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

Mon Sep 29 05:48:21 EDT 2014

  Were mutations in PGM3 considered in these "non-22q11 / DiGeorge like" 
patients?
The phenotype of PGM3 deficiency is probably highly variable and 
includes SCID-like disease with complex skeletal malformations: 
http://www.ncbi.nlm.nih.gov/pubmed/24931394
The mouse model also has renal and testical abnormalities.

Dr Norton: Your patients has large regions of homozygosity, including 
chr 6 (maybe you want to check, whether PGM3 is within this region)

Kind regards, Carsten Speckmann

Dr. med. Carsten Speckmann
Funktionsoberarzt/Consultant Immunologist
Zentrum fuer Kinderheilkunde und Jugendmedizin
Centrum fuer Chronische Immundefizienz - CCI
Universitaet Freiburg
Mathildenstr. 1
79106 Freiburg
Germany

phone: +49 (0)761-270 43010
mail: carsten.speckmann at uniklinik-freiburg.de
web: www.cci.uniklinik-freiburg.de

Am 28.09.14 19:25, schrieb Prescott Atkinson, M.D.:
> 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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