JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency

被引：79

作者：

Alsohime, Fahad ^{[1
]}

Martin-Fernandez, Marta ^{[5
,6
,7
]}

Temsah, Mohamad-Hani ^{[1
]}

Alabdulhafid, Majed ^{[1
]}

Le Voyer, Tom ^{[10
,11
]}

Alghamdi, Malak ^{[1
]}

Qiu, Xueer ^{[5
,6
,7
]}

Alotaibi, Najla ^{[1
]}

Alkahtani, Areej ^{[1
,3
]}

Buta, Sofija ^{[5
,6
,7
]}

Jouanguy, Emmanuelle ^{[8
,10
,11
]}

Al-Eyadhy, Ayman ^{[1
]}

Gruber, Conor ^{[5
,6
,7
]}

Hasan, Gamal M. ^{[1
,14
]}

Bashiri, Fahad A. ^{[1
]}

Halwani, Rabih ^{[2
,15
]}

Hassan, Hamdy H. ^{[4
]}

Al-Muhsen, Saleh ^{[1
,2
]}

Alkhamis, Nouf ^{[1
]}

Alsum, Zobaida ^{[1
]}

Casanova, Jean-Laurent ^{[8
,9
,10
,11
,12
]}

Bustamante, Jacinta ^{[8
,10
,11
,13
]}

Bogunovic, Dusan ^{[5
,6
,7
]}

Alangari, Abdullah A. ^{[1
]}

机构：

[1] King Saud Univ, Coll Med, Dept Pediat, POB 2925, Riyadh 11461, Saudi Arabia

[2] King Saud Univ, Coll Med, Dept Pediat, Immunol Res Lab, Riyadh, Saudi Arabia

[3] Imam Mohammed bin Saud Univ, Coll Med, Dept Pediat, Riyadh, Saudi Arabia

[4] King Saud Univ Med City, Dept Radiol & Med Imaging, Riyadh, Saudi Arabia

[5] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[7] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[8] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[9] Howard Hughes Med Inst, New York, NY USA

[10] Paris Descartes Univ, Imagine Inst, Paris, France

[11] Necker Hosp Sick Children, AP HP, INSERM, Unite 1163,Necker Branch,Lab Human Genet Infect D, Paris, France

[12] Necker Hosp Sick Children, AP HP, Pediat Hematol & Immunol Unit, Paris, France

[13] Necker Hosp Sick Children, AP HP, Ctr Study Primary Immunodeficiencies, Paris, France

[14] Assiut Univ, Assiut Fac Med, Dept Pediat, Assiut, Egypt

[15] Univ Sharjah, Coll Med, Dept Clin Sci, Sharjah Inst Med Res, Sharjah, U Arab Emirates

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2020年 / 382卷 / 03期

基金：

美国国家卫生研究院;

关键词：

I INTERFERONOPATHIES; ISG15; RUXOLITINIB; UBP43;

D O I：

10.1056/NEJMoa1905633

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.) A neonate with a loss-of-function mutation in USP18 and exuberant expression of interferon-stimulated genes was experimentally treated with ruxolitinib, which suppresses interferon signaling. The initiation of treatment was followed by an improvement in the child's clinical course.

引用

页码：256 / 265

页数：10

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