[CIS PIDD] [cis-pidd] 17 mo M with autoimmune cytopenias, hypotonia, 3rd nerve palsy

Tue Jun 23 20:23:08 EDT 2015

? CSF findings: Ig/albumin ratio and oligoclonal bands ?

Mel Berger

Sent from my iPhone

On Jun 23, 2015, at 18:18, Jonathan Tam <kiditamae at gmail.com<mailto:kiditamae at gmail.com>> wrote:

Thank you for the responses.  We're hopefully getting whole exome sequencing and will look carefully at these areas.  The child is on pulse dose steroids, but still having cytopenia.

@ Mikko Seppänen - the B cell numbers were normal (1021 cells/uL)

@Elena Hsieh - do you send your apoptosis assays somewhere or do them in house at Stanford?

@Markus G. Seidel - we check his mitogen proliferation - which was present but low.  We did not directly to CD3 though.  We have not sent sIL2R yet, but will. As far as I know we still haven't really proven that the ptosis is autoimmune, but we haven't found any other cause either.

Best,

Jonathan

On Tue, Jun 23, 2015 at 10:53 AM, Seidel, Markus <markus.seidel at medunigraz.at<mailto:markus.seidel at medunigraz.at>> wrote:
Dear Jonathan,
the most striking lab result for me is the absence of naïve T cells and low absolute T cell count. This is not typical of LRBA deficiency or ALPS. Disregard relative DNT frequency in this situation. In my opinion the course is much more suggestive of CID, potentially a Ca-channelopathy. Did you check CD3/CD28-induced lymphocyte proliferation in vitro? I did not understand whether it was ruled out that the ptosis was autoimmune mediated. What about the IgE concentration, uric acid, sIL2R?
Before eliminating B cells with rituximab I would suggest to try something "reversible" first like steroids, MMF, or even sirolimus while waiting for the results of a PID gene panel. Might consider a bone marrow analysis before that.
Kind regards,
Markus

Markus G. Seidel, M.D., Assoc.Prof.
Consultant| Div. of Pediatric Hematology-Oncology | Dept. of Pediatric and Adolescent Medicine | Medical University Graz | Auenbruggerpl. 34/2 | A-8036 Graz | Austria | T. 0043 316 385 80215| F. 0043 316 385 13717 | Secr. 0043 316 385 13485 |
Head of the Research Unit for Pediatric Hematology and Immunology |  Coordinator of the Working Group for Pediatric Immunology of the Austrian Society of Pediatrics and Adolescent Medicine

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-----Ursprüngliche Nachricht-----
Von: Jonathan Tam [mailto:kiditamae at gmail.com<mailto:kiditamae at gmail.com>]
Gesendet: Freitag, 19. Juni 2015 20:49
An: CIS-PIDD
Betreff: [cis-pidd] 17 mo M with autoimmune cytopenias, hypotonia, 3rd nerve palsy

We here at CHLA have a case of a 17 month old M with autoimmune cytopenias (thrombocytopenia, hemolytic anemia and neutropenia), hypotonia and new 3rd nerve palsy with no focal findings on MRI.

He was increase in double negative T cells (CD3+ CD4-CD8-, TCR a/b 5.1%), but no palpable lymphadenopathy (only LAD on CT) and normal looking nodes on biopsy.

Any input would be appreciated.

Thoughts on Rituxan for for this patient?
Further diagnositic studies?

*Patient Summary*:

Patient is a now 13-month-old boy with a history of developmental delay, hypotonia and febrile seizure who was first seen 12/2014 with
thrombocytopenia that was responsive to IVIG.   He was then hospitalized
4/26-4/28/15 for fever, hypoxemia found to be +metapneumovirus.  He represented on 4/29 to an outside hospital due to persistent fever, possible febrile seizure, and respiratory distress.  At the OSH he was treated for PNA diagnosed on CXR with vancomycin and ceftriaxone x14 days.
He was noted to have thrombocytopenia and received 6 g IVIG on 5/21/15.
Developed new dysconjugate gaze with L lid half closed, evaluated by peds neuro with *MRI brain and orbits reported negative *except for right sphenoid and ethmoid sinus disease.  He was subsequently transferred back to our care.

Repeat MRI/MRA/MRV did not detect any focal lesions in the brain.  CT of the chest abdomen and pelvis did note hilar, mediastinum, retroperitoneum, and groin adenopathy.  Additionally in the chest there was patchy “bilateral lung opacities both upper and lower lungs that may be infectious/inflammatory, but areas of atelectasis/scarring not excluded”.

LN biopsy on a node from the groin did not show any significant abnormalities (no cancer, not consistent with ALPS).  Bone marrow was similarly underwhelming.

Ophtho and neurology calling the new ptosis Miller-Fisher variant Guillain-Barre syndrome.  Neuronal ab screen (Hu) was positive, but western blot was negative.

 FH:

--No consanguinty.  No history of recurrent infections.

--The patient's mother is of Filipino and Mexican descent. The patient's father is of Mexican descent.

