[CIS PIDD] [MARKETING][cis-pidd] 13yo boy with exome variants

[CIS-PIDD]

Thanks, Mikko.  As always, great suggestions.  JC

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Monday, January 25, 2016 11:46 AM
To: CIS-PIDD
Subject: Re: [MARKETING][cis-pidd] 13yo boy with exome variants

Hi Joe,

Cannot claim that I would know what he has.

However, his combination of symptoms and findings would make me double check all the known 10 dyskeratosis congenita genes from the available exomes, and also check his telomere length (not all DKC genes and disease-causing mutations are known yet, maybe you found another, novel one?). This could also be x-linked, hemizygous or de novo?


At his age, the telltale signs of DKC may still be mostly missing.
I would still look for any signs of telengiectasiae and pigmentation changes in the sun exposed areas like where the dermatitis is, for oral leukoplakia asf and ask about family members (AR, AD, x-linked) with idiopathic  pulmonary fibrosis and skin cancers, early graying and ageing, hematologic diseases?

Just a thought...?

Hope this helps,

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 25.1.2016 kello 17.29:
Colleagues:

We recently started to follow a 13yo boy with the following:

·         Chronic, severe, restrictive lung disease (bronchiectasis with only dilated alveolar spaces and peribronchiolar inflammation on biopsy)

·         Marked growth failure, possibly related to growth hormone insensitivity

·         Eczematoid rash on face and neck, non-pruritic; biopsy showed "mild chronic spongiotic dermatitis."  Dermatologists concerned for Bloom syndrome.

·         Combined immune deficiency

IgG 494;  IgA 52;  IgM 18  Low antibodies to measles, tetanus and Hib; poor response to pneumovax (+2/23); positive antibody to VZV

CD3+ 45% (285);  CD4+ 20% (127);  CD8+ 23% (144);  NK 21% (135);  poor responses to mitogens

CD19+ 33% (207);  Naïve 97%;  Switched <1%;  Switched memory <1%

·         Chromosomal Microarray:  no clinically relevant genomic deletions or duplications were identified

·         Exome sequencing: both de novo/not observed in either parent, and neither reported previously.

-       Variant of uncertain significance in DOCK8 (pR1380H, c4139 G>A).  This results in a conservative amino acid substitution in a non-conserved position, and is predicted unlikely to alter protein structure/function.

-       Variant of uncertain significance in NFE2L2 (nuclear factor, erythroid 2-like 2)(pG31R, c91G>A).  This results in a non-conservative amino acid substitution in a position that is conserved across species.  It is likely to impact secondary protein structure as the residues differ in polarity, charge and size.  It is predicted to be damaging.  This gene encodes a transcription factor that regulates antioxidant responses.

Has anyone seen variants in NFE2L2 associated with immune deficiency etc?

Is anyone interested in in vitro study of this variant?

Joe Church
Children's Hospital Los Angeles




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