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   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

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Sneddon syndrome

Livedo reticularis

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!   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

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!   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

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!  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.

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* * * *

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.

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!   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.