[CIS-PAGID] Infant with lymphopenia, elevated IgG and IgM, bony changes, PCP

[Sergio Rosenzweig]

Hi Tamara,
Some of the characteristics on your patient resemble what Bosco de
Oliveira at NIH described on his KRAS/NRAS mutated patients. I forwarded
him your email and he will be happy to help.
Kind regards,
Sergio


Sergio D. Rosenzweig, MD, PhD
Chief, Infectious Diseases Susceptibility Unit
Laboratory of Host Defenses, NIAID, NIH
10 Center Dr., Bldg. 10, CRC 5W-3888
Bethesda, MD 20892-1456
Phone (301) 451 8971
Fax (301) 451 7901
Cell (240) 361 7617
Pager 102 10678
srosenzweig at niaid.nih.gov
 
Disclaimer: The information in this e-mail and any of its attachments is
confidential and may contain sensitive information. It should not be
used by anyone who is not the original intended recipient. If you have
received this e-mail in error please inform the sender and delete from
your mailbox or any other storage devices. National Institute of Allergy
and Infectious Diseases shall not accept liability for any statements
made that are senders own and not expressly made on behalf of the NIAID
by one of its representatives.

>>> "Tamara Pozos" <Tamara.Pozos at childrensmn.org> 12/01/10 10:03 PM >>>

Hello all - thanks in advance for thinking about this concerning patient
with me.  Below are a short version of the case, my questions, and then
a more detailed summary.

3-month-old Laotian girl with thrombocytopenia, splenomegaly, failure
to thrive, resolved complex rash (panniculitis on two biopsies, mild
eczema), abnormal neuroimaging, bony abnormalities.
Immunologic abnormalities: lymphopenia (~2000, lower after steroids),
elevated IgM at 327, elevated IgG >1000;    IgE normal.  
NO fever, no thrush, no diarrhea.  Soon after hospitalization she
developed PCP, now intubated in the ICU, clinically improving on
steroids and TMP/SMX (and other broad antimicrobials).  HIV negative.

my differential for now:
High concern for BMT-requiring diagnoses: SCID, hyper IgM.  
Eczematous rash was very mild, normal IgE/eos, lymphopenic,  IgG and
IgM high, so not classic for OS.  
There are suggestive data in support of HLH as well (very high sIL2R,
low NK function), but lacking some classic features (like fever or
hemophagocytosis) - and recognizing that severe immune deficiency and
HLH are not mutually exclusive diagnoses.
Given bony and immune abnormalities, RMRP mutation possible (one recent
report of a Thai child with cartilage-hair-hypoplasia).  
Our patient’s rash did not evolve to pustules, and her bony changes,
per radiology, are less consistent with those reported for DIRA.  
JMML still possible per oncology, but less likely.   

Questions:
Is further pursuing hyperIgM or RMRP mutations indicated now?  CD25
deficiency? Other favored diagnoses?
Has anyone seen a similar case with panniculitis as the initial rash? 
Are the features of HLH strong enough to consider etoposide as well as
continuing steroids (she is clinically improving with steroids alone)? 


Any other diagnostic or treatment thoughts from your collective
experience are very welcome.  more details are below.

Thank you very much for your time,

Tamara Pozos, MD PhD
Pediatric Infectious Diseases and Immunology 
Children's Hospitals and Clinics of Minnesota 
St. Paul, MN 
tamara.pozos at childrensmn.org 
651-220-6444 (main office) - 6293 (personal line)

 



Summary of case:
Born at term to a 33-year-old prima gravida.  FHx neg for
immunodeficiency. No cosanguinity known.
1st week of life nodular/plaque rash on her arms and legs – biopsy:
lobular panniculitis
1.5 months of life, splenomegaly first noted, thrombocytopenia (95K),
anemia (7), monocytosis also noted but has not progressed. Positive
alpha thal trait. workup for neonatal lupus and malignancy negative inc
NB and JMML: normal marrow.
Developed mild dry eczematous skin over face, chest and arms, never
became pustules. Improved during hospitalization with moisturizing
alone.
Anemia somewhat improved, Hgb to 10, but platelets dropped to 50K. 
CMV PCR + for 4K copies. Head ultrasound showed mild dilatation of
lateral ventricles ancalcifications or hemorrhage.  Retinas and hearing normal.  Other
infectious diseases testing negative.

