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Steven M Holland - One of the best experts on this subject based on the ideXlab platform.
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stat3 Hyper IgE Syndrome
2020Co-Authors: Amy P Hsu, Steven M Holland, Joie Davis, Jennifer M Puck, Alexandra F FreemanAbstract:Clinical characteristics STAT3 Hyper IgE Syndrome (STAT3-HIES) is a primary immune deficiency Syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint Hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency. Diagnosis/testing The diagnosis of STAT3-HIES is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing. Management Treatment of manifestations: The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear. Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of lung infections. Culture of skin lesions and sputum samples helps direct therapy. Routine screening of adolescents for early signs of scoliosis is recommended. Dental monitoring is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Evaluation for coronary artery and cerebral aneurysms every three years in adulthood is recommended as well as monitoring for lymphadenopathy due to increased incidence of lymphoma. Genetic counseling STAT3-HIES is inherited in an autosomal dominant manner. The majority of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with STAT3-HIES has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible once the STAT3 pathogenic variant in the family has been identified.
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stat3 modulates reprogramming efficiency of human somatic cells insights from autosomal dominant Hyper IgE Syndrome caused by stat3 mutations
Biology Open, 2020Co-Authors: Natalia I Dmitrieva, Steven M Holland, Alexandra F Freeman, Avram D Walts, Xianfeng Ping, Hui Jin, Yangtengyu Liu, Elisa A Ferrante, Lugui Qiu, Guibin ChenAbstract:Human iPSC technology has opened exciting opportunities for stem cell-based therapy. However, its wide adoption is precluded by several challenges including low reprogramming efficiency and potential for malignant transformation. Better understanding of the molecular mechanisms of the changes that cells undergo during reprograming is needed to improve iPSCs generation efficiency and to increase confidence for their clinical use safety. Here, we find that dominant negative mutations in STAT3 in patients with autosomal dominant Hyper IgE Syndrome (AD-HIES; Job's Syndrome) result in greatly reduced reprograming efficiency of primary skin fibroblasts derived from skin biopsies. Analysis of normal skin fibroblasts revealed upregulation and phosphorylation of endogenous STAT3 and its binding to the NANOG promoter following transduction with OKSM factors. This coincided with upregulation of NANOG and appearance of cells expressing pluripotency markers. Upregulation of NANOG and number of pluripotent cells were greatly reduced throughout the reprograming process of AD-HIES fibroblasts that was restored by over-expression of functional STAT3. Human specific NANOG retrogene that is often expressed in human cancers, NANOGP8, was also induced during reprogramming, to very low but detectable levels, in a STAT3-dependent manner. Our study revealed the critical role of endogenous STAT3 in facilitating reprogramming of human somatic cells.
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generation of human induced pluripotent stem cell lines nihtvbi011 a nihtvbi012 a nihtvbi013 a from autosomal dominant Hyper IgE Syndrome ad hies patients carrying stat3 mutation
Stem Cell Research, 2019Co-Authors: Hui Jin, Amy P Hsu, Natalia I Dmitrieva, Dan Yang, Robin Schwartzbeck, Keron Navarengom, Yangtengyu Liu, Cornelia Cudrici, Elisa A Ferrante, Steven M HollandAbstract:Abstract Autosomal dominant Hyper IgE Syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.
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Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry
Journal of Allergy and Clinical Immunology: In Practice, 2018Co-Authors: Yael Gernez, Steven M Holland, Alexandra F Freeman, Kathleen E Sullivan, Jennifer M Puck, Elizabeth Garabedian, Niraj C. Patel, Javeed Akhter, Elizabeth Secord, Karin ChenAbstract:BACKGROUND: Autosomal dominant Hyper-IgE Syndrome (AD-HIES) is a rare condition. OBJECTIVE: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. METHODS: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. RESULTS: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P chi(2) = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007). DISCUSSION: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES. (C) 2017 American Academy of Allergy, Asthma & Immunology
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autosomal dominant Hyper IgE Syndrome in the usidnet registry
The Journal of Allergy and Clinical Immunology: In Practice, 2017Co-Authors: Yael Gernez, Steven M Holland, Alexandra F Freeman, Kathleen E Sullivan, Jennifer M Puck, Elizabeth Garabedian, Niraj C. Patel, Javeed Akhter, Elizabeth Secord, Karin ChenAbstract:Background Autosomal dominant Hyper-IgE Syndrome (AD-HIES) is a rare condition. Objective Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. Methods A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. Results Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa ( P Fisher's exact test = .029) or A. fumigatus ( P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions ( P χ 2 = .01; odds ratio: 4.03 [1.2-12.97]), depression ( P Fisher's exact test = .036), and lower Karnofsky index scores ( P Mann-Whitney = .007). Discussion Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.
