Browsing by Author "Peckham-Gregory, Erin C."

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    Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis
    (2018) Chinn, Ivan K.; Eckstein, Olive S.; Peckham-Gregory, Erin C.; Goldberg, Baruch R.; Forbes, Lisa R.; Nicholas, Sarah K.; Mace, Emily M.; Vogel, Tiphanie P.; Abhyankar, Harshal A.; Diaz, Maria I.; Heslop, Helen E.; Krance, Robert A.; Martinez, Caridad A.; Nguyen, Trung C.; Bashir, Dalia A.; Goldman, Jordana R.; Stray-Pedersen, Asbjørg; Pedroza, Luis A.; Poli, Cecilia; Aldave-Becerra, Juan C.; McGhee, Sean A.; Al-Herz, Waleed; Chamdin, Aghiad; Coban-Akdemir, Zeynep H.; Jhangiani, Shalini N.; Muzny, Donna M.; Cao, Tram N.; Hong, Diana N.; Gibbs, Richard A.; Lupski, James R.; Orange, Jordan S.; McClain, Kenneth L.; Allen, Carl E.
    The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.
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    Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders
    (2022) Forbes, Lisa R.; Eckstein, Olive S.; Gulati, Nitya; Peckham-Gregory, Erin C.; Ozuah, Nmazuo W.; Lubega, Joseph; El-Mallawany, Nader K.; Agrusa, Jennifer E.; Poli, Cecilia; Vogel, Tiphanie P.; Chaimowitz, Natalia S.; Rider, Nicholas L.; Mace, Emily M.; Orange, Jordan S.; Caldwell, Jason W.; Aldave-Becerra, Juan C.; Jolles, Stephen; Saettini, Francesco; Chong, Hey J.; Stray-Pedersen, Asbjorg; Heslop, Helen E.; Kamdar, Kala Y.; Rouce, R. Helen; Muzny, Donna M.; Jhangiani, Shalini N.; Gibbs, Richard A.; Coban-Akdemir, Zeynep H.; Lupski, James R.; McClain, Kenneth L.; Allen, Carl E.; Chinn, Ivan K.
    Background: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. Objective: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. Methods: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. Results: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. Conclusions: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

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