Unusual skin changes in 4-year-old SCID patient

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

2. Registry of PIDs in CMHI1980–2006 n = 102129 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 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 21 m.o. - bronchitis obturativa, extensive oral thrush, failure to thrive, papulo-erthrodermatous eruptions on extremities, buttocks and face DIAGNOSIS: lymphoma benignum cutis

14. 32 m.o. - bronchitis obturativa, uticaria pigmentosa, failure to thrive, normal immunoglobuline concentration (IgG-550 mg/dl) DIAGNOSIS: mastocytosis 36 m.o. - bronchitis obturativa, failure to thrive,leukopenia with agranulocytosis (WBC 2200; N-11%) 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 DIAGNOSIS:primary immunodeficiency disorder

15. WBC - 5,4 K/ul N-77% L-17% E-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 Basic blood tests

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 - 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

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 Thanks to Dr T. Langerak Erasmus University

24. Genetical diagnosis 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 +15 day - good haematological reconstitution +20 day - GVHD II stagein skin (CsA, steroids) +27 day – reactivation of HCMV infection (Gancyclovir, Foscarnet) +39 day - complete chimerism • +75 day – good condition, no infection, still skin changes, chimerism pending