[CIS PIDD] [cis-pidd] Hypogammaglobulinemia

Wed Sep 27 03:55:29 EDT 2017

Hi, Mikko, Soheil:

This sounds fascinating.  This certainly sounds like the clinical + lab phenotype mentioned.

The mannosyl-oligosaccharide glucosidase defect (congenital disorder of glycosylation type IIb) described in Sadat, Rosenzweig, et al., NEJM 2016, did come to mind.  Hypogamma due to shortened IgG in vivo half-life.  But, of course, the rest of the clinical stuff in the paper (congenital dysmorphisms + neurologic defects) does not look like presented case.

     - K

Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
Scientist II and Assistant Director, Center for Infectious Diseases and Immunology
RGH Research Institute | Rochester General Hospital | Rochester Regional Health
1425 Portland Ave., Rochester, NY   14621
Tel  585-922-3709  |  Fax  585-922-2415

________________________________________
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: Wednesday, September 27, 2017 1:07 AM
To: CIS-PIDD
Subject: Re: [cis-pidd] Hypogammaglobulinemia

I'll try to make myself more clear, why I suggest dystrophia myotonica, and why that suggestion and Soheil's suggestion are closely linked:

Like Soheil notes, low albumin and IgG w/o apparent losses suggest hypercatabolism, and B2mg is indeed an option (nice call, Soheil!). Like Klaus Warnatz's group has shown, the patients usually have expanded CD8+ g/d T cell population. That disease has been called "familial complete FcRn deficiency" (FcRn being deficient due to B2mg deficiency) as well in literature. I have never met such patients, but don't they have a rather more severely low albumin?

Similar FcRn-related hypercatabolism due to impaired recycling of IgG takes place in myotonic dystrophy (a more common disease with very insidious onset of symptoms), usually IgG is more severely affected and albumin much less so, apparently since albumin-FcRn interactions remain (largely) normal.

Clin Immunol. 2007 Feb;122(2):146-55

Age of onset of MD/DM depends on the number of repeats, as may the extent of IgG losses (conflicting data).
Clin Neurol Neurosurg. 2011 Jul;113(6):464-8. doi: 10.1016/j.clineuro.2011.02.003.
J Neuroimmunol. 2003 Nov;144(1-2):100-4.

I have over the years given IgGRT to two DM/MD patients,
1) to a young woman, since she was highly symptomatic (kept her out of hospital and severe infections for >4-5? years) by having recurrent infections (rare in DM) -she also had somewhat low albumin and appeared grossly somewhat catabolic, but nutritional factors might have affected her wellbeing as well.
2) another one - a middle-aged man- I remitted twice to neurology due to DM/MD suspicion (family history +), after prolonged follow up and more pronounced and progressive fatigue, they were finally able to show dystrophia myotonica in repetitive stimulation EMG, but only after its second assessment. Albumin was normal. A tricky disease indeed, especially with later onset and lower numbers of repeats.

Both my MD/DM patients claimed that their fatigue was (only temporarily, for a short period) initially helped by IVIG?

I am not saying your patient has specifically DM/MD, but like Soleil, I am thus also wondering about some hypercatabolic state, since no urine/fecal losses have been detected?

Outside these two, are any other such hypercatabolic states affecting IgG springing to your minds, dear colleagues?
Her story does not sound like anorexia either?

ATB

Mikko

Mikko Seppänen
Head, Rare Disease Center,
Helsinki University Hospital (HUH)
FINLAND
phone +358 947180201
GSM +358 50 4279606
fax +358 9 47174703

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

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CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> kirjoitti 27.9.2017 kello 6.23:

Selectively decreased IgG and albumin in the absence of documented urinary or GI losses and with apparently normal immunoglobulin production could suggest hypercatabolic hypoproteinemia, which is quite a rare condition. The references below report about two siblings from a consanguinous marriage with a mutation in beta 2 microglobulin resulting in defective fetal Fc receptor function.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458798/
www.ncbi.nlm.nih.gov/pmc/articles/PMC329849/

Checking serum beta 2 microglobulin level is simple but it does not rule out this condition as the defect may be due to a mutation in the fetal Fc receptor alpha chain.

Best of luck in your search,
Soheil Chegini
__________________________________________
On Tue, Sep 26, 2017 at 4:25 PM, CIS-PIDD
<cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:

Think for a while about myotonic dystrophy (type I or II), if muscle fatigue is a prominent feature and only IgG low?

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 26.9.2017 kello 22.15:

Hi,

Does normal endoscopy mean normal biopsies?

I would also consider video capsule to rule out intestinal lymphangiectasia.

David Hagin
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On Tue, Sep 26, 2017 at 8:34 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:
All,

I am seeking advice about a 10 year old female with low IgG. who first came to my attention 3 years ago. At that time, she had low energy, abdominal pain and low-grade fevers (99.9-100.4). She also has asthma. There were no obvious findings on physical exam other than a skinny, sad, child.

Her immune work-up revealed an IgG level of 260 with normal IgM and IgA levels. She has vaccine responses to strep pneumo, tetanus, and diphtheria. She had a normal total B cell count with switch to memory cells.

She was started on IVIG and her symptoms disappeared right away. She had to be maintained on IVIG Q2 weeks to keep her level > 600 to keep her asymptomatic. Her teachers even commented on how much better she was at school after starting the IVIG.

Last year, the family decided to come off the IVIG. Again her symptoms have returned. She is missing 2-3 days of school/week. She is having abdominal pain daily. She has no energy and feels the need to nap all the time (even at school).

Repeat immune testing is consistent with her previous testing with the low IgG being the only abnormality. In addition, she had B-cell immunophenotyping which was normal. Inflammatory markers (ESR and CRP were normal). CBC is normal. She does have a mildly low albumin that fluctuates from 2.9-3.

She has had an endoscopy, colonoscopy which were normal. Stool studies are normal. Urine micro and  urinalysis were normal.

It does not seem like a primary production issue. So, is she losing her IgG somewhere and if so, where? Where else should I be looking?

In the meantime, she is going to re-start her IVIG because it does seem to make a big difference in her overall health and quality of life.

Thank you for your thoughts.

-Evan

Evan Shereck, MD, MEd
Associate Professor of Pediatrics
Director, Pediatric Hematology/Oncology Fellowship
Block Co-Director, Blood and Host Defense
Oregon Health & Science University I  3181 SW Sam Jackson Park Rd Mail Code: CDRCP  I  Portland, OR 97239
(Office): 503-494-0829  I  (Fax): 503-494-0714
(E-mail): shereck at OHSU.edu

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