Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition
None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monoc...
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| Veröffentlicht in: | Journal of allergy and clinical immunology 2019-10, Vol.144 (4), p.1122-1125.e6 |
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| creator | Gernez, Yael de Jesus, Adriana A. Alsaleem, Hanouf Macaubas, Claudia Roy, Amitava Lovell, Daniel Jagadeesh, Karthik A. Alehashemi, Sara Erdman, Laura Grimley, Michael Talarico, Susanna Bacchetta, Rosa Lewis, David B. Canna, Scott W. Laxer, Ron M. Mellins, Elizabeth D. Goldbach-Mansky, Raphaela Weinacht, Katja G. |
| description | None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost [p.*192C*24]) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile) |
| doi_str_mv | 10.1016/j.jaci.2019.06.017 |
| format | Article |
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Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost [p.*192C*24]) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile) <3rd <3rd 5th <3rd <3rd 5th 3rd 3rd 3rd 5th <3rd <3rd 10th Appetite Poor Improved Normal Poor Improved Improved Poor Improved Improved Normal Poor Decreased Normal Spleen size∗ (cm [patient age; SM or normal, UL for age]) 11.4 (12 mo; SM, UL 8.0) 8 (15 mo; normal, UL 8.0) 8 (18 mo; normal, UL 8.0) 11.2 (neonatal; SM, UL 6.0) NA 10.1 (12 mo; SM, UL 8.0) 9.2 (neonatal; SM, UL 6.0) 9.9 (5 mo; SM, UL 6.5) 10.8 (16 mo; SM, UL 8.0) 11.9 (6 y; SM, UL 10.0) Hepatomegaly and SM 6.7 (15 mo old; normal, UL 8.0) NA Painful rash Daily None None Bimonthly Monthly None Daily Resolved Resolved Resolved Daily Recurrent None Ibuprofen intake Daily None None None None None None None None None None None None Severe infections None None None None None None None Lymphadenitis Lymphadenitis Lymphadenitis, streptococcal sepsis None Yes† Lymphadenitis Yes‡ Biological parameters Platelet (103/μL) 72 155 141 182 267 276 13 22 148 202 54 381 307 Hemoglobin (g/dL) Transfusion-dependent anemia (Hb, <7 g/dL) 13.8 13.3 Transfusion-dependent anemia (Hb, <7 g/dL) 11.2 11.7 8.1 7.9 10.1 12.3 7.4 13.3 13.5 RBC transfusion Monthly None None Q2-3 mo None None Weekly or biweekly Sporadic Rare Rare Multiple None None Platelet transfusion None None None None None None Multiple Sporadic Rare Rare Multiple None None LDH (ng/mL) 540 NA 547 584 269 271 817 998 1,115 1,633 NA 284 353 ESR (mm/h) >130 16 32 51 22 40 62 65 39 22 140 26 21 CRP (mg/L) 55 2 4 56 3.4 8.8 14.2 3.6 5.6 0.2 Increased 28.8 1.54 Ferritin (ng/mL [<400]) 2,364 801 680 614 316 126 5,191 3,682 1,329 557 NA 172 51 IL-6 (pg/mL [<5]) 18 NA <5 NA NA NA NA NA 15.9 11.0 NA NA NA IL-18§ (pg/mL [100-500]) 35,616 27,803 22,690 36,479‖ NA 83,268 NA NA 28,407 26,402 NA 19,025 21,535 IL-18BP§ (pg/mL [1,000-6,000]) 14,418 8,557 6,264 NA NA 14,653 NA NA 11,803 NA NA 23,986 9,626 CXCL9§ (pg/mL [500-3,500]) 8,457 2,978 4,975 NA NA 2,064 NA NA 3,942 NA NA 11,473 4,278 Table I Clinical phenotype and biological parameters of the reported patients before and after therapy with IL-1 inhibitors TKS C-terminal∗ mutations in CDC42 Group 1 