[CIS PIDD] [cis-pidd] T-B+NK- SCID

Wed May 9 12:34:38 EDT 2018

Hi Nikita - with the anomalies you described I would worry about a thymic abnormality in which case HCT is unlikely to be successful.  I recommend looking closely at the VUS, could image for a thymus but not that isn’t too reliable.  You could also look for markers of thymic egress on the few T cells present, but again probably not sensitive.

I think reviewing the genetics is your best bet.

Best,

Megan

Megan Cooper, MD, PhD
Washington University in St. Louis

On May 9, 2018, at 12:00 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:

Dear all,

I would appreciate your input on this case.

Thanks in advance,

Nikita Raje | MD
Division of Allergy/Asthma/Immunology
Children’s Mercy Kansas City
Assistant Professor of Internal Medicine and Pediatrics
UMKC School of Medicine
P: (816) 960-8885 (ext. 68885) | F: (816) 960-8888
E: nraje at cmh.edu<mailto:nraje at cmh.edu> | W: childrensmercy.org<http://www.childrensmercy.org/>
2401 Gillham Road | Kansas City, MO 64108

<image001.png>

Summary:
My patient is a now 4 week old boy who had abnormal newborn screen for SCID -absent TRECs.
He is a 34 weeker born to consanguineous Kurdish parents. His prenatal ultrasounds were concerning for polyhydramnios, echogenic kidneys, abnormal fetal brain with colpocephaly and possible absent corpus callosum and cavum septum pellucidum, micrognathia, ecogenic kidneys, low set and malrotated ears with bilateral skin tags, bilateral clinodactyly, short long bones, and increased nuchal fold at 20 weeks. NIPS negative. Amniocentesis denied.
Mom received 2 doses of steroids prior to delivery. Trach was placed after birth due to inability to intubate.
Post-natally, 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.
Had an episode of metabolic acidosis and had septic work up at DOL#2 – which was negative.

Lab results (See below for details after my questions section):
- Flow cytometry results from today 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 CD8--> 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 and areas of loss of heterozygosity noted
- Exome- no pathogenic variants identified

Sister is a match for HSCT.

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

·         Has anyone come across similar case? We thought of these candidate genes –CHARGE syndrome, VICI syndrome and BCL11B- (but not found on exome await official results to check for VUS).

·         Any other testing you would consider?

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

·         Any words of wisdom for conditioning regimen that you would consider for T-B+NK+ SCID

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.

Chromosome Region

             Size (bp)

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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