[CIS PIDD] [cis-pidd] FOXN1 heterozygous phenotype?

CIS-PIDD cis-pidd at lists.clinimmsoc.org
Tue Jan 3 18:38:49 EST 2017 

Perfect, thanks Karin. Catherine/Lisa, please get in touch with Louise (sorry, the email above is incorrect!)

Gigi

Sent from my iPhone

> On Jan 3, 2017, at 6:31 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
> 
> Louise Markert has been collecting data.
> 
> 
> Karin Chen, MD
> Assistant Professor
> Department of Pediatrics
> Division of Allergy & Immunology
> University of Utah
> karin.chen at hsc.utah.edu
> 
> ________________________________________
> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
> Sent: Tuesday, January 03, 2017 4:02 PM
> To: CIS-PIDD
> Cc: lisa.bartnikas at childrens.harvard.edu; catherinemarybiggs at gmail.com; mmarkert at duke.edu; cooper_m at kids.wustl.edu
> Subject: Re: [cis-pidd] FOXN1 heterozygous phenotype?
> 
> Dear Megan, dear Louise, dear all,
> 
> At Boston Children's we also had a similar case of T cell lymphopenia with heterozygous FOXN1 mutation (and the mother of the infant had a similar phenotype). Drs Biggs and Bartnikas have followed the case.
> I think it would be very important to collect these cases. Louise and Megan, is one or both of you doing this? We would love to add our experience!
> 
> Best regards
> 
> Gigi
> 
> Luigi D Notarangelo
> Deputy Chief, Laboratory of Host Defenses
> National Institute of Allergy and Infectious Diseases
> NIH
> Bldg 10 CRC, arm 5-3950
> 10 Center Drive
> Bethesda, MD 20892
> Tel: (301)-761-7550
> Email: Luigi.notarangelo2 at nih.gov
> 
> Sent from my iPhone
> 
>> On Dec 31, 2016, at 1:14 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org> wrote:
>> 
>> Hi Megan,
>> 
>> We picked up a T-B+NK+ girl via TREC screening with a heterozygous FOXN1 mutation (targeted SCID panel). Normal exam, normal hair/nails. +Small amount of thymic tissue seen on ultrasound. Her T cell counts (~100) did not improve by 2.5 months of age.  Cord blood transplant was not successful and she awaits thymic transplant.
>> 
>> We completed whole genome sequencing on the family quartet. Father and full sibling had the same FOXN1 mutation (we plan to immunophenotype and will try to get out-of-state TREC results on the older brother). No other significant pathogenic mutations in known PID genes except for a heterozygous mutation in ITGB2/CD18.
>> 
>> We searched deeply for FOXN1 intronic variants upstream/downstream in the proband and mother, and nothing was found that would have fit an autosomal recessive inheritance pattern.
>> 
>> I can send you more info if you'd like. Would be willing to share data per Gigi's email as well.
>> 
>> Best,
>> Karin
>> 
>> 
>> Karin Chen, MD
>> Assistant Professor
>> Department of Pediatrics
>> Division of Allergy & Immunology
>> University of Utah
>> karin.chen at hsc.utah.edu
>> 
>> ________________________________________
>> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
>> Sent: Friday, December 30, 2016 10:14 AM
>> To: CIS-PIDD
>> Cc: M Louise Markert, M.D., Ph.D.
>> Subject: Re: [cis-pidd] FOXN1 heterozygous phenotype?
>> 
>> I have a case in WI with predicted pathogenic and novel FOXN1 mutation not
>> found in parents and another mutation  which was maternal.  Baby picked up
>> with 0 TREC, T cell lymphopenia and low naïve T cells. No nail or hair
>> abnormalities.
>> 
>> We did WGS.  I agree it would be valuable to combine cases and review
>> genetics data.  As previously mentioned, Louise Markert has expressed an
>> interest in this.
>> 
>> Chris
>> 
>> 
>> Christine M. Seroogy MD,  FAAAAI
>> Associate Professor
>> University of Wisconsin School of Medicine and Public Health
>> Department of Pediatrics
>> Division of Allergy, Immunology & Rheumatology
>> 1111 Highland Avenue
>> 4139 WIMR
>> Madison, WI  53705-2275
>> phone: 608-263-2652
>> fax: 608-265-0164
>> 
>> 
>> 
>> 
>> 
>> 
>>> On 12/30/16, 9:27 AM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> wrote:
>>> 
>>> I agree with Mike. However, we should not dismiss the possibility of
>>> digenic inheritance, where haploinsufficiency for FOXN1 - in combination
>>> with some other gene defect - may cause a phenotype. It would be great if
