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