Alexandra F Freeman - One of the best experts on this subject based on the ideXlab platform.
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stat3 Hyper IgE Syndrome
2020Co-Authors: Amy P Hsu, Steven M Holland, Joie Davis, Jennifer M Puck, Alexandra F FreemanAbstract:Clinical characteristics STAT3 Hyper IgE Syndrome (STAT3-HIES) is a primary immune deficiency Syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint Hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency. Diagnosis/testing The diagnosis of STAT3-HIES is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing. Management Treatment of manifestations: The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear. Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of lung infections. Culture of skin lesions and sputum samples helps direct therapy. Routine screening of adolescents for early signs of scoliosis is recommended. Dental monitoring is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Evaluation for coronary artery and cerebral aneurysms every three years in adulthood is recommended as well as monitoring for lymphadenopathy due to increased incidence of lymphoma. Genetic counseling STAT3-HIES is inherited in an autosomal dominant manner. The majority of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with STAT3-HIES has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible once the STAT3 pathogenic variant in the family has been identified.
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stat3 modulates reprogramming efficiency of human somatic cells insights from autosomal dominant Hyper IgE Syndrome caused by stat3 mutations
Biology Open, 2020Co-Authors: Natalia I Dmitrieva, Steven M Holland, Alexandra F Freeman, Avram D Walts, Xianfeng Ping, Hui Jin, Yangtengyu Liu, Elisa A Ferrante, Lugui Qiu, Guibin ChenAbstract:Human iPSC technology has opened exciting opportunities for stem cell-based therapy. However, its wide adoption is precluded by several challenges including low reprogramming efficiency and potential for malignant transformation. Better understanding of the molecular mechanisms of the changes that cells undergo during reprograming is needed to improve iPSCs generation efficiency and to increase confidence for their clinical use safety. Here, we find that dominant negative mutations in STAT3 in patients with autosomal dominant Hyper IgE Syndrome (AD-HIES; Job's Syndrome) result in greatly reduced reprograming efficiency of primary skin fibroblasts derived from skin biopsies. Analysis of normal skin fibroblasts revealed upregulation and phosphorylation of endogenous STAT3 and its binding to the NANOG promoter following transduction with OKSM factors. This coincided with upregulation of NANOG and appearance of cells expressing pluripotency markers. Upregulation of NANOG and number of pluripotent cells were greatly reduced throughout the reprograming process of AD-HIES fibroblasts that was restored by over-expression of functional STAT3. Human specific NANOG retrogene that is often expressed in human cancers, NANOGP8, was also induced during reprogramming, to very low but detectable levels, in a STAT3-dependent manner. Our study revealed the critical role of endogenous STAT3 in facilitating reprogramming of human somatic cells.
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Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry
Journal of Allergy and Clinical Immunology: In Practice, 2018Co-Authors: Yael Gernez, Steven M Holland, Alexandra F Freeman, Kathleen E Sullivan, Jennifer M Puck, Elizabeth Garabedian, Niraj C. Patel, Javeed Akhter, Elizabeth Secord, Karin ChenAbstract:BACKGROUND: Autosomal dominant Hyper-IgE Syndrome (AD-HIES) is a rare condition. OBJECTIVE: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. METHODS: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. RESULTS: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P chi(2) = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007). DISCUSSION: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES. (C) 2017 American Academy of Allergy, Asthma & Immunology
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autosomal dominant Hyper IgE Syndrome in the usidnet registry
The Journal of Allergy and Clinical Immunology: In Practice, 2017Co-Authors: Yael Gernez, Steven M Holland, Alexandra F Freeman, Kathleen E Sullivan, Jennifer M Puck, Elizabeth Garabedian, Niraj C. Patel, Javeed Akhter, Elizabeth Secord, Karin ChenAbstract:Background Autosomal dominant Hyper-IgE Syndrome (AD-HIES) is a rare condition. Objective Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. Methods A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. Results Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa ( P Fisher's exact test = .029) or A. fumigatus ( P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions ( P χ 2 = .01; odds ratio: 4.03 [1.2-12.97]), depression ( P Fisher's exact test = .036), and lower Karnofsky index scores ( P Mann-Whitney = .007). Discussion Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.