Group 2 Group 3 Clinical presentation Failure to thrive, postnatal weight (weight <2 SD) 3/5 2/4 3/4 4/4 Intellectual disability 5/5 4/4 2/6 1/4 Facial dysmorphism, including frontal bossing and large forehead 2/5 2/4 1/6 3/4 Cardiac abnormality 3/5 2/4 2/5 0/4 Rash 0/5 0/4 0/5 4/4 Recurrent severe infections 4/5 3/4 1/6 3/4 (2/3 were receiving immunosuppression) Biological parameters Thrombocytopenia 4/4 1/3 0/5 4/4 Anemia NA NA NA 4/4 Systemic inflammatory syndrome: increased CRP level, ESR, and ferritin level NA NA NA 4/4 Table E1 Comparison of the clinical phenotypes and biological parameters of patients with TKS and of our cohort of 4 patients with a de novo heterozygous C-terminal mutation in CDC42 Patient 1 CDC42 c.563G>A p.C188Y De novo Possibly pathogenic: 0.337∗ Patient 2 CDC42 LYST LPIN2 MEFV c.563G>A c.1686G>C c.446C>T c.442G>C p.C188Y p.Q562H p.P149L p.E148Q De novo Possibly pathogenic: 0.337∗ Possibly pathogenic: 0.035 Possibly pathogenic: 0.049 Likely benign: 0.024 Patient 3 CDC42 LYST UNC13D c.556C>T c.4545G>C c.2764G>A p.R186C p.E1515D p.A922T De novo Heterozygous from father Heterozygous from mother Possibly pathogenic: 0.053∗ Likely benign: 0.003 Possibly pathogenic: 0.047 Patient 4 CDC42 WAS c.576A>C (stop lost) c.706G>A p.*192C*24 p.A236T De novo X-linked from mother Possibly pathogenic: 0.053∗ Possibly pathogenic: 0.964 Table E2 WES analysis of all 4 reported patients No.]]></description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2019.06.017</identifier><identifier>PMID: 31271789</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Age ; Amino acids ; Anemia ; Appetite ; Benign ; Cdc42 protein ; Cell division ; Consanguinity ; Exanthema ; Eye ; Ferritin ; Forehead ; Genetics ; Hemoglobin ; Homology ; Ibuprofen ; Immunosuppression ; Infections ; Inflammation ; Inflammatory diseases ; Interleukin 1 ; Interleukin 18 ; Interleukin 6 ; Intracranial pressure ; Labeling ; Laboratories ; Mutation ; Neonates ; Optic nerve ; Patients ; Phenotypes ; Platelets ; Proteins ; Retina ; Spleen ; Swelling ; Transfusion</subject><ispartof>Journal of allergy and clinical immunology, 2019-10, Vol.144 (4), p.1122-1125.e6</ispartof><rights>2019 American Academy of Allergy, Asthma & Immunology</rights><rights>2019. American Academy of Allergy, Asthma & Immunology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-ab0c4199d1407cd85004f97f1c96b09a65b0b382f988de8ed698e4bdcd1ac7763</citedby><cites>FETCH-LOGICAL-c499t-ab0c4199d1407cd85004f97f1c96b09a65b0b382f988de8ed698e4bdcd1ac7763</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674919308309$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31271789$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gernez, Yael</creatorcontrib><creatorcontrib>de Jesus, Adriana A.</creatorcontrib><creatorcontrib>Alsaleem, Hanouf</creatorcontrib><creatorcontrib>Macaubas, Claudia</creatorcontrib><creatorcontrib>Roy, Amitava</creatorcontrib><creatorcontrib>Lovell, Daniel</creatorcontrib><creatorcontrib>Jagadeesh, Karthik A.