Long-term results of bone marrow transplantation in complete DiGeorge syndrome

Land, Michael H.; Garcia-Lloret, M.; Borzy, Michael S.; Rao, P. Nagesh; Aziz, Najib; McGhee, Sean; Chen, Karin; Gorski, Jack; Stiehm, E. Richard

doi:10.1016/j.jaci.2007.08.048

Cited by 46 publications

(29 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hematopoietic stem cell transplantation for complete DiGeorge was reported with a combined mortality rate of greater than 40%. [48][49][50][51] In summary, our report of a distinct Rag-deficient phenotype characterized by granulomatous inflammation and autoimmunity, with a relatively normal number of T-and B-lymphocytes and normal TCR repertoire, expands the spectrum of clinical pathology associated with Rag deficiency. In addition to defective central tolerance and peripheral regulation, our data suggest that dysregulated hyperinflammatory responses to viral antigens can lead to destructive granulomatous destruction, thus adding hyperinflammation to the current known Rag-deficiency features of infection and autoimmunity ( Figure 6).…”

Section: Discussionmentioning

confidence: 72%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

114

View full text Add to dashboard Cite

IntroductionProgressive granulomatous tissue destruction of the midface and the upper airways is most commonly caused by Wegener granulomatosis (WG) or malignancies such as natural killer (NK)/T-cell lymphomas and, to a lesser extent, cocaine abuse or infections. 1,2 The hallmark pathologic finding of destructive midline granulomatous (DMG) disease is caseating granulomas characteristically involving the nose, sinuses, palate, and upper airways, especially the subglottis. Although WG usually includes renal involvement and circulating antineutrophil antibodies (ANCAs), local nasopharyngeal WG without associated antibodies occurs. 3 Standard therapy for these diseases involves immunoablative chemotherapy to halt disease progression, in contrast to immunosupportive measures required to treat primary immune deficiencies. We describe in this report the first patient with clinical manifestations of a WG-like destructive midline granulomatosis with underlying novel compound heterozygote mutations in Rag1.The recombination activation genes, Rag1 and Rag2, perform a critical role in the somatic rearrangement and assembly of the modular genes for variable (V), diversity (D), and joining (J) gene segments of immunoglobulins and of antigen receptor genes. [4][5][6] After binding to conserved recombination signal sequences (RSSs) that flank individual V, D, or J gene segments, the Rag1/2 complex introduces a nick in the DNA, followed by formation of a coding end hairpin. Nonhomologous end joining DNA repair then takes place to generate the diverse VDJ contiguous regions that are essential for defense against many different pathogens. In addition to initiating the double-strand DNA breaks, the Rag complex stabilizes recombination intermediates to promote repair and editing of the modified genes. 6,7 Rag proteins are indispensable for lymphocyte development and differentiation, and defects in Rag manifests as T-and B-deficient severe combined immunodeficiency (T-B-SCID) or Omenn syndrome (OS) in infancy. These syndromes are characterized by early-onset profound deficiency in T and B cells for SCID and by early-onset erythroderma, hepatosplenomegaly, eosinophilia, and hyper immunoglobulin E (IgE) in OS.In stark contrast, our patient presented for evaluation of a DMG process at 14 years of age with normal numbers of CD3 ϩ T and CD19 ϩ /CD20 ϩ B cells and with normal total IgG levels. Evaluation in subsequent years showed dysregulated hyperinflammatory responses with appearance of new granulomatous lesions after environmental or viral triggers. This report further extends the clinical spectrum of Rag mutations, and our data support the view that, in addition to susceptibility to infections and autoimmunity, hyperinflammation is an important component of Rag deficiency and may be the primary clinical manifestation leading to diagnosis when lymphocyte counts are normal. Hypomorphic Rag mutations should be considered in "idiopathic" destructive granulomatous disease. MethodsThe subjects were enrolled on protocol 05-I-213 approved by...

show abstract

Section: Discussionmentioning

confidence: 72%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

114

View full text Add to dashboard Cite

show abstract

“…With a further 9 patients reported in the literature 7,9,12,13,21,22 (supplemental Table 1, available on the Blood Web site; see the Supplemental Materials link at the top of the online article), details of 26 transplanted patients are available.…”

Section: Discussionmentioning

confidence: 99%

“…9,21,22 Humoral immune function in survivors is good, with only 2 of 7 of the survivors in the survey group requiring immunoglobulin treatment (data not available from the literature group) and good antibody responses to protein or conjugate vaccines when tested. No data were available on polysaccharide antibody responses.…”

Section: Org Frommentioning

confidence: 99%

Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly

Janda

Sedláček

Hönig

et al. 2010

Blood

View full text Add to dashboard Cite

“…Therefore, prompt reconstitution of the immune function is required to prevent fatal infectious complications. The common treatments for immunological reconstitution in complete-type DiGeorge sequence are thymic and bone marrow transplantation [13,15]. Although thymic transplantation would be more reasonable from the physiological point of view, it is not ethically approved in Japan.…”

Section: Discussionmentioning

confidence: 99%

Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism

et al. 2010

View full text Add to dashboard Cite

It is rare that coloboma, heart anomalies, choanal atresia, retarded growth and development, and genital and ear anomalies (CHARGE) syndrome patients have DiGeorge sequence showing severe immunodeficiency due to the defect of the thymus. Although the only treatment to achieve immunological recovery for these patients in countries where thymic transplantation is not ethically approved would be hematopoietic cell transplantation, long-term survival has not been obtained in most patients. On the other hand, it is still not clarified whether hypoparathyroidism is one of the manifestations of CHARGE syndrome. We observed a CHARGE syndrome patient with chromodomain helicase DNA-binding protein 7 mutation showing DiGeorge sequence including the defect of T cells accompanied with the aplasia of the thymus, severe hypoparathyroidism, and conotruncal cardiac anomaly. He received unrelated cord blood transplantation without conditioning at 4 months of age. Recovery of T cell number and of proliferative response against mitogens was achieved by peripheral expansion of mature T cells in cord blood without thymic output. Although he is still suffering from severe hypoparathyroidism, he is alive without serious infections for 10 months.

show abstract

Long-term results of bone marrow transplantation in complete DiGeorge syndrome

Cited by 46 publications

References 23 publications

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Multicenter survey on the outcome of transplantation of hematopoietic cells in patients with the complete form of DiGeorge anomaly

Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism

Contact Info

Product

Resources

About