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Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)

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Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). / Pagel, Julia; Beutel, Karin; Lehmberg, Kai; Koch, Florian; Maul-Pavicic, Andrea; Rohlfs, Anna-Katharina; Al-Jefri, Abdullah; Beier, Rita; Lilian, Bomme Ousager; Ehlert, Karoline; Gross-Wieltsch, Ute; Jorch, Norbert; Kremens, Bernhard; Pekrun, Arnulf; Sparber-Sauer, Monika; Mejstrikova, Ester; Wawer, Angela; Ehl, Stephan; Zur Stadt, Udo; Janka-Schaub, Gritta.

In: BLOOD, Vol. 119, No. 25, 25, 21.06.2012, p. 6016-6024.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Pagel, J, Beutel, K, Lehmberg, K, Koch, F, Maul-Pavicic, A, Rohlfs, A-K, Al-Jefri, A, Beier, R, Lilian, BO, Ehlert, K, Gross-Wieltsch, U, Jorch, N, Kremens, B, Pekrun, A, Sparber-Sauer, M, Mejstrikova, E, Wawer, A, Ehl, S, Zur Stadt, U & Janka-Schaub, G 2012, 'Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)', BLOOD, vol. 119, no. 25, 25, pp. 6016-6024. https://doi.org/10.1182/blood-2011-12-398958

APA

Pagel, J., Beutel, K., Lehmberg, K., Koch, F., Maul-Pavicic, A., Rohlfs, A-K., Al-Jefri, A., Beier, R., Lilian, B. O., Ehlert, K., Gross-Wieltsch, U., Jorch, N., Kremens, B., Pekrun, A., Sparber-Sauer, M., Mejstrikova, E., Wawer, A., Ehl, S., Zur Stadt, U., & Janka-Schaub, G. (2012). Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). BLOOD, 119(25), 6016-6024. [25]. https://doi.org/10.1182/blood-2011-12-398958

Vancouver

Pagel J, Beutel K, Lehmberg K, Koch F, Maul-Pavicic A, Rohlfs A-K et al. Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5). BLOOD. 2012 Jun 21;119(25):6016-6024. 25. https://doi.org/10.1182/blood-2011-12-398958

Bibtex

@article{e269142408a6401689b4716bed9ce2b2,
title = "Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)",
abstract = "Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.",
keywords = "Adult, Humans, Male, Female, Adolescent, Young Adult, Cohort Studies, Child, Child, Preschool, Infant, Models, Biological, Infant, Newborn, DNA Mutational Analysis, Genetic Association Studies, Basophil Degranulation Test, Epistasis, Genetic, Lymphohistiocytosis, Hemophagocytic/classification/ethnology/*genetics, Munc18 Proteins/*genetics/physiology, *Mutation/physiology, Qa-SNARE Proteins/genetics, Adult, Humans, Male, Female, Adolescent, Young Adult, Cohort Studies, Child, Child, Preschool, Infant, Models, Biological, Infant, Newborn, DNA Mutational Analysis, Genetic Association Studies, Basophil Degranulation Test, Epistasis, Genetic, Lymphohistiocytosis, Hemophagocytic/classification/ethnology/*genetics, Munc18 Proteins/*genetics/physiology, *Mutation/physiology, Qa-SNARE Proteins/genetics",
author = "Julia Pagel and Karin Beutel and Kai Lehmberg and Florian Koch and Andrea Maul-Pavicic and Anna-Katharina Rohlfs and Abdullah Al-Jefri and Rita Beier and Lilian, {Bomme Ousager} and Karoline Ehlert and Ute Gross-Wieltsch and Norbert Jorch and Bernhard Kremens and Arnulf Pekrun and Monika Sparber-Sauer and Ester Mejstrikova and Angela Wawer and Stephan Ehl and {Zur Stadt}, Udo and Gritta Janka-Schaub",
year = "2012",
month = jun,
day = "21",
doi = "10.1182/blood-2011-12-398958",
language = "English",
volume = "119",
pages = "6016--6024",
journal = "BLOOD",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "25",

}

RIS

TY - JOUR

T1 - Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)

AU - Pagel, Julia

AU - Beutel, Karin

AU - Lehmberg, Kai

AU - Koch, Florian

AU - Maul-Pavicic, Andrea

AU - Rohlfs, Anna-Katharina

AU - Al-Jefri, Abdullah

AU - Beier, Rita

AU - Lilian, Bomme Ousager

AU - Ehlert, Karoline

AU - Gross-Wieltsch, Ute

AU - Jorch, Norbert

AU - Kremens, Bernhard

AU - Pekrun, Arnulf

AU - Sparber-Sauer, Monika

AU - Mejstrikova, Ester

AU - Wawer, Angela

AU - Ehl, Stephan

AU - Zur Stadt, Udo

AU - Janka-Schaub, Gritta

PY - 2012/6/21

Y1 - 2012/6/21

N2 - Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.

AB - Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined hyperinflammatory syndrome caused by uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. STXBP2 mutations have recently been associated with FHL5. To better characterize the genetic and clinical spectrum of FHL5, we analyzed a cohort of 185 patients with suspected FHL for mutations in STXBP2. We detected biallelic mutations in 37 patients from 28 families of various ethnic origins. Missense mutations and mutations affecting 1 of the exon 15 splice sites were the predominant changes detectable in this cohort. Patients with exon 15 splice-site mutations (n = 13) developed clinical manifestations significantly later than patients with other mutations (median age, 4.1 year vs 2 months) and showed less severe impairment of degranulation and cytotoxic function of NK cells and CTLs. Patients with FHL5 showed several atypical features, including sensorineural hearing deficit, abnormal bleeding, and, most frequently, severe diarrhea that was only present in early-onset disease. In conclusion, we report the largest cohort of patients with FHL5 so far, describe an extended disease spectrum, and demonstrate for the first time a clear genotype-phenotype correlation.

KW - Adult

KW - Humans

KW - Male

KW - Female

KW - Adolescent

KW - Young Adult

KW - Cohort Studies

KW - Child

KW - Child, Preschool

KW - Infant

KW - Models, Biological

KW - Infant, Newborn

KW - DNA Mutational Analysis

KW - Genetic Association Studies

KW - Basophil Degranulation Test

KW - Epistasis, Genetic

KW - Lymphohistiocytosis, Hemophagocytic/classification/ethnology/genetics

KW - Munc18 Proteins/genetics/physiology

KW - Mutation/physiology

KW - Qa-SNARE Proteins/genetics

KW - Adult

KW - Humans

KW - Male

KW - Female

KW - Adolescent

KW - Young Adult

KW - Cohort Studies

KW - Child

KW - Child, Preschool

KW - Infant

KW - Models, Biological

KW - Infant, Newborn

KW - DNA Mutational Analysis

KW - Genetic Association Studies

KW - Basophil Degranulation Test

KW - Epistasis, Genetic

KW - Lymphohistiocytosis, Hemophagocytic/classification/ethnology/genetics

KW - Munc18 Proteins/genetics/physiology

KW - Mutation/physiology

KW - Qa-SNARE Proteins/genetics

U2 - 10.1182/blood-2011-12-398958

DO - 10.1182/blood-2011-12-398958

M3 - SCORING: Journal article

C2 - 22451424

VL - 119

SP - 6016

EP - 6024

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 25

M1 - 25

ER -