unusual skin changes in 4-year-old scid patient edyta heropolitańska-pliszka magdalena...
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Unusual skin changes in Unusual skin changes in 4-year-old SCID patient4-year-old SCID patient
Edyta Heropolitańska-PliszkaEdyta Heropolitańska-PliszkaMagdalena Kurenko-DeptuchMagdalena Kurenko-Deptuch
Immunology DepartmentImmunology DepartmentChildren’s Memorial Health InstituteChildren’s Memorial Health Institute
Warsaw PolandWarsaw Poland
PRAGUE 2007PRAGUE 2007
T cell and combined def.
7 %
Phagocytic def.11%
Complement def.1%
Others23%
Humoral def.58%
Registry of PIDs in CMHIRegistry of PIDs in CMHI19801980 –– 2002006 6 n n == 1021 1021
29 SCID / 6 OS29 SCID / 6 OS
Cutaneous disorders in Cutaneous disorders in SCID patientsSCID patients
Recurrent skin abscesses Recurrent skin abscesses Extensive candidiasis in the mouth and diaper area may Extensive candidiasis in the mouth and diaper area may
persist and involve the rest of the skinpersist and involve the rest of the skin Intractable eczemalike dermatitis Intractable eczemalike dermatitis Severe seborrheic dermatitis over the scalp, ears, and Severe seborrheic dermatitis over the scalp, ears, and
nasolabial foldsnasolabial folds Impetigo and severe skin infections with deep ulcers in the Impetigo and severe skin infections with deep ulcers in the
perineum, tongue, and buccal mucosa perineum, tongue, and buccal mucosa Sparse hair and absence of the eyebrows and eyelashesSparse hair and absence of the eyebrows and eyelashes Manifestations of graft-versus-host disease (GVHD) that Manifestations of graft-versus-host disease (GVHD) that
ensue a few days to weeks after transfusion include:ensue a few days to weeks after transfusion include: in the acute setting: a maculopapular or morbilliform rash in the acute setting: a maculopapular or morbilliform rash
with progress to erythroderma and exfoliative dermatitiswith progress to erythroderma and exfoliative dermatitis in chronic GVHD: lichenoid or sclerodermoid lesionsin chronic GVHD: lichenoid or sclerodermoid lesions
Exfoliative erythrodermy in Exfoliative erythrodermy in Omenn SyndromeOmenn Syndrome
on CsA treatment
Impetigo and severe skin Impetigo and severe skin infectioninfection
Skin changes in BCG-itisSkin changes in BCG-itis
Extensive fungal infectionExtensive fungal infection
Extensive candidiasisExtensive candidiasis
Materno-fetal engraftmentMaterno-fetal engraftment
Acute GVHD after non-irradiated, Acute GVHD after non-irradiated, non-filtrated blood transfusionnon-filtrated blood transfusion
Chronic GVHD 150 days after HSCTChronic GVHD 150 days after HSCT
4-year-old girl:4-year-old girl:
young, non-young, non-consanguinous parents consanguinous parents
healthy, elder brother,healthy, elder brother, II-nd pregnancy, II-nd II-nd pregnancy, II-nd
delivery after cdelivery after caaesaresareeanan operationoperation, b.w. 3030g , b.w. 3030g
vaccinated with BCG and vaccinated with BCG and hepatitis Bhepatitis B after birth after birth
breast-fed breast-fed for for 16 months16 months
2 m.o.2 m.o. - - dermatitis atopica dermatitis atopica
18 m.o18 m.o.. - - pneumonitis pneumonitis, diarrhea, maculo-papular, diarrhea, maculo-papular skin skin changes on extremitieschanges on extremities,, lymphopenia (WBC 9100; L-9%)lymphopenia (WBC 9100; L-9%)
20 m.o.20 m.o. - - erosive stomatitis erosive stomatitis, failure to thrive, , failure to thrive, papulo-papulo-
vescicular eruptions onvescicular eruptions on extremities, extremities, lymphopenia (WBC 9300; L-14%)lymphopenia (WBC 9300; L-14%)
DIAGNOSIS:DIAGNOSIS: benign histiocytosisbenign histiocytosis
21 m.o.21 m.o. - - bronchitis obturativa, bronchitis obturativa, extensive oral thrush, extensive oral thrush, failure to thrive, papulo-erthrodermatous eruptions on failure to thrive, papulo-erthrodermatous eruptions on extremities, buttoextremities, buttoccks and faceks and face
DIAGNOSISDIAGNOSIS: : lymphoma benignum cutislymphoma benignum cutis
32 m.o.32 m.o. - - bronchitis obturativa, uticaria bronchitis obturativa, uticaria pigmentosa pigmentosa , , failure to thrive, normal immunoglobuline concentration failure to thrive, normal immunoglobuline concentration (IgG-550 mg/dl)(IgG-550 mg/dl)
DIAGNOSISDIAGNOSIS:: mastocytosis mastocytosis
36 m.o.36 m.o. - - bronchitis obturativa bronchitis obturativa, failure to thrive,, failure to thrive, leukopenia with agranulocytosis (WBC 2200; N-11%) leukopenia with agranulocytosis (WBC 2200; N-11%)