--Maternal uncle, paternal uncle, and grandmother with asthma.  Mom with atopic dermatitis.  Paternal uncle with allergic rhinitis.  No family history of thrombocytopenia

SH: Recently moved to LA from New Mexico.  2 dogs at home.  No smokers at home.  Lives with mom, dad, paternal uncle, and paternal grandparents.

Birth history: Born full term via NSVD.  No complications. Birth weight 5 lbs 6 oz.  No NICU stay. Born in New Mexico (no newborn screen)

Developmental history:  Crawls (started at age 12 months), Cruises (started at 15 months), Says mama and dada (started at 10 months), Reaches for objects

*Labs/Imaging*:

*CD3+                                 17.5 %*

*Abs CD3+                        296 Cells/uL*

*CD3+CD4+                       9.0 %*

*Abs CD4+                        152 Cells/uL*

*CD3+CD8+                       6.3 %*

*Abs CD8+                         106 Cells/uL*

*CD3+ CD4-CD8-, TCR a/b    5.1%*

*CD3/4+ CD45RA+           2%*

*CD31+CD45RA+            <1%*

TREC sent to Viracor >950 (normal >801)

*CD25+CD127dim+         4%*

CD3-CD16+CD56+         20.0 %

Abd NK                             338 Cells/uL

CD3+HLA DR+                 5 %

CD19+                                60.3 %

Abs CD19+                       1,021 Cells/uL

IgD-CD27+CD19+           10%

NK function normal

IgG 1,760 mg/dL  (one week after IVIg for thrombocytopenia)

IgM 387 mg/dL
IgA 128 mg/dL

C3            88 mg/dL
C4            22 mg/dL
CH50       238 Unit

12/23/14

12/27/14

3/11/15

4/24/15

5/28/15

WBC

6.22 K/uL

7.19 K/uL

 3.43 K/uL

5.45 K/uL

*3.60 K/uL*

ANC

2150

2000

1960

600

*0*

ALC

2740

3390

1280

3160

1690

RBC

3.52 M/uL

4.10 M/uL

3.20 M/uL

3.53 M/uL

2.64 M/uL

HGB

9.0 g/dL

10.9 g/dL

8.3 g/dL

9.6 g/dL

*7.8 g/dL*

HCT

27.4 %

32.3 %

26.6 %

29.3 %

24.7 %

MCV

77.8 fL

78.8 fL

83.1 fL

83.0 fL

93.6 fL

MCH

25.6 pg

26.6 pg

25.9 pg

27.2 pg

29.5 pg

MCHC

32.8 %

33.7 %

31.2 %

32.8 %

31.6 %

PLT

*13 K/uL*

218 K/uL

*41 K/uL*

107 K/uL

*9 K/uL*

RDW

14.8 %

14.9 %

H 15.6 %

H 16.7 %

H 18.2 %

O+, *DAT+ and warm antibody positive.*

Neuronal (Hu) ab screen positive, but western blot *negative*

HIV, EBV, CMV HSV PCR negative

Free T4     0.72 ng/dL
TSH            1.81 uIU/mL
Thyroid Stim Immunoglobulin    * <89 % baseline
Thyroglobulin ab    * <244 I.U./mL (Negative)
TPO    * <33.4 I.U./mL (Negative)

LKM ab <20
Smooth muscle ab 29 (normal <20)

LN biopsy - Both H\T\E stained sections demonstrate benign lymph nodes with mild follicular hyperplasia and mild paracortical expansion.
Germinal centers are well formed with a crisp mantle zone. The paracortex is composed of a heterogeneous population of small lymphocytes, immunoblasts, plasma cells and with mild vascular proliferation. There is focal sinus histiocytosis (A2)

Abd US:  Nonspecific coarsened echotexture within the liver, which can be seen in infiltrative processes such as steatosis. No discrete liver lesion or evidence of biliary duct dilatation.

MRI/MRA/MRV Brain/Orbits:

--No evidence of acute infarct, hemorrhage, hydrocephalus, or mass.

--No signal abnormality or abnormal enhancement within the orbits.

--Normal course and caliber the visualized portions of the circle of Willis.

--No evidence of occlusion or high-grade stenosis of the major dural venous sinuses.

CT Chest/Abd/Pelvis:

1. Patchy bilateral lung opacities both upper and lower lungs that maybe infectious/inflammatory, but areas of atelectasis/scarring not excluded.
Greatest area is at right base where it seems more consolidated.

2. Right hilar, mediastinum, retroperitoneum, groin adenopathy of which some are partially calcified at the right groin along with

hepatosplenomegaly. Would wonder about granulomatous disease whether TB or cocci since calcified nodes are less typical for histiocytosis

or cat scratch. Otherwise could relate to other rheumatologic/infectious/inflammatory process. Further down the differential would be leukemia/lymphoma (not typical for neuroblastoma).

 Swallow study normal.

---------------------------------------------------

Jonathan Tam, MD

Assistant Professor of Pediatrics

Division of Clinical Immunology & Allergy

Children’s Hospital Los Angeles

4650 Sunset Blvd, MS#75

Los Angeles, CA 90027

jstam at chla.usc.edu<mailto:jstam at chla.usc.edu>

Phone: 323.361.2501<tel:323.361.2501>

Fax: 323.361.1191<tel:323.361.1191>

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