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

Tue Jan 12 00:03:26 EST 2016

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.

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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.
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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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