[CIS PIDD] [cis-pidd] Help with 3 mo boy with ?XLA, cytopenias

Wed Jan 13 08:01:11 EST 2016

Dear Federico,

Although PJP was not proven in your case, but only suspected, it is
important to mention that it is not uncommon in XLA, and is most often
seen at onset of disease or whenever there is concurrent neutropenia. I
did not see an ANC in your summary, hence I cannot comment more on this.
However, the fact that BTK MFI was reduced may have important
implications. Do you know whether the mother is heterozygous for the same
variant?
If so, I would perform flow for BTK in the mother and check expression of
BTK in B cells and in monocytes. XLA carriers have a random X-inactivation
in monocytes, hence it might be possible to see two populations of
BTK-expresing cells (one dimmer, one brighter). I should say that the
fold-difference of BTK expression may be too subtle to demonstrate this.
In B cells, there is non random X-inactivation (although again, one could
speculate that the selective advantage for cells expressing the wild-type
allele may not be as pronounced if the mutant allele is hylomorphic). One
could also use molecular tools (analysis of methylation status at the
HUMARA locus) but this would require to separate B cells and monocytes
from the mother. All what I want to say is that the hypothesis of a leaky
XLA should not be excluded. Lastly, B cells in patients with XLA tend to
be very bright for IgM. Did you see the same?

Best regards

Gigi

Luigi D. Notarangelo, MD
Prince Turki Bin Abdul-AzizAl-Saud Professor of Pediatrics
Harvard Medical School
Division of Immunology, Boston Children's Hospital
Karp Research Building, Room 10217
1, Blackfan Circle
Boston, MA 02115
USA

tel: (617)-919-2277
FAX: (617)-730-0709

On 1/13/16, 7:48 AM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> wrote:

