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Newborn Screening for Severe Combined Immunodeficiency in Delaware: Results of the First 3 Years
AB14 Abstracts
SATURDAY
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Hemophagocytic Lymphohistiocytosis (HLH) in Noonan's Syndrome (NS) Successfully Treated with Anti-IL-1beta Therapy Bob Geng, MD1, Maria Garcia-Lloret, MD, FAAAAI2, Deborah McCurdy, MD3, Eric Yen, MD3, Tanesha Moss3; 1UCLA, Los Angeles, CA, 2Division of Allergy and Immunology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 3UCLA. RATIONALE: HLH is a syndrome characterized by uncontrolled macrophage activation. NS is an autosomal dominant disorder involving RAS-MAPKinase pathway associated with multiple end-organ defects, short stature, and dysmorphic features. We present the first reported case of HLH in NS who improved with use of anti-IL-1beta therapy. METHODS: Genetic Screening for Familial HLH; Bone-Marrow Biopsy; NK-cell cytotoxicity assay; Familial Mediterranean fever (FMF) genetic test. RESULTS: Five-year-old female with NS (KRAS c40g>a), gastroparesis with G-tube placement, mitral valve prolapse and chronic anemia presented with recurrent fevers. Multiple admissions yielded negative work-up for infectious etiology. Fevers associated with joint pain and increased abdominal discomfort. She met 5 of 8 criteria for HLH: Ferritin >20,000ng/ml; hepatosplenomegaly; fevers; decreased NK-cell activity, and hemophagocytosis on bone-marrow biopsy. Primary HLH genetic screening was negative. FMF evaluation was negative. Other period fever syndrome evaluations are pending. Systemic steroids led to some improved symptoms. She was initiated on IL-1beta receptor antagonist (anakinra), which led to resolution of fevers and reduction in joint symptoms. She transitioned to long-acting anti-IL-1beta monoclonal antibody (canakinumab), which maintained control of symptoms. CONCLUSIONS: While HLH has not been a reported feature of NS, RAS-MAPKinase pathway is a crucial component of cell signaling that controls transcription of inflammatory mediators. This case illustrates importance of considering autoinflammatory conditions in NS patients with recurrent fevers. Steroids and cytoreductive agents are currently standard of care for HLH. Efficacy of IL-1beta blockade in this case highlights importance of considering these agents as alternative or adjunctive treatment for HLH.
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Nijmegen Breakage Syndrome Detected By Newborn Screening for T Cell Receptor Excision Circles (TRECs) Jay Patel, MD1, Jennifer M. Puck, MD2, Kunal Kundu3, Uma Sunderam3, Christina Brown4, Rajgopal Srinivasan, Ph.D.3, Steven E. Brenner, Ph.D.5, Richard A. Gatti, MD4, Joseph A. Church, MD, FAAAAI6; 1Division of General Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, CA, 2Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA, 3TCS Innovation Labs Hyderabad, 4Departments of Human Genetics and Pathology & Laboratory Medicine, University of California Los Angeles School of Medicine, 5Department of Plant and Microbial Biology, University of California Berkeley, 6Division of Clinical Immunology, Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA. RATIONALE: Severe combined immunodeficiency (SCID) encompasses a group of disorders characterized by reduced or absent T-cell number and function and identified by newborn screening utilizing T-cell receptor excision circles (TRECs). This screening has also identified infants with T lymphopenia who lack mutations in typical SCID genes. We report an infant with low TRECs and non-SCID T lymphopenia, who proved upon whole exome sequencing to have Nijmegen breakage syndrome (NBS). METHODS: Exome sequencing of DNA from the infant and his parents was performed. Genomic analysis revealed deleterious variants in the NBN gene. Confirmatory testing included Sanger sequencing and immunoblotting and ratiosensitivity testing of patient lymphocytes. RESULTS: Two novel nonsense mutations in NBN were identified in genomic DNA from the family. Immunoblotting showed absence of nibrin
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
protein. A colony survival assay demonstrated radiosensitivity comparable to patients with ataxia telangiectasia. CONCLUSIONS: Although TREC screening was developed to identify newborns with SCID, it has also identified T lymphopenic disorders that may not otherwise be diagnosed until later in life. Timely identification of an infant with T lymphopenia allowed for prompt pursuit of underlying etiology, making possible a diagnosis of NBS, genetic counseling, and early intervention to minimize complications.
