[CIS PIDD] [cis-pidd] work up and therapeutic advise for patient with possible Omenn Syndrome

Sun Sep 28 13:25:54 EDT 2014

Hi Allison:  I neglected to mention that our patient also is negative for the 22q11.2 deletion, as have been all of the five or so complete DiGeorge patients we have had at UAB over the past 20 years.  Other details: Complex congenital anomalies with right aortic arch/left ligamentum (vascular ring), absent left kidney, absent left testis, spinal anomalies, dextrocardia, absent left 4th rib.  He has had a negative CGH array.  As I mentioned, analysis of his TCR alpha-beta gene utilization for signs of clonality showed multiple bands c/w oligoclonality.  After consultation with Dr. Markert, we have been treating our patient with cyclosporine and IVIG.  About the time he had his vascular ring divided on July 11th preparatory to transfer to Duke, his respiratory status deteriorated and he has not been able to be weaned off the ventilator - no clear infectious etiology identified as yet - has been treated with multiple courses of antibacterial and anti fungal antibiotics and bactrim prophylaxis.   He does have enterovirus persistent in his stool.

Over the past 3 weeks in an effort to wean him in the absence of any clear pathogen, he has been treated with IV solumedrol and most recently with a single dose of ATGAM. He had developed severe peripheral edema which resolved with solumedrol but his respiratory status didn't change.  His circulating B cells had disappeared over the past two months and they have rebounded to normal numbers after the ATGAM supporting our suspicion that they were being targeted by autoreactive T cells.  Unfortunately, near ablation of his T cells with ATGAM, while triggering a pretty significant amount of acute inflammation, has not yet resulted in sufficient improvement in his respiratory status for him to be extubated, although he has weaned a little on his FiO2. I am still hopeful that at least part of his respiratory problems are due to his autoreactive T cells and that he will yet improve, perhaps with another dose of ATGAM.

Prescott

T. Prescott Atkinson, MD PhD, Professor and Director

Division of Pediatric Allergy, Asthma & Immunology

University of Alabama at Birmingham

Tel: 205-939-9072

Fax: 205-975-7080

________________________________
From: Jyonouchi, Soma C [JYONOUCHI at email.chop.edu]
Sent: Saturday, September 27, 2014 3:21 PM
To: CIS-PIDD
Subject: Re: [cis-pidd] work up and therapeutic advise for patient with possible Omenn Syndrome

B cell numbers were normal for your patient so less likely to be rag/Artemis.  You could also think about excluding omenn SCID due to gamma chain/jak3 since nk cells were on the low side

Soma

Sent from my iPhone

On Sep 27, 2014, at 3:58 PM, "Prescott Atkinson, M.D." <PAtkinson at peds.uab.edu<mailto:PAtkinson at peds.uab.edu>> wrote:

I agree - we have a similar patient who Louise has agreed to transplant but we have been having a lot of trouble getting him stable enough for transfer.  TCR clonality studies returned showing oligoclonality.

T. Prescott Atkinson, MD PhD, Professor and Director

Division of Pediatric Allergy, Asthma & Immunology

University of Alabama at Birmingham

Tel: 205-939-9072

Fax: 205-975-7080

________________________________
From: Kate Sullivan [sullivak at mail.med.upenn.edu<mailto:sullivak at mail.med.upenn.edu>]
Sent: Saturday, September 27, 2014 2:48 PM
To: CIS-PIDD
Subject: Re: [cis-pidd] work up and therapeutic advise for patient with possible Omenn Syndrome

Sounds like atypical digeorge syndrome.  See Louise markerts paper.

Kate Sullivan
Sent from my iPhone

On Sep 27, 2014, at 3:42 PM, "Norton, Allison" <allison.norton at Vanderbilt.Edu<mailto:allison.norton at Vanderbilt.Edu>> wrote:

Hi, I have a 5 month old male patient with a history of tetralogy of Fallot s/p BT shunt, choledochal cyst s/p excision, unilateral renal agenesis, with multiple chromosome homozygosities( FISH negative 22q11.2) with a phenotype concerning for Omenn's syndrome (diffuse erythrodermic peeling rash, progressive alopecia, splenomegaly, high IgE levels (1664), persistant eosinophilia (4000) and 99% CD4+CD45RO+ memory T cells with no naive T cells on T cell phenotyping).  He was admitted initially for rhinovirus and required ventilatory support about one month ago, then developed daily fevers and noted to have the progressive rash and eosinophilia.  He is rhinovirus free now but quickly outgrowing his shunt and requiring oxygen.  He has normal number of B cells, slight T cell lymphocytosis, normal immunoglobulins except for high IgE, and low response to Con A using 3H-thymidine but normal response to PHA and pokeweed.  He had no response to diptheria, tetanus, or pneumococcal vaccine.  He had essentially normal bone marrow biopsy with trilineage hematopoiesis, no overt dysplasia and negative FISH for PDGFRB.  He was negative for maternal cells in identity study.  Skin biopsy revealed Epidermal acanthosis and mixed dermal inflammation with scattered multinucleated giant cells and evidence of granuloma formation. His initial CXR revealed very little thymus and operative report from cardiac surgery states that there was essentially no thymus present.

