Morgan Similuk

Randomized Noninferiority Trial of Telephone vs In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer: A 12-Month Follow-Up

Abstract Background Telephone delivery of genetic counseling is an alternative to in-person genetic counseling because it may extend the reach of genetic counseling. Previous reports have established the noninferiority of telephone counseling on short-term psychosocial and decision-making outcomes. Here we examine the long-term impact of telephone counseling (TC) vs in-person counseling (usual care [UC]). Methods We recruited high-risk women for a noninferiority trial comparing TC with UC. Of 1057 potentially eligible women, 669 were randomly assigned to TC (n = 335) or UC (n = 334), and 512 completed the 12-month follow-up. Primary outcomes were patient-reported satisfaction with genetic testing decision, distress, and quality of life. Secondary outcomes were uptake of cancer risk management strategies. Results TC was noninferior to UC on all primary outcomes. Satisfaction with decision (d = 0.13, lower bound of 97.5% confidence interval [CI] = –0.34) did not cross its one-point noninferiority limit, cancer-specific distress (d = –2.10, upper bound of 97.5% CI = –0.07) did not cross its four-point noninferiority limit, and genetic testing distress (d = –0.27, upper bound of 97.5% CI = 1.46), physical function (d = 0.44, lower bound of 97.5% CI = –0.91) and mental function (d = –0.04, lower bound of 97.5% CI = –1.44) did not cross their 2.5-point noninferiority limit. Bivariate analyses showed no differences in risk-reducing mastectomy or oophorectomy across groups; however, when combined, TC had significantly more risk-reducing surgeries than UC (17.8% vs 10.5%; χ2= 4.43, P = .04). Conclusions Findings support telephone delivery of genetic counseling to extend the accessibility of this service without long-term adverse outcomes.

Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency

STAT3 haploinsufficiency caused by a novel STAT3 splice site mutation is associated with elevated IgE, allergic rhinitis, eosinophilic esophagitis, and invasive aspergillosis. This case expands our understanding of the spectrum of disease associated with STAT3 mutations.

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

In these studies, we evaluated the contribution of the NLRP3 inflammasome to Crohn’s disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified the affected individuals as having a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1&bgr; in the affected individuals were increased compared with those in healthy controls, and their peripheral monocytes produced increased amounts of IL-1&bgr; when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 failed to downregulate the NLRP3 inflammasome because it did not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerted a dominant-negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impeded their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevented NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti–TNF-&agr;, but did respond to IL-1&bgr; inhibitors. Thus, patients with anti–TNF-&agr;–resistant CD may respond to this treatment option.

Predispositions to Lymphoma: A Practical Review for Genetic Counselors.

This review provides a synopsis for genetic counselors of the major concepts of lymphoma predisposition: genomic instability, immune deficiency, inappropriate lymphoproliferation, and chronic antigen stimulation. We discuss syndromes typifying each of these mechanisms. Importantly, our review of the genetic counseling literature reveals sparse discussion of genetically-based immune-mediated lymphoma predisposition, which we address in depth here. We aim to increase awareness among genetic counselors and colleagues in oncology about familial susceptibility and facilitate critical thinking about lymphoma risk assessment. Clinical application of this knowledge is aided by recommendations for collection of personal and family history to guide risk assessment and testing. Lastly, we include a special discussion of genetic counseling issues including perceptions of the context, nature, and magnitude of lymphoma risk, as well as coping with awareness of susceptibility to lymphoma.

Life with a Primary Immune Deficiency: a Systematic Synthesis of the Literature and Proposed Research Agenda.

PurposeThe clinical immunology literature is punctuated with research on psychosocial dimensions of illness. Studies investigating the lived experiences and stated needs of patients with primary immune deficiencies and their families are essential to improving clinical management and determining the research questions that matter to patients and other stakeholders. Yet, to move the field forward, a systematic review of literature and proposed agenda is needed.MethodsA systematic review was conducted via PubMed and Scopus to include original research on psychological, social, or behavioral aspects of primary immune deficiencies published between 1999 and 2015. A Title/Abstract keyword search was conducted, 317 candidate article abstracts were manually reviewed, and forward/backward reference searches were completed.ResultsTwenty-nine studies met inclusion criteria. These illuminate the complex psychological, social, and emotional experiences of primary immune deficiency. Themes included the potential for negative psychosocial impact from disease; adaptation over time; the multi-dimensional assessments of quality of life; familial impact; the important roles of hope, developing a sense of control, social support; and addressing anxiety/depression in our patients and their families. Methodological considerations and areas for improvement are discussed.ConclusionWe propose the research agenda focus on study creativity and rigor, with improved engagement with existing literature and critical study design (e.g., methodology with adequate statistical power, careful variable selection, etc.). This review highlights opportunities to advance psychosocial research and bring a brighter future to clinicians, researchers, and families affected by primary immune deficiency.

De novo STAT3 Mutation in a Patient with Fatal, Treatment-Refractory Sino-orbital Aspergillosis

Abstract Background Signal transducer and activator of transcription 3 (STAT3) loss-of-function mutations in humans result in Job’s syndrome, characterized by elevated IgE, bacterial infections, chronic mucocutaneous candidiasis, pulmonary aspergillosis due to structural lung disease, and connective tissue abnormalities. Methods Whole exome sequencing (WES) was performed on a putatively immunocompetent patient with sino-orbital aspergillosis and his parents. Evaluation of STAT3 phosphorylation (pSTAT3) was performed by flow cytometry on peripheral blood mononuclear cells after IL-6 stimulation. Results A 37-year-old-male with a history of eosinophilic esophagitis developed a locally invasive sino-orbital infection with progressive cavernous sinus involvement associated with facial numbness, diplopia, and visual loss. Biopsy showed chronic inflammation and invasive fungal hyphae. Cultures grew an isolate of Aspergillus fumisynnematus that was identified by morphology and the sequences of β-tubulin and Mcm7. MICs (in µg/ml) for the isolate were: micafungin <=0.015, amphotericin 2, posaconazole 0.25, terbinafine 0.06, and voriconazole 0.25. The patient underwent multiple surgical debridements and was treated over time with various antifungals (amphotericin B, micafungin, terbinafine, voriconazole, posaconazole), adjunct cytokines (IFN-γ, GM-CSF), and hyperbaric oxygen. However, the infection progressed into the right middle cranial fossa and meninges and the patient died 1 year after symptoms began. WES revealed a de novo splice-site mutation in STAT3 (c.1140-3C>G). cDNA sequencing showed nonsense mediated decay of the affected allele. No mutations in CARD9 or NADPH oxidase subunits were found; a DHR test was normal. The patient had normal blood myeloid cell subsets. Serum IgE level was elevated at 833 IU/ml. After stimulation with IL-6, the patient’s memory CD4+ T cells and CD11c+ myeloid cells had reduced pSTAT3 levels compared with control cells. Cellular analysis of SOCS3, a STAT3-dependent downstream target, is underway to evaluate for functional STAT3 haploinsufficiency. Conclusion A novel de novo STAT3 splice site mutation results in impaired pSTAT3, and is associated with elevated IgE, eosinophilic esophagitis, and sino-orbital aspergillosis without other common features of Job’s syndrome Disclosures All authors: No reported disclosures.