Let`s go for the diagnosis! Yazeed Toukan, MD Pediatric Pulmonary Institute, Ruth Rappaport Children`s Hospital July 2016

Transcription

1 Let`s go for the diagnosis! Yazeed Toukan, MD Pediatric Pulmonary Institute, Ruth Rappaport Children`s Hospital July 2016

2 Case report 20 months old girl Israeli Arab Muslim family, consanguineous marriage Pregnancy, delivery, birth weight uneventful FTT

3 Case report 1 st admission Presented at the age of 10 months Vomiting and diarrhea Cow's milk protein allergy Nutramigen

4 Case report Respiratory episodes From birth: noisy breathing, snoring Recurrent episodes of wheezing Inhaled steroid treatment d/t symptoms resembling asthma - w/o improvement

5 Case report 2 nd admission - May 2016 Fever, cough, respiratory distress CBC WBC 11,700; Hb 7; Ret 23%; PLT 41,000 Blood smear schistocytes LDH Normal Hb electrophoresis

6 Case report 2 nd admission - May 2016 Normal renal and hepatic functions Following results Negative for viruses and bacteria EBV, CMV, Mycoplasma, Legionella, Toxoplasma, Pertussis, HIV, Respiratory viruses Celiac serology - negative Normal Immunoglobulins + specific Ab responses Normal Immunophenotyping

7 Case report 2 nd admission - May 2016 CXR - pneumonia RML Normal ECHO study Normal abdominal US

8 Thrombocytopenia Platelet count < 150,000mm 3 Microangiopathic hemolysis Hb Schistocytes LDH Fever Thrombotic thrombocytopenic purpura (TTP) -??? ADAMTS13 Activity & Ab?

9 Case report ADAMTS13 activity < 0.01 ADMTS13 AB high >93

10 Thrombotic thrombocytopenic purpura (TTP)

11 Thrombotic thrombocytopenic purpura (TTP) A rare (~3.7 cases/million) Pentad of symptoms Thrombocytopenia Microangiopathic hemolytic anemia (intravascular hemolysis, peripheral schistocytes) Fever Neurological symptoms Renal dysfunction

12 Thrombotic thrombocytopenic purpura (TTP) The large majority of patients initially present with Thrombocytopenia Peripheral blood evidence of microangiopathy

13 Thrombotic thrombocytopenic purpura (TTP) Congenital (rarely) Defect in the ADAMTS13 gene decreased/absent enzyme activity Acquired (far more commonly) Primary or idiopathic (the most frequent type) Secondary - associated with distinctive clinical conditions (medications, hematopoietic stem cell/solid organ transplantation, sepsis, )

14 Thrombotic thrombocytopenic purpura (TTP) IgG autoantibody frequently found in patients with acquired TTP ADAMTS13 is the target for this IgG autoantibody, leading to a functional deficiency of ADAMTS13

15 ADAMTS13 Von Willebrand factor - cleaving protease A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13

16 TTP & Respiratory manifestations -?

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18 Results & conclusions 7 out of 56 pts with an established diagnosis of TTP were identified as having ARDS It is recommended that all patients with ARDS and unexplained thrombocytopenia be evaluated for unrecognized TTP

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20 Results & conclusions 1 of 74 pts had clinically important pulmonary involvement (transient PaO2, 42 mm Hg; arterial O2 saturation, 78%; normal CXR) Clinically important pulmonary involvement may be rare in patients with TTP because (i) pulmonary microvasculature may be inherently resistant to the formation of platelet thrombi (ii) pulmonary function can be maintained in spite of multiple microvascular thrombi

21 Back to our patient

22 Thrombocytopenia Platelet count < 150,000mm 3 Microangiopathic hemolysis Hb Schistocytes LDH Fever Thrombotic thrombocytopenic purpura (TTP) Thrombotic thrombocytopenic purpura (TTP) Acquired -??? ADAMTS13 activity Activity ; ADMTS13 & Ab? AB

23 Case report Plasmapheresis? But after starting systemic steroid treatment - Good clinical and laboratory response

24 Case report Last admission June 2016 Fever, cough, respiratory distress

25 Case report

26 Case report Last admission June 2016 BAL Pneumocystic jirovecii PCR positive Ziehl-Neelsen (acid fast) stain negative Nocardia culture negative

27 Case report TTP (autoimmunity) + Respiratory involvement (immunodeficiency) + FTT (systemic disease) LAT is the diagnosis A relative presented with similar symptoms Let`s go for the diagnosis Loss-of-function mutation in LAT

28 The adapter protein Linker for Activation of T cells

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31 The adapter protein linker for activation of T cells (LAT) The authors describe for the first time the clinical course in a family with a homozygous loss-offunction mutation in LAT (chr16, exon 5) This defect leads to a premature stop codon

32 The adapter protein linker for activation of T cells (LAT) The 3 patients presented from early childhood with combined immunodeficiency and profound immune dysregulation disease

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37 DISCUSSION All patients suffered from early onset autoimmune manifestations with normal lymphocyte counts and Ig levels During the progression of the disease Lymphocytopenia Hypogammaglobulinemia Opportunistic as well as other infections

38 Back to our patient Summary and future plans

39 Summary and future plans LAT dysfunction: combined autoimmunity & immunodeficiency Treated with Systemic steroids Antibiotics: Ampiciliin + Resprim IVIG Planned for HSCT

40 Take home message Consanguineous marriage is an endemic phenomenon in our region Autoimmunity should raise possibility of immunodeficiency Exome sequencing may be more helpful than thorough investigation

41 Thank you