Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.

OBJECTIVE: The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p. Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. METHODS: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were performed by both Sanger and amplicon-based deep sequencing, mRNA studies were performed by both cDNA subcloning and mRNA sequencing. RESULTS: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis from patients' samples demonstrated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. CONCLUSION: Here we describe the abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and support for a complete gene evaluation in those candidate patients for VEXAS syndrome.

Facial lichen striatus in children: retracing the lines of Blaschko.

We report seven patients with facial lichen striatus along the lines of Blaschko who presented to our pediatric dermatology unit between 2003 and 2009. The mean age of diagnosis was 4.6 years (range 2.5-9 years). Three of the cases were associated with atopic dermatitis, and one case presented with vitiligo. In the six patients for whom we have follow-up, all lesions resolved without pigmentary changes in an average of 11 months. This case series describes the distribution, presentation, and natural history of lichen striatus along facial lines of Blaschko. From our experience, clinical diagnosis and monitoring without biopsy is a reasonable approach to the management of uncomplicated lichen striatus, particularly when the face is involved.

Pompholyx and eczematous reactions associated with intravenous immunoglobulin therapy.

INTRODUCTION: Intravenous immunoglobulin (IVIG) is used to treat many inflammatory and autoimmune disorders and although generally well tolerated, cutaneous side effects occur. OBJECTIVE: We reviewed reports of pompholyx and eczematous reactions associated with IVIG. METHODS: A literature search was performed using the PubMed and MEDLINE databases with the search terms "intravenous immunoglobulin pompholyx," "intravenous immunoglobulin eczema," "intravenous immunoglobulin cutaneous adverse effects," "intravenous immunoglobulin cutaneous effects," "intravenous immunoglobulin skin effects," and "intravenous immunoglobulin adverse effects." Relevant English-language articles or articles in other languages cited in English-language articles were included. RESULTS: We identified 64 cases of eczematous reactions associated with IVIG therapy, including a patient treated on our inpatient consult service. In reported cases, the majority of patients (62.5%) had pompholyx alone or a combination of pompholyx on the hands or feet and two or fewer additional body surfaces involved. The majority of reported cases (75%) experienced the eczematous reaction after their first IVIG treatment. Neurologic conditions were the most common (85.9%) diseases for which IVIG was used. Most patients responded well to topical steroids or did not require treatment. LIMITATIONS: Some reported cases had insufficient descriptions to be included in this review. A literature review may underestimate the frequency of eczematous reactions to IVIG because these reactions are often limited and may not be reported. CONCLUSIONS: With the use of IVIG increasing, it is important for dermatologists to recognize this cutaneous side effect of IVIG.

Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a common complication of allogeneic stem cell transplantation. It is usually treated with high doses of corticosteroids and other immunosuppressive agents. When cutaneous features are predominant, narrowband ultraviolet B (NB-UVB) phototherapy may be an attractive option for its steroid-sparing effect. OBJECTIVE: We sought to examine the clinical efficacy of NB-UVB in the treatment of steroid-refractory and steroid-dependent cutaneous aGvHD. METHODS: We conducted a retrospective chart review of patients with steroid-refractory and steroid-dependent aGvHD, who received NB-UVB between 2005 and 2009 at our institution. RESULTS: We identified 14 patients with aGvHD treated with NB-UVB between 2005 and 2009. The median number of treatments was 15, administered over a median of 43 days. Eight of 14 patients (57%) achieved a complete response at the end of treatment; an additional 3 patients (21%) achieved a partial response; and 3 patients (21%) showed no improvement at the time when phototherapy was discontinued (nonresponders). Four patients developed chronic graft-versus-host disease (GvHD). Three of the 8 complete responders remained free of GvHD at 6 months' follow-up. LIMITATIONS: The rarity of steroid-refractory aGvHD limited the study to a small number of participants. Because GvHD is variable in its presentation and course, and life-threatening in many cases, large controlled prospective trials for potential therapies are difficult. CONCLUSIONS: NB-UVB is a viable option for the treatment of steroid-refractory and steroid-dependent aGvHD of the skin.

Effect of probiotic bacteria on microbial host defense, growth, and immune function in human immunodeficiency virus type-1 infection.

The hypothesis that probiotic administration protects the gut surface and could delay progression of Human Immunodeficiency Virus type1 (HIV-1) infection to the Acquired Immunodeficiency Syndrome (AIDS) was proposed in 1995. Over the last five years, new studies have clarified the significance of HIV-1 infection of the gut associated lymphoid tissue (GALT) for subsequent alterations in the microflora and breakdown of the gut mucosal barrier leading to pathogenesis and development of AIDS. Current studies show that loss of gut CD4+ Th17 cells, which differentiate in response to normal microflora, occurs early in HIV-1 disease. Microbial translocation and suppression of the T regulatory (Treg) cell response is associated with chronic immune activation and inflammation. Combinations of probiotic bacteria which upregulate Treg activation have shown promise in suppressing pro inflammatory immune response in models of autoimmunity including inflammatory bowel disease and provide a rationale for use of probiotics in HIV-1/AIDS. Disturbance of the microbiota early in HIV-1 infection leads to greater dominance of potential pathogens, reducing levels of bifidobacteria and lactobacillus species and increasing mucosal inflammation. The interaction of chronic or recurrent infections, and immune activation contributes to nutritional deficiencies that have lasting consequences especially in the HIV-1 infected child. While effective anti-retroviral therapy (ART) has enhanced survival, wasting is still an independent predictor of survival and a major presenting symptom. Congenital exposure to HIV-1 is a risk factor for growth delay in both infected and non-infected infants. Nutritional intervention after 6 months of age appears to be largely ineffective. A meta analysis of randomized, controlled clinical trials of infant formulae supplemented with Bifidobacterium lactis showed that weight gain was significantly greater in infants who received B. lactis compared to formula alone. Pilot studies have shown that probiotic bacteria given as a supplement have improved growth and protected against loss of CD4+ T cells. The recognition that normal bacterial flora prime neonatal immune response and that abnormal flora have a profound impact on metabolism has generated insight into potential mechanisms of gut dysfunction in many settings including HIV-1 infection. As discussed here, current and emerging studies support the concept that probiotic bacteria can provide specific benefit in HIV-1 infection. Probiotic bacteria have proven active against bacterial vaginosis in HIV-1 positive women and have enhanced growth in infants with congenital HIV-1 infection. Probiotic bacteria may stabilize CD4+ T cell numbers in HIV-1 infected children and are likely to have protective effects against inflammation and chronic immune activation of the gastrointestinal immune system.

