[CIS PIDD] [cis-pidd] 16 y/o F with lung and CNS lesions, lymphopenia, absent NK cells, hypocellular bone marrow and lymphohistocytic infiltrate in lung

Mon Dec 1 17:09:45 EST 2014

Dear Dr. Tam,
My suggestion is CTAL4 deficiency (or - alternatively - LRBA deficiency
with quite late onset thoughŠ)
The diagnosis of CTLA4 deficiency is best/quickest via genetics.
I can offer to do this if you wish, alternatively you may wish to contact
Dr. Gulbu Uzel from the NIH?
Best,
Bodo

****************************************
Univ.-Prof. Dr. med. B. Grimbacher

Scientific-Director
CCI-Center for Chronic Immunodeficiency
UNIVERSITÄTSKLINIKUM FREIBURG
Tel.: 0761 270-77731  Fax: -77744
Engesserstraße 4, 79108 Freiburg
bodo.grimbacher at uniklinik-freiburg.de
www.uniklinik-freiburg.de/cci

and 

Consultant Immunologist
Institute of Immunity & Transplantation
Dept of Immunology
Royal Free Hospital

UNIVERSITY COLLEGE LONDON
Pond Street
London NW3 2QG
b.grimbacher at ucl.ac.uk
www.centreforimmunodeficiency.com

Am 01.12.14 21:00 schrieb "Jonathan Tam" unter <kiditamae at gmail.com>:

