Publications by authors named "Tiphanie P Vogel"

37 Publications

Case Report: Hyper IgE, but Not the Usual Suspects-Kimura Disease in an Adolescent Female.

Front Pediatr 2021 20;9:674317. Epub 2021 Jul 20.

Texas Children's Hospital, Houston, TX, United States.

Elevated immunoglobulin E (IgE) levels can be associated with infectious, allergic and inflammatory disorders, and rarely as a manifestation of an inborn error of immunity. Here we report the case of an adolescent female who presented with a gradually enlarging neck mass, lymphadenopathy, eosinophilia and highly elevated IgE levels. Laboratory and histopathologic evaluation revealed an unlikely diagnosis of Kimura Disease. We discuss the differential diagnosis of a neck mass with prominent eosinophils on histology, and review support for T-helper type 2 (Th2) cell activation and hyper-IgE in Kimura Disease.
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http://dx.doi.org/10.3389/fped.2021.674317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329340PMC
July 2021

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

J Allergy Clin Immunol 2021 Jul 28. Epub 2021 Jul 28.

Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. Electronic address:

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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http://dx.doi.org/10.1016/j.jaci.2021.07.015DOI Listing
July 2021

Extracorporeal Membrane Oxygenation Support for Antineutrophil Cytoplasmic Antibody-associated Vasculitides: An ELSO Registry Analysis.

ASAIO J 2021 Jul 27. Epub 2021 Jul 27.

From the Department of Pediatrics, Baylor College of Medicine, Houston, Texas Children's National Hospital, Washington, District of Columbia The Extracorporeal Life Support Organization, Ann Arbor, Michigan.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides with pulmonary involvement include granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis, and can present with life-threatening pulmonary hemorrhage in up to 40% of patients. Mortality in those patients who require intubation and mechanical ventilation can reach 77%. Extracorporeal membrane oxygenation (ECMO) can be used to support these patients through definitive diagnosis and treatment, although minimizing the risk of ventilator-induced lung injury. We aimed to determine factors associated with favorable outcomes in patients with (ANCA)-associated vasculitides supported on ECMO. We performed a retrospective observational study using the Extracorporeal Life Support Organization registry of pediatric and adult patients with ANCA-associated vasculitis supported on ECMO from 2010 to 2020. One hundred thirty-five patients were included for analysis. Many patients had renal involvement (39%) in addition to pulmonary involvement (93%). Survival was 73% in AAV patients supported on ECMO. The presence of pulmonary hemorrhage was not associated with worse outcomes in our cohort. Older age, the use of venoarterial ECMO, ECMO-cardiopulmonary resuscitation, or sustaining a cardiac arrest before ECMO was associated with decreased survival. In conclusion, venovenous ECMO should be considered as a supportive bridge to definitive diagnosis and treatment in (ANCA)-associated vasculitides, regardless if pulmonary hemorrhage is present.
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http://dx.doi.org/10.1097/MAT.0000000000001539DOI Listing
July 2021

Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature.

Front Pediatr 2021 20;9:673957. Epub 2021 May 20.

Facultad de Medicina Universidad del Desarrollo-Clínica Alemana, Santiago, Chile.

Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in . The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.
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http://dx.doi.org/10.3389/fped.2021.673957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172984PMC
May 2021

Complicated Diagnosis and Treatment of HA20 due to Contiguous Gene Deletions involving 6q23.3.

J Clin Immunol 2021 Aug 25;41(6):1420-1423. Epub 2021 May 25.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

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http://dx.doi.org/10.1007/s10875-021-01048-wDOI Listing
August 2021

Immune thrombocytopenia following multisystem inflammatory syndrome in children (MIS-C) - a case series.

Pediatr Hematol Oncol 2021 Oct 5;38(7):663-668. Epub 2021 May 5.

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Patients with coronavirus disease 2019 (COVID-19) from novel coronavirus (SARS-CoV-2) infection may present with immune thrombocytopenia (ITP). Multisystem inflammatory syndrome in children (MIS-C) is a serious complication of SARS-CoV-2 causing systemic organ dysfunction. This case series presents the first reported cases of patients who developed ITP following MIS-C, while completing corticosteroid tapers. These patients responded to standard of care therapies for ITP and had appropriate platelet count recovery. We emphasize the importance of careful monitoring of those recovering from COVID-19 or MIS-C, to proactively identify clinical and laboratory abnormalities, in addition to long-term cardiovascular sequelae.
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http://dx.doi.org/10.1080/08880018.2021.1917737DOI Listing
October 2021

Multisystem inflammatory syndrome in children associated with SARS-CoV-2 in a solid organ transplant recipient.

