[CIS PIDD] [cis-pidd] Hypogammaglobulinemia and light chain deposition in kidneys

[Seppänen Mikko]

Dear Juthaporn, 

since nobody else seems to respond...

LCDD is a rare disease, I have personally seen only one, thus cannot boast much experience in that. 
If your patient had no amyloid in staining, and has no clear clinically evident plasma cell dyscrasia in the normal work up, she belongs to a 25% minority. She has already surpassed the median survival, about a third are still alive more than 8 years after dg. She seems to have no extrarenal manifestations (heart, peripheral nerves?). Does she have LC measured from serum?, usually kappa would be high. My guess would be, since CH50 is normal (can be low in e.g. CLL, MM due to clone-related consumption) that her LC binds C4 and interferes with the assay?? No transplant has been performed, though in literature it is generally regarded as safe and can at least early on reverse the renal failure. She probably has not been deemed eligible for transplant? 

She also has multiple late-onset autoimmune diseases. Evans, bullous pemphigoid, pustular psoriasis. Some of the autoantibodies in bullous pemphigoid are expressed in the gut as well, and I have seen a patient with BP and eosinophilia, who had a similar bout of sterile diarrhea, responded only to steroids. I do not think this would be well recorded in the literature though. Fecal calprotectin and antitrypsin to exclude chronic loss to gut as well? Autoimmunity preceding LCDD has been reported as rather common occasionally in literature LCDD reviews.

She has asymptomatic but severe IgG hypogammaglobulinemia. In nephrosis, IgA is not affected and IgM is relatively increased in follow up. Severity of hypogamma in nephrotic sdr usually follows serum albumin levels. So her IgG seems somewhat low, but other features and findings follow SID, purely due to nephrotic sdr? 
Anti-PnP responses to Pneumovax? If she becomes symptomatic, I would first attempt antibiotic prophylaxis? S
he sounds like SID to me, (but I have for example two brothers in follow up, of whom the other has clear adult-onset CVID, the other symptomatic CVID-like hypogamma, but in  the latter first a small MGUS and then smoldering myeloma was diagnosed, no known gene mutation in WES). I have seen a couple of other MGUS patients with symptomatic hypogamma out of proportion compared with plasma cells being below 5% in BM and MGUS being truly small. Usually the monoclonal gammopathy in MM and Waldenstrom is quite prominent before the low IgG develops. Why occasionally this is not the case I do not know. Your patient's low IgG sounds like a combination of nephrotic sdr and loss and similarly low production of  normal IgG due to monoclonal LC production??

Thus, in practice I would treat her as SID, would not be eager to attempt IgGRT as first line therapy,  especially since she is still asymptomatic. And I would only use IgGRT if anti-PnP are low (though evaluation might be uncertain due to the very low IgG). But whether there are genes or a gene involved as well, I can only wonder. 

I do not know if this was of any help? 

Mikko Seppänen, Helsinki, Finland

________________________________________
Lähettäjä: Juthaporn COWAN [jtp.cowan at gmail.com]
Lähetetty: 27. kesäkuuta 2014 21:55
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] Hypogammaglobulinemia and light chain deposition in kidneys

Hello all,

Please advice what you think and what should be done for this case.

A 58 yo woman with history of mild mental retardation from fetal alcohol syndrome. She was well up until 2009 when she was found to have proteinuria. Kidney bx showed light chain deposition without evidence of myeloma or even MGUS by bone marrow studies. She then had ITP +/- AIHA X 3 since 2009, responded to steroids and IVIG. She was also diagnosed with bullous pemphigoid and pustular psoriasis in 2012 based on skin biopsy when she presented with rash. Early this year, she began to have profuse diarrhea lasted for several weeks and nothing found on work up in terms of infection. Colonoscopy might have been done but result was not available.

We are seeing her for hypogammaglobulinemia of 1.1 g/L (Persistently low as of this year). Her IgG level was 5.9 in 2009 when she was diagnosed with light chain deposition in her kidneys and ITP. IgA and IgM are always in normal range. Interestingly, she also has very low C4 level <0.001 g/L with normal CH50. There is no feature of SLE.

The question is 'could this all be PID or SID?' Is her hypogammaglobulinemia caused by protein loss? (serum albumin is noted to be 25.. not very low, proteinuria is about 1.5-2 g/day). Does she have hematologic malignancy that is not picked up by BM biopsy?

No history of recurrent or unusual infection.

I am looking forward to hearing from you. Thank you.


Juthaporn Cowan
Ottawa, Canada

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