[CIS PIDD] [cis-pidd] Persistent panlymphopenic 17 years old boy, HIV negative and non-steroid treatment. Remarkably benign infectios history without receiving prophylaxis

Fri Apr 13 14:08:41 EDT 2018

Dear colleagues. 
My name is Lourdes Tricas, MD and I'm working for Hospital Universitario Central de Asturias (Oviedo, Spain). 
I would greatly appreciate your comments on this case of severe lymphopenia (HIV negative and non-steroid treatment) in a boy since age of 14 years old whose cause we can't find. 

Questions: 
1st.- If it´s a secondary immunodeficiency, what other causes should we look for? 
2nd.- Can it be a primary immunodeficiency despite the fact that at age of 11 years old a whole blood count showed normal number of lymphocytes and the genetic study is normal? 

Clinical summary: 
Birth date: November 2000. 
No family consanguinity, two sisters, the oldest has brain paralysis possibly due to CMV infection during pregnancy. 
HIV negative. 
Non-steroid treatment. 

History of infections without receiving any prophylaxis: 
At age of 5 years: Varizella with normal evolution and recovery. 
At age of 16 years: Herpes Zoster in hemitorax and recovery with antiviral treatment. 
At age of 16 years: Fungus skin infection with good evolution with treatment. 
No history of Bacteria infections. 

Laboratory findings: 
In 2011 (boy was 11 years old) normal whole blood count: Leucocytes=6100 cells /μL, Neutrophils = 2900 cells/μL, Lymphocytes = 1700 cells/μL, Monocytes=400 cells/μL, Eosinophils=1100 cells/μL and Basophils =0 cells/μL. 

>From December 2014 to the present time whole blood counts showed severe lymphopenia: Leucocytes = 3278±716 cells/μL, Neutrophils = 2566±693 cells/μL, Lymphocytes = 194±53 cells/μL, Monocytes = 396±148 cells/μL, Eosinophils = 75±30 cells/μL and Basophils = 13±5 cells/μL. 

Absolute counts of T and B lymphocyte subsets are very low and absolute count of NK cells is normal but in low limit. 
>From 2017 to 2018: T cells = 86±11 cells/μL (normal range= 800-3500 cells/μL), TCD4 = 35±3 cells/μL (normal range= 400-2100 cells/μL), TCD8 = 51±8 cells/μL (normal range= 200-1200 cells/μL), B cells = 6±1 cells/μL 
(normal range = 200-600 cells /μL), NK cells = 72±15 cells /μL (normal range = 72±15 cells/μL (normal range = 70-1200 cells/μL) and ratio TCD4/TCD8= 0.67±0.1 ( normal range = 0.9-3.4). 

CD4+ Recent Thymic Emigrants (RTEs) CD4+CD45RA+CD31+ cells in peripheral blood are normal = 13%. (reference range for age 18-25 years = 6-51%). 
In peripheral blood: T-CD132+ = 100%, T-HLA-DR+ = 28%, TCRαβ+ = 26%, TCRγδ+ = 4%. 

Normal proliferation of Peripheral Blood Mononuclear Cells after 5 and 7 days in vitro stimulated with PHA and monoclonal antibodies anti-CD3 and anti-CD28 respectively. 

Normal study of bone marrow. 

ADA y PNP activity is Normal. 

Serology: 
Normal sera Immunoglobulins: IgG = 6.3 g/L (normal range = 6.6-16.2 g/L), IgA = 0.6 g/L (normal range = 0.6-3.5 g/L), IgM = 0.4 g/L (normal range = 0.4-2.4g/L) and IgE = 35.3 KU/L (normal range = 0-85 KU/L). 
No presence of autoantibodies anti-lymphocytes checked by flow cytometry. 
Normal production of antibodies: measles IgG, parotiditis IgG, varizella zoster IgG, EBV-VCA IgG, EBV-EBNA IgG and CMV IgG. 
No antibodies againts HTLV1+2 IgG and Herpes Simplex 1+2 IgG. 

Viral study: 
Normal viral study in peripheral blood: Not detectable: DNA-CMV, DNA-EBV, DNA-Herpes type 6, DNA-Herpes type 7, DNA-Adenovius, RNA-HIV, RNA-HTLV. 
Normal viral study in pharingeal swab: Not detectable: RNA-Influenza A , RNA-Influenza B, RNA-VRS, RNA-Metapneumovirus, RNA-Parainfluenza, RNA-Coronavirus, RNA-Rhinovirus, RNA-Enterovirus, DNA-Adenovirus, DNA-Herpes type 7, DNA-CMV but recently DNA-EBV = 5686 copies/1000 cells and DNA-Herpes type 6 = 74349 copies/1000 cells. 

Genetc Study: 
A molecular cause for this persistent lymphopenia has not been determined. All coding bases of RAG1, RAG2, DCLRE1C, IL2Rϒ and 99.58% of JAK3 have been sequenced and not clearly pathogenic variant was identified. The following heterozygous sequence variants of uncertain clinical significace were identified and not confirmed: IL7R c.1357T>C p.(Ser453Pro), RFX5 c.1409G>A p. (Arg470Gln). All coding bases of IL7R and RFX5 have been sequenced and no second variant was identified. 

Thank you very much in advance for your comments and help. 
Best regards 
Lourdes Tricas, MD, PhD 
Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain. 

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