Am J Transplant 2021 07 2;21(7):2596-2599. Epub 2021 Apr 2.

Texas Children's Hospital, Houston, Texas.

We present the case of a 3-year-old female liver transplant recipient with a history of Caroli disease who presented with positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) test and was ultimately diagnosed with multisystem inflammatory syndrome in children (MIS-C) complicated by portal vein thrombosis. To the best of our knowledge, this is the first case report of MIS-C in a pediatric solid organ transplant (SOT) recipient. Based on our patient, MIS-C could be a potential complication of Coronavirus disease 2019 (COVID-19) in SOT recipients and may have a negative outcome on transplant graft function.
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http://dx.doi.org/10.1111/ajt.16572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250508PMC
July 2021

Pulmonary Histopathology Findings in Patients With STAT3 Gain of Function Syndrome.

Pediatr Dev Pathol 2021 May-Jun;24(3):227-234. Epub 2021 Mar 2.

Department of Pediatric Immunology, University of Florida.

Introduction And Aim: Multiorgan autoimmunity and interstitial lung disease (ILD) are reported in patients with STAT3 GOF syndrome.

Results: We present lung histopathology findings in 3 such children, two of whom underwent wedge biopsies with adequate diagnostic material. Wedge biopsies showed interstitial cellular expansion with linear and nodular aggregates of CD8 positive T lymphocytes, plasma cells, and histiocytes; consistent with lymphocytic interstitial pneumonia pattern (LIP). CD4+ T cells and CD20+ B cells were present but infrequent in the interstitium. FOXP3 cells ranged from 0-5%. Focal interstitial and intraalveolar histiocytes were also seen. Neutrophils and eosinophils were rare/absent. Non-occlusive peribronchial lymphoid aggregates showed equal T and B cells; likely reactive in nature. Pulmonary vessels appeared normal without vasculitis or hypertensive change. There was no interstitial or subepithelial fibrosis or organizing pneumonia. Interlobular septa and visceral pleura were unremarkable.

Conclusion: Children with multi-system autoimmune disorders with ILD should be investigated for STAT3 GOF syndrome. Lung wedge biopsies are more informative than transbronchial biopsies, if a tissue sampling is indicated. CD8 dominant T cell inflammation seems to be a key driver of ILD. Although interstitial fibrosis was not seen in our small sample, longer follow up is needed to understand the natural history.
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http://dx.doi.org/10.1177/1093526620980615DOI Listing
March 2021

Multisystem inflammatory syndrome in children and adults (MIS-C/A): Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

Vaccine 2021 05 25;39(22):3037-3049. Epub 2021 Feb 25.

Texas Children's Hospital, Houston, TX, USA; Departments of Pediatrics, Section of Infectious Diseases, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

This is a Brighton Collaboration Case Definition of the term "Multisystem Inflammatory Syndrome in Children and Adults (MIS-C/A)" to be utilized in the evaluation of adverse events following immunization. The case definition was developed by topic experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2. The format of the Brighton Collaboration was followed, including an exhaustive review of the literature, to develop a consensus definition and defined levels of certainty. The document underwent peer review by the Brighton Collaboration Network and by selected expert external reviewers prior to submission. The comments of the reviewers were taken into consideration and edits incorporated into this final manuscript.
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http://dx.doi.org/10.1016/j.vaccine.2021.01.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904456PMC
May 2021

Successful treatment of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with tofacitinib.

Pediatr Dermatol 2021 Mar 29;38(2):528-529. Epub 2021 Jan 29.

Baylor College of Medicine, Houston, TX, USA.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.
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http://dx.doi.org/10.1111/pde.14517DOI Listing
March 2021

Pulmonary manifestations and outcomes in paediatric ANCA-associated vasculitis: a single-centre experience.

Rheumatology (Oxford) 2021 07;60(7):3199-3208

Division of Pulmonary Medicine, Baylor College of Medicine.

Objectives: ANCA-associated vasculitis (AAV) usually involves the renal and respiratory systems, but the paediatric literature on pulmonary manifestations and outcomes is limited. We aimed to describe pulmonary manifestations and outcomes after therapy in a cohort of paediatric AAV (pAAV) patients.

Methods: A retrospective chart review of all patients <19 years presenting to our institution with AAV between 1/2008 and 2/2018 was conducted. Patient demographics, clinical presentation, diagnostic testing, therapy and pulmonary outcomes over the first 3 years after presentation were evaluated.

