[CIS PIDD] [cis-pidd] Questions about SKIV2L

Tue Jun 2 13:04:35 EDT 2015

Dear all,

Thanks Kathleen for your comments. I am very surprised with the use of immunosuppressants for enteric disease in TTC37 deficiency. I understood the secretory diarrhea was due a defect or mislocation of enterocyte brush-border ion transporter proteins and not to an immune dis regulation disorder.
We follow a TTC37 deficiency patient and inputs regarding immunosuppressive treatment to wean the patient out of total parental nutrition are welcome.

Thanks in advance,

Laia Alsina, MD, PhD

Adjunta de la Secció d'Immunoal.lèrgia; Unitat Funcional d'Immunologia, Hospital Sant Joan de Déu-Hospital Clínic.
Cap d'Estudis i Presidenta de la Comisió Local de Docència de l'Hospital Sant Joan de Déu, Barcelona.

El 29/5/2015, a las 18:37, Sullivan, Kathleen <SULLIVANK at email.chop.edu<mailto:SULLIVANK at email.chop.edu>> escribió:

I can only tell you about our TTC37 THE patient.  I will say that the French group was extremely helpful in thinking through our two cases.

This is what I learned from the French group and was true for our two patients.

The gut never heals completely pathologically but nutrition improves and the immune deficiency improves once absorption gets better.  The susceptibility to infections is not usually persistent.  We did immune suppress (Steroids/FK506) our successful patient (one died) for about the first five years of life and it did improve her absorption.  She came off and now she is short and slightly delayed but otherwise functioning normally.  Her gut is not normal but she has 1-2 stools a day.  Our patient continues to have poor B cells and is on Hizentra.

Kate Sullivan, MD PhD
Wallace Chair
Chief of Allergy Immunology
ARC 1216 CHOP
3615 Civic Center Blvd.
Philadelphia, PA 19104
(p) 215-590-1697
(f) 267-426-0363

On May 29, 2015, at 12:00 PM, Maite de la Morena <Maite.delaMorena at UTSouthwestern.edu<mailto:Maite.delaMorena at UTSouthwestern.edu>> wrote:

Dear colleagues
I would appreciate your insights on a complex patient

We have been following a now 7 month old female with clinical features of Trico-hepatic-enteric syndrome who recently has a confirmed ( Fulgent) molecular diagnosis of a novel defect in SKIV2L ( normal TTC37 sequencing) . SKIV2L mutations: NM_006929.4:c.1452 del p.Val485Cysfs*45 in exon 14 (heterozygous) and NM_006929.4:  c.3541-2A>G p.? ( heterozygous).

Also heterozygous for CF: F508del (c. 1521_1523delCTT; p.Phe508del) + benign variant c.1408A>G, p Met470val
PID panel (196 genes) normal ( Baylor)

Her clinical presentation is as follows:
Born at 37 weeks (normal NBS for SCID; Normal TRECS), h/o IUGR 1.9 kg, requiring admission to NICU for NG tube, hypoglycemia and temperature instability on day 2 of life.
Admitted at age  8weeks  for  FTT (2.1 kg), watery diarrhea, transaminitis, and CMV viremia (2.6 million copies/ml)
Treated with TPN, ganciclovir,  cytogam initially alternating with IVIG, now on q3 weeks IVIG also placed on prophylaxis including pentamidine and nystatin
She is TPN dependent. Intermittent tachypnea , never O2 requirement,  MRI of head and abdomen is normal . No generalized lymphadenopathy, spleen palpable
Social development seems appropriate

Has trichorrexis nodosa
Gut biopsies:
1st 1 week after starting ganciclovir ( age 3 mo)showed:

·         Gastric body: crypt apoptosis, lamina propria edema mild chronic inflammation no CMV

·         Duodenum villous blunting , mild inflammation crypt apoptosis rare CMV + cells no plasma cells

·         Esophagus: + rare CMV + cells

·         Rectosigmoid: Crypt apoptosis, rare CMV +
2nd: Gastric body Age 7 mo (CMV viral load <1000 copies/ml)

·         Esophagus: normal CMV negative-

·         Gastric body: single CMV + cell; oxyntic mucosa with increased apoptosis

·         Duodenum atypical CMV  negative plasmacytic infiltrate ( Kappa restricted), CD20 negative; CD3+ lymphocytic infiltrate with normal distribution of CD4 and CD8

·         Rectrum: mild cyptitis increased crypt apoptosis CMV negative

Liver  biopsy (7 mo) :  periportal lymphoplasmacytic infiltrate CD3+ and plasma cells Kappa restricted similar to gut, some early feature of fibrosis
Skin biopsies ( 6 mo) performed for raised non-pruritic appearing erythematous rash initially over scalp ( ~ 3mo) then progressed to face, antecubital areas and extremities (by 7 mo)

·         Interface dermatitis : mild focal spongiosis, crusting with rare neutrophils presence of eosinophils, histiocyts and lymphocytes at the dermal-epidermal junction no bullae or epidermal/subepidermal blistering: C3 and IgA shows no deposition

Bone marrow: Not consistent with malignancy, however flow suggestd of kappa restricted  final analysis pending

SPEP: Monoclonal detection 2 spike IFE patterns shows IgG kappa and IgA kappa biclonal proteins

Selection of immunology studies are outlined below, please note the highlighted items:
<image003.jpg>

Questions to the group:

1.       Is there someone who is studying these patients? Would be happy to send sample; Does anyone have a SKIV2L KO?

2.       The IgA gammapathy has been described, however I have not seen evidence in the literature of such tissue plasma cell expansion as described in this patient. Has anyone else seen this?

3.       Is the absence of B cells primary or secondary to CMV? I have seen absence of B cells in the setting of Hep A but usually recovers after 6-9 months

4.       Is the reversal of CD4 to CD8 due to CMV or primary to SKIV2L and type 1 interferon driven? Has anyone seen CMV associated with SKIV2L?

5.       SKIV2L is expressed in the majority of human tissues although seems highest in immune compartment. Therefore, while I think I could potentially correct the Immune deficiency with HCT I am concerned that it will not work  and if in fact the “immune deficiency” is controlling somewhat the autoimmune propensity of this syndrome (???), after transplant that protection is lost and would favor an autoimmune phenotype that may be difficult to control. In the literature report of HCT in 1 patient with THES was unsuccessful

6.       I would like to start a trial of steroids. I anticipate rash will improve, wonder about the gut and liver ( literature is variable) . That said, if benefit and considering the interferon signature   would a JAK-inhibitor (IFN signals through JAK-mediated pathway) work? Any experience?

Thanks for your insights sorry for the long email

Maite

Maite de la Morena, MD
Professor of Pediatrics  and Internal Medicine
Division of Allergy and Immunology
University of Texas Southwestern Medical Center in Dallas
5323 Harry HInes Blvd
Dallas, Texas 75390-9063
Phone 214 456-5161
Fax: 214 456-8317
Email: maite.delamorena at utsouthwestern.edu<mailto:maite.delamorena at utsouthwestern.edu>

________________________________

UT Southwestern

Medical Center

The future of medicine, today.

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