[CIS-PAGID] Infant onset fever, rash, hepatosplenomegaly with hypogamm, lymphopenia, persistent viral infections

[Infante, Anthony J]

Dan Kastner was at our place recently and mentioned the intersection of hypogammglobulinemia and auto-inflammatory syndromes. The attached reference also tries to draw them together.

Tony Infante
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of John Ziegler
Sent: Thursday, August 11, 2011 8:08 PM
To: pagid at list.clinimmsoc.org
Cc: Paul Gray
Subject: [CIS-PAGID] Infant onset fever, rash, hepatosplenomegaly with hypogamm, lymphopenia, persistent viral infections

Dear Colleagues

We are seeking ideas and suggestions regarding an 18 month old girl born to non-consanguineous Caucasian parents, with neonatal-onset diffuse subcutaneous rash, fever, hepatosplenomegaly, raised inflammatory markers, and failure to thrive (grows when disease controlled).  She has a humoral immunodeficiency with lymphopenia, severe hypogammaglobulinaemia and relatively asymptomatic but prolonged carriage of RSV & norovirus.  She has had episodes of macrophage activation syndrome with anaemia and thrombocytopenia, high ferritin and LDH, and on one occasion acute neuro involvement. She is non-dysmorphic and her development is relatively normal.  She was discovered incidentally to have an old vertebral crush fracture at one year of age, but has otherwise normal skeletal survey.

Histopath:
Skin: lobular panniculitis with a mild histiocyte infiltrate (CD1a negative). No cytophagia.
Liver: homogeneously enlarged with intralobular fibrosis at 5 months and extramedullary haematopoiesis.
Bone marrow: showed fibrosis at 1 year, but not myelofibrosis with a few histiocytic cells and cell counts are generally normal.

Infectious screen (Direct detection methods (e.g. PCR/ IF)):
Negative on numerous tissues for adenovirus, HSV, EBV, CMV, enterovirus, HHV6, parvovirus and VZV.
Stool negative for cryptosporidium, yersinia, salmonella, shigella, campylobacter and giardia; HIV -ive, PCP neg on liver/ BM and no evidence of Tb, histoplasmosis or leishmaniasis
NPA was RSV +ve for c. 2 months with no lung disease, and stool norovirus positive for several months

Immune testing:
Lymphopenia (0.4 - 1.4):
B-cells: Normal percentage but incapable of isotype switching.  Absent IgA, extremely low IgG, and IgM which varies between normal and low.  BTK gene normal, CD40 expression (flow) normal.  CD40L not tested (girl), while UNG/AID not tested as not felt to offer sufficient explanation for her symptoms.
T-cell: Normal T-cell percentage and PHA mitogen stimulation with normal Vb subsets but a preponderance of CD4 positive T-cells (ratio >4), and excess naïve CD45RA positive T-cells.
NK cell: normal numbers, function (chromium release K562 cells) and perforin expression.
Other:  Complement function, AFP, ADA and PNP normal.  No SP110 mutations.

Metabolic studies:
Normal transferrin isoforms, VLCFAs, urinary GAGs, lysosomal enzymes, skin fibroblast enzymology for Farber's, and urinary oligosaccharides.

Cancer studies:  No suggestion of an abnormal population on biopsy to suggest cutaneous lymphoma.

Progress:
Her inflammatory  symptoms are largely steroid responsive and are almost completely abrogated by anti-TNF (Infliximab or adalimumab), but with an apparent reduced response over time.  She was refractory to anakinra.

Strangely, every time she comes under control for her inflammatory symptoms her transaminases rise (ALT = 800).   This is independent of the immunosuppressive agent!


Differentials:

1)     Genetic haemophagocytosis (e.g. Munc18-2 deficiency assoc with hypogamma)

a.      Unlikely given normal Nk cell function



2)     PID

a.      hyper IgM, AR agamma, wouldn't explain the inflammatory flavour and lymphopenia;

b.      VODI excluded;

c.      DNA repair defect (normal AFP - formal testing not available)



3)     A primary autoinflammatory condition

a.      CINCA wouldn't explain the hypogamma or non-responsiveness to anakinra

b.      Infantile panniculitis/ granulomatous disease - no granulomas to date/ PID out of keeping

c.      CANDLE syndrome or PSMB8 syndromes - rash is inconsistent and not hypogamma diseases



4)     Macrophage activation syndrome secondary to either a persisting infection (in the context of a PID) or an undiagnosed inflammatory condition.

Thanks for your thoughts,

John




A/Prof. John B. Ziegler
Department of Immunology & Infectious Diseases
Level 4 South, Emergency Wing
Sydney Children's Hospital
High St., Randwick NSW 2031
Australia
T: (02) 93821515
F: + 61 + 2 93821580
E: j.ziegler at unsw.edu.au<mailto:j.ziegler at unsw.edu.au>

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