>I would like any input possible on a case of a 16 y/o
>girl with 10 month h/o neurologic changes
>with disseminated CNS lesions on MRI, then acute development of
>hypoxemia and extensive nodular and
>ground-glass opacities throughout the lungs progressing to respiratory
>failure,
>found to have lymphopenia, absent NK cells now improved following
>steroids and
>IVIg.   She was on azathioprine from
>6/2014 -10/29/14.  Her lung biopsy shows diffuse
>lymphohistiocytic proliferation and she has hypocellular bone marrow.
> 
>Case:
>16-year-old
>female who initially presented to OSH 12/ 2013 with bilateral lower
>extremity
>spasticity and urinary retention.  She
>was initially diagnosed with ADEM by the OSH and responded well to 5 days
>of IV
>solumedrol with outpatient taper. She had symptomatic recurrence and in
>Feb
>2014 presented her at CHLA with improvement on steroids. By June 2014,
>she was
>started on azathioprine (stopped 10/29/14) the working diagnosis of
>antibody-negative NMO vs. MS.
>Neuro-ophthalmology evaluation July 2014 showed no ocular
>manifestations.   
> 
>She was
>admitted 10/15/14-10/18/14 with worsening bilateral lower extremity
>spasticity
>and urinary retention; repeat brain/spine MRI showed ³Multiple patchy
>scattered foci of T2 hyperintensity throughout the
>cervical and thoracic spinal cord, increased in number and enhancement
>since
>the prior MRI spine of 7/31/2014.
> 
>10/24/14 she
>presented with 3 days of dyspnea, dry cough, and fevers to Tmax 101.  CT
>chest/abdomen/pelvis was significant for
>diffuse nodular and ground-glass opacities in both lungs as well as a
>lesion in
>spleen. Her hypoxemia worsened and eventually needed intubation and
>transfer to
>PICU.  She slowly improved on high dose
>steroids and high dose IVIg.  During her
>PICU stay she developed hypercalcemia (now resolved).  Extensive work-up
>was performed looking for
>malignancy and paraneoplastic process but all negative.  Bone marrow
>biopsy showed hypocellular marrow.
> 
>Labs:
> 
>Absolute
>monocytes have ranged from 100-900 (despite monocytes in discussion with
>NIH
>for GATA2 testing)
> 
>Lymphocyte enumeration (11/10/14) only off azathioprine 12 days
> 
>Low
>absolute lymphocyte count (ALC 560).
>Low
>absolute CD4 T cell count (CD4+ H 68.2 %, 383 Cells/uL).
>Low
>absolute CD8 T cell count (CD8+ 19.9 %, 112 Cells/uL).
>CD45RA
>66%
>CD25+CD127dim/CD4
>4%
>The
>T cell compartment demonstrates an increase in their activation state
>(HLADR+
>CD3+ 11%).
> 
>The absolute value of NK
>called is significantly decreased for age (CD16+ CD56+ 4 Cells/uL).
>The percentage of NK cells
>is low (0.7 %). 
> 
>Low absolute B cell count
>(C19+10.1 %, 57 Cells/uL).
> 
>IgD+
>CD27-Cd19+/CD19 90%
>IgD+
>CD27+Cd19+/CD19 7%
>IgD-CD27+Cd19+/CD19
>2%
> 
>IgG
>787 mg/dL
>IgM
>130 mg/dL
>IgA
>114 mg/dL
>IgE
>119 kU/L
> 
>Tetanus
>ab 0.69 I.U./mL
>H
>Flu ab  1.88 mcg/mL
>Pneumococcal ab 0/13
>protective; <0.3 mcg/mL for all 23 serotypes
> 
>NBT
>(11/10): normal
> 
>-BAL
>path (10/28): Macrophages, lymphocytes, and
>bronchial epithelial cells. Gram stain negative for intracellular
>bacteria. GMS
>stain negative for fungi, including pneumocystis.
>-BAL
>cell count (10/28): 2000 RBC, 258 WBC (86%L)
> 
>Lung Biopsy (prelim
>per Dr. Dishop University of Colorado):   Diffuse lymphohistiocytic
>proliferation, consistent with immunologic dysregulation.
> 
>The abnormal lymphohistiocytic infiltrate appears benign,
>and there is no evidence of lymphoma. The pattern is abnormal in that
>there are
>no reactive lymphoid follicles (germinal centers) and instead is composed
>of
>sheets of predominantly T lymphocytes and histiocytes, spanning the
>interstitium, perivascular regions, and peribronchiolar regions. Absence
>of CD
>56 staining is consistent with the history of absent NK cells in the
>peripheral
>blood , and supports a form of immunodeficiency or immune dysregulation.
> 
>-Chromosomal
>microarray CSF (11/6): normal
>-Paraneoplastic
>ab panel (10/17): negative
> 
>-BM
>bx  path (11/13): Hypocellular bone marrow (30-40%) with trilineage
>hematopoiesis and no
>morphologic or immunophenotypic evidence of a lymphoproliferative
>process. 
> 
>-ANA
>(10/15): undetected
>-dsDNA
>(10/27): negative
>-Cold
>agglutinin (10/27): negative
>-ENA-RNP
>(10/27): negative
>-ENA-Sm
>Ab (10/27): negative
>-Proteinase-3
>ab (C-ANCA) (10/27): negative
>-Myeloperoxidase
>ab (P-ANCA) (10/27): negative
>-FVIII
>assay (11/17): normal
>-ACE
>serum (10/27): normal
>-ACE
>CSF (11/6): negative
>-ESR
>(10/27): 7
>-Ferritin
>(multiple): 264-308
>-IL-6
>(11/5): 6.82 
>-C3
>(11/15): normal
>-C4
>(11/15): normal
>-Total
>complement (10/27): 312
>-Total
>complement send out (11/15): 292
> 
>Infectious labs:
>-Bacterial
>gram stain and cx (CSF): negative
>-Bacterial
>gram stain and cx (BAL): negative
>-Bacterial
>gram stain and cx (lung bx): negative
>-Bacterial
>gram stain and cx (bm bx): negative
>-Mycoplasma
>PCR (BAL): negative
>-ASO
>(10/15): negative
>-Lyme
>EIA (10/17): negative
