1. Unusual skin changes in 4-year-old SCID patient Edyta Heropolitańska-Pliszka Magdalena Kurenko-Deptuch Immunology Department Children’s Memorial Health Institute Warsaw Poland PRAGUE 2007 PRAGUE 2007

2. Registry of PIDs in CMHI 1980 – 2006 n = 1021 29 SCID / 6 OS

3. Cutaneous disorders in SCID patients  Recurrent skin abscesses  Extensive candidiasis in the mouth and diaper area may persist and involve the rest of the skin  Intractable eczemalike dermatitis  Severe seborrheic dermatitis over the scalp, ears, and nasolabial folds  Impetigo and severe skin infections with deep ulcers in the perineum, tongue, and buccal mucosa  Sparse hair and absence of the eyebrows and eyelashes  Manifestations of graft-versus-host disease (GVHD) that ensue a few days to weeks after transfusion include: in the acute setting: a maculopapular or morbilliform rash with progress to erythroderma and exfoliative dermatitis in the acute setting: a maculopapular or morbilliform rash with progress to erythroderma and exfoliative dermatitis in chronic GVHD: lichenoid or sclerodermoid lesions in chronic GVHD: lichenoid or sclerodermoid lesions

4. Exfoliative erythrodermy in Omenn Syndrome on CsA treatment

5. Impetigo and severe skin infection

6. Skin changes in BCG-itis

7. Extensive fungal infection

8. Extensive candidiasis

9. Materno-fetal engraftment

10. Acute GVHD after non-irradiated, non-filtrated blood transfusion

11. Chronic GVHD 150 days after HSCT

12. 4-year-old girl:  young, non- consanguinous parents  healthy, elder brother,  II-nd pregnancy, II-nd delivery after caesarean operation, b.w. 3030g  vaccinated with BCG and hepatitis B after birth  breast-fed for 16 months

13.  2 m.o. - dermatitis atopica  18 m.o. - pneumonitis, diarrhea, maculo-papular skin changes on extremities, lymphopenia (WBC 9100; L-9%)  20 m.o. - erosive stomatitis, failure to thrive, papulo- vescicular eruptions on extremities, lymphopenia (WBC 9300; L-14%) DIAGNOSIS: benign histiocytosis DIAGNOSIS: benign histiocytosis  21 m.o. - bronchitis obturativa, extensive oral thrush, failure to thrive, papulo-erthrodermatous eruptions on extremities, buttocks and face DIAGNOSIS: lymphoma benignum cutis DIAGNOSIS: lymphoma benignum cutis

14.  32 m.o. - bronchitis obturativa, uticaria pigmentosa, failure to thrive, normal immunoglobuline concentration (IgG-550 mg/dl) DIAGNOSIS: mastocytosis DIAGNOSIS: mastocytosis  36 m.o. - bronchitis obturativa, failure to thrive, leukopenia with agranulocytosis (WBC 2200; N-11%) DIAGNOSIS: systemic disease DIAGNOSIS: systemic disease  40 m.o. – admitted to Immunology Department CMHI failure to thrive, papulo-macular skin changes with small scales and scarring on extremities, buttoks, face, obturative bronchopneumonia failure to thrive, papulo-macular skin changes with small scales and scarring on extremities, buttoks, face, obturative bronchopneumonia DIAGNOSIS: primary immunodeficiency disorder DIAGNOSIS: primary immunodeficiency disorder

15. Basic blood tests  WBC - 5,4 K/ul N-77% N-77% L-17% L-17% E-3% E-3% B-3% B-3%  RBC - 3,66 M/ul  Hgb - 12,2 g/dl  Plt - 260 K/ul  GOT – 42 U/l  GPT – 35 U/l  CRP <0,2 mg/dl  LDH – 265 U/l

16. Microbiological investigation  Pneumocystis carini PCR in blood and BAL – negative  Mycoplasma sp., Chlamydia sp., Legionella sp. – negative  Mycobacterium tuberculosis PCR in BAL – negative  HIV-1 PCR – negative  HHV 6 PCR – negative  HSV DNA - negative  HCMV PCR DNA in leukocytes and urine – both positive  Aspergillus sp. index ELISA (0,660) and PCR (+)