Results: A total of 38 patients were included; all had ANCA positivity by immunofluorescence. A total of 23 had microscopic polyangiitis (MPA), 13 had granulomatosis with polyangiitis and 2 had eosinophilic granulomatosis with polyangiitis. A total of 30 (79%) had pulmonary manifestations, with cough (73%) and pulmonary haemorrhage (67%) being the most common. Abnormalities were noted in 82% of chest CT scans reviewed, with nodules and ground-glass opacities being the most common. At 6, 12 and 36 months follow-up, respectively, 61.8%, 39.4% and 29% of patients continued to show pulmonary manifestations. Five MPA patients with re-haemorrhage are described in detail.

Conclusion: MPA was more common than granulomatosis with polyangiitis, with pulmonary involvement being common in both. MPA patients had more severe pulmonary manifestations. Chest CT revealed abnormal findings in a majority of cases. A subgroup of young MPA patients experienced repeat pulmonary haemorrhage. Treatment modality and response were comparable in different subtypes of AAV, except for this young MPA group. Additional prospective studies are needed to better understand the different phenotypes of pAAV.
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http://dx.doi.org/10.1093/rheumatology/keaa769DOI Listing
July 2021

Lung biopsy in the diagnosis of pediatric ANCA-associated vasculitis.

Pediatr Pulmonol 2021 01 9;56(1):145-152. Epub 2020 Nov 9.

Division of Pulmonary Medicine, Texas Children's Hospital, Houston, Texas, USA.

Objective: To investigate pulmonary histopathologic features in a cohort of pediatric patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) who underwent a lung biopsy as part of their evaluation. We report the safety and the findings of lung biopsies in this population.

Methods: After IRB approval, we performed a retrospective chart review of all patients <18 years of age presenting to our institution with a diagnosis of pediatric AAV (pAAV) who underwent lung biopsy. We reviewed histopathologic features, serologies, the timing of biopsy, and complications.

Results: Fourteen patients met inclusion criteria, nine patients with microscopic polyangiitis (MPA), and five patients with granulomatosis with polyangiitis (GPA). All patients had positive ANCA serology. 13/14 patients required admission on initial presentation for respiratory symptoms; 11/13 required respiratory support. The indication for biopsy was confirmation of diagnosis before initiating therapy in 11 patients (78%), part of the infectious evaluation in two (14%), and part of interstitial lung disease evaluation in one (7%). 11/14 (78%) biopsies had findings consistent with AAV diagnosis: 6/9 (67%) of the MPA patients compared with 5/5 (100%) of the GPA patients. The most common findings on histopathology were vascular inflammation and signs of alveolar hemorrhage. The only reported complication after lung biopsy was pneumothorax in four patients (28%).

Conclusion: Lung biopsy had a higher diagnostic yield in GPA compared with MPA patients. In our cohort, a diagnosis of AAV could be made with clinical features and positive serology but was confirmed by lung histopathology in the majority of cases. Obtaining a lung biopsy for diagnostic purposes in pAAV should be reserved for uncertain cases where the diagnosis cannot be confirmed clinically and with serology.
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http://dx.doi.org/10.1002/ppul.25151DOI Listing
January 2021

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor.

Case Reports Immunol 2020 26;2020:8841571. Epub 2020 Aug 26.

Texas Children's Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, TX, USA.

X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later.
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http://dx.doi.org/10.1155/2020/8841571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474360PMC
August 2020

A Zebra at the Rodeo: Dyspnea, Hematuria, and a Family History of Arthritis.

Arthritis Care Res (Hoboken) 2020 Jun 29. Epub 2020 Jun 29.

Division of Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

An 18-year-old, previously healthy female was admitted for urgent evaluation and management of symptomatic anemia after presenting to her primary care physician with fatigue and shortness of breath. The initial outpatient evaluation was remarkable for hypochromic, microcytic anemia with a hemoglobin of 6.7 g/dL.
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http://dx.doi.org/10.1002/acr.24368DOI Listing
June 2020

A Remarkable Response of Granulomatous Hypophysitis to Infliximab in a Patient With a Background of Crohn's Disease-A Case Report.

Front Endocrinol (Lausanne) 2020 29;11:350. Epub 2020 May 29.

Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, United States.

