Novel SAMD9 Mutation in a Patient With Immunodeficiency,
Neutropenia, Impaired Anti-CMV Response, and Severe
Gastrointestinal Involvement

J 2019

Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement

FORMANKOVA, Renata, Veronika KANDEROVA, Marketa RACKOVA, Michael SVATON, Tomas BRDICKA et. al.

Základní údaje

Originální název

Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement

Autoři

FORMANKOVA, Renata (203 Česká republika), Veronika KANDEROVA (203 Česká republika), Marketa RACKOVA (203 Česká republika), Michael SVATON (203 Česká republika), Tomas BRDICKA (203 Česká republika), Petr RIHA (203 Česká republika), Petra KESLOVÁ (203 Česká republika), Ester MEJSTRIKOVA (203 Česká republika), Marketa ZALIOVA (203 Česká republika), Tomáš FREIBERGER (203 Česká republika, domácí), Hana GROMBIŘÍKOVÁ (203 Česká republika, domácí), Zuzana ZEMANOVA (203 Česká republika), Marcela VLKOVÁ (203 Česká republika, domácí), Filip FENCL (203 Česká republika), Ivana COPOVA (203 Česká republika), Jiri BRONSKY (203 Česká republika), Petr JABANDŽIEV (203 Česká republika, domácí), Petr SEDLACEK (203 Česká republika), Jana ŠOUKALOVÁ (203 Česká republika, domácí), Ondrej ZAPLETAL (203 Česká republika), Jan STARY (203 Česká republika), Jan TRKA (203 Česká republika), Tomas KALINA (203 Česká republika), Karolina KRAMARZOVA (203 Česká republika), Eva HLAVÁČKOVÁ (203 Česká republika, domácí), Jiří LITZMAN (203 Česká republika, domácí) a Eva FRONKOVA (203 Česká republika, garant)

Vydání

Frontiers in Immunology, LAUSANNE, FRONTIERS MEDIA SA, 2019, 1664-3224

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30102 Immunology

Stát vydavatele

Švýcarsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.085

Kód RIV

RIV/00216224:14110/19:00111013

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.3389/fimmu.2019.02194

UT WoS

000486387300001

Klíčová slova anglicky

SAMD9; MIRAGE; immunodeficiency; neutropenia; cytomegalovirus infection; dysphagia; hematopoietic stem cell transplantation; gastrointestinal disorder

Štítky

14110114, 14110317, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 26. 3. 2021 09:40, Mgr. Tereza Miškechová

Anotace

V originále

Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G >A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months Frontiers of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells. Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.

Citovat

FORMANKOVA, Renata, Veronika KANDEROVA, Marketa RACKOVA, Michael SVATON, Tomas BRDICKA, Petr RIHA, Petra KESLOVÁ, Ester MEJSTRIKOVA, Marketa ZALIOVA, Tomáš FREIBERGER, Hana GROMBIŘÍKOVÁ, Zuzana ZEMANOVA, Marcela VLKOVÁ, Filip FENCL, Ivana COPOVA, Jiri BRONSKY, Petr JABANDŽIEV, Petr SEDLACEK, Jana ŠOUKALOVÁ, Ondrej ZAPLETAL, Jan STARY, Jan TRKA, Tomas KALINA, Karolina KRAMARZOVA, Eva HLAVÁČKOVÁ, Jiří LITZMAN a Eva FRONKOVA. Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement. Frontiers in Immunology. LAUSANNE: FRONTIERS MEDIA SA, 2019, roč. 10, SEP 18 2019, s. 1-8. ISSN 1664-3224. Dostupné z: https://dx.doi.org/10.3389/fimmu.2019.02194.

@article{1572137,
   author = {Formankova, Renata and Kanderova, Veronika and Rackova, Marketa and Svaton, Michael and Brdicka, Tomas and Riha, Petr and Keslová, Petra and Mejstrikova, Ester and Zaliova, Marketa and Freiberger, Tomáš and Grombiříková, Hana and Zemanova, Zuzana and Vlková, Marcela and Fencl, Filip and Copova, Ivana and Bronsky, Jiri and Jabandžiev, Petr and Sedlacek, Petr and Šoukalová, Jana and Zapletal, Ondrej and Stary, Jan and Trka, Jan and Kalina, Tomas and Kramarzova, Karolina and Hlaváčková, Eva and Litzman, Jiří and Fronkova, Eva},
   article_location = {LAUSANNE},
   article_number = {SEP 18 2019},
   doi = {http://dx.doi.org/10.3389/fimmu.2019.02194},
   keywords = {SAMD9; MIRAGE; immunodeficiency; neutropenia; cytomegalovirus infection; dysphagia; hematopoietic stem cell transplantation; gastrointestinal disorder},
   language = {eng},
   issn = {1664-3224},
   journal = {Frontiers in Immunology},
   title = {Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement},
   url = {https://www.frontiersin.org/articles/10.3389/fimmu.2019.02194/full},
   volume = {10},
   year = {2019}
}

TY  - JOUR
ID  - 1572137
AU  - Formankova, Renata - Kanderova, Veronika - Rackova, Marketa - Svaton, Michael - Brdicka, Tomas - Riha, Petr - Keslová, Petra - Mejstrikova, Ester - Zaliova, Marketa - Freiberger, Tomáš - Grombiříková, Hana - Zemanova, Zuzana - Vlková, Marcela - Fencl, Filip - Copova, Ivana - Bronsky, Jiri - Jabandžiev, Petr - Sedlacek, Petr - Šoukalová, Jana - Zapletal, Ondrej - Stary, Jan - Trka, Jan - Kalina, Tomas - Kramarzova, Karolina - Hlaváčková, Eva - Litzman, Jiří - Fronkova, Eva
PY  - 2019
TI  - Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement
JF  - Frontiers in Immunology
VL  - 10
IS  - SEP 18 2019
SP  - 1-8
EP  - 1-8
PB  - FRONTIERS MEDIA SA
SN  - 16643224
KW  - SAMD9
KW  - MIRAGE
KW  - immunodeficiency
KW  - neutropenia
KW  - cytomegalovirus infection
KW  - dysphagia
KW  - hematopoietic stem cell transplantation
KW  - gastrointestinal disorder
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2019.02194/full
L2  - https://www.frontiersin.org/articles/10.3389/fimmu.2019.02194/full
N2  - Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G >A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months Frontiers of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells. Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.
ER  -

FORMANKOVA, Renata, Veronika KANDEROVA, Marketa RACKOVA, Michael SVATON, Tomas BRDICKA, Petr RIHA, Petra KESLOVÁ, Ester MEJSTRIKOVA, Marketa ZALIOVA, Tomáš FREIBERGER, Hana GROMBIŘÍKOVÁ, Zuzana ZEMANOVA, Marcela VLKOVÁ, Filip FENCL, Ivana COPOVA, Jiri BRONSKY, Petr JABANDŽIEV, Petr SEDLACEK, Jana ŠOUKALOVÁ, Ondrej ZAPLETAL, Jan STARY, Jan TRKA, Tomas KALINA, Karolina KRAMARZOVA, Eva HLAVÁČKOVÁ, Jiří LITZMAN a Eva FRONKOVA. Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement. \textit{Frontiers in Immunology}. LAUSANNE: FRONTIERS MEDIA SA, 2019, roč.~10, SEP 18 2019, s.~1-8. ISSN~1664-3224. Dostupné z: https://dx.doi.org/10.3389/fimmu.2019.02194.

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