Homeostasis in Partial DiGeorge Syndrome (pDGS) ... RATIONALE: Hiper-IgM syndrome (HIGM) due to mutations in the ... Lys531Glu, In Hyper-IgE Syndrome.
S86 Abstracts
319
SUNDAY
Serum Interleukin-7 (IL-7) Level May Be a Marker of T-Cell Homeostasis in Partial DiGeorge Syndrome (pDGS) U. Tantibhaedhyangkul, C. M. Davis, L. M. Noroski, I. C. Hanson, W. T. Shearer, J. Chinen; Texas Children’s Hospital, Baylor College of Medicine, Houston, TX. RATIONALE: IL-7 is an essential cytokine for T-cell development. pDGS patients present with a wide spectrum of T-cell numbers. It is unclear why some patients improve their T-cell counts, while others remain lymphopenic. We hypothesize that IL-7 is associated with T-cell homeostasis in pDGS. METHODS: Blood samples of consecutive pDGS children with chromosome 22q11.2 deletion (median age: 45 months, range: 1-231 months) were analyzed for lymphocyte phenotypes by flow cytometry (n 5 27), T cell receptor excision circles (TRECs) by real time PCR (n 5 24) and IL-7 levels by ELISA (n 5 19). RESULTS: pDGS patients with CD31 T-cell numbers lower than 10th percentile of normal range (n 5 13) had significantly lower TRECs (p 5 0.01) but higher IL-7 levels (p 5 0.04) than those with normal CD31 T-cells (n 5 14). Median numbers of TRECs/1000 mononuclear cells and IL-7 in pg/ mL were 38.0, 7.3 and 97.6, 3.3 in each group, respectively. TRECs were significantly correlated with CD4CD45RA1, CD31 and CD41 Tcells (p 5 0.01; p < 0.001 and p < 0.001 respectively). CD41 T-cell numbers similarly correlated with TRECs and IL-7 levels. Patients with normal ranges of CD41 T-cells had relatively lower IL-7 levels. Patients with CD41 T-cells below 10th percentile of normal range but detectable TRECs had normal or elevated IL-7 levels. Two patients with CD41 T-cells below normal range, poor CD4CD45RA1 T-cells and TRECs had low IL-7 levels. No significant correlation was found between IL-7 and age. CONCLUSIONS: Serum IL-7 level is associated with markers of new T cell production and may reflect the ability of pDGS patients to develop Tcell homeostasis.
320
Novel AICDA Mutation In Two Brazilian Sisters With HiperIgM Syndrome: Case Report A. C. Pastorino1, P. H. Reis1, G. P. Stefani1, N. Carata˜o2, C. M. A. Jacob1, V. M. Barreto2, M. Carneiro-Sampaio1; 1DEPTO. OF PEDIATRICS, Sa˜o Paulo, Brazil, 2Epigenetics and Soma Laboratory, Instituto Gulbenkian de Cieˆncia, Lisbon, Portugal. RATIONALE: Hiper-IgM syndrome (HIGM) due to mutations in the Activation-Induced Cytidine Deaminase (AID) gene (AICDA) is a rare autossomic recessive primary immunodeficiency and a new genetic defect has been described in a Brazilian family. CASE REPORT: Two Brazilian sisters from a consanguineous family were diagnosed with HIGM at ages 9 and 14 years old. The youngest one presented severe pneumonia, meningitis and deafness. Serum IgM level was 1.505 mg% and other immunoglobulins were all undetectable before IVIG replacement. The other sister presented more respiratory tract infections (>6 episodes of URT infections, 4 pneumonias, requiring ICU support once). She also had dental abscesses twice. BAL culture was positive for Pseudomonas stutzeri and Neisseria sp. At diagnosis serum IgM level was 2.237mg%, while IgA and IgE were undetectable and IgG very low. Flow cytometry indicated normal number of B-lymphocytes. Both presented hyperplasia of tonsils and cervical lymphadenopathy at diagnosis. Thorax CT-scan showed bronchiectasis in both patients, micro nodular calcifications and pleural thickening in the older one. RESULTS: Preliminary sequencing analysis of the exons from AICDA revealed that the sisters are homozygous for a single non-silencing C to G transversion in the third position of codon 15, which replaces a conserved Phe with a Leu. CONCLUSIONS: To our knowledge, this is a new addition to the collection of AICDA mutants found in HIGM patients. Functional studies are ongoing to evaluate the effect of this mutation in the activity of the AID.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
321
