[CIS PIDD] [cis-pidd] absent T cells and anomalies

Thu May 17 11:37:58 EDT 2018

>From my side of things, I agree with Nikita and David and would not rush to hematopoietic stem cell transplantation without a better idea of whether the patient’s fundamental defect is inherent to the bone marrow precursors or due to thymic aplasia, especially if the sibling is only 3 years of age and most likely has not encountered the vast array of pathogens that an individual might face during a lifetime.

I probably wouldn’t hesitate to reach out to Louise Markert at Duke and Gigi Notarangelo at the NIH to get their thoughts.

Ivan Chinn, M.D.

From: <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>> on behalf of CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Date: Thursday, May 17, 2018 at 3:22 AM
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: AW: [cis-pidd] absent T cells and anomalies

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Hi Dave,
if he has a matched sib, why not just infuse bone marrow without conditioning asap?
BR
Michael Albert

Von: cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net> [mailto:cis-pidd at lyris.dundee.net] Im Auftrag von CIS-PIDD
Gesendet: Mittwoch, 16. Mai 2018 18:38
An: CIS-PIDD
Betreff: Re: [cis-pidd] absent T cells and anomalies

Dear Colleagues,

I am posting this case on behalf of a colleague.  I had agreed with looking for genetic etiologies (e.g. CHD7, TBX1, etc.).  I thought that complete DGS was a consideration.  I wasn't excited about rushing immediately to a hematopoietic cell transplant given the question of DGS.  Although... certainly concerning with the absence of T cells and thymic output.
Any thoughts / queries are welcome...

Dave Buchbinder

CASE -

We are involved in evaluating a 4-week old former preemie with absent TRECs on newborn screen, diagnosis of SCID, and dysmorphology. My colleague Dr. Nikita Raje in Immunology (nraje at cmh.edu<mailto:nraje at cmh.edu>) is overseeing his workup and management.

He is a 34 weeker born to consanguineous Kurdish parents. His prenatal ultrasounds were concerning for polyhydramnios, abnormal fetal brain with possible absent corpus callosum, micrognathia, and other findings. NIPS negative. Amniocentesis denied. Mom received 2 doses of steroids prior to delivery. Tracheostomy was placed after birth due to inability to intubate.

Postnatally, he has agenesis of corpus callosum with colpocephaly, polymicrogyria, micrognathia, cleft palate, abnormal ears, low hair line, asymmetric pupils/ bilateral optic nerve hypoplasia, right club foot, and ambiguous genitalia. Renal ultrasound normal. Thymic shadow is present on chest x-ray

He had an episode of metabolic acidosis and had septic work up at DOL#2 – which was negative.

Lab results (See below for details):
Flow cytometry continue to show extremely low T lymphocytes (essentially absent T lymphocytes). B lymphocyte counts are now normal for age (previously mildly low). NK cell counts remain normal.-

DOL #29: (corrected term): CD3 30, CD4 30, CD8 0

1 CD4 Naïve T cell, 0 Naïve CD8à DOL #15 same as DOL#4

IgG 400 mg/dL- low, IgM 26 mg/dL- slightly high, IgA < the 7 mg/dL lower limit of detection for our lab on IVIG

Lymphocyte proliferation to mitogens: absent CD45+ total lymphocyte and CD3+ T cell proliferative responses to PHA
Expression of CD127 and CD132 are normal (on the B and NK cells)

ADA, PNP levels normal
STR analysis negative for maternal cells

Microarray results as above; VUS with 20 kb loss within chromosome band 7q21.11 that contains exons 2 and 3 of CD36. Several large regions of absence of heterozygosity, not surprising give the consanguinity

Exome in process

Diagnosis at this time: T-B+NK+ SCID but has prematurity and congenital anomalies.

Some questions:

Has anyone come across similar case? We thought of these candidate genes –CHARGE syndrome, VICI syndrome and BCL11B

Would you agree that despite her prematurity (maternal steroid doses) and anomalies, she fulfils SCID criteria and is a candidate for HCT? Would you wait to see if T cell count will come up? (3 year old sister is a match)

Could this be DGS or CHARGE (not typical clinical phenotype)?

Conditioning regimen for a matched-sib donor transplant?

Detailed labs:

DOL 0-1 TREC Ct level was >45, and repeat TREC Ct on DOL2 was 42.57,

TRECS absent (Mayo lab)

- 4/13: IgG 400- low, IgM 26- slightly high, IgA < the 7 mg/dL lower limit of detection for our lab [Received IVIG 1 gram ~ 500 mg/kg on 4/13

- 4/13 flows: essentially absent T lymphocytes (5 total T cells which were CD4+), B lymphocytes 262- low, normal NK

- 4/23 flows: 12 CD3+ cells (consistent with previous flow on 4/13; absent T cells), 6 CD4+ T cells, 0 CD8+ T cells (other 6 CD3+ cells are likely double negative T cells: CD4-/CD8-), 444 B lymphocytes (now normal), 158 NK cells (normal).