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Newborn Screening for Severe Combined Immunodeficiency in Delaware: Results of the First 3 Years Stacey Galowitz, DO1,2, Stephen J. McGeady, MD, FAAAAI1,2, Louis Bartoshesky, MD, MPH3, Magee L. DeFelice, MD1,2; 1Thomas Jefferson University Hospital, Philadelphia, PA, 2Nemours/AI duPont Hospital for Children, Wilmington, DE, 3Christiana Care Health Care System, Newark, DE. RATIONALE: Severe Combined Immunodeficiency (SCID) is fatal if not diagnosed and treated within the first few months of life. Prior to development of the T-cell receptor excision circle (TREC) assay, the diagnosis of SCID was frequently missed, largely due to the often normal physical exam of these infants. Since 2010, 23 states, the District of Columbia, and the Navajo Nation have begun statewide newborn screening for SCID, leading to earlier detection and markedly improved clinical outcomes. In September 2011, Delaware initiated its pilot program and in July 2012, Delaware officially began screening newborns for SCID using the TREC assay. Data from Delaware newborn screening for SCID is unique in that Nemours/AI duPont Hospital for Children (AIDHC) is the only referral center in the state. METHODS: Approximately 33,000 infants were screened in Delaware from Sept 2011 - August 2014. All infants with a positive screen were referred to AIDHC for diagnostic evaluation. RESULTS: Twenty four infants with positive screens were referred. Of _36 weeks gestation). Further evaluation these, 5 patients were premature (< identified 2 patients with SCID, 3 patients with partial DiGeorge syndrome, 10 patients with unspecified T-cell lymphopenia, and 9 patients with normal T cell counts. CONCLUSIONS: As newborn screening for SCID is still in early stages, the clinical characteristics, laboratory features, and long-term outcomes of patients with abnormal TREC values identified by newborn screening are not yet well described. The SCID newborn screening program in Delaware has successfully identified 2 infants with SCID and 13 with non-SCID lymphopenia.
SATURDAY
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Hemophagocytic Lymphohistiocytosis (HLH) in Noonan's Syndrome (NS) Successfully Treated with Anti-IL-1beta Therapy Bob Geng, MD1, Maria Garcia-Lloret, MD, FAAAAI2, Deborah McCurdy, MD3, Eric Yen, MD3, Tanesha Moss3; 1UCLA, Los Angeles, CA, 2Division of Allergy and Immunology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 3UCLA. RATIONALE: HLH is a syndrome characterized by uncontrolled macrophage activation. NS is an autosomal dominant disorder involving RAS-MAPKinase pathway associated with multiple end-organ defects, short stature, and dysmorphic features. We present the first reported case of HLH in NS who improved with use of anti-IL-1beta therapy. METHODS: Genetic Screening for Familial HLH; Bone-Marrow Biopsy; NK-cell cytotoxicity assay; Familial Mediterranean fever (FMF) genetic test. RESULTS: Five-year-old female with NS (KRAS c40g>a), gastroparesis with G-tube placement, mitral valve prolapse and chronic anemia presented with recurrent fevers. Multiple admissions yielded negative work-up for infectious etiology. Fevers associated with joint pain and increased abdominal discomfort. She met 5 of 8 criteria for HLH: Ferritin >20,000ng/ml; hepatosplenomegaly; fevers; decreased NK-cell activity, and hemophagocytosis on bone-marrow biopsy. Primary HLH genetic screening was negative. FMF evaluation was negative. Other period fever syndrome evaluations are pending. Systemic steroids led to some improved symptoms. She was initiated on IL-1beta receptor antagonist (anakinra), which led to resolution of fevers and reduction in joint symptoms. She transitioned to long-acting anti-IL-1beta monoclonal antibody (canakinumab), which maintained control of symptoms. CONCLUSIONS: While HLH has not been a reported feature of NS, RAS-MAPKinase pathway is a crucial component of cell signaling that controls transcription of inflammatory mediators. This case illustrates importance of considering autoinflammatory conditions in NS patients with recurrent fevers. Steroids and cytoreductive agents are currently standard of care for HLH. Efficacy of IL-1beta blockade in this case highlights importance of considering these agents as alternative or adjunctive treatment for HLH.