Novel Association of Mannose-binding Lectin Variant Genotypes with Dermatological Infectious and Inflammatory Conditions C. W. T. Miller, M. Michael, G. Youngberg, D. S. Chi, T. A. Giorgadze, G. Krishnaswamy; Quillen College of Medicine, Johnson City, TN. RATIONALE: Mannose-binding lectin (MBL) participates in immune surveillance within the skin, binding apoptotic keratinocytes and inducing phagocytosis. Deficient levels cause accumulation and disintegration of apoptotic cells, triggering immune cell infiltration and a Th1-type cytokine profile, with reactive clone and autoantibody formation. MBL also responds to invading organisms by promoting opsonophagocytosis, limiting dissemination. We describe 6 patients presenting recurrent inflammatory skin conditions and low MBL levels. METHODS: Genotype analysis of MBL2 and MASP-2 genes, along with a functional MBL pathway - C4b deposition assay, was performed (IBT laboratories, Lenexa, Kansas) in patients with documented serum MBL deficiency (< 50 ng/mL) and recurrent inflammatory/infectious skin disease. RESULTS: 6/6 patients had mutations in the MBL promoter and severely deficient functional pathway, 5/6 (83%) were wild-type for MASP-2 gene while only 1/6 (17%) had a variant form of MASP-2 (A/G). MBL variant genotypes included LYPB/HYPD (2), LXPA/LYPB (2), LYPB/LYPB (1), and HYPD/HYPD (1). Additional work-up was benign except for C4 deficiency in 1/6. Five patients presented recurrent pustular skin infections, including one with severe cellulitis, one with recurrent abdominal wall abscesses and another with pacemaker site infection. One patient had concurrent Grover’s disease. Another patient had recurrent ulcerative pustules due to a fungal pathogen. A forme fruste of Behcxet’s disease partially responsive to hydroxychloroquine was also documented. Response to antimicrobials was partial, with frequent recurrences. These factors identified candidates for possible MBL replacement therapy, not yet available in this country. CONCLUSIONS: We believe this is the first case series associating MBL deficiency with infectious and inflammatory skin disorders.
322
A Novel Mutation In The Linker Domain Of The STAT3 Gene, p.Lys531Glu, In Hyper-IgE Syndrome J. Kim1,2, H. Kim3, K. Ahn1, S. Lee1; 1Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 2Department of Pediatrics, College of Medicine, Chung-Ang University, Seoul, Republic of Korea, 3Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. RATIONALE: Hyperimmunoglobulin E syndrome (HIES) is a rare multisystem immunodeficiency disease characterized by high serum immunoglobulin E (IgE) levels, eczema, and recurrent infections. Recent study reported signal transducer and activator of transcription 3 (STAT3) gene mutations localized to regions encoding the DNA binding or SRC homology 2 (SH2) domains, but we found de novo mutation in linker domain of STAT3 gene in a HIES patient. METHODS: We sequenced the STAT3 gene in our patient and validated the missense sequence variation. RESULTS: A 5-year-old boy with a history of atopic dermatitis and recurrent infections was admitted to the hospital with fever and cough for a week. He had neither perinatal problem nor family history of allergic and immunologic diseases. Serum IgE levels were greatly elevated at 3,980 IU/mL. He had National Institutes of Health (NIH) score of 45. De novo mutation in linker domain of the STAT3 was identified in the patient (c.1591A > G, p.Lys531Glu). His parents and his 3-year-old younger sister were homozygous for the wild-type allele. Sequence alignment showed that the K531 residue in the linker domain is perfectly conserved across different species. Functional prediction of the variation predicted probably damaging and deleterious. We observed that the variation was not occurring in 200 control chromosomes. CONCLUSIONS: This is the first case to identify that de novo mutation in the linker domain of the STAT3 gene could be causative for HIES, in addition to the previous finding of a causative mutations in DNA binding and SH2 domain of the STAT3 gene.