</creatorcontrib><creatorcontrib>Alehashemi, Sara</creatorcontrib><creatorcontrib>Erdman, Laura</creatorcontrib><creatorcontrib>Grimley, Michael</creatorcontrib><creatorcontrib>Talarico, Susanna</creatorcontrib><creatorcontrib>Bacchetta, Rosa</creatorcontrib><creatorcontrib>Lewis, David B.</creatorcontrib><creatorcontrib>Canna, Scott W.</creatorcontrib><creatorcontrib>Laxer, Ron M.</creatorcontrib><creatorcontrib>Mellins, Elizabeth D.</creatorcontrib><creatorcontrib>Goldbach-Mansky, Raphaela</creatorcontrib><creatorcontrib>Weinacht, Katja G.</creatorcontrib><title>Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description><![CDATA[None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost [p.*192C*24]) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile) <3rd <3rd 5th <3rd <3rd 5th 3rd 3rd 3rd 5th <3rd <3rd 10th Appetite Poor Improved Normal Poor Improved Improved Poor Improved Improved Normal Poor Decreased Normal Spleen size∗ (cm [patient age; SM or normal, UL for age]) 11.4 (12 mo; SM, UL 8.0) 8 (15 mo; normal, UL 8.0) 8 (18 mo; normal, UL 8.0) 11.2 (neonatal; SM, UL 6.0) NA 10.1 (12 mo; SM, UL 8.0) 9.2 (neonatal; SM, UL 6.0) 9.9 (5 mo; SM, UL 6.5) 10.8 (16 mo; SM, UL 8.0) 11.9 (6 y; SM, UL 10.0) Hepatomegaly and SM 6.7 (15 mo old; normal, UL 8.0) NA Painful rash Daily None None Bimonthly Monthly None Daily Resolved Resolved Resolved Daily Recurrent None Ibuprofen intake Daily None None None None None None None None None None None None Severe infections None None None None None None None Lymphadenitis Lymphadenitis Lymphadenitis, streptococcal sepsis None Yes† Lymphadenitis Yes‡ Biological parameters Platelet (103/μL) 72 155 141 182 267 276 13 22 148 202 54 381 307 Hemoglobin (g/dL) Transfusion-dependent anemia (Hb, <7 g/dL) 13.8 13.3 Transfusion-dependent anemia (Hb, <7 g/dL) 11.2 11.7 8.1 7.9 10.1 12.3 7.4 13.3 13.5 RBC transfusion Monthly None None Q2-3 mo None None Weekly or biweekly Sporadic Rare Rare Multiple None None Platelet transfusion None None None None None None Multiple Sporadic Rare Rare Multiple None None LDH (ng/mL) 540 NA 547 584 269 271 817 998 1,115 1,633 NA 284 353 ESR (mm/h) >130 16 32 51 22 40 62 65 39 22 140 26 21 CRP (mg/L) 55 2 4 56 3.4 8.8 14.2 3.6 5.6 0.2 Increased 28.8 1.54 Ferritin (ng/mL [<400]) 2,364 801 680 614 316 126 5,191 3,682 1,329 557 NA 172 51 IL-6 (pg/mL [<5]) 18 NA <5 NA NA NA NA NA 15.9 11.0 NA NA NA IL-18§ (pg/mL [100-500]) 35,616 27,803 22,690 36,479‖ NA 83,268 NA NA 28,407 26,402 NA 19,025 21,535 IL-18BP§ (pg/mL [1,000-6,000]) 14,418 8,557 6,264 NA NA 14,653 NA NA 11,803 NA NA 23,986 9,626 CXCL9§ (pg/mL [500-3,500]) 8,457 2,978 4,975 NA NA 2,064 NA NA 3,942 NA NA 11,473 4,278 Table I Clinical phenotype and biological parameters of the reported patients before and after therapy with IL-1 inhibitors TKS C-terminal∗ mutations in CDC42 Group 1 Group 2 Group 3 Clinical presentation Failure to thrive, postnatal weight (weight <2 SD) 3/5 2/4 3/4 4/4 Intellectual disability 5/5 4/4 2/6 1/4 Facial dysmorphism, including frontal bossing and large forehead 2/5 2/4 1/6 3/4 Cardiac abnormality 3/5 2/4 2/5 0/4 Rash 0/5 0/4 0/5 4/4 Recurrent severe infections 4/5 3/4 1/6 3/4 (2/3 were receiving immunosuppression) Biological parameters Thrombocytopenia 