>-Babesia
>microti IgG and IgM (10/31): negative
> 
>-M.
>tuberculosis PCR (BAL): negative
>-M.
>avium DNA (BAL): negative
>-M.
>intracellularae (BAL): negative
>-Quantgold
>(10/26): negative with good mitogen response
>-PPD
>(10/29): 0mm induration
>-AFB
>stain sputum (10/27, 10/28): negative
>-AFB
>stain (BAL): negative
>-AFB
>stain (lung bx): negative
> 
>-Fungal
>stain and cx (CSF): negative
>-Fungal
>stain and cx (sputum): negative
>-Fungal
>stain and cx (BAL): negative
>-Fungal
>stain and cx (lung bx): negative
>-Fungal
>stain and cx (bm bx): negative
>-Aspergillus
>ag (BAL): negative
>-Galactomannan
>(10/29): negative
>-Cryptococcal
>ag (BAL): negative
>-Cryptococcal
>ag (serum) 10/29: negative
>-PCP
>PCR (BAL): negative
>-Fungitell
>(10/29): negative
>-Cocci
>CF serum (10/27): negative
> 
>-RVP
>1 and 2 (NP): negative
>-RVP
>1 and 2 (BAL): negative
>-HSV
>1&2 PCR NP wash (10/27): negative
>-VZV
>PCR NP wash (10/27): negative
>-CMV
>PCR NP wash (10/27): negative
>-CMV
>PCR (bm bx): negative
>-EBV
>PCR serum (11/13): negative
>-EBV
>PCR (bm bx): negative
>-EBV
>and EBER (lung bx): negative
>-EBV
>IgG, IgM, EBNA (11/5): negative
>-Adenovirus
>PCR(bm bx): negative
>-HHV6
>(bm bx): negative
>-West
>nile IgG IgM (CSF): negative
>-Enterovirus
>PCR (CSF): negative
>-HIV
>ab (11/10): non-reactive
>-HTLV
>I/II Western Blot (10/15): non-reactive
> 
>-Toxoplasma
>IgG serum (11/15): negative
> 
>-Can¹t
>find Toxocara, Brucella, Ehrlichia, Anaplasma, Chlamydia DAA
>-16s
>and 18s/ITS sequencing (bm bx): pending
>-AFB
>cx (bm bx, lung): pending
> 
>Antibiotics
>courses:
>Azithromycin
>(10/24-10/28)
>Ceftriaxone
>(10/24-10/25), then Unasyn (10/26-10/30), then Cefepime (10/30-11/3)
>Fluconazole
>(10/29- 11/4)
>Clarithromycin
>(10/29-11/5) for non-tuberculous mycobacteria
>RIPE:
>(10/29-11/4)
>Vancomycin
>(11/8-11/12)
>Cefepime (11/9
> 11/25)
>Doxy (11/13  )
>Plan for a 14 day course, last day 11/26
>Ambisome (
>11/14  11/25)
> 
>Imaging: 
> 
>-CT
>chest/abd/pel (10/30): 1.
>Diffuse nodular and groundglass opacities throughout the lungs, most
>significant and consolidative within the lower lobes suggestive of diffuse
>fungal, typical, and/or atypical pneumonia. 2. Splenomegaly with large
>hypodense lesion arising from the superior anterior portion. Question of
>adjacent gastroesophageal involvement. Multiple other scattered
>hypodensities
>throughout the splenic parenchyma. Differential considerations include
>lymphoma
>versus disseminated fungal or granulomatous (TB, sarcoid) disease. 3.
>Hilar
>lymphadenopathy. 4. Enlarged gastroepiploic/perisplenic lymph nodes.
>Multiple
>perisplenic subcentimeter lymph nodes. 5. Hepatomegaly.
> 
>-MRI
>Brain w/ and w/o contrast (10/17): Interval
>marked increase in size and number of now innumerable T2 hyperintense,
>enhancing, punctate foci throughout the brain parenchyma, brainstem, and
>throughout the cerebellum, with some of these lesions likely
>leptomeningeal in
>location. Some of these lesions also demonstrate mild diffusion
>restriction.
>Differential considerations again include lymphoma, infectious and
>noninfectious granulomatous disease, as well as metastatic disease from an
>unknown primary malignancy. Demyelinating processes such as multiple
>sclerosis
>are less likely given the distribution of these enhancing foci.
> 
>-MRI
>spec (10/17): MRS is not specific considering the large partial volume of
>surrounding tissue. The nevertheless elevated Cho and Lac may indicate
>significant abnormal Cho and Lac levels within lesions when extrapolated.
> 
>-MRI
>cervical and thoracic spine (10/17): Multiple
>patchy scattered foci of T2 hyperintensity throughout the cervical and
>thoracic
>spinal cord, increased in number and enhancement since the prior MRI
>spine of
>7/31/2014. Additionally, there is more pronounced leptomeningeal
>enhancement
>compared to prior exam, particularly involving the lower thoracic spinal
>cord.
>Given the concurrent findings within the brain, differential
>considerations
>again include lymphoma, leptomeningeal spread of tumor, or granulomatous
>disease. A demyelinating process is considered less likely. Recommend CSF
>sampling.
> 
>-LP
>(11/6): RBC 2, WBC 2(99%L)
>-LP
>(10/15): RBC 1, WBC 2 (100%L)
>-MS
>panel (CSF) (10/15): normal other than oligoclonal bandfs
>-Oligoclonal
>bands (10/15): The patient's CSF contains multiple restriction bands that
>are
>also present in the patient's corresponding serum sample. We are unable to
>define whether these gammaglobulins are of systemic or intracerebral
>origin
> 
>-NMO/AQP-IgG4
>(10/17): negative
>-Fundoscopic
>and anterior chamber exam by ophto (10/29): normal
> 
>-ECHO
>(11/14): nl
>
>
>--------------------------------
>
>Jonathan Tam, MD
>Assistant Professor of
>Pediatrics
>Division of Clinical
>Immunology & Allergy
>Children¹s Hospital Los
>Angeles
>4650 Sunset Blvd, MS#75
>Los Angeles, CA 90027
>jstam at chla.usc.edu
>Phone: 323.361.2501
>Fax: 323.361.1191
>
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