3/31/15
1
Medical Dermatology Society 2015 Annual Mee8ng Edward W. Cowen, MD, MHSc Head, Dermatology Consulta:on Service Dermatology Branch Center for Cancer Research Na:onal Cancer Ins:tute
“No relevant financial rela:onships with commercial interests”
CANDLE
NOMID DADA2 DIRA PLAID
DITRA
SAVI
DADA2 2014
CANDLE 2010
PLAID 2012
SAVI 2014
CAPS
Br J Dermatol 1965 (Apr); 77:180-5.
Ian Bruce Sneddon (1915-87)
! Vascular occlusion or inflamma:on? ! Polyarteri:s nodosa ! Skin biopsies à uninforma:ve ! An:-‐phospholipid Ab (aPL):
0-‐85% of Sneddon pts.
Br J Dermatol 1965 (Apr); 77:180-5.
! Livedo re:cularis ! Physiologic
! Temp-‐dependent ! Non-‐physiologic
! SLE ! Vasculi:s (PAN) ! Obstruc:ve (APS)
! Livedo racemosa ! Irregular, ‘broken’
circles derm
aam
in.c
om
derm
ques
t.com
Sneddon syndrome
Livedo reticularis
3/31/15
2
! Familial SnS (Eur J Dermatol 2003) ! Age 28, 37, 42: CVA (2 ischemic, 1 hemorrhagic) +
livedo
Medicine (Baltimore). 1999 Jul;78(4):209-19.
! 2 siblings with early onset CVA ! L. re:cularis (age 3, age 10) ! Fever, elevated inflammatory markers (ESR, CRP) ! Nerve palsies (age 5, 10) ! Subcutaneous nodules during flare
370;10 march 6, 2014
OMIM: 615688
! Case defini:on (NIH) ! Fever, early onset stroke, livedo, HSM, systemic vasculopathy
! Whole exome sequencing ! CERC1 (cat eye chromosome region, candidate 1) à
adenosine deaminase 2 (ADA2) ! Enzyme assay, immunblofng, IHC, cytokine profiling
! Func:onal studies (zebrafish) ! cerc1b (paralog) mopholino knockdown à IC hemorrhage
NEJM 370;10, 2014
Uninjected cecr1b-specific morpholino
NEJM 370;10 march 6, 2014
3/31/15
3
! Convert adenosine to inosine and 2ʹ′-‐deoxyadenosine to 2ʹ′-‐deoxyinosine (ADA1 > 2)
! ADA(1)-‐SCID ! Intracellular: toxic accumula:on of
deoxyadenosine ! Profound lymphopenia, recurrent
infec:on ! Mul:ple atrophic DFSP tumors ! Tx: Pegylated-‐ADA1, gene therapy
! ADA2 ! Secreted à growth factor, endothelial,
lymphocyte development (mild immunodeficiency)
! Primary source: monocytes/macrophages ! Tx: Fresh frozen plasma, HSCT?
! Allogeneic HSCT ! 4 yo: livedo, HSM, hypercoaguable, red-‐cell aplasia
! Serum ADA2 normalized ! Resolu:on of cytopenia, skin lesions
! 1yo: PID, cytopenia, lymphoprolifera:ve disease ! Hemorrhagic CVA D+36, resolu:on of all symptoms
! TNF-‐a inhibi>on (etanercept) ! 10 yo: livedo, CVA, HSM, lymphopenia à resolu:on of Sx
! Tocilizumab (an>-‐IL6) ! 5 yo: Castleman’s-‐like disease, recurrent fever,
splenomegaly, incr. IL-‐6 à complete suppression of Sx
N Engl J Med 2014; 371:478-481.
! DADA2 ‘childhood/familial Sneddon S’ ! Childhood stroke/livedo ! Fever, elevated ESR/CRP, CVA ! Evolving/expanding clinical phenotype:
familial PAN, HSM, immunodeficiency, cytopenias, lymphoprolifera:ve disease
! Adult SnS, CVA risk factor? ! Familial SnS (Eur J Dermatol 2003)
! Confirmed CERC1 muta:on (NEJM 2014)
! CVA: 4th leading cause of mortality ! 34% < 65 years of age
NEJM 2014:921-31.
! Could ADA2 heterozygosity be a risk factor for adult-‐onset CVA or PAN in general popula:on? ! NHLBI exome sequence database ! CERC1 heterozygote carriers à late-‐onset lacunar CVA
SAVI (STING-‐Associated Vasculopathy with onset in Infancy)
2014;371:507-18.
OMIM: 615934
3/31/15
4
! Autosomal dominant (de novo) ! TMEM173: s:mulator of interferon genes (STING) ! Gain-‐of-‐func:on muta:on à Cons:tu:ve
ac:va:on ! Elevated INFB1 transcrip:on à autoinflamma:on
Neonatal onset
NEJM 2014;371:507-18.
! Telangiectasia (6/6) ! Nasal septal perfora:on (4/6)
NEJM 2014;371:507-18.
3/31/15
5
* * * *
IgM IgM C3
bone resorption surgical amputation seropositive RA
! High mortality (3/7) ! Unresponsive to mul:ple agents
! Pred, CYP, AZA, CSA, MTX, MMF, IVIG, belimumab, HCQ, TNF-‐α inh., leflunamide, RTX, ASA, nifedipine
! Interferon pathway-‐specific Tx
Arthritis Rheumatol 2015 Mar;67(3):808.
3/31/15
6
! SAVI
! Aicardi-‐Gou:ères syndromes (AGS1-‐7) ! Encephalopathy ! Familial chilblain lupus: acrocyanosis, purpura,
petechiae ! Re:nal vasculopaty/cerebral leukodystrophy ! Dyschromatosis symmetrica hereditaria
Aicardi-Goutières S. 2 yo girl with mild developmental delay, white matter changes, +ANA homozygous missense mutation in SAMHD1. Courtesy Julie Schaffer, MD
! SAVI
! Aicardi-‐Gou:ères syndromes (AGS1-‐7) ! Encephalopathy ! Familial chilblain lupus: acrocyanosis, purpura,
petechiae ! Re:nal vasculopaty/cerebral leukodystrophy ! Dyschromatosis symmetrica hereditaria
! CANDLE syndrome/Proteosome associated autoinflammatory syndromes (PRAAS)
! Perinatal ! Fevers, persistent erythematous, annular
plaques ! Late infancy
! Periorbital erythema, digital edema ! Early childhood
! Lipodystrophy, LAD, anemia, arthri:s/arthralgia ! Late childhood
! Hepatomegaly, cardiomyopathy
J Am Acad Dermatol 2010;62:489-95. Arthritis Rheum 2012; 64:895-907.