Tofacitinib for the treatment of lichen planopilaris: A case series.

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia for which many different therapies are attempted with varying success. The Janus kinase (JAK) inhibitor, tofacitinib, has been shown to be effective in treating the noncicatricial alopecia, alopecia areata. As in alopecia areata, upregulation of interferon and JAK signaling may play a role in LPP. We retrospectively reviewed the cases of 10 patients with recalcitrant LPP who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg twice or three times daily for 2-19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). Reduction in LPPAI ranged from 30 to 94%. One patient complained of 10 pound (4.5 kg) weight gain after 12 months on tofacitinib. No other adverse effects were reported. Treatment with oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP.

JAK2-positive cutaneous myelofibrosis presenting as sclerosing extramedullary hematopoietic tumors on the scalp: case presentation and review of the literature.

We report the second case of cutaneous myelofibrosis with a documented JAK2 activating mutation involving the scalp of a 67-year-old woman with primary myelofibrosis in her marrow. In contrast to the previous case, the biopsy revealed extensive lesional collagen deposition and closely mimicked a fibrohistiocytic proliferation. Similar rare lesions occurring in the setting of myeloproliferative neoplasms have been called sclerosing extramedullary hematopoietic tumors. These entities appear histomorphologically and etiologically distinct from extramedullary hematopoiesis, and their diagnosis should prompt the workup for a myeloproliferative neoplasm in the absence of an antecedent diagnosis. The presence of the JAK2 mutation in our case confirmed that the lesions represented skin involvement by a neoplastic myeloid proliferation and not compensatory extramedullary hematopoiesis. Our patient died of disease several months following the appearance of her lesions, which is in keeping with other reports that suggest that cutaneous myelofibrosis may serve as an independent poor prognostic sign in otherwise advanced primary myelofibrosis. A review of the literature further emphasizes the importance of distinguishing this entity from mesenchymal neoplasms and acute myeloid leukemia involving the skin.

N-acetylglucosamine modification in the lumen of the endoplasmic reticulum.

BACKGROUND: O-linked ß-N-acetylglucosamine (O-GlcNAc) modification of epidermal growth factor (EGF) domains catalyzed by EGF domain O-GlcNAc transferase (EOGT) is the first example of GlcNAc modification in the lumen of the endoplasmic reticulum (ER). SCOPE OF REVIEW: This review summarizes current knowledge on the EOGT-catalyzed O-GlcNAc modification of EGF domains obtained through biochemical characterization, genetic analysis in Drosophila, and identification of human EOGT mutation. Additionally, this review discusses GTDC2-another ER protein homologous to EOGT that catalyzes the GlcNAc modification of O-mannosylated α-dystroglycan-and other components of the biosynthetic pathway involved in GlcNAc modification in the ER lumen. MAJOR CONCLUSIONS: GlcNAc modification in the ER lumen has been identified as a novel type of protein modification that regulates specific protein function. Moreover, abnormal GlcNAc modification in the ER lumen is responsible for Adams-Oliver syndrome and Walker-Warburg syndrome. GENERAL SIGNIFICANCE: Elucidation of the biological function of GlcNAc modification in the ER lumen will provide new insights into the unique roles of O-glycans, whose importance has been demonstrated in multifunctional glycoproteins such as Notch receptors and α-dystroglyan.

Autosomal recessive Adams-Oliver syndrome caused by homozygous mutation in EOGT, encoding an EGF domain-specific O-GlcNAc transferase.

Autosomal recessive Adams-Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams-Oliver syndrome genes, identifying a single-homozygosity ∼1.8-Mb novel locus common to affected individuals (LOD score 3.37). Whole-exome sequencing followed by Sanger sequencing identified only a single mutation within this locus, shared by all affected individuals and found in patients from five additional apparently unrelated Bedouin families: a 1-bp deletion mutation in a predicted alternative splice variant of EOGT, leading to a putative truncated protein. RT-PCR demonstrated that the EOGT-predicted alternative splice variant is ubiquitously expressed. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine transferase, responsible for extracellular O-GlcNAcylation of epidermal growth factor-like domain-containing proteins, and is essential for epithelial cell-matrix interactions. F-actin staining in diseased fibroblasts showed apparently intact cell cytoskeleton and morphology, suggesting the EOGT mutation acts not through perturbation of cytoskeleton but through other mechanisms yet to be elucidated.