Pertinant labs as follows:
CMV/ EBV quantification negative
Vitamin B12: 1268
Tryptase 4.5

IgA 18 IgM 87 IgG 308  IgE 1664

 LYMPHS (ABS)                      <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+LYMPAB>    4.55       x10(3)/mcL (2.50-9.80)
  PAN T CD3 %                       <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD3%>    80* % (58-69)
  CD3 #/CUMM                        <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD3%23>    3640* #/cumm (1700-3600)
  T HELPER CD4 %                    <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD4%>    58* % (30-50)
  T HELPER CD4 #/CUMM               <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD4%23>    2639       #/cumm (1000-2800)
  CD8(CD3+)/CD45 %                  <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD8/3%>    22         % (18-32)
  CD8(CD3+)/CD45 #/CUMM             <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD8/3%23>    1001       #/cumm (800-1500)
  CD16+56 (NK) %                    <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+56%2B16%>    3* % (8-17)
  CD16+56 #/CUMM                    <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+56%2B16%23>    136* #/cumm (200-700)
  PAN B CD19 %                      <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD19%>    16* % (19-31)
  CD19 #/CUMM                       <https://star69.mc.vanderbilt.edu/cgi-bin/sp/graphs.cgi?-i:037262227.vumc:037262227.ohc+-load+037262227+B&Tsubsets+Normal+CD19-%23>    728        #/cumm (500-1500)

FISH IMPRESSION:
No evidence of a deletion within the 22q11.2 Deletion syndrome critical region (see comments).
FISH KARYOTYPE:
nuc ish 22q11.2(HIRAx2),22q13.3(ARSAx2)

No maternal DNA was detected using multiplex fluorescent PCR for 15 independently segregating polymorphic loci and one gender-specific locus, Amelogenin (AMEL). Amplicons of varying lengths were detected by capillary electrophoresis and analyzed.

Microarray result:

Increased regions of homozygosity detected.
Microarray interpretation:
SNP chromosomal microarray analysis (CMA) of this patient's peripheral blood sample demonstrated no copy number changes of known clinical significance.
Several large regions of homozygosity (approximately 3 Mb or larger) were detected, encompassing >2.4% of this patient's genome. This result is not diagnostic of a specific condition, but raises the possibility of a recessive disorder for which the causative gene is located within these regions. We recommend genetic counseling for the parents of this patient. Regions of homozygosity are listed below.
chr1:47218172-57275564
chr2:95341387-98816010
chr3:1424744-6211233
chr3:73398682-80384839
chr3:48456768-52506491
chr3:31092370-34407028
chr5:70671938-79480620
chr6:184718-3466022
chr8:39230311-39386952
chr8:46913605-52048415
chr11:63142527-67465968
chr14:106329183-106717343
chr16:34449594-34765444
chr16:68829020-72276824
chr16:31133409-35220544
chr16:494410-6263633
chr22:38832511-42296703

 T cell phenotyping was sent to Mayo lab and revealed total CD4 lymphocytosis. Practically all the T cells in the blood were in the memory T cell subsets with complete absence of naive CD4+ and CD8+ T cells. Almost all the T cells are the activated phenotype, expressing MHC class II-Hla DR. 99% CD4+CD45RO+ memory T cells with no naive T cells.

Pending studies include Rag 1/2, artemis mutations and chimerism studies. We are also planning to send TRECS, repeat lymphocyte proliferation to Pha using flow via Mayo clinic, TCR vbeta via spectrotyping, CD4 RTE for thymic emigrants, Anti CD3 panel.

We need help with this diagnosis and therapy.  He has phenotypic features of both DiGeorge syndrome (TOF, unilateral renal agenesis, choledochal cyst) and Omenn syndrome(rash, splenomegaly, high IgE, eosinophilia, no naive T cells).  So the question is does he have Omenn syndrome and how could I differentiate that from an atypical DiGeorge?  Would he require a thymus transplant, bone marrow transplant, or neither?

We are concerned about waiting too long before transplanting, if he requires this, because he is rapidly outgrowing his shunt and his eosinophilia continues to rise (today 8000), in addition to the infection risk.

Thank you for your time with this difficult patient.

Allison Norton, MD
Pediatric Allergy and Immunology
Vanderbilt University
Nashville, TN

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