[CIS PIDD] [cis-pidd] XLP on screening

Thu Oct 19 09:18:58 EDT 2017

Dear All:

Thank you for your comments thus far; they have been insightful and stimulating.

As suggested by all, protein detection will be performed (this is being organized as a send-out to a lab in the US).
Presuming that the genetics analysis is correct, as Mikko reiterated, this is predicted to be a hemizygous stop-gain mutation in exon 2, and thus a profoundly truncated protein. Nonetheless, I will also recommend them to assess protein function.
We will pursue the fecal studies and further phenotypic evaluation of the pedigree (I think this latter has already been done, but will ensure this, focusing on the broad presentations of XIAP deficiency).

However, should the obvious occur (i.e. no resulting functional protein), I am intrigued by Dr. Albert's assessment of risk. When you say that he is "not very likely to have a fatal first disease manifestation", would you be able to send me any numbers/references on that risk? This is going to be important for discussions with family regarding management options (i.e. watch and wait vs. HSCT).
As a corollary, Mikko: on a brief search, I could not find any reports on a genotype-phenotype, or more relevantly, cellular phenotype-clinical phenotype correlation of XIAP mutations. The reports I did find are the typical ones, of mutation identification in the context of active or recently-treated HLH, rather than as in this case, i.e. incidental finding.

I think this also highlights the need that, for PIDs with broad manifestations, biomarkers (either genomics or proteomic, or other) are needed, to provide more precise care.

Thanks again. Please continue to send your inputs, as I am collating them for the referring team.

Best,
Don

Donald C. Vinh, MD, FRCP(C)
Director, Infectious Disease Susceptibility Program
Lilian Wilkins Associate Professor, FRQS Clinician-Scientist
Dept of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology)
Dept of Medical Microbiology; Dept of Human Genetics

McGill University Health Centre - Research Institute
1001 Decarie Blvd; Block E; Rm EM3-3230 (Mail Drop: EM3-3211)
Montreal, Quebec,  Canada H4A 3J1

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From: cis-pidd at lyris.dundee.net <cis-pidd at lyris.dundee.net> on behalf of CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
Sent: October 19, 2017 8:20 AM
To: CIS-PIDD
Subject: AW: [cis-pidd] XLP on screening

This really is an interesting one. I would definitely also do the XIAP expression (which can be normal in some affected individuals) plus functional testing. And I would test calprotectin in his stool to screen for gut inflammation, which may still be subclinical.

And I would screen the male relatives on the maternal side. There may be other asymptomatic or not quite so asymptomatic individuals. There may be uncles or cousins with “Crohns disease” or “severe acne” or unexplained splenomegaly or funny autoimmunity…

As for HSCT, I am close to Elies position. But in a three year old, I would also feel fine to maybe wait a little. He is not very likely to have a fatal first disease manifestation especially if he is seen by a doctor every time he develops a fever, so if he develops gut disease, he’d still be a good HSCT candidate. Enough time to get to know the family and their perspective, look for the best donor….

BR

Michael

_______________________________________________

Prof. Dr. med. Michael Albert

Oberarzt

Abteilung für Pädiatrische Hämatologie/Onkologie

Leiter der Stammzelltransplantation

Dr. von Haunersches Kinderspital der LMU

Lindwurmstr.4

80337 München

Tel: 089 4400 52785

Fax: 089 4400 54819

Michael Albert, MD

Professor

Department of Pediatric Hematology/Oncology

Head SCT Program

Dr. von Haunersches Children's Hospital

Lindwurmstr.4

80337 Munich

Germany

Tel: +49 89 4400 52785

Fax: +49 89 4400 54819

Von: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] Im Auftrag von CIS-PIDD
Gesendet: Donnerstag, 19. Oktober 2017 03:43
An: CIS-PIDD
Betreff: Re: [cis-pidd] XLP on screening

Hi

if I got it correctly, this boy has an early truncating mutation in a large X-encoded gene (54.000+ bp gene with 9 exons)..... not much function at all to be expected??? And he is still EBV neg at age 3.

