Follow-up of a patient Follow-up of a patient with with

CERNUNNOS deficiencyCERNUNNOS deficiency

Edyta Heropolitańska-PliszkaEdyta Heropolitańska-PliszkaImmunology DepartmentImmunology Department

Children’s Memorial Health Institute Children’s Memorial Health Institute Warsaw, PolandWarsaw, Poland

CERNUNNOS / XLFCERNUNNOS / XLF

a new type of a new type of radiosensitive radiosensitive

T-B-NK+ SCIDT-B-NK+ SCID

DNA-repair disordersNBS

HIGM1 or 3

SCID Lig IV def

cernunnos

Cernunnos deficiencyCernunnos deficiency core componentscore components

consanguinity consanguinity recurrent bacterial and opportunistic infections recurrent bacterial and opportunistic infections microcephaly microcephaly severe growth retardation severe growth retardation dysmorfic features dysmorfic features hypogammaglobulinemia IgG and IgAhypogammaglobulinemia IgG and IgA fluctuating level of IgMfluctuating level of IgM mild to severe B and T lymphopenia, NK cells not mild to severe B and T lymphopenia, NK cells not

affectedaffected all T cells of memory phenotype (CD45 RO+)all T cells of memory phenotype (CD45 RO+) impaired response of T cells to PHAimpaired response of T cells to PHA chromosomal translocations in lymphocyteschromosomal translocations in lymphocytes increased radiosensitivity increased radiosensitivity

8-year-old boy8-year-old boy

irrelevant family historyirrelevant family history recurrent bacterial and recurrent bacterial and

viral infections of upper viral infections of upper and lower respiratory and lower respiratory tract since infancy tract since infancy period (otitis, bronchitis period (otitis, bronchitis and pneumonitis every and pneumonitis every 2 months)2 months)

significant significant microcephaly (-5 SD)microcephaly (-5 SD)

birdlike facebirdlike face growth retardation (<3 growth retardation (<3

pc)pc)

Immunologic investigationImmunologic investigation IgG 120-530 mg/dl,IgG 120-530 mg/dl, IgA 6-18 mg/dl,IgA 6-18 mg/dl, IgM 921-1390 mg/dl IgM 921-1390 mg/dl

CD19+ 4,3% - 81 cells/ulCD19+ 4,3% - 81 cells/ul CD3+ 32% - 380 cells/ulCD3+ 32% - 380 cells/ul CD16+56+ 43% - 665 cells/ulCD16+56+ 43% - 665 cells/ul CD4+ CD45RO+ 91,8% - 600 cells/ul CD4+ CD45RO+ 91,8% - 600 cells/ul CD8+ CD45RO+ 64.7% - 466 cells/ulCD8+ CD45RO+ 64.7% - 466 cells/ul

PHA 2635+/-7 PHA 2635+/-7 anty-CD3 838+/-65 anty-CD3 838+/-65

spontaneous chromosomal fragility spontaneous chromosomal fragility increased radiosensitivity of patient’s fibroblastsincreased radiosensitivity of patient’s fibroblasts

CERNUNNOS deficiencyCERNUNNOS deficiency

homozygous homozygous stop codon mutationstop codon mutation

Y167XY167X

HSCTHSCT March 2006 - MUD PBPC March 2006 - MUD PBPC

(CD34+ 12,7x10(CD34+ 12,7x1066/kg b.m)/kg b.m)

Conditioning regimen reduced because of Conditioning regimen reduced because of breakage of chromosomes (FluCyATG)breakage of chromosomes (FluCyATG)

Early outcome:Early outcome: +12 day - GVHD II stage+12 day - GVHD II stage in skin (steroids) in skin (steroids) +17 day - good haematological +17 day - good haematological

reconstitutionreconstitution +27 day - complete chimerism+27 day - complete chimerism

+ 62 day+ 62 day good clinical condition, good clinical condition,

no symptoms of no symptoms of infectioninfection

complete chimerism, complete chimerism, no signs of GVHDno signs of GVHD

immunosupression: CsA immunosupression: CsA and steroids (Encorton and steroids (Encorton 0,5 mg/kg b.m.)0,5 mg/kg b.m.)

prophylaxis: Co-prophylaxis: Co-trimoxazole, trimoxazole, Azithromycin, Acyclovir, Azithromycin, Acyclovir, Fluconazole Fluconazole

+155 day+155 day

hemorrhagic cysthemorrhagic cystiitis of tis of unknown origin unknown origin ((polioma-, adeno-, polioma-, adeno-, CMV, EBV CMV, EBV excluded)excluded)

ttreatmentreatment: f: forced orced diuresis, IVIG diuresis, IVIG substitutionsubstitution,, intravenous Acyclovirintravenous Acyclovir

+210 day – good +210 day – good clinical condition, clinical condition, normal blood and normal blood and urine tests, complete urine tests, complete chimerismchimerism

+385 day+385 day Protracted fever with Protracted fever with

lymphadenopathy, skin lymphadenopathy, skin changes (chronic GVHD)changes (chronic GVHD)

CMV PCR (-)CMV PCR (-) Aspergillus ELISA 0,452 Aspergillus ELISA 0,452

PCR (-)PCR (-) Cryptosporidium sp. PCR (-)Cryptosporidium sp. PCR (-) EBV DNA 140-560 copiesEBV DNA 140-560 copies Diagnosis: EBV infectionDiagnosis: EBV infection Treatment: Azithromycin, Treatment: Azithromycin,

Co-trimoxazol, Acyclovir, Co-trimoxazol, Acyclovir, Worikonazol, IVIG every 10 Worikonazol, IVIG every 10 days, UDCA, Gancyclovirdays, UDCA, Gancyclovir

WBC – 7,8 K/ulWBC – 7,8 K/ul N-29% L-35%N-29% L-35% E-27% AL-2%E-27% AL-2% M-7%M-7% Hgb – 10,2 g/dlHgb – 10,2 g/dl Plt - 135 K/ulPlt - 135 K/ul GOT – 110 U/lGOT – 110 U/l GGTP – 335 U/lGGTP – 335 U/l CRP - 1,2 mg/dlCRP - 1,2 mg/dl LDH – 245 U/lLDH – 245 U/l

+425 day - last follow-up+425 day - last follow-up IgG 590 mg/dl,IgG 590 mg/dl, IgA 41 mg/dl,IgA 41 mg/dl, IgM 60 mg/dl IgM 60 mg/dl CD19+ 12,3% - 405 cells/ulCD19+ 12,3% - 405 cells/ul CD3+ 69% - 2310 cells/ulCD3+ 69% - 2310 cells/ul CD16+56+ 13% - 469 cells/ulCD16+56+ 13% - 469 cells/ul Alone 337+/-80Alone 337+/-80 PHA 16871+/-645PHA 16871+/-645 CD3 16199+/-125CD3 16199+/-125 Complete chimerismComplete chimerism

Thank you for attentionThank you for attention