4/4 1/3 0/5 4/4 Anemia NA NA NA 4/4 Systemic inflammatory syndrome: increased CRP level, ESR, and ferritin level NA NA NA 4/4 Table E1 Comparison of the clinical phenotypes and biological parameters of patients with TKS and of our cohort of 4 patients with a de novo heterozygous C-terminal mutation in CDC42 Patient 1 CDC42 c.563G>A p.C188Y De novo Possibly pathogenic: 0.337∗ Patient 2 CDC42 LYST LPIN2 MEFV c.563G>A c.1686G>C c.446C>T c.442G>C p.C188Y p.Q562H p.P149L p.E148Q De novo Possibly pathogenic: 0.337∗ Possibly pathogenic: 0.035 Possibly pathogenic: 0.049 Likely benign: 0.024 Patient 3 CDC42 LYST UNC13D c.556C>T c.4545G>C c.2764G>A p.R186C p.E1515D p.A922T De novo Heterozygous from father Heterozygous from mother Possibly pathogenic: 0.053∗ Likely benign: 0.003 Possibly pathogenic: 0.047 Patient 4 CDC42 WAS c.576A>C (stop lost) c.706G>A p.*192C*24 p.A236T De novo X-linked from mother Possibly pathogenic: 0.053∗ Possibly pathogenic: 0.964 Table E2 WES analysis of all 4 reported patients No.]]></description><subject>Age</subject><subject>Amino acids</subject><subject>Anemia</subject><subject>Appetite</subject><subject>Benign</subject><subject>Cdc42 protein</subject><subject>Cell division</subject><subject>Consanguinity</subject><subject>Exanthema</subject><subject>Eye</subject><subject>Ferritin</subject><subject>Forehead</subject><subject>Genetics</subject><subject>Hemoglobin</subject><subject>Homology</subject><subject>Ibuprofen</subject><subject>Immunosuppression</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Inflammatory diseases</subject><subject>Interleukin 1</subject><subject>Interleukin 18</subject><subject>Interleukin 6</subject><subject>Intracranial pressure</subject><subject>Labeling</subject><subject>Laboratories</subject><subject>Mutation</subject><subject>Neonates</subject><subject>Optic nerve</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Platelets</subject><subject>Proteins</subject><subject>Retina</subject><subject>Spleen</subject><subject>Swelling</subject><subject>Transfusion</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kc-K1TAUxosozp3RF3AhATfOojXpvyQgA1L_DVxwoa5DmpzOTUmba5JW5mV8CB_EZzLljoNuXCXhfOd3Tr4vy54RXBBM2ldjMUplihITXuC2wIQ-yHYEc5q3rGweZjuMOclbWvOz7DyEEad3xfjj7KwiJSWU8V324zOs4AHJJTozD1ZOk4zGzcjMqEbHdIc5BvTdxAPq8gh-MrO0aJXeyK2QZAqsRdqsJmx9ys3RO4uO3kXYICU6uMlZd4Nedm-7urxEYVEKQhgWa29R9CAj6NOE631Ofv1M0IPpzbbGk-zRIG2Ap3fnRfb1_bsv3cd8_-nDdfdmn6ua85jLHquacK5JjanSrMG4HjgdiOJtj7lsmx73FSsHzpgGBrrlDOpeK02korStLrKrE_e49BNolT7tpRVHbybpb4WTRvxbmc1B3LhVsLpsKMUJ8OIO4N23BUIUo1t8siqIssKYJO-rJqnKk0p5F4KH4X4CwWLLVIxiy1RsmQrcipRpanr-9273LX9CTILXJwEkh1YDXgSVYlOgjQcVhXbmf_zfAMS2nQ</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Gernez, Yael</creator><creator>de Jesus, Adriana A.</creator><creator>Alsaleem, Hanouf</creator><creator>Macaubas, Claudia</creator><creator>Roy, Amitava</creator><creator>Lovell, Daniel</creator><creator>Jagadeesh, Karthik A.</creator><creator>Alehashemi, Sara</creator><creator>Erdman, Laura</creator><creator>Grimley, Michael</creator><creator>Talarico, Susanna</creator><creator>Bacchetta, Rosa</creator><creator>Lewis, David B.