[PAGID] lymphopenic infant

[Jack Bleesing]

Hi Jan:

I would tentatively classify this as a patient with a hybrid bone marrow failure (BMF) phenotype and perhaps a syndrome of premature chromatid separation (SPC). My gut feeling is - as we see in other patients wit BMF - that immunodeficiency features are not neatly defined or easily connected in a simplistic fashion, using standard immunologic testing. We looked at a cohort of Fanconi Anemia patients, who show select (but consistent) immunologic abnormalities (that may or may not be relevant for their clinical phenotype - e.g. cancer prone). We see similar features in patients with ribosome biogenesis disorders, such as Shwachman Diamond Syndrome (SDS) and Diamond-Blackfan Anemia (DBA). Another typical feature is that for every clearly defined (including genotype) SDS or DBA patient, we see many more with atypical presentations, including  clinical manifestations of  immunodeficiency that lack the typical immunologic findings, such as abnormal mitogen responses in a case of PCP.

I would consider more detailed immunophenotyping of T- and B-cells, especially related to thymic origin and CD45RA/RO expression. I would take a good look at the bone marrow (maybe at more than one occasion - with concomitant peripheral blood neutropenia) from the perspective of BMF scenarios. Consider FA (excluded by DEB testing), RIDDLE syndrome, NBS, seckel syndrome, etc. Consider telomere length measurement to determine the possibility of a DKC-like disorder.

As she is still young, more pieces of the puzzle may become apparent in the near future.

Regards

JB

PS: great address (Level 5, Starship)!

---------------------------------------------------------------------------
Jack J.H. Bleesing, M.D., Ph.D.
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Avenue, MLC 7015
Cincinnati, OH 45229
513-636-4266 (phone)
513-636-3549 (fax)
Jack.Bleesing at CCHMC.org
http://www.cincinnatichildrens.org/immunodeficiencies/



>>> "Jan Sinclair" <JanS at adhb.govt.nz> 4/30/2008 12:01:20 AM >>>

Hi all

I would appreciate any ideas about a patient:

5 month old infant born in New Zealand. She presented to us at 4 months
with failure to thrive, feeding difficulties and mild respiratory signs
and symptoms, with PCP on BAL. Mild thrush. No nodes palpable and no
hepatosplenomegaly.

*	Indian parents (non consanguineous, and from different regions
India).
*	Ex 28 week gestation - uneventful neonatal course except for
significant lymphopenia at birth (0.4 x 109) which has persisted since
(0.4-0.7). 
*	Mild neutropenia in first few weeks which had resolved.
(Recurred this week with neutrophils 0.5)

Only other clinical finding is marked microcephaly (35.6cm; 4 cm<3%).
Not dysmorphic. Eye exam, hearing, head ultrasound all normal and
developmentally appropriate except for marked oral aversion needing ng
feeds.

Other investigations:
*	IgG 0.8g/l, IgA 0.4g/l, IgM 7g/l (was increased to 12g/l now
back down to 7 - not monoclonal).
*	Biochemistry normal, uric acid normal, ADA awaited.
*	T and B cell numbers markedly reduced (CD3 50%, 295, CD4:CD8
3.1, CD19 20%, 118). NK numbers normal (25%, 148). 
*	Proliferation to PHA and CD3 normal (CPM equal to control,
stimulation index ~80).
*	No evidence T cell clonality looking at Vb by flow.
*	No evidence maternal engraftment (clinically or chimerism).
*	Karyotype normal XX.
*	Wondered about Cernunnos but she is not radiosensitive with
radiation studies reported as "no increased breakage but a subpopulation
of lymphocytes with an odd appearance (condensed in appearance -
premature chromatid separation but no aneuploidy in that
subpopulation)".  

Clinically she is now well having finished treatment for PCP, on
prophylaxis and IVIG replacement. Any thoughts or comments about
possible underlying diagnosis / other investigations to pursue welcome.

With thanks, Jan


Dr Jan Sinclair
Paediatric Allergy and Clinical Immunology
Level 5, Starship
Private Bag 92024
Auckland, New Zealand
 
Phone: +649 307 4949 #6429
Fax: +649 307 8977
Mob: 021 365 445
E mail: JanS at adhb.govt.nz