Hypophysitis is primary or idiopathic or secondary to another disease process. The histologic subtypes of hypophysitis are lymphocytic, granulomatous, xanthomatous, xanthogranulomatous, or IgG4-related. Granulomatous hypophysitis is the second most common form and is characterized by multinucleated giant cells with granulomas and histiocytes. It can be idiopathic or secondary to another process such as infection, sarcoidosis, vasculitis, dendritic cell disorders, Crohn's disease (CD) or a reaction to rupture of a Rathke's cyst or pituitary adenoma. We present a case of granulomatous hypophysitis in a patient with CD who had resistance to corticosteroids but a dramatic response to immunosuppressive therapy with anti-tumor necrosis factor (TNF)-α therapy. A 43-year-old woman with a 9-year history of ileal and colonic CD presented to the Pituitary Center with headaches, visual disturbance, fatigue, nausea, and secondary amenorrhea. She was not on active therapy for her CD at the time of presentation and had no gastrointestinal symptoms. Hormonal evaluation revealed hyperprolactinemia, secondary hypothyroidism and adrenal insufficiency. MRI revealed a 12 × 12 × 19 mm sellar lesion abutting the optic chiasm, reported as a macroadenoma. The patient underwent endoscopic transsphenoidal biopsy of the pituitary mass. Pathology revealed granulomatous hypophysitis. Evaluation for secondary causes of hypophysitis, apart from CD, was negative. Despite a course of high dose prednisone, her symptoms and MRI findings worsened and she developed symptoms consistent with diabetes insipidus. Using a personalized medicine approach, she was started on anti-(TNF)-α therapy with infliximab combined with azathioprine, which are indicated for treatment of CD. Her headaches and polyuria resolved and her menstrual cycles resumed. MRI at 3 months and more than 1.5 years after initiation of anti-TNF-α therapy revealed durable resolution of the pituitary mass. To our knowledge, this is the first report of successful use of anti-TNF-α therapy for a patient with granulomatous hypophysitis, in this case associated with a previous diagnosis of CD. Although glucocorticoids are used frequently as first-line therapy for primary hypophysitis, granulomatous hypophysitis can be corticosteroid resistant and other immunosuppressive approaches may need to be considered within the context of the patient.
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http://dx.doi.org/10.3389/fendo.2020.00350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272571PMC
May 2021

Subclinical Pulmonary Granulomatosis With Polyangiitis With Dramatic Response to Treatment.

J Clin Rheumatol 2021 Sep;27(6):e243-e244

Rheumatology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.

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http://dx.doi.org/10.1097/RHU.0000000000001378DOI Listing
September 2021

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

J Exp Med 2020 06;217(6)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
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http://dx.doi.org/10.1084/jem.20191804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971136PMC
June 2020

Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.

Neuron 2020 05 12;106(4):589-606.e6. Epub 2020 Mar 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-oxidation pathway in peroxisomes and leads to HO production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.
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http://dx.doi.org/10.1016/j.neuron.2020.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289150PMC
May 2020

Genetic Disorders Should Be Considered Prior to Diagnosing Interstitial Pneumonia With Autoimmune Features: Comment on the Review by Wilfong et al.

Arthritis Rheumatol 2019 12 23;71(12):2132-2133. Epub 2019 Oct 23.

Baylor College of Medicine and Texas Children's Hospital, Houston, TX.

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http://dx.doi.org/10.1002/art.41081DOI Listing
December 2019

Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease.

FEBS J 2019 07 27;286(14):2628-2644. Epub 2019 May 27.

Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Members of the mammalian inflammatory caspase family, including caspase-1, caspase-4, caspase-5, caspase-11, and caspase-12, are key regulators of the innate immune response. Most studies to date have focused on the role of caspase-1 in the maturation of the proinflammatory cytokine interleukin-1β and its upstream regulation by the inflammasome signaling complexes. However, an emerging body of research has supported a role for caspase-4, caspase-5, and caspase-11 in both regulating caspase-1 activation and inducing the inflammatory form of cell death called pyroptosis. This inflammatory caspase pathway appears essential for the regulation of cytokine processing. Consequently, insight into this noncanonical pathway may reveal important and, to date, understudied targets for the treatment of autoinflammatory disorders where the inflammasome pathway is dysregulated. Here, we will discuss the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.
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http://dx.doi.org/10.1111/febs.14926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065599PMC
July 2019

A Novel Mutation in a Qatari Patient With Hyper-IgE Syndrome.

Front Pediatr 2019 24;7:130. Epub 2019 Apr 24.

Section of Immunology, Allergy and Rheumatology, Department of Pediatrics, Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States.

