Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities

Lyons, Jonathan J.; Sun, Guangping; Stone, Kelly D.; Nelson, Celeste M.; Wisch, Laura; O’Brien, Michelle; Jones, Nina; Lindsley, Andrew; Komarow, Hirsh D.; Bai, Yun; Scott, Linda M.; Cantave, Daly; Marić, Irina; Abonia, J. Pablo; Rothenberg, Marc E.; Schwartz, Lawrence B.; Milner, Joshua D.; Wilson, Todd M.

doi:10.1016/j.jaci.2013.11.039

Cited by 114 publications

(96 citation statements)

References 9 publications

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“…However, studies of these families have provided information about EoE pathoetiology, since acquired loss of DSG1 and impaired barrier function in the esophagus are general features of non-syndromic EoE. 26, 27 Furthermore, EoE has been reported in 2 other atopy-associated Mendelian disorders: autosomal dominant hyper-IgE syndrome, caused by loss-of-function mutations in STAT3 28 , and a syndrome characterized by increased levels of mast cell tryptase in the blood and associated with CTD 29 . Figure 2 contains a Table that summarizes the genes and Mendelian disorders associated with EoE.…”

Section: Heritabilitymentioning

confidence: 99%

Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis

2015

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Eosinophilic esophagitis (EoE) was historically distinguished from gastroesophageal reflux disease on the basis of histology and lack of responsiveness to acid suppressive therapy, but it is now appreciated that esophageal eosinophilia can respond to proton pump inhibitors. Genetic and environmental factors contribute to risk for EoE—particularly early-life events. Disease pathogenesis involves activation of epithelial inflammatory pathways (production of eotaxin-3 [encoded by CCL26]), impaired barrier function (mediated by loss of desmoglein-1), increased production and/or activity of transforming growth factor-β, and induction of allergic inflammation by eosinophils and mast cells. Susceptibility has been associated with variants at 5q22 (TSLP) and 2p23 (CAPN14), indicating roles for allergic sensitization and esophageal specific protease pathways. We propose that EoE is a unique disease characterized by food hypersensitivity, strong hereditability influenced by early-life exposures and esophageal specific genetic risk variants, and allergic inflammation and that the disease is remitted by disrupting inflammatory and T-helper type 2 cytokine–mediated responses and through dietary elimination therapy.

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Section: Heritabilitymentioning

confidence: 99%

Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis

2015

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“…The new generation of immunoassays should avoid this problem. **Recently, rare genetic syndromes have been associated with increased tryptase and atopy (51).…”

Section: Fundingmentioning

confidence: 99%

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

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Broesby‐Olsen

et al. 2014

Allergy

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Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis

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“…Recently, we and others described family cohorts with symptom complexes conforming to these functional presentations but found them in association uniquely with elevated basal serum levels of tryptase—a mast cell mediator commonly used to assist in the diagnosis of mast cell–associated diseases 7,11 . Mast cells have often been implicated in certain functional disorders; however, our patients did not have evidence of clonal mast cell disease or evidence of mast cell activation, whereas many did have connective tissue manifestations overlapping with those seen in EDS III.…”

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confidence: 99%

“…Manifestations such as cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility have been attributed to a number of disparate etiologies, including neurological, immunological, physical, and psychological mechanisms 3–6 . Despite a lack of diagnostic clinical findings, many of these symptoms are comorbid and often follow a dominant inheritance pattern in affected families 7–10 . Furthermore, many of these features have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers–Danlos syndrome type III (hypermobility type, EDS III).…”

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confidence: 99%

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

et al. 2016

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Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1, 2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

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Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities

Cited by 114 publications

References 9 publications

Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis

Molecular, Genetic, and Cellular Bases for Treating Eosinophilic Esophagitis

Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

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