[CIS PIDD] [cis-pidd] PNP deficiency patient resurfaces after 3 years...surprisingly well despite her lab findings

[CIS-PIDD]

Dear Colleagues and Mentors,

A 10 year old female patient with PNP deficiency walked into my immunology clinic a few days ago after a 3 year absence from follow-up.  She had been off all prophylaxis with only a few minor concerns: a little rash on the forehead (a few molluscum), a little rash on the foot (small patch of tinea) and a chronic cough (CXR clear, viral PCR panel negative, sputum culture +MSSA and responded to Levaquin).  She has been in school (no isolation what-so-ever) and overall quite well according to mom.  She had one other antibiotic in the last year for a cough.  The only significant event in the last year was when she was treated for an "asthma exacerbation" with prednisone and she develop esophageal candidiasis with dehydration requiring hospitalization for a few days.  She has not had spontaneous thrush or opportunistic infections.

History: She was diagnosed with CP (limitation in ambulation requiring leg braces, some speech and intellectual delays).  She received all live viral vaccinations without consequence.   She cleared norovirus in less than  2 weeks.
Early in childhood, she had profound anemia and was followed by heme/onc.  They discovered EBV viremia and felt this may be causing her anemia.  She required several transfusions and improved shortly thereafter; she had not required additional transfusions.  She then was evaluated by allergy and immunology in 2010 and noted to have a profound lymphopenia on multiple CBCs.  She also had significant sinopulmonary disease confirmed on CT.  She had a substantial allergy and immunology evaluation that culminated in a diagnosis of purine nucleoside phosphorylase deficiency.  Confirmatory testing with Michael Hershfield's lab at Duke has verified close to complete absence of PNP activity and genetics revealed a novel homozygous missense mutation.  She received a HSCT work-up at our institution and the family ultimately refused transplant.  We recommended a second-opinion at the NIH, however they did not go....and then they didn't come back.

Thankfully I now have her back on Bactrim, Fluconazole, Acyclovir and IVIG prophylaxis.  Her labs are worrisome to me and I think we really need to re-address a transplant conversation.


1)      I typically worry about radiation sensitivity among those with DNA repair defects, however I found a mouse paper demonstrating radiation sensitivity in a PNP knock-out.  She has terrible spirometry, history of 3 pneumonias, chronic "asthma" and needs a pre-transplant work-up. I would like to know if she has bronchiectasis so I can aim for an appropriate IVIG trough and put airway clearance measures in place as needed.  She is currently scheduled for a CT chest as this is more sensitive that MRI for early bronchiectasis, however if anyone thinks it is worth sedating her for an MRI and save her the radiation exposure I can try to make arrangements.  Does anyone have experience with PNP deficiency and radiation sensitivity?

2)      Given how "relatively well" she has been to date the parents are still not interested in bone marrow transplant.  I was wondering if anyone knew of gene therapy trials available for PNP?

3)      There have been some reports as improvement in the neurological symptoms with HSCT.  Do you think that there would be any likelihood in improvement in a 10 year old undergoing transplant or gene therapy?

Thank you for your thoughts.  Her labs are copied below.

Kind regards,

Megan

Megan Morsheimer, MD, MPH
Attending Physician
Division of Allergy & Immunology
A.I. duPont Hospital for Children/Thomas Jefferson University


Component
    Latest Ref Rng

7/20/2016

Absolute CD3+ Cells
    865 - 3618 cells/mcL

126 (L)

Absolute CD19+ Cells
    106 - 1101 cells/mcL

27 (L)

Absolute NK CELLS
    69 - 691 cells/mcL

32 (L)

Absolute CD4+ Cells
    497 - 2267 cells/mcL

105 (L)

Absolute CD8+ Cells
    243 - 1303 cells/mcL

14 (L)

CD4+CD45+Ra:Ro ratio 1:8

Lymphocyte Mitogen Stimulation (Mayo Clinic assay)
Component
    Latest Ref Rng

7/20/2016

Max Prolif of PWM AS % CD45
    >=4.5 %

23.6

Max Prolif of PWM AS %CD3
    >=3.5 %

31.2

Max Prolif of PWM AS % CD19
    >=3.9 %

23.3

Max Prolif of PHA AS %CD45
    >=49.9 %

52.6

Max Prolif of PHA AS % CD3
    >=58.5 %

65.6

Interpretation: "Normal lymphocyte proliferative responses to PHA and PWM."

Per Dr. Hershfield "The patient has no detectable PNP activity"

Genetics: Homozygous c.655A>G (pM219V) - this was a novel mutation in the PNP gene as of 2013

Component
    Latest Ref Rng

7/20/2016

IgG
    698 - 1560 mg/dL

887

IgA
    51 - 220 mg/dL

64

IgM
    53 - 194 mg/dL

70

Unprotective Tetanus, diphtheria, pneumococus titres

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