>Thanks Mikko, 
>
>I felt like you (also adult physician) not the right person to comment
>and had otherwise exactly the same thoughts.
>CARD11 was on my mind as well, all of the patients I know of presented
>with PjP; agamma is unusual most patients had decreasing amounts of
>immunoglobulins but I would not exclude this and may be this would
>This is easy to test: Phenotype of B cells mostly transitional and no
>response to PMA 
>
>Greetings Klaus
>
>Prof. Dr. med. Klaus Warnatz
>
>MEDICAL CENTER - UNIVERSITY OF FREIBURG
>Center for Chronic Immunodeficiency - CCI
>Department of Rheumatology and Clinical Immunology
>
>Breisacher Str. 117, 79106 Freiburg, Germany
>Tel. +49 761 270 77640 / FAX -71000 / Pager 12-7100
>klaus.warnatz at uniklinik-freiburg.de
>
>www.uniklinik-freiburg.de/cci
>
>
>-----Ursprüngliche Nachricht-----
>Von: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
>Gesendet: Mittwoch, 13. Januar 2016 12:21
>An: CIS-PIDD
>Cc: Casanova Jean-Laurent
>Betreff: Re: [cis-pidd] Help with 3 mo boy with ?XLA, cytopenias
>
>Dear Federico,
>
>Since no one else replies (though I am an adult specialist, so filter
>accordingly!), just briefly:
>
>Possible PJP pneumonitis and Pseudomonas together suggest a T cell
>deficiency, not a pure B cell PIDD like XLA. Just like you seemingly have
>thought. Some susceptibility may partly however be explained by
>prematurity (but only 4 weeks and counts TRECs normal)???
>Thus, a genetic variant of unknown significance plus noncompatible
>infection profile does make one think of other alternatives as well?
>
>You thus might need to consider combined PIDDs without T cell penia but
>with nonfunctional T cells. Gigi Notarangelo has written a recent
>excellent review on these (Adv Immunol 2014). Agamma makes this case
>interesting. It may suggest - of known PIDs - CARD11???
>
>Jean-Laurent Casanova's group might be interested to assess this patient
>further?
>
>And - I also would definitely try to use solely PCR, ag testing and
>cultures for infection diagnoses.
>
>Hope this helps,
>
>Mikko
>
>
>Oyl Mikko Seppänen
>Harvinaissairauksien yksikkö (HAKE)
>
>Head, Rare Disease Center,
>Helsinki University Hospital (HUH)
>FINLAND
>
>phone +358 947180201
>GSM +358 50 4279606
>fax +358 9 47174703
>
>> CIS-PIDD <cis-pidd at lists.clinimmsoc.org> kirjoitti 12.1.2016 kello
>>16.50:
>> 
>> 
>> 
>> Dr. Laham:
>> 
>> I leave others to comment more authoritatively if XLA is a good enough
>> diagnosis, or if more digging is needed.  (It smells enough like XLA
>> to me to have the infant on IVIG)
>> 
>> As far as the brain findings, I would suggest that Toxoplasma should be
>>ruled out by additional diagnostics.  If the infant is indeed
>>B-deficient, negative serology (unless you have one from the mother) is
>>insufficient to rule out toxoplasmosis.  I believe the Univ. of
>>Washington has a Toxoplasma gondii PCR available for CSF.   The same
>>might be said for rubella -- this should be a consideration if there is
>>a cluster of rubella cases in your community.  If mom's RPR is negative,
>>I'm probably okay in not going for a Treponema PCR (Quest Dx has one in
>>case you would).
>> 
>> If the mother has travel to the Southern Hemisphere during or shortly
>>before pregnancy, the recent zikavirus epidemic should be a
>>consideration.  That said, this would be a different picture
>>(microcephaly) ... though who knows how this infection would present if
>>the patient has an underlying B cell defect?
>> 
>> If the patient's head circumference stabilized when he was on IV
>>Bactrim, then shot up again when you dropped it, or changed to PO, then
>>maybe Toxo goes up the list (?).
>> 
>> Good luck.
>> 
>> -  K
>> 
>> Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
>> Instructor of Pediatrics (Pediatric Infectious Diseases) University of
>> Chicago - Comer Children's Hospital
>> 5841 S Maryland Ave, MC 6054, Chicago IL 60637
>> Pager:  773-702-6800   x1744
>> Fax:  773-702-1196
>> Lab phone (Bubeck Wardenburg laboratory): 773-834-6976
>> 
>> 
>> ________________________________________
>> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
>> Sent: Monday, January 11, 2016 11:03 PM
>> To: CIS-PIDD
>> Subject: [cis-pidd] Help with 3 mo boy with ?XLA, cytopenias
>> 
>> 3 month old infant male 36wk premature presenting to an outside
>>hospital with irritability and poor feeding, difficulty breathing x2days
>>and vomiting for 7 days. In the ED, O2 sats were 40-50%, WBC 30K, Hb
>>10.8 and Plt 156.  Intubated, CXR showed diffuse interstitial
>>infiltrates. Then found to have IgG <<300, and with these findings SCID
>>or XLA were suspected:
>> 
>> - Pneumonia due to methicillin-susceptible S.aureus and Pseudomonas
>>aeruginosa.