Cryptococcal panniculitis in an immunocompromised patient: a case report and review of the literature.

Cryptococcus neoformans is a dimorphic fungus known to cause disease predominately in immuno-compromised patients. It is not uncommon for cryptococcal disease to manifest within the cutaneous tissues of these patients, and it can have drastically varied presentations, from ulcerated nodules to a more subtle cellulitis. We present a patient who underwent a cardiac transplant and developed a fever and mildly erythematous, indurated plaques on his legs and flank several years later. Skin biopsy revealed cryptococcal panniculitis and C neoformans subsequently grew from both the biopsy culture and the cerebrospinal fluid (CSF). This case report highlights the varied and subtle presentations of cutaneous cryptococcosis in immunocompromised patients and encourages a high index of suspicion for this potentially fatal disease in the setting of immunosuppression.

Necrolytic acral erythema as a cutaneous marker of hepatitis C: report of two cases and review.

Necrolytic acral erythema (NAE) is a member of the necrolytic erythemas, which include necrolytic migratory erythema (NME), acrodermatitis enteropathica, and various dermopathies secondary to nutritional deficiencies. NAE is distinct from the other necrolytic erythemas by virtue of its consistent association with hepatitis C (HCV) together with the acral distribution of its lesions, in particular, dorsal hands and feet. Although its etiology is unknown, NAE has been reported to respond to zinc replacement, suggesting a causal relationship. Two patients with HCV infection presented with scaly acral plaques and histopathologic features consistent with NAE while also demonstrating atypical palmoplantar accentuation of lesions. Both patients were found to have zinc deficiency, and their lesions responded to zinc supplementation. Awareness of NAE as a unique cutaneous marker for HCV infection is important not only for accurate dermatologic diagnosis but also for appropriate management of associated morbidity and prompt detection of potentially undiagnosed underlying HCV.

Development of lichen sclerosus et atrophicus while receiving a therapeutic dose of imatinib mesylate for chronic myelogenous leukemia.

BACKGROUND: Imatinib mesylate (Gleevec) is a selective Bcr-Abl protein tyrosine-kinase inhibitor, and it also inhibits the receptor tyrosine kinases for stem cell factor (c-kit) and platelet-derived growth factor (PDGFR). It is being investigated for use in the treatment of sclerosing dermatoses. OBSERVATION: A 44-year-old woman with a history of chronic myelogenous leukemia (CML) was referred for the evaluation of a pruritic eruption that developed over 6 months. Examination revealed atrophic plaques confined to the groin, vulva, axillae, inframammary region, trunk, antecubital and popliteal fossae, and posterior thighs bilaterally. A biopsy showed lichen sclerosus et atrophicus (LSetA). At the time of presentation, the patient was receiving imatinib mesylate 400 mg daily for CML. CONCLUSION: This is the first report of development of LSetA, a sclerosing dermatosis, while receiving a therapeutic dose of imatinib mesylate, a drug thought to have anti-sclerotic properties.

Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma.

INTRODUCTION: Vorinostat, an orally active histone deacetylase inhibitor, was approved in October 2006 by the US Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease during or after treatment with 2 systemic therapies. PATIENTS AND METHODS: A multicenter, open-label phase IIb trial evaluated the activity and safety of vorinostat 400 mg orally daily in patients with > or = stage IB, persistent, progressive, or treatment-refractory mycosis fungoides or Sézary syndrome CTCL subtypes. We report the safety and tolerability of long-term vorinostat therapy in patients who experienced clinical benefit in the previous phase IIb study. RESULTS: As of December 11, 2008, 6 of 74 patients enrolled in the original study had received vorinostat for > or = 2 years: median age, 65 years; median number of previous therapies, 2.5; median time from diagnosis to enrollment, 1.8 years. At enrollment into the continuation phase, 5 of the 6 patients had achieved an objective response, and 1 patient had prolonged stable disease. During the follow-up study, the most common drug-related grade 1-4 adverse events (AEs) were diarrhea, nausea, fatigue, and alopecia (6, 5, 4, and 3 patients, respectively). Incidence of grade 3/4 AEs was low: anorexia (n = 1), increased creatinine phosphokinase (n = 1), pulmonary embolism (n = 1), rash (n = 1), and thrombocytopenia (n = 1). Five patients have discontinued the study drug, and 1 patient is continuing therapy. CONCLUSION: This post hoc subset analysis provides evidence for the long-term safety and clinical benefit of vorinostat in heavily pretreated patients with CTCL, regardless of previous treatment failures.