DIAGNOSISDIAGNOSIS:: systemic diseasesystemic disease 40 m.o.40 m.o. – – admitted to Immunology Department CMHI admitted to Immunology Department CMHI failure to thrive,failure to thrive, papulo-macular skin changes with small papulo-macular skin changes with small
scales and scarring on extremities, buttoks, face,scales and scarring on extremities, buttoks, face, obturativobturativee bronch bronchopneumonia opneumonia
DIAGNOSISDIAGNOSIS:: primary immunodeficiency primary immunodeficiency disorderdisorder
Basic blood testsBasic blood tests
WBC - 5,4 K/ulWBC - 5,4 K/ul N-77% N-77% L-17% L-17% E-3%E-3% B-3%B-3% RBC - 3,66 M/ulRBC - 3,66 M/ul Hgb - 12,2 g/dlHgb - 12,2 g/dl Plt - 260 K/ulPlt - 260 K/ul
GOT – 42 U/lGOT – 42 U/l GPT – 35 U/lGPT – 35 U/l CRP <0,2 mg/dlCRP <0,2 mg/dl LDH – 265 U/lLDH – 265 U/l
Microbiological investigationMicrobiological investigation
Pneumocystis cariniPneumocystis carini PCR in blood and BAL – negative PCR in blood and BAL – negative Mycoplasma sp., Chlamydia sp., Legionella sp.Mycoplasma sp., Chlamydia sp., Legionella sp. – –
negative negative Mycobacterium tuberculosisMycobacterium tuberculosis PCR in BAL – negative PCR in BAL – negative HIV-1 HIV-1 PCR – negative PCR – negative HHV 6HHV 6 PCR – negative PCR – negative HSV HSV DNA - negativeDNA - negative HCMVHCMV PCR DNA in leukocytes and urine – both positive PCR DNA in leukocytes and urine – both positive
Aspergillus sp.Aspergillus sp. index ELISA (0,660) and PCR (+) index ELISA (0,660) and PCR (+)
Humoral immunityHumoral immunity IgG IgG 1020 – 20131020 – 2013 mg/dl mg/dl IgA IgA 21 21 mg/dl mg/dl IgM IgM 147147 mg/dl mg/dl IgE IgE 5252 KU/L KU/L
IgG1 IgG1 990990 mg/dl mg/dl IgG2 IgG2 <11<11 mg/dl mg/dl IgG3 IgG3 1616 mg/dl mg/dl IgG4 IgG4 <0,4<0,4 mg/dl mg/dl
Monoclonal gammapathy IgG kappaMonoclonal gammapathy IgG kappa
Anty-HBs 0,0 after triple vaccination, anty-diphteria and Anty-HBs 0,0 after triple vaccination, anty-diphteria and anty-tetanus 0,0 after four-time-vaccinationanty-tetanus 0,0 after four-time-vaccination
Cellular immunityCellular immunity
CD45+/SSC low – CD45+/SSC low – 15171517 kom/ul kom/ul CD3+/CD45+ - CD3+/CD45+ - 40,6 40,6 % % 615615 kom/ul kom/ul CD3+CD8+/CD45+ - CD3+CD8+/CD45+ - 15,5 15,5 % % 235235 kom/ul kom/ul CD3+CD4+/CD45+ - CD3+CD4+/CD45+ - 18,2 18,2 % % 275275 kom/ul kom/ul CD16+56+/CD45+ - CD16+56+/CD45+ - 43,9 43,9 % % 665 665 kom/ulkom/ul CD19+/CD45+ - CD19+/CD45+ - 10,510,5% % 160160 kom/ul kom/ul
Control Control 117 +/- 28117 +/- 28 PHA PHA 675 +/- 84675 +/- 84 CD3 CD3 2654 +/- 3702654 +/- 370
Chimerism VNTR – no maternal engraftmentChimerism VNTR – no maternal engraftment
Imaging studiesImaging studies
USGUSG - thymus present, no hepatosplenomegaly, - thymus present, no hepatosplenomegaly, lymphoadenopathy in lymphoadenopathy in nitch of nitch of liver and spleenliver and spleen
Chest radiographChest radiographss – interstitial – interstitial pneumonitispneumonitis in both in both lunglungss
CT scansCT scans – – enlarged lymph nodes in mediastinum; enlarged lymph nodes in mediastinum; interstitial interstitial infiltrationinfiltration with fibrous changes in both apexes with fibrous changes in both apexes
HRCTHRCT – permanent fibrous changes in both apexes; – permanent fibrous changes in both apexes; enlarged lymph nodes enlarged lymph nodes in in mediastinum mediastinum
Histologic findingsHistologic findings BMABMA – – no signs of malignancyno signs of malignancy Skin biopsySkin biopsy - microscopy: predominantly histiocytic infiltrates - microscopy: predominantly histiocytic infiltrates
with lymphocytes present in the dermis and with lymphocytes present in the dermis and subcutaneous tissue with tendency to form subcutaneous tissue with tendency to form granulomatous forms; In T cell population granulomatous forms; In T cell population predominance of T cytotoxic, less amount of T predominance of T cytotoxic, less amount of T helper, the least of B cellshelper, the least of B cells
- immunohistochemical reactions: CD1a - immunohistochemical reactions: CD1a negative, CD68 positive (abundant reaction), negative, CD68 positive (abundant reaction), Ki67 and CD20 positive in small part of Ki67 and CD20 positive in small part of lymphocytes, CD3 positive in most lymphocytes.lymphocytes, CD3 positive in most lymphocytes.
