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

[Seidel Markus]

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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