Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies.

PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. RESULTS: WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. CONCLUSIONS: We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.

Lysinibacillus massiliensis Panniculitis Masquerading as Erythema Nodosum: A Case Report.

Lysinibacillus massiliensis, formerly Bacillus massiliensis, is an environmental Gram-positive bacillus that is generally non-pathogenic. Rare case reports in immunosuppressed patients have described sepsis with this organism. In this study, we report a case of L massiliensis as a cause of infectious panniculitis mimicking erythema nodosum after infusion of autologous adipose-derived stem cells in an immunosuppressed patient with refractory Crohn's disease. This case highlights the importance of care providers to consider exposures and host factors when interpreting culture results with otherwise benign organisms.

Sublingual Immunotherapy Dosing Regimens: What Is Ideal?

Sublingual immunotherapy (SLIT) is a treatment for allergic respiratory diseases that has demonstrated efficacy and safety. Several formulations of SLIT are now available worldwide for treatment of allergic rhinitis (AR). Grass tablets containing 15 to 25 µg of group 5 major allergen reduced combined AR symptoms and medication use by 23% to 41% in 3 treatment years and 2 follow-up years. Ragweed pollen tablets (12 µg of Ambrosia artemisiifolia 1) and liquid extracts (50 µg of Ambrosia artemisiifolia 1) reduced combined AR symptoms and medication use by 26% and 43%, respectively. House dust mite tablets containing 300 index of reactivity (16 µg of Dermatophagoides pteronyssinus 1 and 68 µg of Dermatophagoides farinae 1) reduced AR symptoms by 17.9% and 17.0% in 1 treatment year and 1 follow-up year, respectively. A different house dust mite tablet (12 standardized quality house dust mite) was able to reduce the risk of asthma exacerbation compared with placebo (hazard ratio, 0.69; 95% CI, 0.50-0.96). Most adverse events were local and mild to moderate in severity. For SLIT products reviewed herein, effective doses range from 1.12 to 84 µg of major allergen(s). However, allergen content is not uniformly standardized, can be expressed in arbitrary or proprietary units (depending on the manufacturer), and assays for determination of allergen content are highly variable. Thus, results from one study of a given product cannot be extrapolated to other products. Despite these limitations, this Clinical Management Review aims to provide practitioners with relevant information on the dosing of selected SLIT formulations in the treatment of allergic respiratory disease.

Hematologic Malignancies Identified in Patients with Hypereosinophilia and Hypereosinophilic Syndromes.

BACKGROUND: Certain hematologic malignancies are associated with hypereosinophilia or tissue eosinophilia. It is unclear if patients with hypereosinophilia are more likely to develop one of these malignancies. OBJECTIVE: This study sought to quantify the specific hematologic malignancies that developed in patients with preexisting hypereosinophilia. METHODS: Adult patients with eosinophilia associated with the development of hematologic malignancy were identified by a retrospective review of the Mayo Clinic patient database between 2000 and 2013. RESULTS: Of 2642 patients identified with eosinophilia, hypereosinophilia, or hypereosinophilic syndrome, 25 (aged 28.8 to 86.1 years; 13 male; 12 female) had a diagnosis of either lymphoma or leukemia. The majority of these patients had non-Hodgkin lymphoma (17 of 25). T-cell-derived lymphomas were more common (12 of 17) than B-cell-derived lymphomas (4 of 17). In patients with leukemia (8 of 25), chronic lymphocytic leukemia (4 of 8) was most common, followed by chronic eosinophilic leukemia (3 of 8). Approximately 5.1% of patients with hypereosinophilia developed a hematologic malignancy. On average, the malignancy developed 30.0 ± 42.7 months after the onset of hypereosinophilia. CONCLUSIONS: The development of hematologic malignancies in this referral population with eosinophilia was rare (0.2%), but more common in those with hypereosinophilia (5.1%). Non-Hodgkin's lymphomas, particularly T-cell-derived malignancies, were most commonly diagnosed. Patients with preexisting hypereosinophilia were diagnosed with hematologic conditions that were rarer within the general population.

Ventricular septal defect and bivalvular endocarditis.

A 63-year-old man presented with generalized fatigue, chills, malaise, dyspnea, intermittent fevers, and 50-pound weight loss of 4 months' duration. Blood cultures were positive for pan-sensitive Streptococcus anginosus. Transesophageal echocardiography showed an 11 mm × 3 mm mobile mass attached to the mitral valve, a 16 mm × 16 mm mobile mass attached to the pulmonary valve, and a small membranous ventricular septal defect. The patient received 12 weeks of intravenous (IV) antibiotics with eventual resolution of the masses. Multi-valve endocarditis involving both the left and right chambers is rarely reported without prior history of IV drug use or infective endocarditis. Our case emphasizes the importance of careful assessment for ventricular septal defects or extra-cardiac shunts in individuals who present with simultaneous right and left-sided endocarditis.