[CIS PIDD] [cis-pidd] work up and therapeutic advise for patient with possible Omenn Syndrome
Dylan Mordaunt
d.a.mordaunt at gmail.com
Mon Sep 29 22:20:30 EDT 2014
Dear Carsten and Allison,
PGM3 is not within the regions of homozygosity (
http://www.ccs.miami.edu/cgi-bin/ROH/ROH_analysis_tool.cgi). Unfortunately
it looks like transferrin isoforms are normal in PGM3-CDG, but
abnormalities can be detected on serum N-glycan analysis- the only clinical
lab I am aware of that offers this in the US is the Mayo Clinic. Without a
history of consanguinity, homozygosity mapping doesn't tend to be very
useful. If there is a history of consanguinity, it might be worth asking
the array lab to re-send the coordinates with the >3Mb limit removed and
enter them into the linked website.
In the absence of a deletion on microarray, a multigene panel and exon
array would probably be the quickest way to verify your diagnosis. Many of
these labs will expedite testing in your circumstances-
https://www.nextgxdx.com/apps/search/#/compare?tC=%5B%2255e70ae2341945748a1ea2f100229461%22%5D
http://www.ncbi.nlm.nih.gov/gtr/tests/501119/
Kind regards,
Dylan
Clinical and Metabolic Genetics Fellow
South Australian Clinical Genetics Service
Dylan Mordaunt
Mobile: + 61 468 516 283
Email: d.a.mordaunt at gmail.com
On 29 September 2014 19:18, Dr. Carsten Speckmann <
carsten.speckmann at uniklinik-freiburg.de> wrote:
> 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> 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]
> *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> 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 % 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 % 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 % 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) % 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 % 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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>
On 29 September 2014 19:18, Dr. Carsten Speckmann <
carsten.speckmann at uniklinik-freiburg.de> wrote:
> 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> 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]
> *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> 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 % 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 % 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 % 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) % 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 % 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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