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molecular typing of staphylococcus aureus isolated from patients with autosomal dominant Hyper IgE Syndrome
Pathogenetics, 2017Co-Authors: Inka Sastalla, Alexandra F Freeman, Ian A Myles, Erik D Anderson, Kelli W Williams, Jensen D Reckhow, Marlene Espinozamoraga, Sandip K DattaAbstract:Autosomal dominant Hyper IgE Syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.
Ellen D Renner - One of the best experts on this subject based on the ideXlab platform.
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retained primary teeth in stat3 Hyper IgE Syndrome early intervention in childhood is essential
Orphanet Journal of Rare Diseases, 2020Co-Authors: Iris Meixner, Beate Hagl, Carolin Kroner, Benedikt D Spielberger, Gregor Duckers, Ekaterini Paschos, Tim Niehues, Ronny Hesse, Ellen D RennerAbstract:STAT3 Hyper-IgE Syndrome (STAT3-HIES) is a rare primary immunodeficiency that clinically overlaps with atopic dermatitis. In addition to eczema, elevated serum-IgE, and recurrent infections, STAT3-HIES patients suffer from characteristic facies, midline defects, and retained primary teeth. To optimize dental management we assessed the development of dentition and the long-term outcomes of dental treatment in 13 molecularly defined STAT3-HIES patients using questionnaires, radiographs, and dental investigations. Primary tooth eruption was unremarkable in all STAT3-HIES patients evaluated. Primary tooth exfoliation and permanent tooth eruption was delayed in 83% of patients due to unresorbed tooth roots. A complex orthodontic treatment was needed for one patient receiving delayed extraction of primary molars and canines. Permanent teeth erupted spontaneously in all patients receiving primary teeth extraction of retained primary teeth during average physiologic exfoliation time. The association of STAT3-HIES with retained primary teeth is important knowledge for dentists and physicians as timely extraction of retained primary teeth prevents dental complications. To enable spontaneous eruption of permanent teeth in children with STAT3-HIES, we recommend extracting retained primary incisors when the patient is not older than 9 years of age and retained primary canines and molars when the patient is not older than 13 years of age, after having confirmed the presence of the permanent successor teeth by radiograph.
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reduced immunoglobulin ig g response to staphylococcus aureus in stat3 Hyper IgE Syndrome
Clinical Infectious Diseases, 2017Co-Authors: Sebastian Stentzel, Beate Hagl, Felicitas Abel, Barbara C Kahl, Anita Rackhoch, Barbara M Broker, Ellen D RennerAbstract:STAT3 Hyper-IgE Syndrome (STAT3-HIES) patients presented with significantly lower Staphylococcus aureus-specific serum IgG compared to cystic fibrosis patients despite recurrent S. aureus infections. Immunoglobulin replacement therapy increased S. aureus-specific IgG in STAT3-HIES patients and attenuated the clinical course of disease suggesting a role of humoral immunity in S. aureus clearance.
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lung parenchyma surgery in autosomal dominant Hyper IgE Syndrome
Journal of Clinical Immunology, 2013Co-Authors: Alexandra F Freeman, Joie Davis, Amy P Hsu, Beate Hagl, Ellen D Renner, Carolyn Henderson, Anne Langenbeck, Kenneth N Olivier, Annette Boos, Beatriz E MarcianoAbstract:Autosomal dominant Hyper-IgE Syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. More than 50 % of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection.