17. Humoral immunity  IgG 1020 – 2013 mg/dl  IgA 21 mg/dl  IgM 147 mg/dl  IgE 52 KU/L  IgG1 990 mg/dl  IgG2 <11 mg/dl  IgG3 16 mg/dl  IgG4 <0,4 mg/dl  Monoclonal gammapathy IgG kappa  Anty-HBs 0,0 after triple vaccination, anty-diphteria and anty-tetanus 0,0 after four-time-vaccination

18. Cellular immunity  CD45+/SSC low – 1517 kom/ul  CD3+/CD45+ - 40,6 % 615 kom/ul  CD3+CD8+/CD45+ - 15,5 % 235 kom/ul  CD3+CD4+/CD45+ - 18,2 % 275 kom/ul  CD16+56+/CD45+ - 43,9 % 665 kom/ul  CD19+/CD45+ - 10,5% 160 kom/ul  Control 117 +/- 28  PHA 675 +/- 84  CD3 2654 +/- 370  Chimerism VNTR – no maternal engraftment

19. Imaging studies  USG - thymus present, no hepatosplenomegaly, lymphoadenopathy in nitch of liver and spleen  Chest radiographs – interstitial pneumonitis in both lungs  CT scans – enlarged lymph nodes in mediastinum; interstitial infiltration with fibrous changes in both apexes  HRCT – permanent fibrous changes in both apexes; enlarged lymph nodes in mediastinum

20. Histologic findings  BMA – no signs of malignancy  Skin biopsy - microscopy: predominantly histiocytic infiltrates with lymphocytes present in the dermis and subcutaneous tissue with tendency to form granulomatous forms; In T cell population predominance of T cytotoxic, less amount of T helper, the least of B cells - microscopy: predominantly histiocytic infiltrates with lymphocytes present in the dermis and subcutaneous tissue with tendency to form granulomatous forms; In T cell population predominance of T cytotoxic, less amount of T helper, the least of B cells - immunohistochemical reactions: CD1a negative, CD68 positive (abundant reaction), Ki67 and CD20 positive in small part of lymphocytes, CD3 positive in most lymphocytes. - immunohistochemical reactions: CD1a negative, CD68 positive (abundant reaction), Ki67 and CD20 positive in small part of lymphocytes, CD3 positive in most lymphocytes. DIAGNOSIS: histiocytoma eruptivum generalisatum

22. DIAGNOSIS OMENN SYNDROME T- B- NK+ SCID T- B- NK+ SCID

23.  Frozen skin biopsy – PCR analysis of the T-cell receptor (TCR) genes analysis of TCRB / TCRG repertoire showed reproducible oligoclonal patterns with predominant clones shared between the two samples. It might reflect (antigen- driven?) selective outgrowth of T cells, which might be compatibile with an inflammatory reaction in the context of the presumed SCID syndrome analysis of TCRB / TCRG repertoire showed reproducible oligoclonal patterns with predominant clones shared between the two samples. It might reflect (antigen- driven?) selective outgrowth of T cells, which might be compatibile with an inflammatory reaction in the context of the presumed SCID syndrome Thanks to Dr T. Langerak Thanks to Dr T. Langerak Erasmus University Erasmus University

24. Genetical diagnosis OMENN SYNDROME: OMENN SYNDROME:  RAG-1/RAG-2 – excluded  Artemis – excluded on the basis of low radiosensitivity  IL7RA – not tested  Others ??? Thanks to Prof. J.J. van Dongen Dr M. van der Burg

25. Treatment  antibacterial (PCP prophylaxis + broad- spectrum antibiotics)  antiviral agents (Gancyclovir)  antifungal therapy (Amphomoronal, Worikonazol)  IVIG every 7-10 days  immunosupressive treatment (CsA, Encorton (1mg/kg.b.))

26. HSCT  March 2007 MUD PBPC  Conditioning regimen (BuCyATG)  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 in skin (CsA, steroids) +20 day - GVHD II stage in skin (CsA, steroids) +27 day – reactivation of HCMV infection (Gancyclovir, Foscarnet) +27 day – reactivation of HCMV infection (Gancyclovir, Foscarnet) +39 day - complete chimerism +39 day - complete chimerism  +75 day – good condition, no infection, still skin changes, chimerism pending