[CIS-PAGID] Infant with severe enteropathy and T cell defect

[Seppänen Mikko]

Dear Bodo,

since not all of us have the opportunity to attend the CIS meeting nor were at the recent Dutch or Freiburg meetings, I would be intrigued to hear just a little more about the LRBA def, if possible? If not, I do understand. 

However, since Bodo brought the subject up?:

a) what exactly is the level of IgE in LRBA def pts? High (e.g. through preferential CSR to directly to IgE not to IgG1  as described in some PIDDs in the same meeting by Gigi's group) or absent (like in most but not all CVID)?
b) approximately what proportion of early-onset severe CIS/CVIDs were LRBA def? Judging by the list of authors of the abstract quite a few ID centers participated in the screening, thus the commonness of this would be nice to hear? If it was found in 4 families, sounds like only a small proportion of CIS/CVID, while early-onset CIS/CVID with severe AI is not that rare, though AR pattern narrows it down a bit... And CVID/CIS with GVHD-like enteropathy and increased apoptosis in the gut biopsy together with autoimmunity phenotype would not be that infrequent either...(though this specific finding is not mentioned in the abstract).

For those of You who had no ability to attend CIS meeting, nor are included in the participating centers, I have pasted the published abstract of CIS meeting/J Clin Immunol (the list of authors is long and found in J Clin Immunol, includes centers from Europe, SA, Middle East and NA) I hope no one is offended for lack of acknowledgement in an e-mail): 

"Genetic causes of childhood-onset hypogammaglobulinemia
are currently not well understood. Patients are sporadic,
but autosomal dominant (AD) and recessive (AR) inheritance
have been described. We performed genetic linkage
analysis in AR-families with hypogammaglobulinemia.
Four AR-families with childhood-onset humoral immune
deficiency (ID) and autoimmunity (AI) shared evidence for
a linkage interval on chromosome 4q. Sequencing of candidate
genes revealed that patients carried a distinct homozygous
mutation in LRBA. All mutations segregated with the
disease, homozygous individuals showed symptoms, while
heterozygous were healthy. Mutations caused loss of protein
expression, defective B cell activation, increased susceptibility
to apoptosis and reduced autophagy. Phosphorylation
of the pro-apoptotic protein BAD was reduced but transient
expression of full-length LRBA in LRBA-deficient B cells
restored BAD phosphorylation. We conclude that mutations
in LRBA cause an ID characterized by defects in B cell
activation, autophagy and susceptibility to apoptosis that is
associated with a phenotype of hypogammaglobulinemia
and AI."

Congratulations to all authors!

mikko

________________________________________
Lähettäjä: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] käyttäjän bodo.grimbacher at uniklinik-freiburg.de [bodo.grimbacher at uniklinik-freiburg.de] puolesta
Lähetetty: 5. huhtikuuta 2012 0:26
Vastaanottaja: pagid at list.clinimmsoc.org
Kopio: pagid at list.clinimmsoc.org; <pagid at list.clinimmsoc.org>
Aihe: Re: [CIS-PAGID] Infant with severe enteropathy and T cell defect

Dear Jane,
just for completeness, what is the IgE?
Could it be LRBA deficiency, our new gene for early-onset severe "CVID/CID"?
These infants have a lot of autoimmunity and enteropathy...
Yours, Bodo


Prof. Dr. B. Grimbacher
Scientific Director


UNIVERSITY HOSPITAL FREIBURG
CCI - Centre of Chronic Immunodeficiency


Engesserstr. 4; 2nd floor
79108 Freiburg, Germany
telephone: +49(0)761-270-77731
e-mail: bodo.grimbacher at uniklinik-freiburg.de


-----pagid-bounces at list.clinimmsoc.org schrieb: -----
An: "<pagid at list.clinimmsoc.org>" <pagid at list.clinimmsoc.org>
Von: "Notarangelo, Luigi"
Gesendet von: pagid-bounces at list.clinimmsoc.org
Datum: 04.04.2012 12:43
Kopie: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>
Betreff: Re: [CIS-PAGID] Infant with severe enteropathy and T cell defect

Dear Jane:

NEMO is certainly a possibility given the large variability of phenotypes. The low number of memory and switched memory B at his age are not surprising. Other leaky SCIDs seem unlikely given the good number of naive T cells. Did you perform a skin biopsy? If you have fibroblasts, you could easily check for NEMO defects. This could be done in parallel as you search for a mutation.

