[CIS PIDD] [cis-pidd] Disregulatory Syndrome + masive splenomegaly + autoimmune hepatitis + cytopenias + pericarditis

[CIS-PIDD]

Hi Maria, I would consider gain of function mutations in the p110 delta subunit of pik3cd in this patient. nodular lymphoid hyperplasia, splenomegaly, cytopenias, autoimmunity, PSC, hyper IgM, cd4 lymphopenia (especially naive), and increased transitional B cells have all been described in the clinical phenotype. Sirolimus has offered good response in some patients.

Kelli

On Jun 9, 2017, at 6:10 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:



Dear collegues, we would appreciate your thoughts about this case:
17 years old girl. Full term baby with recurrent acute diarrhea since first year of life.
At the age of 3, diagnosed with celiac disease is made by biopsy and positive auto antibodies (MARSH III).
At 4 years of age, began with splenomegaly + anemia + thrombocytopenia (with normal Bone marrow)
At the age of 5: Nephrytic syndrome.  Due to ASMA +, liver biopsy suggestive of Sclerosing cholangitis with two normal Colangio resonances.
At the age of 6, he started treatment with methylprednisone and azathioprine, suspended due to severe neutropenia at the age of 7.
10 years: duodenal video endoscopy revealed chronic duodenitis, MARSH1. Video colonoscopy informed as nodular lymphoid hyperplasia.
New liver biopsy: Sclerosing cholangitis with cirrhosis evolution (Normal colangio renonance). Recurrent thrush
12 years: Mononucleosis with (IgM + EBV). Later on time EBNA +.
14 years: In the context of increased liver enzymes and increased hepatosplenomegaly, Restart aziatoprine treatment. 3 months later suspended for neutropenia.
New Bone Marrow Aspiration revealed: Hypercellularity, myeloid hyperplasia and megakaryocytic cells with abnormalities.
At 15 years (September 2014): hospitalization due to severe ulcero-necrotizing periodontitis and pancitopenia with response to Neupogen. Oral candidiasis treated with VO Fluconazol. Common germs swab for herpes: Negative. (She required flexible ferules on her teeth due to the great gum compromise)
Received IVIG  plus methylprednisolone pulses for 3 days and then MP 40 mg / day for thrombocytopenia.
Bone Marrow: cellularity ++++. Thrombocytopenia assumed as autoinmune.
At almost 16 years : weight 44 kg (percentile 3-10), Height 146.5 cm (<percentile 3).
Abdominal ecography:  spleen 237 mm with enlarged liver. New liver Bx: moderate inflammatory infiltrate with lymphocyte predominance and moderate plasmocytes and eosinophils. Chronic moderate hepatitis - Knodell 11 (8 + 3). Asumed as Autoimmune hepatitis. Treatment with meprednisone 8 mg/day. Sclerosing cholangitis discarded.
2 episodes of periodontitis without hospitalization in the last 2 years and Microsporidium + in stool sample
2016: Ankles arthralgia. Eco Doppler: normal. New neutropenia episode with ankles celullitis. Rheumatology Unit discarded rheumatologic pathology up to date
Abdominal ecography: hepatomegaly with isolated adenomegalies and gallstones. Cardiology evaluation: ECG with repolarization disorder. MNR: pericarditis
Episode of adenophlegmon. Persist with splenomegaly, neutropenia and monocitosis. New bone marrow: myeloid hyperplasia. Flow: 1.5% of mature monocytes with monoblasts and pro-monocytes.
New eco cardiography: Left auricle dilatation, Ventricle with normal diastolic function
May 2017: hospitalization due to neutropenia and severe preseptal eye cellulitis.
Immunological work up:

*      Hipergammaglobulinemia > 2SD (IgG, IgA and IgM). Nowadays low IgE.

*      Good response to proteic and polysaccharide antigens.

*      C3/C4: previously normal. In actual lab low with normal CH50 and AH50 (consumption?).

*      Autoantobodies: Positive ANA (low titer- dot pattern). Anti-Ro: Positive , IgA ASCA: Positive. Low titers of IgA anti-transglutaminase and Positive IgG anti-deaminated gliadin peptides.

*      Normal Lymphoproliferation assay with different mitogens (CFSE)
  Lymphocyte subsets: Lymphocyte count 1.320 cells/mm3

*        CD3: 72 %  / CD4: 50% (660) / CD8: 21% / CD20: 25.5%  / CD56: 1.6% (21) (Normal dim/bright ratio)

*        Double Negative: 2 % in different opportunities

*        High Vitamine B12 dosage. Pending FASL

*        Alpha-Beta/Gamma-Delta: normal ratio

*        Low Naïve T cells with LT memory expansion. Low memory B cells with slightly high transitional B cells.

*        High LTCD4 Th17+ cells (in different opportunities). Low FOXp3+ cells.

*        Normal CD25 up regulation assay.

*        Normal degranulation assay (CD107a)

*        Pending: NK cells cytotoxity assay.
Treatment

1.      TMS 5 mg/k/dose 3 times a week

2.      Vitamin D- Calcium

3.      Meprednisone 8mg/d

4.      Omeprazol

5.      Ursodesoxicolic acid

6.      Sirolimus 1-2mg/m2/d

K-RAS / N-RAS (Possible diagnose??)

Please, we will be happy of receiving your suggestions about any diagnostic key and treatment.

Many thanks in advance

María Soledad Caldirola
Biochemsit, PhD fellow
Ricardo Gutierrez Children's Hospital
Buenos Aires, Argentina

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