</creator><creator>Canna, Scott W.</creator><creator>Laxer, Ron M.</creator><creator>Mellins, Elizabeth D.</creator><creator>Goldbach-Mansky, Raphaela</creator><creator>Weinacht, Katja G.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>5PM</scope></search><sort><creationdate>20191001</creationdate><title>Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition</title><author>Gernez, Yael ; de Jesus, Adriana A. ; Alsaleem, Hanouf ; Macaubas, Claudia ; Roy, Amitava ; Lovell, Daniel ; Jagadeesh, Karthik A. ; Alehashemi, Sara ; Erdman, Laura ; Grimley, Michael ; Talarico, Susanna ; Bacchetta, Rosa ; Lewis, David B. ; Canna, Scott W. ; Laxer, Ron M. ; Mellins, Elizabeth D. ; Goldbach-Mansky, Raphaela ; Weinacht, Katja G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-ab0c4199d1407cd85004f97f1c96b09a65b0b382f988de8ed698e4bdcd1ac7763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Age</topic><topic>Amino acids</topic><topic>Anemia</topic><topic>Appetite</topic><topic>Benign</topic><topic>Cdc42 protein</topic><topic>Cell division</topic><topic>Consanguinity</topic><topic>Exanthema</topic><topic>Eye</topic><topic>Ferritin</topic><topic>Forehead</topic><topic>Genetics</topic><topic>Hemoglobin</topic><topic>Homology</topic><topic>Ibuprofen</topic><topic>Immunosuppression</topic><topic>Infections</topic><topic>Inflammation</topic><topic>Inflammatory diseases</topic><topic>Interleukin 1</topic><topic>Interleukin 18</topic><topic>Interleukin 6</topic><topic>Intracranial pressure</topic><topic>Labeling</topic><topic>Laboratories</topic><topic>Mutation</topic><topic>Neonates</topic><topic>Optic nerve</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Platelets</topic><topic>Proteins</topic><topic>Retina</topic><topic>Spleen</topic><topic>Swelling</topic><topic>Transfusion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gernez, Yael</creatorcontrib><creatorcontrib>de Jesus, Adriana A.</creatorcontrib><creatorcontrib>Alsaleem, Hanouf</creatorcontrib><creatorcontrib>Macaubas, Claudia</creatorcontrib><creatorcontrib>Roy, Amitava</creatorcontrib><creatorcontrib>Lovell, Daniel</creatorcontrib><creatorcontrib>Jagadeesh, Karthik A.</creatorcontrib><creatorcontrib>Alehashemi, Sara</creatorcontrib><creatorcontrib>Erdman, Laura</creatorcontrib><creatorcontrib>Grimley, Michael</creatorcontrib><creatorcontrib>Talarico, Susanna</creatorcontrib><creatorcontrib>Bacchetta, Rosa</creatorcontrib><creatorcontrib>Lewis, David B.</creatorcontrib><creatorcontrib>Canna, Scott W.</creatorcontrib><creatorcontrib>Laxer, Ron M.</creatorcontrib><creatorcontrib>Mellins, Elizabeth D.</creatorcontrib><creatorcontrib>Goldbach-Mansky, Raphaela</creatorcontrib><creatorcontrib>Weinacht, Katja G.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gernez, Yael</au><au>de Jesus, Adriana A.</au><au>Alsaleem, Hanouf</au><au>Macaubas, Claudia</au><au>Roy, Amitava</au><au>Lovell, Daniel</au><au>Jagadeesh, Karthik A.</au><au>Alehashemi, Sara</au><au>Erdman, Laura</au><au>Grimley, Michael</au><au>Talarico, Susanna</au><au>Bacchetta, Rosa</au><au>Lewis, David B.</au><au>Canna, Scott W.</au><au>Laxer, Ron M.