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successful long term correction of autosomal recessive Hyper IgE Syndrome due to dock8 deficiency by hematopoietic stem cell transplantation
Klinische Padiatrie, 2010Co-Authors: T C Bittner, Bernd H Belohradsky, Ellen D Renner, Ulrich Pannicke, G Notheis, Florian Hoffmann, Uwe Wintergerst, M Hauser, B Klein, Klaus SchwarzAbstract:Autosomal dominant Hyper-IgE Syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.
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novel signal transducer and activator of transcription 3 stat3 mutations reduced t h 17 cell numbers and variably defective stat3 phosphorylation in Hyper IgE Syndrome
The Journal of Allergy and Clinical Immunology, 2008Co-Authors: Ellen D Renner, Stacey Rylaarsdam, Stephanie Aňoversombke, Anita Rack, Janine Reichenbach, John C Carey, Qili Zhu, Annette F Jansson, Julia BarbozaAbstract:Background Hyper-IgE Syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES. Objective To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES. Methods We sequenced the STAT3 gene in 38 patients with HIES (National Institutes of Health score >40 points) from 35 families, quantified T H 17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3. Results Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD; 22/35 families) or Src homology 2 (SH2) domain (10/35) and were missense mutations. We identified 2 intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified 2 mutations located in the transactivation domain downstream of the SH2 domain: a 10–amino acid deletion and an amino acid substitution. In 1 patient, we were unable to identify a STAT3 mutation. T H 17 cells were absent or low in the peripheral blood of all patients who were evaluated (n = 17). IL-6–induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations but comparable to normal controls in patients with mutations in the DBD. Conclusion Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T H 17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.
John P Carulli - One of the best experts on this subject based on the ideXlab platform.
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whole genome sequencing reveals a chromosome 9p deletion causing dock8 deficiency in an adult diagnosed with Hyper IgE Syndrome who developed progressive multifocal leukoencephalopathy
Journal of Clinical Immunology, 2015Co-Authors: Aaron G Daywilliams, Ilijas Jelcic, Helen Mclaughlin, Tim Harris, Roland Martin, John P CarulliAbstract:Purpose A 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-Hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE Syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing.
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whole genome sequencing reveals a chromosome 9p deletion causing dock8 deficiency in an adult diagnosed with Hyper IgE Syndrome who developed progressive multifocal leukoencephalopathy
Journal of Clinical Immunology, 2015Co-Authors: Aaron G Daywilliams, Ilijas Jelcic, Helen Mclaughlin, Tim Harris, Roland Martin, Chao Sun, John P CarulliAbstract:A 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-Hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE Syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing. Whole genome sequencing was completed to 30X coverage, and whole genome SNP typing was used to complement these data. The methods revealed single nucleotide variants, structural variants, and copy number variants across the genome. Genome-wide data were analyzed for homozygous or compound heterozygous null mutations for all protein coding genes. Mutations were confirmed by PCR and/or Sanger sequencing. Whole genome analysis revealed deletions near the telomere of both copies of chromosome 9p. Several genes, including DOCK8, were impacted by the deletions but it was unclear whether each chromosome had identical or distinct deletions. PCR across the impacted region combined with Sanger sequencing of selected fragments confirmed a homozygous deletion from position 10,211 to 586,751. While several genes are impacted by the deletion, DOCK8 deficiency is the most probable cause of HIES in this patient. DOCK8 deficiency may have also predisposed the patient to develop PML.
Amy P Hsu - One of the best experts on this subject based on the ideXlab platform.