>> - PJP pneumonitis (PCR positive on trach aspirate)
>> - No BAL could be performed, resp viral PCR x2 neg, EBV/CMV PCRs neg
>> 
>> Treated with Cefepime, IV Bactrim, micafungin (later discontinued). The
>>brain US on admission also showed "moderate ventriculomegaly,
>>periventricular calcifications, leticulostriate vasculopathy which could
>>be secondary to TORCH".
>> 
>> Evaluation so far:
>> 
>> Normal newborn screen, normal TREC
>> Negative CMV urine culture and CMV blood and trach aspirate PCR; CMV
>>IgG positive.
>> AFB respiratory stain/cultures negative Negative toxo, herpes and
>> rubella serologies; negative Parvo PCR
>> 
>> 12/10 IgG <300, IgG1 56, IgG2 <20, IgG3 10, IgG4 <1 Received IVIG x2
>> 
>> 12/16 Ferritin 361, Triglycerides 110, Fibrinogen 619
>> 
>> 
>> 
>> Date     12/11/15                        12/14/15
>> 12/23/15
>> ALC      4000                 3700                 3860
>> CD3      1969 (94%)       1806 (75%)       3418 (96%)
>> CD4      1513 (72%)       1163 (49%)       2330 (70%)
>> CD8      457 (21%)         603 (25%)         884 (26%)
>> B          97 (4.7%)          584 (24%)         92 (2.5%)
>> NK        12 (0.6%)          8 (0.3%)            44 (1.2%)
>> 
>> 
>> 
>> 12/15 Normal Lymphocyte proliferation to mitogens
>> 12/14 TREC 15,014 (normal)
>> 
>> - T-cell phenotype showed predominant naive CD4 and CD8 cells, few
>>memory cells, appeared normal for age.
>> - Karyotype: normal male 46XY
>> 
>> 
>> HIV PCR negative
>> 
>> 12/22 Lymphocyte B cell subsets
>> 
>>            Overall very reduced absolute cell counts (total B: 72
>>cells, 4% of total lymphocytes)
>>            CD19+ 21.3 (1.1%) low
>>            CD20+ 31 (1.6%) low
>>            CD27+ 2.4 (1.6%) low
>>            Overall preserved percentages with markedly reduced total
>>cells.
>> 
>> ------------------------
>> B-cell BTK flow and genotype came back today:
>> Flow:  CD20+ were only 1%.  BTK protein was reduced in B cells (MFI =
>> 4.60) and monocytes (1.93) compared to controls (6.56 and 4.26) A
>>variant of unknown significance was detected in the BTK gene: Intron 2,
>>c.141+11C>T. According to the report this variant has been reported in
>>one male with XLA compatible phenotype, but no functional analyses were
>>performed (Human Mutat 21(4):451).  The report mentions that in-silico
>>analysis predicts that this is unlikely to affect RNA splicing.
>> ------------------------
>> 
>> 
>> BONE MARROW BIOPSY:
>> CELLULAR (80-90%) BONE MARROW WITH MATURING TRILINEAGE HEMATOPOIESIS,
>> ADEQUATE MEGAKARYOCYTES, AND SLIGHT INCREASE IN RETICULIN FIBROSIS. No
>> organisms
>> 
>> FLOW CYTOMETRY OF THE BONE MARROW:
>> CD34+ MYELOBLASTS ARE NOT INCREASED, <1% OF TOTAL NUCLEATED CELLS. NO
>>MONOCLONAL B-CELLS OR IMMUNOPHENOTYPICALLY ABNORMAL T-CELLS ARE
>>DETECTED. THE CD4:CD8 RATIO IS APPROXIMATELY 2:1.
>> 
>> Comments:
>> There is extremely mild increase in reticulin fibrosis (MF1 of 3). This
>>is a nonspecific finding that may be seen in association with systemic
>>infections, collagen vascular disorders, autoimmune disorders, metabolic
>>disorders, following chemotherapy, radiation exposure, or a toxic
>>insult, and vitamin D deficiency.
>> ------------------------
>> 
>> The baby is clinically well, pneumonia resolved. During the therapy
>>with cefepime/Bactrim, developed progressive neutropenia attributed to
>>the antibiotics, which is slowly correcting (had a week of neupogen),
>>but more importantly, a PERSISTENT, SEVERE THROMBOCYTOPENIA which has
>>been in the 20-60K range.  Developed progressive hydrocephalus with
>>dramatic ventriculomegaly, periventricular calcifications, no retinitis.
>>We have sent a urine CMV PCR (in addition to the prior workup) which is
>>pending. Our recent considerations (until receiving the BTK today) were
>>XLA or perhaps HyperIgM. We asked Hematology and they do not think he
>>has reticular dysgenesis and other marrow defects. SCID appears ruled
>>out too.
>> 
>> My questions:
>> 
>> 1. With this presentation, lab findings and especially the BTK results,
>>would you pursue any further diagnosis or would you settle with XLA?
>> 2. Since autoimmune anemia and thrombocytopenia have been described
>>with XLA, for how long one should expect it? Of note, a second dose of
>>IVIG did not increase the platelet count.
>> 3. Any suggestions regarding the etiology of these cerebral
>>calcifications? CMV (and other TORCHes) appears to be reasonably
>>excluded so far.
>> 
>> Sorry for the long email... and thanks in advance!
>> 
>> Cheers,
>> 
>> Federico Laham, MD, MSc
>> 
>> Pediatric Infectious Diseases,
>> Arnold Palmer Hospital for Children
>> Florida Hospital for Children
>> Orlando, Florida
>> 
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