[CIS-PAGID] family with AI cytopenias, liver and islet cell autoantibodies...

[Seppänen Mikko]

Dear Markus

since - surprisingly - nobody else seems to respond (at least I have received absolutely no responses to this in 12 days), my thoughts:

a) I personally would probably directly consult the French, who have an ongoing nationwide study on familial AIHA / Evans (and its novel genes, as far as I know?),  
check the recent paper Haematologica. 2011 May;96(5):655-63, well worth reading 
... among authors was prof Alain Fischer/ Inserm 

b) Sister Z's story sounds to me like a very typical and ever more common "secondary but permanent CVID" after RTX (where one wonders if she would have developed CVID anyway, even w/o RTX), and it is possible that both sisters and their mother "simply" represent polygenic CVIDs genetics at play (with autoimmune diseases being common in CVID patients' siblings and close relatives). Also there is considerable overlap btw CVIDs clinical phenotypes and ALPS + related conditions and FLH types (and it seems in recent literature that one might find ALPS and FHL gene mutations from phenotypic autoimmune/cytopenic CVIDs patients) and might explain sister D's findings??

b) ... and yes, I would probably still go directly to exome sequencing, homozygosity mapping (even full genome sequencing... ) and check if however a monogenic (novel, or ALPS, FHL related genetic, possibly hypomorphic) trait could be found from the family?

Hope this helps, but I certainly would love to hear what better AIHA, ALPS, FHL and CVID genetics specialists might want to add?

Yours

mikko

Mikko Seppänen, Immunodeficiency Unit, Helsinki, Finland

________________________________________
Lähettäjä: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] käyttäjän Seidel Markus [markus.seidel at medunigraz.at] puolesta
Lähetetty: 13. maaliskuuta 2012 9:49
Vastaanottaja: pagid at list.clinimmsoc.org
Aihe: [CIS-PAGID] family with AI cytopenias,    liver and islet cell autoantibodies...

Dear Community,
Your helpful advice is welcome in the workup of a consanguineous family with a multiorgan-autoimmunity trait:
Girl D, now 16yo, underwent PBSCT from her HLA-identical mother for “ALPS type 3” ( non-classic), after suffering from chronic ITP starting from her 2nd year of life and recurrent bacterial infections, developing into generalized lymphadenopathy and splenomegaly, DNT cells were between 2-10 percent (not always gated for TCRab), apoptosis assays normal, lymph node histology “compatible” with ALPS, but CD95, CD95L, Caspase 8 and 10 (hot spots) were normal; CTLA c.49A/A (not predisposing). Later, her mother and herself were found to be positive for liver autoantibodies (AMA, M2). Mother is clinically asymptomatic, but under observation because of the risk of primary biliary cirrhosis. Soon after SCT (100% donor chimerism), chronic ITP recurred in D. , she is stable under treatment with romiplostim. Both mother and D. had and have normal Ig levels and antibodies against viral and vaccine antigens. No invasive infections any longer in D. or need of iv-antibiotics.
The younger sister, Z., was diagnosed with AIHA at the age of 5 years, but had positive Coombs test already at 2yrs of age. Because of the then severe phenotype of her sister, she was soon treated with rituximab, B cells and Ig levels being normal prior to anti-CD20 therapy. AHIA was under control after rituximab with FK506 and MMF, which was tapered within months. However, the girl developed a persistent CVID-like syndrome with very low B cell numbers (<50µL) and hypogammaglobulinemia (substituted), chronic Norovirus infection / inflammatory bowel disease, growth arrest from 5,5 years until now (8 years, shifted from 75-90 percentile to 3rd percentile in length and weigth), elastase in stool is low-normal, but vitamins D, A, E are all low despite substitution, she is hypothyreotic and hypocalciemic with secondary hyperparathyreoidism. Antibodies against 21-OH-ase, parathyroid, adrenal tissue negative, but Z. also has anti-liver (AMA, M2) and islet-cell, insulin and glutamate decarboxylase antibodies (without manifestation of diabetes nor pathologic oral glucose tolerance), growth hormones and hypophyseal stimulation tests normal. Norovirus in stool, CMV in urin and throat swabs, adenovirus in throat swabs; 4-5 watery stools per day, used to respond to budenosid, but diarrhea is rather intractable now. abDNT cells <0.05%. Vitamin B12 normal. Serologic HLA-DQ8 positive (all females). Bowel Histology showed lymphocytic infiltrations and vilous atrophy (under multiple viral infections, despite repeated courses of valganciclovir treatment).
No history of remarkable EBV infection in any family member, Z and D have no viremia. Cyclosporidia and cryptosporidiae in stool negative, no history of candidiasis or signs of ectodermal dysplasia, no eczema, no muscular hypotonia, no syndrome stigmata, no dysmorhpies, no cardial defects; platelet size normal, sweat electrolytes normal.
One brother, now 3yo, healthy without signs of autoimmunity.
Seven maternal siblings and their children as well as six paternal siblings are all healthy / unremarkable regarding autoimmunity / hematology / immunology history.

Questions:
Dominant or recessive? Should we search for candidate genes, skewed X-inactivation, or directly to homozygosity mapping and exome sequencing? Which functional / immune phenotypical tests could lead the right way?

Thank you all for your thoughts and time,
Sincerely,
Markus Seidel

Markus G. Seidel, M.D., Assoc.Prof.
Consultant| Dept.of Pediatric Hematology-Oncology | Univ.Clinics of Pediatric and Adolescent Medicine | Auenbruggerpl. 34/2 | A-8036 Graz | Austria | T. 0043 316 385 80215| F. 0043 316 385 13450
Coordinator of the Working Group for Pediatric Immunology of the Austrian Society of Pediatrics and Adolescent Medicine

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