient with G349C, OI fibroblast and osteoblast collagen synthesized in the presence of alpha,alpha'-dipyridyl co-migrated on gels, demonstrating that the electrophoretic discrepancy resulted from differences in post-translational modification. Melting temperature curves for stability of the collagen helix yielded an identical Tm for control fibroblast and osteoblast collagen (41.2 degrees C). By contrast, for collagen with the gly349-->cys substitution, the Tm of the fibroblast collagen was 1 degree C lower than the Tm of the osteoblast collagen. These data indicate that the metabolism of mutant collagen might be cell-specific and has significant implications for understanding the phenotype/genotype correlations and the pathophysiology of OI.