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stat3 Hyper IgE Syndrome
2020Co-Authors: Amy P Hsu, Steven M Holland, Joie Davis, Jennifer M Puck, Alexandra F FreemanAbstract:Clinical characteristics STAT3 Hyper IgE Syndrome (STAT3-HIES) is a primary immune deficiency Syndrome characterized by elevated serum IgE, eczema, and recurrent skin and respiratory tract infections, together with several nonimmune features. This disorder typically manifests in the newborn period with a rash (often diagnosed as eosinophilic pustulosis) that subsequently evolves into an eczematoid dermatitis. Recurrent staphylococcal skin boils and bacterial pneumonias usually manifest in the first years of life. Pneumatoceles and bronchiectasis often result from aberrant healing of pneumonias. Mucocutaneous candidiasis is common. Nonimmune features may include retained primary teeth, scoliosis, bone fractures following minimal trauma, joint Hyperextensibility, and characteristic facial appearance, which typically emerges in adolescence. Vascular abnormalities have been described and include middle-sized artery tortuosity and aneurysms, with infrequent clinical sequelae of myocardial infarction and subarachnoid hemorrhage. Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations (some of which are associated with diverticuli). Fungal infections of the GI tract (typically histoplasmosis, Cryptococcus, and Coccidioides) also occur infrequently. Survival is typically into adulthood, with most individuals now living into or past the sixth decade. Most deaths are associated with gram-negative (Pseudomonas) or filamentous fungal pneumonias resulting in hemoptysis. Lymphomas occur at an increased frequency. Diagnosis/testing The diagnosis of STAT3-HIES is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing. Management Treatment of manifestations: The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections. Use of antibiotics and antifungal agents depends on the nature of the infection and the extent of involvement. Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial. Medications such as histamine-1 antagonists to control pruritus are helpful for more significant eczema. There is no known treatment or prevention for the nonimmunologic characteristics, although optimization of calcium and vitamin D intake may be considered to improve bone health. The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear. Surveillance: Periodic chest imaging and high clinical suspicion assist in early detection of lung infections. Culture of skin lesions and sputum samples helps direct therapy. Routine screening of adolescents for early signs of scoliosis is recommended. Dental monitoring is necessary to ensure timely removal of primary teeth to allow eruption of secondary teeth. Evaluation for coronary artery and cerebral aneurysms every three years in adulthood is recommended as well as monitoring for lymphadenopathy due to increased incidence of lymphoma. Genetic counseling STAT3-HIES is inherited in an autosomal dominant manner. The majority of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with STAT3-HIES has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible once the STAT3 pathogenic variant in the family has been identified.
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generation of human induced pluripotent stem cell lines nihtvbi011 a nihtvbi012 a nihtvbi013 a from autosomal dominant Hyper IgE Syndrome ad hies patients carrying stat3 mutation
Stem Cell Research, 2019Co-Authors: Hui Jin, Amy P Hsu, Natalia I Dmitrieva, Dan Yang, Robin Schwartzbeck, Keron Navarengom, Yangtengyu Liu, Cornelia Cudrici, Elisa A Ferrante, Steven M HollandAbstract:Abstract Autosomal dominant Hyper IgE Syndrome (AD-HIES), a rare immune deficiency affecting fewer than one per million people, is caused by heterozygous deleterious mutations in STAT3. STAT3 signaling plays crucial roles in basic cellular functions affecting broad aspects of cellular homeostasis. Accordingly, in addition to immunological deficits, patients experience severe multisystem non-immunological features. Human induced pluripotent stem cells (hiPSC) are well established as in vivo disease models for various human pathologies. We describe the generation of iPSC from three AD-HIES patients. These iPSCs express pluripotency markers, differentiate into three germ layers, have normal karyotype and similar genome identity to parental cells.
