[CIS PIDD] [cis-pidd] 14 yo boy with myelodysplasia needing heart transplant.

[Yeşim Yılmaz Demirdağ]

Dear all,
I would like to ask your opinion about a young boy with myelodysplasia
since 2.5 yrs of age who developed congestive heart failure and is in need
of a heart transplant. The question was about lymphopenia and recurrent
infections and how this would impact immunosuppression if he gets the
cardiac transplant. Below is the summary of his findings:

14 yo boy with:

Persistent cytopenias (thrombocytopenia at 20-40K, mild anemia) with
myelodysplastic marrow since 2.5 yrs of age:

-       BM always consistent with normo or hypercellular, increased
megakaryocytes including hypolobated forms.

-       He was on steroids from 12/2003 to 4/2007 with no obvious benefit

-       WES – Heterozygous FANCM mutation (inherited from father) and 2
mutations in FANCA (inherited from mother). None of the mutations have been
described in the literature (variant of unknown significance). (Targeted
exome sequencing performed on the proband’s and parental blood samples
identified three missense heterozygous variants of uncertain clinical
significance (VOUS) in autosomal recessive disease: 1). FANCM (c.5708A >G,
p.E1903G) (Chr14, 45665742), 2). FANCA (c.377C >T; p.T126M) (Chr16,
89877386) and 3). FANCA (c.1928C >G; p.P643R) (Chr16, 89839765). In-silico
analysis predictions on amino acid changes that effects protein function
were consistent for FANCM (c.3852C >A) and FANCA (c.1928C >G) as
deleterious and damaging. Whereas predictions for FANCA (c.377C >T) were
predicted as neutral & tolerated by Provean and SIFT.)

-       Fanconi (DEB stimulated chromosomal breakage) negative x 3

-       Telomere length study was normal

-       PNH (CD59)- negative

-       Soluble vitamins and trypsinogen to R/O Schwachman-Diamond – normal

-       AFP to R/O ataxia-telangiectasia – normal

-       Skeletal survey – normal



INFECTIONS:

-       Fungemia (Candida) while on steroids (11/2004)

-       Recurrent perforated otitis media in 2006 during chronic steroid
treatment

-       Skin abscess (1/2011)- grew MSSA

-       MSSA bacteremia in 2013

-       12/2014: MRSA sepsis

-       On co-trimoxazole prophylaxis - no infections since Dec 2014.



OTHER:

-       Failure to thrive

-       Developmental delay – no dysmorphism, no café au lait

-       Mitral valve insufficiency diagnosed at 3 yrs of age –has been on
Enalapril and Digoxin

-       Vitreous hemorrhage in 2009, s/p L eye evacuation

-       1 to 6/2015: Subsequent weight loss, increased exercise intolerance
and fatigue due to progressively worsening mitral regurg.




Immunology work-up (2015):

            Immunoglobulins G normal (921) or elevated (up to 1500), IgA
slightly low (26), M low (20)

            Protective titers to pneumococcus, tetanus, Hib, MMRV, HepB

            Low CD3 (355), CD4 (150), CD8 (171), B-cell: low (25), NK cell;
normal (188)

            Mitogen and antigen proliferation: pending



Family History: negative for any known blood or genetic disorders. Parents
are not consaguinous. Mother is Puerto-Rican, father is half African
American, half Puerto-Rican.




In addition to team's question regarding lymphopenia and concerns about
immunosuppression, I wanted to ask your opinion about FANCA and FANCM
mutations. Could this case still be a Fanconi anemia case? Does negative
DEB stimulation always rule out Fanconi? Is there any other test you would
recommend?


Thanks for reading and your input,


Yesim


Yesim Yilmaz Demirdag, MD

Columbia University Medical Center

phone: (212) 305 2300

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