- Lymphocyte proliferation to PHA (was drawn 4/16- insufficient number of mononuclear cells). Resent today (likely will be abnormal given flow results)

- PNP and ADA1 (Duke/Dr. Hershfield's lab): Normal

- Patient's CMV PCR blood; CMV urine: both negative

- CD127 (IL7Ralpha): Normal expression (on B and NK cells)

- CD132 (Common gamma chain): Normal expression (on B and NK cells)

- Mom's CMV PCR-blood, urine CMV, CMV IgG and IgM: negative

- Microarray Interpretation:
1) Variant of Unknown Significance - Loss arr[GRCh37] 7q21.11(80256737_80276691)x1
Microarray analysis shows an ~20 kb loss within chromosome band 7q21.11 that contains exons 2 and 3 of CD36 (NM_001001547.2). There is a single copy of this region instead of two copies (normal) per diploid genome.

2) Absence of Heterozygosity (AOH)
Several large regions of absence of heterozygosity (AOH) were detected in this individual, encompassing ~2.4% of the autosomal genome. This result is not diagnostic of, but raises the possibility for, a recessive disorder.

Regions >3Mb are listed in the AOH table below.
7p21.3p21.2(11841780_15944974)x2 hmz 4,103,194

8q24.13q24.23(124153516_139445680)x2 hmz 15,292,164
11p12q12.3(41944266_62031379)x2 hmz 20,087,113

13q14.222.1(47315983_74222584)x2 hmz 26,906,601

16p11.2p11.1(31860422_35220544)x2 hmz 3,360,122

04/23/2018 09:00

HEMATOLOGY
WBC 11.93 x10(3) mcL 5.00 - 21.00
HGB 14.5 gm/dL 12.0 - 16.0
HCT 41.4 % 39.0 - 67.0
Platelet 310 x10(3) mcL 150 - 450
Absolute Immature Gran 0.35 H x10(3) mcL 0.00 - 0.04
Absolute Band 0.18 x10(3) mcL - <=1.20
Absolute Neutrophil Count 10.02 H x10(3) mcL 1.50 - 9.00
Absolute Lymphocyte Count 0.61 L x10(3) mcL 2.00 - 11.00
Absolute Monocyte Count 0.35 x10(3) mcL 0.20 - 2.00
Absolute Eosinophil Count 0.61 x10(3) mcL 0.00 - 0.90
Absolute Basophil Count 0.00 x10(3) mcL 0.00 - 0.10
% Immature Gran 2.9 %
% Band 1.5 %
% Segmented Neutrophils 82.5 %
% Lymphocyte 5.1 %
% Monocyte 2.9 %
% Eosinophil 5.1 %
% Basophil 0.0 %
Differential Method Manual D
RBC 4.44 x10(6) mcL 3.60 - 6.60
Mean Cell Volume 93.2 fL 86.0 - 124.0
Mean Cell Hemoglobin 32.7 pg 28.0 - 40.0
MCHC 35.0 gm/dL 31.5 - 36.5
RDW 16.6 H % 11.5 - 14.5
Absolute Nucleated RBC 0.03 x10(3) mcL
Nucleated RBC 0.3 /100 WBC
RBC Fragments Few
Ovalocytes Few
Platelet Estimate Normal
Mean Platelet Volume 13.5 H fL 8.2 - 12.4
Giant Platelets Present
Smear Morphology Reviewed

Collection: 04/23/2018 09:00

FLOW CYTOMETRY
T, B & Natural Killer Cell Spec Type Peripher
Common Leukocyte Antigen (CD45) % 99.90 % 95.00 - 100.00
Total T Cells (CD3+) % 2 %
Total T Cells (CD3+) Absolute 12 L mm3 1600 - 5500
T Helper Cells % 1 %
T Helper Cells Absolute 6 L mm3 1200 - 4200
T Cytotoxic Cells % 0 %
T Cytotoxic Cells Absolute 0 L mm3 400 - 2100
Helper/Cytotoxic Ratio (CD4/CD8) NA ratio 1.20 - 2.99
Total B Cells (CD19+) % 73 %
Total B Cells (CD19+) Absolute 444 mm3 350 - 600
Natural Killer Cells % 26 %
Natural Killer Cells Absolute 158 mm3 80 - 340

Naïve-Memory Spec Type blood
NAIVE TOTAL T CELL % 23 %
MEMORY TOTAL T CELL % 77 %
NAIVE TOTAL T CELL ABSOLUTE 1 mm3
MEMORY TOTAL T CELL ABSOLUTE 5 mm3
Naive T Helper % 23 %
Memory T Helper % 77 %
Naive T Helper Absolute 1 L mm3 1200 - 3600
Memory T Helper Absolute 5 L mm3 60 - 900
Naive T Suppressor 0 %
Memory T Suppressor % 0 %
Naive T Suppressor Absolute 0 L mm3 380 - 1300
Memory T Suppressor Absolute 0 L mm3 30 - 330
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