DIAGNOSIS:DIAGNOSIS: histiocytoma eruptivum generalisatum histiocytoma eruptivum generalisatum
DIAGNOSISDIAGNOSIS
OMENN SYNDROMEOMENN SYNDROME
T- B- NK+ T- B- NK+ SCIDSCID
Frozen skin biopsyFrozen skin biopsy – PCR analysis of the – PCR analysis of the T-cell receptor (TCR) genesT-cell receptor (TCR) genes
analysis of TCRB / TCRG repertoire analysis of TCRB / TCRG repertoire showed reproducible oligoclonal patterns showed reproducible oligoclonal patterns with predominant clones shared between with predominant clones shared between the two samples. It might reflect (antigen-the two samples. It might reflect (antigen-driven?) selective outgrowth of T cells, driven?) selective outgrowth of T cells, which might be compatibiwhich might be compatibille with an e with an inflammatory reaction in the contexinflammatory reaction in the contextt of the of the presumed SCID syndpresumed SCID syndromerome
Thanks to Dr T. LangerakThanks to Dr T. Langerak Erasmus University Erasmus University
Genetical Genetical diagnosisdiagnosis
OMENN SYNDROME:OMENN SYNDROME:
RAG-1/RAG-2 – excludedRAG-1/RAG-2 – excluded Artemis – excluded on Artemis – excluded on
the basis of low the basis of low radiosensitivityradiosensitivity
IL7RA – not testedIL7RA – not tested Others ???Others ???
Thanks to Prof. J.J. van DongenThanks to Prof. J.J. van DongenDr M. van der BurgDr M. van der Burg
0 1 2 3 4 5 6
Dose of X-ray (Gy)
0.01
0.1
1
10
100
Sur
viva
l (%
)
N=2
VH10-wildtype
ID278-CD3delta
ID468-?
ID124-Artemis
ID369-IL7Ralpha
TreatmentTreatment
antibacterial (PCP prophylaxis + broad- antibacterial (PCP prophylaxis + broad- spectrum antibiotics)spectrum antibiotics)
antiviral agents (Gancyclovir) antiviral agents (Gancyclovir) antifungal therapy (Amphomoronal, antifungal therapy (Amphomoronal,
Worikonazol) Worikonazol) IVIG every 7-10 daysIVIG every 7-10 days immunosupressive treatment (CsA, immunosupressive treatment (CsA,
Encorton (1mg/kg.b.))Encorton (1mg/kg.b.))
HSCTHSCT March 2007 MUD PBPCMarch 2007 MUD PBPC
Conditioning regimen (BuCyATG)Conditioning regimen (BuCyATG)
Early outcome:Early outcome: +10 day – Engraftment Syndrome +10 day – Engraftment Syndrome +15 day - good haematological reconstitution+15 day - good haematological reconstitution +20 day - GVHD II stage+20 day - GVHD II stage in skin (CsA, steroids) in skin (CsA, steroids) +27 day – reactivation of HCMV infection (Gancyclovir, +27 day – reactivation of HCMV infection (Gancyclovir,
Foscarnet)Foscarnet) +39 day - complete chimerism+39 day - complete chimerism
+75 day – good condition, no infection, still skin +75 day – good condition, no infection, still skin changes, chimerism pendingchanges, chimerism pending