Like Don and Kate, I am worried, symptoms yet or not.

Don, you probably went through the literature, previous reports on early truncating mutations and disease course when EBV hits?

ATB

Mikko

Oyl Mikko Seppänen

Harvinaissairauksien yksikkö (HAKE)

Head, Rare Disease Center,

Helsinki University Hospital (HUH)

FINLAND

phone +358 947180201

GSM +358 50 4279606

fax +358 9 47174703

CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> kirjoitti 19.10.2017 kello 1.29:

Hmmm….very interesting debate indeed. I would not be so affirmative on the rule of non transplanting an asymptomatic child. There are many other situations (HLH for example) in which we transplant asymptomatic patients when discovered by screening for an index case as sibling for example.

I agree with XiAP expression as well as MAIT counts, and if these tests appeared to be abnormal, I would go for a transplant. If the tests are normal…. well I don’t know but you would not need to push me very hard to transplant.

Elie

Elie Haddad, MD, PhD,

Professor of Pediatrics, University of Montreal,

Head, Pediatric Immunology and Rheumatology Division,

e-mail: elie.haddad at umontreal.ca<mailto:elie.haddad at umontreal.ca>

Le 2017-10-18 à 18:14, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> a écrit :

Burkitt like lymphoma and SH2D1A mutation make sense for transplant, but an asymptomatic child with an unknown XIAP variant doesn't. Even if it was a known pathologic mutation, I don't think we would recommend transplant yet. You could look for XIAP protein expression by flow and if normal, unlikely this is pathologic. This is a bit hard to comprehend or rather explain, but we need to stick to the science - these assays should not be used as screening tools.

Ashish

Ashish Kumar, MD, PhD

Associate Professor

Director, Pediatric Hematology-oncology fellowship program

Director, Langerhans cell histiocytosis center

Cincinnati Children's Hospital Medical Center

On Oct 18, 2017, at 4:53 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:

We just had a scarily similar case…

Patient had WES for developmental delay.  He came into the seen when the (in his case SH2D1A) mutation was found.  Upon arrival- he had adenopathy and it turned out to be a Burkitts like lymphoma.

I think they can do bad things in unpredictable ways and a three year old is more resilient for a transplant than an older kiddo/adult.

Kate

Sullivan, Kathleen 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

sullivank at email.chop.edu<mailto:sullivank at email.chop.edu>

On Oct 18, 2017, at 4:47 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:

Dear All:

I was consulted on the following case and would appreciate your input:

A 3 year old male, with a family history of Adams-Olivier syndrome, underwent screening when he was a newborn by whole-genome sequencing in what appears to be an accredited diagnostic laboratory in the U.S. (I do not have further details... I think he was screened because of the potential neuro-developmental delays associated with this disorder; he did not have any of the associated malformations).

While he did not have any mutations in genes associated with the targeted syndrome, he was found to have a variant in XIAP (NM_001167; c.340C>T; p.Gln114*). This is obviously predicted to be deleterious.

He is asymptomatic, including no GI symptoms.

He has been treated with IVIG, as prophylaxis against EBV. He has no hypo/dys-gammaglobulinemia (prior to starting IVIG at around 2 years of age).

Given the broad presentations of XIAP deficiency, what recommendations would you make? Specifically, would you recommend going to HSCT ASAP?

Thanks,
Don

Donald C. Vinh, MD, FRCP(C)
Director, Infectious Disease Susceptibility Program
Lilian Wilkins Associate Professor, FRQS Clinician-Scientist
Dept of Medicine (Division of Infectious Diseases; Division of Allergy & Clinical Immunology)
Dept of Medical Microbiology; Dept of Human Genetics

McGill University Health Centre - Research Institute
1001 Decarie Blvd; Block E; Rm EM3-3230 (Mail Drop: EM3-3211)
Montreal, Quebec,  Canada H4A 3J1

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