Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations

P75 nerve growth factor receptor staining is superior to S100 in identifying spindle cell and desmoplastic melanoma

Background: Spindle cell melanoma (SCM) including desmoplastic melanoma (DM) is a rare variant of malignant melanoma that may present diagnostic difficulties particularly when staining with S100 is negative, weak, focal, or a combination of these. Conventional melanocytic markers in SCM are usually negative. Objective: We sought to compare the staining of p75 nerve growth factor receptor (NGF-R) and S100 in SCMs. Methods: We evaluated the staining of p75 NGF-R and S100 in 13 cases of SCMs: 3 SCMs without desmoplasia, 5 pure DMs, and 5 combined DMs with a conventional component. Results: Staining with p75 NGF-R was positive in 13 of 13 (100%) cases of SCMs. In 3 cases the intensity of staining and the percentage of cells staining with this marker were greater than those with S100. One case of SCM was negative for S100 but demonstrated strong expression of p75 NGF-R. One case was focally and weakly positive with S100 but expressed strong positive staining with p75 NGF-R. Absence of staining with p75 NGF-R was noted in the conventional round cell component of two of 5 (40%) combined DMs whereas the same areas were strongly positive for human melanoma black (HMB)-45 and Melan-A. In 5 of 5 (100%) cases of combined DMs the desmoplastic component stained positive with p75 NGF-R, demonstrating an inverse relationship with the staining of conventional melanocytic markers. Limitations: Small study size was a limitation. Conclusion: p75 NGF-R exhibits superior staining characteristics and greater sensitivity in identifying SCM and DMs than S100. P75 NGF-R may be a useful diagnostic and ancillary stain in addition to S100. (J Am Acad Dermatol 2010;63:852-8.

Viral exanthems in children

Viral and paraviral exanthems are the most common exanthems in children and are often the reason for a medical evaluation, especially in pediatric primary care and emergency rooms. Familiarity with the various eruptions is important for early diagnosis and patient management as well as minimizing the risk of infection. In this review, we present the newly described entities reactive infectious mucocutaneous eruptions (RIME) and the pediatric inflammatory multisystem syndrome (PIMS). In addition, atypical manifestations of Gianotti-Crosti syndrome and hand, foot, and mouth disease are discussed

Oncogene and therapeutic target analyses in Atypical fibroxanthomas and pleomorphic dermal sarcomas

Background: Until now, almost nothing is known about the tumorigenesis of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Our hypothesis is that AFX is the non-infiltrating precursor lesion of PDS. Materials and Methods: We performed the world-wide most comprehensive immunohistochemical and mutational analysis in well-defined AFX (n=5) and PDS (n=5). Results: In NGS-based mutation analyses of selected regions by a 17 hotspot gene panel of 102 amplicons we could detect TP53 mutations in all PDS as well as in the only analyzed AFX and PDS of the same patient. Besides, we detected mutations in the CDKN2A, HRAS, KNSTRN and PIK3CA genes. Performing immunohistochemistry for CTNNB1, KIT, CDK4, c-MYC, CTLA-4, CCND1, EGFR, EPCAM, ERBB2, IMP3, INI-1, MKI67, MDM2, MET, p40, TP53, PD-L1 and SOX2 overexpression of TP53, CCND1 and CDK4 was seen in AFX as well as in PDS. IMP3 was upregulated in 2 AFX (weak staining) and 4 PDS (strong staining). FISH analyses for the genes FGFR1, FGFR2 and FGFR3 revealed negative results in all tumors. Conclusion: UV-induced TP53 mutations as well as CCND1/CDK4 changes seem to play essential roles in tumorigenesis of PDS. Furthermore, we found some more interesting mutated genes in other oncogene pathways (activating mutations of HRAS and PIK3CA). All AFX and PDS investigated immunohistochemically presented with similar oncogene expression profiles (TP53, CCND1, CDK4 overexpression) and the single case with an AFX and PDS showed complete identical TP53 and PIK3CA mutation profiles in both tumors. This reinforces our hypothesis that AFX is the non-infiltrating precursor lesion of PDS