Autosomal dominant hyper-IgE syndrome caused by mutations in the transcription factor STAT3 (AD-HIES) is characterized by a collection of immunologic and non-immune features including eczema, recurrent infections, elevated IgE levels, and connective tissue anomalies. We report the case of a Qatari child with a history of recurrent staphylococcal skin infections since infancy, who was found to have a novel, mutation in STAT3 (c.1934T>A, p.L645Q). The absence of mucocutaneous candidiasis and undetectable IgE levels until the age of 7 years prolonged the time to molecular confirmation of the cause for the patient's immune deficiency. STAT3 p.L645Q was found to have decreased transcriptional capacity. The patient also had low levels of Th17 cells and STAT3 phosphorylation was impaired in patient-derived cells. Nearly 100 unique mutations in STAT3 have been reported in association with AD-HIES.
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http://dx.doi.org/10.3389/fped.2019.00130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491627PMC
April 2019

Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):1958-1969.e9. Epub 2019 Feb 27.

Pediatric Pulmonology Department, Hôpitaux pédiatriques de Nice CHU-Lenval, Nice, France; Université de Nice-Sophia Antipolis, Nice, France. Electronic address:

Background: Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) germline mutations have been recently described. A comprehensive overview of this early-onset multiorgan autoimmune and lymphoproliferative disease has not yet been compiled.

Objective: We have conducted a systematic review of published STAT3 GOF cases to describe clinical, diagnostic, and therapeutic aspects of the disease.

Methods: A systematic review including articles published before October 10, 2018, in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed. We described cases of patients with STAT3 GOF germline mutations with genetic analysis and a concordant phenotype if functional analyses were not performed for the mutation.

Results: The search identified 18 publications describing 42 unique patients. Twenty-eight different mutations were described. Onset of disease was very early with an average age of 3 (0.5-5) years. The most frequent manifestations were autoimmune cytopenias (28 of 42), lymphoproliferation (27 of 42), enteropathy (24 of 42), interstitial lung disease (15 of 42), thyroiditis (13 of 42), diabetes (10 of 42), and postnatal growth failure (15 of 21). Immunodeficiency was not always a predominant feature. Most patients required significant immunosuppressive therapy. Five patients received hematopoietic stem cell transplantation, and 4 died from complications. Improvement of symptoms was observed for 8 of 9 patients who received targeted biotherapies.

Conclusions: STAT3 GOF syndrome is a new clinical entity to consider when confronted with a patient with early-onset polyautoimmunity, lymphoproliferation, and growth failure. At this time, precise therapeutic guidelines are lacking, but use of anti-IL-6 receptor and JAK inhibitor biologics is an attractive possibility.
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http://dx.doi.org/10.1016/j.jaip.2019.02.018DOI Listing
September 2020

Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.

Am J Hum Genet 2018 06 24;102(6):1126-1142. Epub 2018 May 24.

Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA. Electronic address:

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992134PMC
June 2018

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Blood 2018 07 9;132(1):89-100. Epub 2018 Apr 9.

Department of Pediatrics, Baylor College of Medicine, Houston, TX.

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 ( < .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 ( < .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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http://dx.doi.org/10.1182/blood-2017-11-814244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034641PMC
July 2018

Somatic mutations and clonal hematopoiesis in congenital neutropenia.

Blood 2018 01 1;131(4):408-416. Epub 2017 Nov 1.

Division of Oncology, Department of Internal Medicine.

Severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS) are congenital neutropenia syndromes with a high rate of leukemic transformation. Hematopoietic stressors may contribute to leukemic transformation by increasing the mutation rate in hematopoietic stem/progenitor cells (HSPCs) and/or by promoting clonal hematopoiesis. We sequenced the exome of individual hematopoietic colonies derived from 13 patients with congenital neutropenia to measure total mutation burden and performed error-corrected sequencing on a panel of 46 genes on 80 patients with congenital neutropenia to assess for clonal hematopoiesis. An average of 3.6 ± 1.2 somatic mutations per exome was identified in HSPCs from patients with SCN compared with 3.9 ± 0.4 for healthy controls ( = NS). Clonal hematopoiesis due to mutations in was present in 48% (13/27) of patients with SDS but was not seen in healthy controls (0/17, < .001) or patients with SCN (0/40, < .001). Our SDS cohort was young (median age 6.3 years), and many of the patients had multiple mutations. Conversely, clonal hematopoiesis due to mutations of was present in patients with SCN but was not detected in healthy controls or patients with SDS. These data show that hematopoietic stress, including granulocyte colony-stimulating factor, do not increase the mutation burden in HSPCs in congenital neutropenia. Rather, distinct hematopoietic stressors result in the selective expansion of HSPCs carrying specific gene mutations. In particular, in SDS there is enormous selective pressure to expand -mutated HSPCs, suggesting that acquisition of mutations is an early, likely initiating event, in the transformation to myelodysplastic syndrome/acute myeloid leukemia in patients with SDS.
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http://dx.doi.org/10.1182/blood-2017-08-801985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790127PMC
January 2018
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