</au><au>Mellins, Elizabeth D.</au><au>Goldbach-Mansky, Raphaela</au><au>Weinacht, Katja G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2019-10-01</date><risdate>2019</risdate><volume>144</volume><issue>4</issue><spage>1122</spage><epage>1125.e6</epage><pages>1122-1125.e6</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><abstract><![CDATA[None of the patients had a family history of consanguinity. Because of the complex nature of their disease, whole-exome sequencing (WES) was performed in all patients and identified 3 distinct monoallelic, heterozygous, possibly pathogenic de novo variants in CDC42. Immunophenotypic changes in monocytes and natural killer cells (Fig 1, A and B) were also noted. Because of the complex nature of the disease, WES was performed and identified a heterozygous and possibly pathogenic de novo variant in CDC42 c.563G>A (p.C188Y; Fig 1). At 8 months, he was found to have retinal detachment, phthisis of his right eye and papilledema of the left eye, both of which were presumed to be secondary to his inflammatory disease and increased intracranial pressure. Because of the patient's phenotypic similarities to patients with NOMID, he was started on prednisone and anakinra at age 8 months, with resolution of systemic inflammation and cytopenias. Patient 1 Patient 2 Patient 3 Patient 4 CDC42 variant c.563G>A (p.C188Y) c.563G>A (p.C188Y) c.556C>T (p.R186C) c.576A>C (stop lost [p.*192C*24]) Dose of anakinra (d) Before anakinra 1 mg/kg 2.5 mg/kg Before anakinra 6 mg/kg 5 mg/kg Before anakinra 3 mg/kg 8.5 mg/kg Canakinumab, 8 mg/kg/mo Before anakinra 3 mg/kg 4.5 mg/kg Clinical presentation Facial dysmorphism Mild frontal bossing, mild hypertelorism, depressed nasal bridge Frontal bossing, macrocephaly, thin sparse hair, depressed nasal bridge None Mild frontal bossing Weight (percentile) <3rd <3rd 5th <3rd <3rd 5th 3rd 3rd 3rd 5th <3rd <3rd 10th Appetite Poor Improved Normal Poor Improved Improved Poor Improved Improved Normal Poor Decreased Normal Spleen size∗ (cm [patient age; SM or normal, UL for age]) 11.4 (12 mo; SM, UL 8.0) 8 (15 mo; normal, UL 8.0) 8 (18 mo; normal, UL 8.0) 11.2 (neonatal; SM, UL 6.0) NA 10.1 (12 mo; SM, UL 8.0) 9.2 (neonatal; SM, UL 6.0) 9.9 (5 mo; SM, UL 6.5) 10.8 (16 mo; SM, UL 8.0) 11.9 (6 y; SM, UL 10.0) Hepatomegaly and SM 6.7 (15 mo old; normal, UL 8.0) NA Painful rash Daily None None Bimonthly Monthly None Daily Resolved Resolved Resolved Daily Recurrent None Ibuprofen intake Daily None None None None None None None None None None None None Severe infections None None None None None None None Lymphadenitis Lymphadenitis Lymphadenitis, streptococcal sepsis None Yes† Lymphadenitis Yes‡ Biological parameters Platelet (103/μL) 72 155 141 182 267 276 13 22 148 202 54 381 307 Hemoglobin (g/dL) Transfusion-dependent anemia (Hb, <7 g/dL) 13.8 13.3 Transfusion-dependent anemia (Hb, <7 g/dL) 11.2 11.7 8.1 7.9 10.1 12.3 7.4 13.3 13.5 RBC transfusion Monthly None None Q2-3 mo None None Weekly or biweekly Sporadic Rare Rare Multiple None None Platelet transfusion None None None None None None Multiple Sporadic Rare Rare Multiple