>>> would be willing to compare the WES data in all of these cases and see
>>> whether other changes are also shared, that could support a digenic
>>> inheritance. This has yet to be demonstrated in PIDs, but is well reported
>>> in other genetic conditions (such as nephropathies).
>>> 
>>> Gigi
>>> 
>>> Luigi D. Notarangelo, M.D.
>>> Deputy Chief, LHD
>>> Laboratory of Host Defenses
>>> DIR, NIAID, NIH, DHHS
>>> 10 Center Drive
>>> Bldg. 10 CRC, Room 5W3940
>>> Bethesda, MD 20892-1456
>>> Phone: 301-761-7550
>>> Fax: 301-480-3810
>>> cell: 301-272-0577
>>> 
>>> 
>>> 
>>> 
>>> 
>>> 
>>>> On 12/30/16, 10:09 AM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> wrote:
>>>> 
>>>> Hi Megan,
>>>> 
>>>> Have the parents been sequenced?   I would question the pathogenicity of
>>>> the mutation if one of the parents were carriers and well.
>>>> 
>>>> You might consider TCR spectratyping to see if there is any qualitative
>>>> abnormalities in the T cell repertoire.
>>>> 
>>>> Best regards,
>>>> Mike
>>>> 
>>>> Michael Keller MD
>>>> Assistant Professor
>>>> Childrens National Medical Center
>>>> 
>>>> 
>>>>> On Dec 30, 2016, at 9:34 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
>>>>> wrote:
>>>>> 
>>>>> Megan - You should touch base with Elena Perez. She follows a leaky
>>>>> SCID patient (picked up be NBS) with FOXN1 mutation that was passed from
>>>>> the father.
>>>>> 
>>>>> Jen Leiding
>>>>> 
>>>>> 
>>>>> 
>>>>> 
>>>>>> On 12/29/16, 10:16 PM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org>
>>>>>> wrote:
>>>>>> 
>>>>>> Normal.
>>>>>> 
>>>>>> CD19 - 957 cells/uL
>>>>>> CD56/16 - 766
>>>>>> 
>>>>>> no other B cell phenotyping, but serum IgM was normal (36).
>>>>>> 
>>>>>> Megan
>>>>>> 
>>>>>> ________________________________________
>>>>>> From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
>>>>>> Sent: Thursday, December 29, 2016 9:09 PM
>>>>>> To: CIS-PIDD
>>>>>> Subject: Re: [cis-pidd] FOXN1 heterozygous phenotype?
>>>>>> 
>>>>>> Hi Megan,
>>>>>> How are the B and NK cells?
>>>>>> Elie
>>>>>> 
>>>>>> Élie Haddad,
>>>>>> CHU Ste-Justine,
>>>>>> University of Montreal, Canada
>>>>>> 
>>>>>> On Dec 29, 2016, at 20:57, CIS-PIDD
>>>>>> <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
>>>>>> wrote:
>>>>>> 
>>>>>> 
>>>>>> Hi,
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> I was wondering if anyone had seen a patient with T cell deficiency
>>>>>> due to a heterozygous FOXN1 deficiency?
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> I'm seeing a 2mo male infant referred for low TREC on newborn screen
>>>>>> (~1/2 normal).  Initial CD3 count was ~900, and has subsequently
>>>>>> dropped to: CD3 - 543, CD4 - 403, CD8 - 121.  All other counts normal.
>>>>>> Proliferation to mitogens has been normal twice, and TREC copies per
>>>>>> CD3 cell was normal.  Slightly increased CD45RO for age (35%
>>>>>> CD4/CD45RO).  HIV negative, Chr22 FISH negative.
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> A SCID gene panel showed a heterozygous FOXN1 variant leading to an
>>>>>> early stop codon (deletion/duplication analysis normal).  He does not
>>>>>> have alopecia universalis as reported in FOXN1 deficient patients.
>>>>>> For now we are monitoring closely, and trying to determine clinically
>>>>>> if there is a need for transplant. (which probably wouldn't be
>>>>>> helpful/needed if this were due to thymic defect with FOXN1).
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> Thanks,
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> Megan
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> 
>>>>>> Megan A. Cooper, MD, PhD
>>>>>> Assistant Professor, Department of Pediatrics
>>>>>> Division of Rheumatology
>>>>>> Washington University School of Medicine
>>>>>> Cooper_m at kids.wustl.edu<mailto:Cooper_m at kids.wustl.edu>
>>>>>> Lab website:
>>>>>> https://urldefense.proofpoint.com/v2/url?u=http-3A__research.peds.wustl
>>>>>> .
>>>>>> edu_Default.aspx-3Falias-3Dresearch.peds.wustl.edu_Labs_Cooper-5FM&d=Dg
>>>>>> I
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>>>>>> Y
>>>>>> ChMemJbkOOltN-4w8rd7UQ&e=
>>>>>> (lab office) 314-286-0262
>>>>>> (lab fax) 314-286-2895
>>>>>> 
>>>>>> 
>>>>>> 
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