Familial tumoral calcinosis (FTC; OMIM 211900) is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues. Using linkage analysis, we mapped the gene underlying FTC to 2q24-q31. This region includes the gene GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O-glycosylation. Sequence analysis of GALNT3 identified biallelic deleterious mutations in all individuals with FTC, suggesting that defective post-translational modification underlies the disease.We assessed 12 individuals with FTC from two large kindreds of Druze and African-American origin (Fig. 1a) that have been extensively described 1,2 . All affected individuals reported recurrent painful, calcified subcutaneous masses of up to 1 kg (Fig. 1b), often resulting in secondary infection and incapacitating mutilation. Three individuals developed deep periarticular tumors (Fig. 1b), and one succumbed to the disease. All affected individuals had hyperphosphatemia (family 1, 6.2-8.5 mg dl -1 ; family 2, 5.2-6.6 mg dl -1 ) but normal levels of calcium, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3.With informed consent of all participants, we obtained DNA samples and carried out a genome-wide scan using 362 microsatellite markers (Research Genetics) in family 1. Consanguinity in this kindred allowed us to apply homozygosity mapping to identify in all affected individuals a 15-Mb segment identical by descent, flanked by D2S142 and D2S2284/D2S2177 on 2q24-q31 (Fig. 1). We obtained a maximum multipoint lod score of 6.7 (HOMOZ 3 ). Multipoint linkage analysis in family 2 using seven markers in this critical region further reduced the interval to 3 Mb flanked by D2S111 and D2S1776 (Fig. 1) and yielded a maximum multipoint lod score of 3.4 (GeneHunter 4 ).Using Mapviewer, we identified 11 genes in the 3-Mb region associated with FTC. Of these, B3GALT1, SCN7A, SCN9A, SCN1A and STK39 have roles in neural or neuroendocrine tissues; the functions of TAIP-2, CMYA3, FLJ11457, LOC90643 and LASS6 are mostly unknown. The last positional candidate gene, GALNT3, encodes the UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (ppGaNTase-T3; ref. 5). ppGaNTase-T3 belongs to a large family of Golgi-associated biosynthetic enzymes that transfer GalNac from the sugar donor UDP-GalNac to serine and threonine residues and are thereby responsible for initiating O-glycan synthesis, a prevalent form of post-translational modification 6 . RT-PCR analysis showed strong expression of GALNT3 in the skin and kidneys, two tissues of functional relevance to the pathogenesis of FTC 1,2 (Fig. 2a). Using balanced primer pairs, we screened PCR amplicons of all ten coding exons and conserved splice sites of GALNT3 for pathogenic mutations in the genomic DNA of affected individuals (primer pairs and PCR conditions are available on request). Members of the Druze family carried a homozygous G→A transition at position 1524+1 (from the ATG ...

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Type I IFNs exert diverse effector and regulatory functions in host immunity to viral and nonviral infections; however, the role of endogenous type I IFNs in leishmaniasis is unclear. We found that type I IFNR-deficient (IFNAR−/−) mice developed attenuated lesions and reduced Ag-specific immune responses following infection with Leishmania amazonensis parasites. The marked reduction in tissue parasites, even at 3 d in IFNAR−/− mice, seemed to be indicative of an enhanced innate immunity. Further mechanistic analyses indicated distinct roles for neutrophils in parasite clearance; IFNAR−/− mice displayed a rapid and sustained infiltration of neutrophils, but a limited recruitment of CD11b+Ly-6C+ inflammatory monocytes, into inflamed tissues; interactions between IFNAR−/−, but not wild-type (WT) or STAT1−/−, neutrophils and macrophages greatly enhanced parasite killing in vitro; and infected IFNAR−/− neutrophils efficiently released granular enzymes and had elevated rates of cell apoptosis. Furthermore, although coinjection of parasites with WT neutrophils or adoptive transfer of WT neutrophils into IFNAR−/− recipients significantly enhanced infection, the coinjection of parasites with IFNAR−/− neutrophils greatly reduced parasite survival in WT recipients. Our findings reveal an important role for type I IFNs in regulating neutrophil/monocyte recruitment, neutrophil turnover, and Leishmania infection and provide new insight into innate immunity to protozoan parasites.

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We saw two newborn infants with striated muscle hamartoma. One patient had numerous associated congenital anomalies. The clinical appearance of both lesions was that of a soft fibroma. Histologically, striated muscle fibers and nerve bundles were seen in the central core and also at the periphery of the lesion, below the epidermis. A marked number of sebaceous glands, vellus hair follicles, and eccrine glands were also present. We propose the term striated muscle hamartoma, which points out the most remarkable feature of these lesions.

We describe 5 new cases of striated muscle hamartoma (SMH) and review the 7 cases previously described in the literature. Eleven of the 12 patients had single lesions centrally located on the chin (4), near the ala of the nose (3), on the upper chest (3), and on the upper lip (1). Histologically all of the lesions were characterized by a central core containing bundles and individual fibers of skeletal muscle as well as other mesenchymal elements. The muscle fibers penetrated the dermis among numerous folliculo-sebaceous structures. Of the 12 cases of SMH, 3 had other associated congenital anomalies including a cleft lip in 1 patient and a thyroglossal duct sinus in another with single lesions, and preauricular sinuses, low-set ears and bilateral sclerocorneas in the case of multiple SMH. The relationship of SMH with oculocerebrocutaneous syndrome is discussed, and we conclude that at least some of the skin appendages associated with that syndrome are SMH.

When the scalp exhibits folds and furrows resembling gyri, it is termed cutis verticis gyrata. The possible etiologies may be categorized as primary essential, primary nonessential, and secondary cutis verticis gyrata. This is based on history, physical examination, and histologic criteria with or without laboratory examinations.