She has not been febrile throughout, except one temp 39 on evening of
first marrow biopsy.  To her parents she was acting and developing
normally. 

Sent to our ID clinic to discuss CMV, found to have diffuse, not
dramatic, lymphadenopathy, larger spleen, newly enlarged liver, and
falling off growth curve -   eczematous rash very mild.   Admitted for
evaluation.
Plt 75, AST/ALT normal.  Repeat CMV PCR revealed no viremia, prior to
antivirals, but given a +CMV IgM and immunologic abnormalities
ganciclovir started.
HIV negative (antibodies and DNA and RNA PCRs) 

Immunologic eval:
Elevated IgG 1280 (sub 2-4 normal) and IgM 181.   IgA and IgE normal. 
Eos normal throughout.

ALC low at 2200 (5000-7900)
CD3+ 75%  absolute 1650 
CD3+ a/b+ 70%, g/d+ 6% 
CD3+ HLA-DR+ 23 % (0 – 8)
CD3+CD4+ 45% absolute 990 (1200-4500)
CD3+CD8+ 25%  absolute 550 
DNTs 0.6% abs 13

CD19+ 13%  abs 286
CD16+56+ 11%  abs 1540

Skeletal survey: abnormal flaring and cupping of distal metaphyses of
the bilateral radii, ulnas, femurs, tibia. Distal metaphyses of the left
metatarsals have a somewhat cupped appearance. Relatively symmetric
increased periostitis along the anterior aspect of the bilateral tibias,
which may be physiologic.  No focal geographic lucencies to suggest
Langerhans cell histiocytosis. 

MRI of head revealed expansion of extra-axial spaces, possibly
consistent with cerebral atrophy given microcephaly (Head size was
normal at 2 months, but stopped growing). 

Clinical evolution – Despite lack of fever and lack of
hemophagocytosis on 1st bone marrow biopsy, labs for HLH sent and
suggestive:	
Interleukin-2 Receptor >6500 U/mL & (H)
Lytic Unit, NK Function 2.6 & (L) (Ref. Range 3.2 - 95.8)
Ferritin 230-260-310 (3 values over time)
Fibrinogen 107-70-133
Triglycerides 306-687-651

Eczematous type rash completely resolved (prior to steroids).  
Worsening respiratory status, O2 need – positive PCP on bronchoscopy
– on steroids and TMP/SMX, intubated in the ICU.  
Panniculitis lesions, splenomegaly and thrombocytopenia improving on
steroids.

LP: 12 WBC, 27 RBC, glucose 29, protein 70.  Cytospin showed no
hemophagocytosis. 
Repeat bone marrow was again negative for hemophagocytosis.

Current status: weaning towards extubation.  
After 5 days of Decadron, lymphocyte numbers decreasing.  IgM
increasing further.
IgG 1170 (age 15 weeks. Nl 169-536)   IgM 327 ( 23-85).   A and M still
normal - IgA 24, IgE 6.7. 

ALC 1155
CD3+ 61%,   abs 705
DR+ activated % 16%
CD4+ 32%   abs 370
CD8+ 26%   abs 300

CD19+ 31%  abs 358
CD16+56+ 8%  abs 92

In terms of possible maternal engraftment: decreased CD8+ CD45RA (68%);

majority of Tcells are not RO+ but at upper limits of normal
(CD4+CD45RO 21%, CD8+CD45RO 13%). 

Mitogen and antigen proliferative responses pending, but also sent
after steroids started.





Confidentiality Statement:
This email/fax, including attachments, may include confidential
and/or proprietary information and may be used only by the
person or entity to which it is addressed. If the reader of 
this email/fax is not the intended recipient or his or her 
agent, the reader is hereby notified that any dissemination, 
distribution or copying of this email/fax is prohibited. If you 
have received this email/fax in error, please notify the sender 
by replying to this message and deleting this email or 
destroying this facsimile immediately.