44
Nijmegen Breakage Syndrome Detected By Newborn Screening for T Cell Receptor Excision Circles (TRECs) Jay Patel, MD1, Jennifer M. Puck, MD2, Kunal Kundu3, Uma Sunderam3, Christina Brown4, Rajgopal Srinivasan, Ph.D.3, Steven E. Brenner, Ph.D.5, Richard A. Gatti, MD4, Joseph A. Church, MD, FAAAAI6; 1Division of General Pediatrics, Children’s Hospital of Los Angeles, Los Angeles, CA, 2Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital, San Francisco, CA, 3TCS Innovation Labs Hyderabad, 4Departments of Human Genetics and Pathology & Laboratory Medicine, University of California Los Angeles School of Medicine, 5Department of Plant and Microbial Biology, University of California Berkeley, 6Division of Clinical Immunology, Children’s Hospital of Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA. RATIONALE: Severe combined immunodeficiency (SCID) encompasses a group of disorders characterized by reduced or absent T-cell number and function and identified by newborn screening utilizing T-cell receptor excision circles (TRECs). This screening has also identified infants with T lymphopenia who lack mutations in typical SCID genes. We report an infant with low TRECs and non-SCID T lymphopenia, who proved upon whole exome sequencing to have Nijmegen breakage syndrome (NBS). METHODS: Exome sequencing of DNA from the infant and his parents was performed. Genomic analysis revealed deleterious variants in the NBN gene. Confirmatory testing included Sanger sequencing and immunoblotting and ratiosensitivity testing of patient lymphocytes. RESULTS: Two novel nonsense mutations in NBN were identified in genomic DNA from the family. Immunoblotting showed absence of nibrin
J ALLERGY CLIN IMMUNOL FEBRUARY 2015
protein. A colony survival assay demonstrated radiosensitivity comparable to patients with ataxia telangiectasia. CONCLUSIONS: Although TREC screening was developed to identify newborns with SCID, it has also identified T lymphopenic disorders that may not otherwise be diagnosed until later in life. Timely identification of an infant with T lymphopenia allowed for prompt pursuit of underlying etiology, making possible a diagnosis of NBS, genetic counseling, and early intervention to minimize complications.
45
Newborn Screening for Severe Combined Immunodeficiency in Delaware: Results of the First 3 Years Stacey Galowitz, DO1,2, Stephen J. McGeady, MD, FAAAAI1,2, Louis Bartoshesky, MD, MPH3, Magee L. DeFelice, MD1,2; 1Thomas Jefferson University Hospital, Philadelphia, PA, 2Nemours/AI duPont Hospital for Children, Wilmington, DE, 3Christiana Care Health Care System, Newark, DE. RATIONALE: Severe Combined Immunodeficiency (SCID) is fatal if not diagnosed and treated within the first few months of life. Prior to development of the T-cell receptor excision circle (TREC) assay, the diagnosis of SCID was frequently missed, largely due to the often normal physical exam of these infants. Since 2010, 23 states, the District of Columbia, and the Navajo Nation have begun statewide newborn screening for SCID, leading to earlier detection and markedly improved clinical outcomes. In September 2011, Delaware initiated its pilot program and in July 2012, Delaware officially began screening newborns for SCID using the TREC assay. Data from Delaware newborn screening for SCID is unique in that Nemours/AI duPont Hospital for Children (AIDHC) is the only referral center in the state. METHODS: Approximately 33,000 infants were screened in Delaware from Sept 2011 - August 2014. All infants with a positive screen were referred to AIDHC for diagnostic evaluation. RESULTS: Twenty four infants with positive screens were referred. Of _36 weeks gestation). Further evaluation these, 5 patients were premature (< identified 2 patients with SCID, 3 patients with partial DiGeorge syndrome, 10 patients with unspecified T-cell lymphopenia, and 9 patients with normal T cell counts. CONCLUSIONS: As newborn screening for SCID is still in early stages, the clinical characteristics, laboratory features, and long-term outcomes of patients with abnormal TREC values identified by newborn screening are not yet well described. The SCID newborn screening program in Delaware has successfully identified 2 infants with SCID and 13 with non-SCID lymphopenia.