Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis
DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory feature...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2021-04-01
|
Series: | Frontiers in Immunology |
Subjects: | |
Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.673487/full |
id |
doaj-11c4159dc3bc47829888aee2a4ed2142 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Francesco Saettini Grazia Fazio Daniele Moratto Marta Galbiati Nicola Zucchini Davide Ippolito Marco Emilio Dinelli Luisa Imberti Mario Mauri Maria Luisa Melzi Sonia Bonanomi Alessio Gerussi Alessio Gerussi Marinella Pinelli Chiara Barisani Cristina Bugarin Marco Chiarini Mauro Giacomelli Rocco Piazza Giovanni Cazzaniga Giovanni Cazzaniga Pietro Invernizzi Pietro Invernizzi Silvia Clara Giliani Raffaele Badolato Andrea Biondi Andrea Biondi |
spellingShingle |
Francesco Saettini Grazia Fazio Daniele Moratto Marta Galbiati Nicola Zucchini Davide Ippolito Marco Emilio Dinelli Luisa Imberti Mario Mauri Maria Luisa Melzi Sonia Bonanomi Alessio Gerussi Alessio Gerussi Marinella Pinelli Chiara Barisani Cristina Bugarin Marco Chiarini Mauro Giacomelli Rocco Piazza Giovanni Cazzaniga Giovanni Cazzaniga Pietro Invernizzi Pietro Invernizzi Silvia Clara Giliani Raffaele Badolato Andrea Biondi Andrea Biondi Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis Frontiers in Immunology primary immumunodeficiencies DOCK 8 EBV - Epstein-Barr Virus sclerosing cholangitis thrombocytopenia lymphopenia |
author_facet |
Francesco Saettini Grazia Fazio Daniele Moratto Marta Galbiati Nicola Zucchini Davide Ippolito Marco Emilio Dinelli Luisa Imberti Mario Mauri Maria Luisa Melzi Sonia Bonanomi Alessio Gerussi Alessio Gerussi Marinella Pinelli Chiara Barisani Cristina Bugarin Marco Chiarini Mauro Giacomelli Rocco Piazza Giovanni Cazzaniga Giovanni Cazzaniga Pietro Invernizzi Pietro Invernizzi Silvia Clara Giliani Raffaele Badolato Andrea Biondi Andrea Biondi |
author_sort |
Francesco Saettini |
title |
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis |
title_short |
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis |
title_full |
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis |
title_fullStr |
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis |
title_full_unstemmed |
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis |
title_sort |
case report: hypomorphic function and somatic reversion in dock8 deficiency in one patient with two novel variants and sclerosing cholangitis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-04-01 |
description |
DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications. |
topic |
primary immumunodeficiencies DOCK 8 EBV - Epstein-Barr Virus sclerosing cholangitis thrombocytopenia lymphopenia |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.673487/full |
work_keys_str_mv |
AT francescosaettini casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT graziafazio casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT danielemoratto casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT martagalbiati casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT nicolazucchini casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT davideippolito casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT marcoemiliodinelli casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT luisaimberti casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT mariomauri casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT marialuisamelzi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT soniabonanomi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT alessiogerussi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT alessiogerussi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT marinellapinelli casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT chiarabarisani casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT cristinabugarin casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT marcochiarini casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT maurogiacomelli casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT roccopiazza casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT giovannicazzaniga casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT giovannicazzaniga casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT pietroinvernizzi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT pietroinvernizzi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT silviaclaragiliani casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT raffaelebadolato casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT andreabiondi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis AT andreabiondi casereporthypomorphicfunctionandsomaticreversionindock8deficiencyinonepatientwithtwonovelvariantsandsclerosingcholangitis |
_version_ |
1721525464882741248 |
spelling |
doaj-11c4159dc3bc47829888aee2a4ed21422021-04-16T04:55:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-04-011210.3389/fimmu.2021.673487673487Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing CholangitisFrancesco Saettini0Grazia Fazio1Daniele Moratto2Marta Galbiati3Nicola Zucchini4Davide Ippolito5Marco Emilio Dinelli6Luisa Imberti7Mario Mauri8Maria Luisa Melzi9Sonia Bonanomi10Alessio Gerussi11Alessio Gerussi12Marinella Pinelli13Chiara Barisani14Cristina Bugarin15Marco Chiarini16Mauro Giacomelli17Rocco Piazza18Giovanni Cazzaniga19Giovanni Cazzaniga20Pietro Invernizzi21Pietro Invernizzi22Silvia Clara Giliani23Raffaele Badolato24Andrea Biondi25Andrea Biondi26Pediatric Hematology Outpatient Clinic, Department of Pediatrics, Fondazione MBBM, Monza, ItalyCentro Ricerca Tettamanti, University of Milano Bicocca, Monza, ItalyFlow Cytometry Laboratory, Diagnostic Department, ASST Spedali Civili, Brescia, ItalyCentro Ricerca Tettamanti, University of Milano Bicocca, Monza, ItalyDivision of Pathology, San Gerardo Hospital, ASST Monza, Monza, ItalyDepartment of Diagnostic Radiology, San Gerardo Hospital, Monza, ItalyEndoscopy Unit, San Gerardo Hospital, ASST, Monza, ItalyCentro di Ricerca Emato-oncologica AIL (CREA), ASST Spedali Civili, Brescia, ItalyDepartment of Medicine and Surgery, University of Milano Bicocca and San Gerardo Hospital, Monza, ItalyDepartment of Pediatrics, Fondazione MBBM, Monza, ItalyPediatric Hematology Outpatient Clinic, Department of Pediatrics, Fondazione MBBM, Monza, Italy0Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy1European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy2Cytogenetic and Medical Genetic Unit, Department of Molecular and Translational medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Spedali Civili, Brescia, Italy2Cytogenetic and Medical Genetic Unit, Department of Molecular and Translational medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Spedali Civili, Brescia, ItalyCentro Ricerca Tettamanti, University of Milano Bicocca, Monza, ItalyFlow Cytometry Laboratory, Diagnostic Department, ASST Spedali Civili, Brescia, Italy2Cytogenetic and Medical Genetic Unit, Department of Molecular and Translational medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Spedali Civili, Brescia, ItalyDepartment of Medicine and Surgery, University of Milano Bicocca and San Gerardo Hospital, Monza, ItalyCentro Ricerca Tettamanti, University of Milano Bicocca, Monza, ItalyDepartment of Medicine and Surgery, University of Milano Bicocca and San Gerardo Hospital, Monza, Italy0Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy1European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy2Cytogenetic and Medical Genetic Unit, Department of Molecular and Translational medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Spedali Civili, Brescia, Italy3Department of Clinical and Experimental Sciences, Pediatrics Clinic and A. Nocivelli Institute for Molecular Medicine A, University of Brescia, ASST-Spedali Civili, Brescia, ItalyPediatric Hematology Outpatient Clinic, Department of Pediatrics, Fondazione MBBM, Monza, ItalyCentro Ricerca Tettamanti, University of Milano Bicocca, Monza, ItalyDOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.https://www.frontiersin.org/articles/10.3389/fimmu.2021.673487/fullprimary immumunodeficienciesDOCK 8EBV - Epstein-Barr Virussclerosing cholangitisthrombocytopenialymphopenia |