[CIS PIDD] [cis-pidd] AW: Puzzling case of Low T cells

Mon Jun 12 08:22:44 EDT 2017

Hi Kiran,

Might also be worth looking at WIPF1 alongside WAS by sanger sequencing or transcript analysis if possible.

Fulgent should be able to provide you with the quality metrics for both genes.  I'm not sure if they can do full gene sequencing, but it can't hurt to ask...

Best
Mike

Michae Keller MD
Children's National Medical Center
Washington DC

On Jun 12, 2017, at 6:42 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:

Hi Kiran,
even though WES was negative, I would do a Sanger sequencing of the WAS gene. Not sure WES would pick up the not infrequent intronic mutations.
BR
Michael Albert
_______________________________________________

Michael Albert, MD
Professor
Department of Pediatric Hematology/Oncology
Head SCT Program
Dr. von Haunersches Children's Hospital
Lindwurmstr.4
80337 Munich
Germany
Tel: +49 89 4400 52785
Fax: +49 89 4400 54819

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: Donnerstag, 8. Juni 2017 22:00
An: CIS-PIDD
Betreff: [cis-pidd] Puzzling case of Low T cells

Hi All,

We were seeing if anyone has seen a similar patient with thoughts on further diagnostic testing. We are planning on a bone marrow transplant for this patient at this time.

11m Male with history of thrombocytopenia (found due to prolonged bleeding after circumcision) and mild eczema who was found on workup for thrombocytopenia to have severe persistent T cell lymphopenia. Patient was started on SCIG at 6 months of age. We have not identified a genetic etiology (WES negative, CGH array shows an 8p23.1 del/dup) for this case. The patient demonstrates puzzling testing with severely abnormal TCRVb repertoire but normal TREC copies for age (Mayo tested 2 samples 1 week apart with similar results).

Summary of workup to date (detailed labs further below):

  *   Low T cells with normal B cells; NK cells are slightly decreased
  *   No maternal engraftment, normal NBS SCID
  *   Decreased %CD3 proliferation to PHA (slightly) and normal to PWM
  *   Decreased IgG, A and M for age

     *   Diphtheria titer 2.0 (s/p 2 vaccinations)
     *   Tetanus titer 0.8 (s/p 2 vaccinations)
     *   1/14 S. Pneumo titers >1.3 (s/p 2 vaccinations)

  *   WASp expression normal (Cincinnati)
  *   Decreased CD127 expression on CD4 and CD8 cells decreased but normal expression on CD16/56 (Cincinnati)
  *   Decreased memory B cells with severe decrease in class switched memory B cells (6 months of age)
  *   Total memory CD8 and CD4 moderately expanded for age primarily in central memory T cell compartment. Naïve T cells expression of CD62L are decreased for age especially in CD8 T cell subset (expression is diffuse on CD8 T cells, atypical).
  *   TREC Copies (10m of age): 9612 per 10^6 CD3 T cells (normal for age)
  *   TCRVb:  Severely abnormal repertoire (23 families assessed); no families show a normal polyclonal Gaussian distribution
  *   CD4 RTE (10m of age): 69% of CD4+CD45RA+ express CD31
  *   Telomere length normal
  *   Bone marrow biopsy is normal for age and US chest demonstrates thymic tissue
  *   Infection History:

     *   6 months of age norovirus diarrhea self resolved without intervention
     *   7 months of age R eye cellulitis

  *   Genetic Testing:

     *   CGH Array: arr[hg19] 8p23.1(6,223,920-6,999,114)x1, 8p23.1p22(11,935,023-14,703,457)x3

        *   The interstitial deletion of 8p includes 9 OMIM genes (MCPH, ANGPT2, AGPAT5, DEFB1, DEF6, DEF4, DEF1, DEF3, DEF5)
        *   The interstitial duplication of 8p includes 6 OMIM genes (USP17L2, FAM86B1, FAM86B2, KIAA1456, DLC1, SGCZ)

     *   Whole Exome (Fulgent): no findings

Ref. Range

1m of age

2m of age

3m of age

6m of age

10m of age

PLATELET COUNT

Latest Ref Range: 150-400 THOU/uL

38 (L)

131 (L)

116 (L)

90 (L)

50 (L)

Ref. Range

6 months of age

9 months of age

TOTAL T LYMPHS(CD3+)%

Latest Ref Range: 49-76 %

32 (L)

30 (L)

ABS TOTAL T LYMPHS (CD3+)

Latest Ref Range: 1900-5900 CELLS/UL

334 (L)

350 (L)

HELPER T CELLS (CD3+CD4+) %

Latest Ref Range: 31-56 %

11 (L)

9 (L)

CD3+CD4+MEMORY%

Latest Ref Range: 4-17 %

29 (H)

43 (H)

CD3+CD4+TRANSITIONAL%

Latest Ref Range: 0-39 %

15

17

CD3+CD4+NAIVE%

Latest Ref Range: 48-98 %

57

41 (L)

ABS HELPER T CELLS (CD3+CD4+)

Latest Ref Range: 1400-4300 CELLS/UL

117 (L)

109 (L)

SUPPRESSOR T CELLS (CD3+CD8+) %

Latest Ref Range: 12-24 %

19

18

ABS SUPPRESSOR T CELLS (CD3+CD8+)

Latest Ref Range: 500-1700 CELLS/UL

201 (L)

214 (L)

CD4CD8 RATIO

Latest Ref Range: 1.20-6.60

0.58 (L)

0.51 (L)

TOTAL B CELLS (CD19+) %

Latest Ref Range: 14-37 %

60 (H)

64 (H)

ABS TOTAL B CELLS (CD19+)

Latest Ref Range: 610-2600 CELLS/UL

625

745

NK CELLS (CD3-CD56+CD16+) %

Latest Ref Range: 3-15 %

7

5

ABS NK CELLS (CD3-CD56+CD16+)

Latest Ref Range: 160-950 CELLS/UL

71 (L)

55 (L)

% CD3

Reference Range

6 months of age

9 months of age

PWM

>3.5

16.3

29.8

PHA

>49.9

38.3

46.9

CA

>3

4.8

TT

>3.3

42.3

Ref. Range

6m

6m

s/p IVIG

9m on SCIG

IGA

Latest Ref Range: 8-120 mg/dL

<31

8

8 (L)

IGG

Latest Ref Range: 225-1400 mg/dL

<140 (L)

90 (L)

760

677

IGM

Latest Ref Range: 32-94 mg/dL

<21 (L)

20 (L)

13 (L)

IGE

Latest Ref Range: 0-15 IU/mL

<2

3

Imaging
ULTRASOUND CHEST :  Visualization of normal-appearing thymic tissue seen within the anterior mediastinum.

Bone marrow biopsy:
The marrow cellularity in this area is estimated at 95%, hypercellular for age. Trilineage hematopoiesis is present with normal myeloid to erythroid ratio. A few megakaryocytes are seen. No increase of immature mononuclear cells is seen. There are no lymphoid aggregates, granulomas or cells extrinsic to the marrow present.

__________________________________________________________
Kiran P. Patel, MD, MS
Associate Program Director Allergy/Immunology Fellowship
Assistant Professor of Pediatrics & Medicine
Emory University School of Medicine/Children's Healthcare of Atlanta

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