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intermediate phenotypes in patients with autosomal dominant Hyper IgE Syndrome caused by somatic mosaicism
The Journal of Allergy and Clinical Immunology, 2013Co-Authors: Amy P Hsu, John I. Gallin, Joie Davis, Kathryn J Sowerwine, Carolyn Henderson, Kol A Zarember, Monica G Lawrence, Mary Garofalo, Douglas B Kuhns, Theo HellerAbstract:Background Autosomal dominant Hyper-IgE Syndrome (AD-HIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3) . We describe 2 subjects in whom somatic mosaicism was associated with intermediate phenotypes. Objective Somatic mosaics might shed light on the pathogenesis of dominant STAT3 mutations and the mechanisms behind the immunologic and nonimmunologic features of the disease. Methods Clinical evaluations were conducted. Mutant STAT3 was amplified from different tissues and sequenced, and the percentage of mosaicism in various cell types was calculated. Flow cytometry was performed to determine percentages of IL-17 + cells, IL-22 + cells, or both. Suction blisters were induced in 1 subject, and exudate fluid was analyzed for whether emigrating neutrophils were STAT3 mutant or wild-type; neutrophils from peripheral blood were simultaneously examined. Results The 2 subjects with STAT3 somatic mosaicism had intermediate phenotypes and were found to have preserved T H 17 cell compartments and apparently normal CD8 cells. However, they still had infections, including mucocutaneous candidiasis. The percentage of STAT3 mutant neutrophils migrating into blisters at 16 hours was the same as in peripheral blood, suggesting normal chemotaxis. Conclusion STAT3 mosaicism accounts for a milder phenotype and allows for further investigation into the pathogenesis of AD-HIES. Despite having a preserved T H 17 cell compartment, both subjects with mosaicism had chronic mucocutaneous candidiasis, suggesting that candidiasis in subjects with AD-HIES is not driven solely by low T H 17 cell numbers. The percentage of STAT3 mutant neutrophils emigrating into a suction blister at 16 hours was the same as the percentage in peripheral blood, suggesting that early chemotaxis of STAT3 neutrophils is normal in vivo .
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lung parenchyma surgery in autosomal dominant Hyper IgE Syndrome
Journal of Clinical Immunology, 2013Co-Authors: Alexandra F Freeman, Joie Davis, Amy P Hsu, Beate Hagl, Ellen D Renner, Carolyn Henderson, Anne Langenbeck, Kenneth N Olivier, Annette Boos, Beatriz E MarcianoAbstract:Autosomal dominant Hyper-IgE Syndrome (AD-HIES) due to heterozygous STAT3 mutation is a primary immunodeficiency characterized by eczema, elevated serum IgE, recurrent infections, and connective tissue and skeletal findings. Healing of pneumonias is often abnormal with formation of pneumatoceles and bronchiectasis. We aimed to explore whether healing after lung surgery is also aberrant. We retrospectively analyzed the medical records of 32 patients with AD-HIES who received lung surgery for the management of pulmonary infections from 1960 to 2011. We collected information including patient demographics, STAT3 mutation status, clinical history, surgical and medical procedures performed, complications, related medical treatments, and outcomes. More than 50 % of lung surgeries had associated complications, with the majority being prolonged bronchopleural fistulae. These fistulae often led to empyemas that necessitated additional interventions including prolonged antibiotics, prolonged thoracostomy tube drainage and re-operations. Lung surgery in AD-HIES patients is associated with high complication rates. STAT3 mutations likely lead to abnormalities in tissue remodelling that are further exacerbated by infection.
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coronary artery abnormalities in Hyper IgE Syndrome
Journal of Clinical Immunology, 2011Co-Authors: Alexandra F Freeman, Joie Davis, Amy P Hsu, Elizabeth Mannino Avila, Pamela A Shaw, Pamela Welch, Jatin R Matta, Colleen Hadigan, Roderic I Pettigrew, Steven M HollandAbstract:Hyper-IgE Syndrome (HIES) is a rare primary immunodeficiency caused by autosomal dominant STAT3 mutations resulting in recurrent infections and connective tissue abnormalities. Coronary artery abnormalities have been reported infrequently. We aimed to determine the frequency and characteristics of coronary artery abnormalities. STAT3-mutated HIES patients (n = 38), ranging in age from 8 to 57 years, underwent coronary artery imaging by computed tomography or magnetic resonance imaging. Images were evaluated for tortuosity, dilation, and aneurysm. Charts were reviewed for cardiac risk factors. To allow blinded image interpretation, an age- and gender-matched non-HIES group was also evaluated (n = 33). Coronary artery tortuosity or dilation occurred in 70% of HIES patients, with aneurysms present in 37%, incidences much higher than in the literature and in our non-HIES group, in which 21% had tortuosity or dilation and 3% had aneurysms. Hypertension was more common in the HIES group than in the general population and was associated with vessel abnormalities. Atherosclerosis was uncommon and mild. Coronary artery aneurysms and tortuosity are common in HIES, despite a paucity of atherosclerosis, suggesting that STAT3 plays an integral role in human vascular remodeling and atherosclerosis.