None None LDH (ng/mL) 540 NA 547 584 269 271 817 998 1,115 1,633 NA 284 353 ESR (mm/h) >130 16 32 51 22 40 62 65 39 22 140 26 21 CRP (mg/L) 55 2 4 56 3.4 8.8 14.2 3.6 5.6 0.2 Increased 28.8 1.54 Ferritin (ng/mL [<400]) 2,364 801 680 614 316 126 5,191 3,682 1,329 557 NA 172 51 IL-6 (pg/mL [<5]) 18 NA <5 NA NA NA NA NA 15.9 11.0 NA NA NA IL-18§ (pg/mL [100-500]) 35,616 27,803 22,690 36,479‖ NA 83,268 NA NA 28,407 26,402 NA 19,025 21,535 IL-18BP§ (pg/mL [1,000-6,000]) 14,418 8,557 6,264 NA NA 14,653 NA NA 11,803 NA NA 23,986 9,626 CXCL9§ (pg/mL [500-3,500]) 8,457 2,978 4,975 NA NA 2,064 NA NA 3,942 NA NA 11,473 4,278 Table I Clinical phenotype and biological parameters of the reported patients before and after therapy with IL-1 inhibitors TKS C-terminal∗ mutations in CDC42 Group 1 Group 2 Group 3 Clinical presentation Failure to thrive, postnatal weight (weight <2 SD) 3/5 2/4 3/4 4/4 Intellectual disability 5/5 4/4 2/6 1/4 Facial dysmorphism, including frontal bossing and large forehead 2/5 2/4 1/6 3/4 Cardiac abnormality 3/5 2/4 2/5 0/4 Rash 0/5 0/4 0/5 4/4 Recurrent severe infections 4/5 3/4 1/6 3/4 (2/3 were receiving immunosuppression) Biological parameters Thrombocytopenia 4/4 1/3 0/5 4/4 Anemia NA NA NA 4/4 Systemic inflammatory syndrome: increased CRP level, ESR, and ferritin level NA NA NA 4/4 Table E1 Comparison of the clinical phenotypes and biological parameters of patients with TKS and of our cohort of 4 patients with a de novo heterozygous C-terminal mutation in CDC42 Patient 1 CDC42 c.563G>A p.C188Y De novo Possibly pathogenic: 0.337∗ Patient 2 CDC42 LYST LPIN2 MEFV c.563G>A c.1686G>C c.446C>T c.442G>C p.C188Y p.Q562H p.P149L p.E148Q De novo Possibly pathogenic: 0.337∗ Possibly pathogenic: 0.035 Possibly pathogenic: 0.049 Likely benign: 0.024 Patient 3 CDC42 LYST UNC13D c.556C>T c.4545G>C c.2764G>A p.R186C p.E1515D p.A922T De novo Heterozygous from father Heterozygous from mother Possibly pathogenic: 0.053∗ Likely benign: 0.003 Possibly pathogenic: 0.047 Patient 4 CDC42 WAS c.576A>C (stop lost) c.706G>A p.*192C*24 p.A236T De novo X-linked from mother Possibly pathogenic: 0.053∗ Possibly pathogenic: 0.964 Table E2 WES analysis of all 4 reported patients No.]]></abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>31271789</pmid><doi>10.1016/j.jaci.2019.06.017</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of allergy and clinical immunology, 2019-10, Vol.144 (4), p.1122-1125.e6 |
| issn | 0091-6749 1097-6825 |
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| source | Elsevier ScienceDirect Journals Complete |
| subjects | Age Amino acids Anemia Appetite Benign Cdc42 protein Cell division Consanguinity Exanthema Eye Ferritin Forehead Genetics Hemoglobin Homology Ibuprofen Immunosuppression Infections Inflammation Inflammatory diseases Interleukin 1 Interleukin 18 Interleukin 6 Intracranial pressure Labeling Laboratories Mutation Neonates Optic nerve Patients Phenotypes Platelets Proteins Retina Spleen Swelling Transfusion |
| title | Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1β inhibition |
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