Gigi

Luigi D. Notarangelo


Sent from my iPhone

Luigi D. Notarangelo, MD
Jeffrey Modell Chair of Pediatric Immunology Research
Division of Immunology
Children's Hospital Boston
Professor of Pediatrics and Pathology
Harvard Medical School
Karp Building, Room 10217
1 Blackfan Circle
Boston, MA 02115

Tel: (617)-919-2276
Fax: (617)-730-0709


On Apr 4, 2012, at 4:16 AM, "Jane Peake" <j.peake at uq.edu.au> wrote:


> Hi

> I was wondering if anyone would have any ideas regarding further investigations, diagnosis or management of this infant.

>

> 13/12 old male

> Born 30/40 Prem, 1/52 neonatal ICU requiring CPAP. NICU stay complicated by a staph infection and very slow to gain weight. Discharged home at term from SCN at 1.9kg.  Failure to thrive since then. Multiple admissions to provincial hospital in first couple of months for diarrhoea and poor weight gain. Otherwise reasonably well, with no further infections and was attending day care 2-3 times per week for 2 months. Couple of mild episodes of oral thrush responded to topical therapy.

> At 9 months had rhinovirus bronchiolitis then LRTI with moraxella and Haemophilus Influenzae on NPS.  Continued poor weight gain on amino acid formula and started on TPN at 9months of age. (Weight 4.3kg <<3rd centile).  Gained weight on TPN with improvement in diarrhoea.  Weight plateaued when TPN weaned and diarrhoea returned when NG feed rate increased beyond >15ml/hour. Has remained TPN dependent.

> At 10/12 had CVL infection with enterococcus faecalis and profoundly neutropaenic requiring GCSF.  BMA was consistent with early marrow regeneration following a myelotoxic insult(eg infection). Neutropenia recovered after one month and has not recurred.

> At 11/12 had a pseudomonas CVL infection - requiring PICU admission.  Recovered quickly. WCC rose, however did not make a CRP response to these infections.

>

> Investigations:

> IgG 1.6g/l (3-13) IgA    0.07g/l (0.3-0.9) IgM    0.5 (0.5-1.6)

> No specific antibody responses of any kind even following repeat booster immunisation

>

> CD3 6170 (72%) CD4 5410 (63%) CD8 860 (10%) CD19 1860 (22%)    CD56/16 470    (6%)

> CD4+CD27+CD45RA+ 91%

> Normal numbers of CD19+ B cells with normal proportion of immature B cells.  Reduced proportion of memory B cells and markedly reduced proportion of isotype switched memory B Cells.

> T cell proliferation: PHA - normal x 3, No antigen response to candida (x3), nor tetanus following immunisation

> CD40L expression normal

> Foxp3 expression normal

> Chromosomes - 46XY.

> Gut biopsy - Evidence of apoptosis, villous blunting, no intra-epithelial lymphocytosis, acute inflammation or granulomata seen and very few plasma cells.  No features of a specific enteropathy identified.

>

> Mother had a brother and an uncle who were both born very premature and died in first few days thought to be as a result of extreme prematurity. One well sister. He has 8 normal teeth and thin "baby" hair. Skin completely normal

>

> I am wondering about possible NEMO and seeing if I can get this done locally but  would appreciate any other thoughts

> Thanks kindly

> Jane

>

> Dr Jane Peake

> Paediatric Immunologist and Allergist

> Senior Lecturer

> University of Queensland

> level 3 Foundation Building

> Royal Children's Hospital

> Herston Rd, Herston QLD 4029

> Tel (61 7) 33655333 or 36365059

> Fax (61 7) 33655455

>

>

>