[CIS PIDD] [cis-pidd] Patient with severe neutropenia and multiple complications

[Nacho Gonzalez]

Dear Abraham,

Very interesting. Three concerns:
1. SDS with development of MDS?
2. Fanconi anemia in mosaic (I am aware of MMC and DEB in this
patient). To the classic Auerbach´s test, adding the chromosomic
fragility index (Castella M, J Med Gen 2011) may identify mosaic FA
(i.e. DEB+ at 96h but normal at 72h)

3. Do we have T,B,NK subsets? Monocytopenia? GATA-2?


Regards

Luis Ignacio Gonzalez-Granado

Immunodeficiencies and Pediatric Infectious Diseases

Hematology & Oncology

Hospital 12 octubre

Madrid. Spain


El 24/01/2014 01:01, "Abraham, Roshini S., Ph.D."
<Abraham.Roshini at mayo.edu> escribió:

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> Colleagues,

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> I am posting this case on behalf of my colleague, Dr. Mrinal Patnaik, Division of Hematology, Mayo Clinic, Rochester.  He would be most grateful to receive feedback and suggestions from the group on this very puzzling and complex patient.  Please see details below.

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>

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> Patient is a 28-year-old female with a long-standing history of neutropenia with recurrent skin and soft tissue infections.  The outline of her history is as follows.

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> 1. The patient presented in 2002 with abdominal pain and hemoptysis.  A CBC revealed a hemoglobin of 11.4, MCV 91, WBC 3.4, 46% neutrophils, 13% plasma cells, and a platelet count of 137,000.  A CT scan revealed mild diffuse thoracic and abdominal lymphadenopathy.  A peripheral smear demonstrated a normochromic/normocytic anemia, mild leukopenia, lymphoplasmacytic response with reactive neutrophils.

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> 2. A detailed evaluation revealed evidence for acute EBV infection (IgM and IgG for the viral capsid antigen were positive).  Notably, the LDH was elevated and serologies for HIV and CMV were negative.

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> 3. Because of persistent neutropenia, the patient in October 2002 underwent a bone marrow biopsy.  This was mildly hypocellular (65%) with mild erythroid hypoplasia and mild megakaryocytic hyperplasia.  The megakaryocytes were small, hyposegmented with focal clustering.  There was an increase in the iron stores.  There was moderate leukopenia with a left shift.  Neutrophils had toxic granules and Dohle bodies.  The cytogenetics were 46,XX.

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> 4. The patient since then has gone on to develop recurrent skin and soft tissue infections.  She has had recurrent episodes of hidradenitis suppurativa, skin abscesses, folliculitis, otitis media, and recurrent throat infections.  In 2007, she was once again seen by hematology. Serologies for HIV, hepatitis B, and hepatitis C were negative.  An antigranulocyte antibody panel was negative.  The rheumatoid factor was elevated with a negative CCP.  A quantitative assessment for T-cell immunity revealed a moderate decrease in the CD4 helper T-cell count.

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> 5. In September 2009, she was initiated on therapy with Neulasta given every three weeks.  She had a modest response but continued to suffer from recurrent skin and soft tissue infections.  In October 2010, the dose of Neulasta was escalated to a two-week schedule.  In spite of this, she continues to have otitis media and abscesses.

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> 6.  On March 16, 2011, the patient had a bone marrow biopsy done here.  The bone marrow was hypercellular (100%) with pan hyperplasia and left-shifted granulopoiesis.  There was minimal atypia in all three cell lines.  There were no diagnostic features for MDS.  No evidence for blasts seen.  A flow cytometry for PNH was negative.  The cytogenetics were normal 46, XX, and a mitomycin-C stress test for Fanconi-like abnormalities was negative.

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> 7.  An MDS FISH panel of the bone marrow picked up -3q21 (RPN1 abnormality) in 99% of analyzed nuclei.  A phytohemagglutinin-stimulated karyotyping of peripheral blood lymphocytes also demonstrated the -3q21 (RPN1 deletion) in 99% of analyzed nuclei, indicating that this was indeed a constitutional (germ line) abnormality.

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> 8.  aCGH (array complete genomic hybridization) of the peripheral blood DNA revealed an interstitial deletion of a 96 oligonucleotide probe length at 3q21.3, spanning approximately 2.1 megabases.  This deleted region contains approximately 21 genes of which RPN1 is a prominent oncogene.

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> 9.  Patient’s mother was also tested by aCGH and was found to be negative for the 3q21 (RPN1) deletion.

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> 10.  A DEB assay for Fanconi anemia was negative.

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> 11.  In March 2013, she presented with worsening cachexia, anorexia, night sweats, hepatosplenomegaly, and fevers.  A bone marrow biopsy on March 8, 2013, demonstrated a cellularity of 90% with moderate granulocytic hyperplasia and megakaryocytic hyperplasia.  There was very subtle atypia noted.  The cytogenetics were 46,XX (20).

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> The most recent visit to the clinic showed a dramatic 90-pound unintentional weight loss over the last 12 months.  She has had a reasonable appetite but is not able to keep much food down and develops early postprandial nausea and vomiting.  In spite of having calories, she continues to have unintentional weight loss.  She complains of extreme fatigue and is currently on disability, living with her mother.  She has developed nondrenching night sweats and intermittent fevers up to 102 degrees Fahrenheit.  She was hospitalized four times in 2013 at HCMC with recurrent pneumonia.  She is currently amenorrheic but has been receiving the Depo-Provera shot q. three months.

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> PMH

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> 1. Severe case of varicella zoster as a child.

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> 2. Recurrent hidradenitis suppurativa, status post bilateral axillary skin grafting in 2009.

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> 3. Pancreatitis without exocrine pancreatic insufficiency in 2002.

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> 4. Recurrent skin abscesses.

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> 5. Recurrent bronchitis, upper respiratory tract infections.

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> 6. Condyloma acuminata, status post laser therapy in December 2005.

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> 7. Status post cholecystectomy in 2003.

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> 8.  Status post LEEP procedure for an HPV-associated cervical dysplasia on May 25, 2011.

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> 9.  Four episodes of pneumonia in 2013.

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> Roshini Abraham

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> Mayo Clinic

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> Rochester, MN

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