The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of thymus transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive thymus transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-transplantation follow-up as long as 13 years. All deaths occurred within 12 months of transplantation. All 25 subjects who were tested 1 year after transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus transplantation was well tolerated and resulted in stable immunoreconstitution in these infants. (Blood. 2007; 109: [4539][4540][4541][4542][4543][4544][4545][4546][4547]

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SUMMARY:Expression of full-length trkB can be found in some highly malignant neuroblastoma tumors with an amplified MYCN gene. This contrasts sympathetic neuroblasts, from which neuroblastomas are thought to arise, which neither express trkB nor are dependent on the p145 trkB ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5, for their normal development. In this study we show that trkB was expressed in two out of five neuroblastoma tumors with amplified MYCN, while no trkB expression was observed when the MYCN gene was overexpressed in a non-MYCN-amplified neuroblastoma cell line. This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA). When SH-SY5Y cells were stimulated with a combination of RA and BDNF, norepinephrine and tyrosine hydroxylase levels were unaltered, showing that the cells did not change toward a more catecholaminergic sympathetic phenotype. However, expression of growth-associated protein 43, indicative of a neuronal phenotype, was elevated. Vesicular acetylcholine transporter, choline acetyl transferase, and neuropeptide tyrosine mRNA levels also increased in RA-BDNF-treated cells, which could suggest that these cells develop into a sympathetic cholinergic phenotype. In addition, treatment with RA-induced expression of the platelet-derived growth factor receptor-␣. As previously shown for BDNF, platelet-derived growth factor stimulated growth of the RA-treated cells, findings that could have clinical relevance. If these receptors mediate a mitogenic signal in vivo also, this might limit the effect of RA treatment on neuroblastoma patients. (Lab Invest 2003, 83:813-823).T he childhood malignancy neuroblastoma is derived from cells of the developing sympathetic nervous system. The neuroblastoma cells are arrested at immature stages of sympathetic differentiation, although the stage of tumor cell maturation varies from one tumor to another and often also within a single tumor. This immaturity is frequently manifested in phenotypic characteristics resembling those of sympathetic progenitor cells such as expression of the embryonic and fetal transcription factors dHAND and human achaete-scute homolog-1 (HASH-1) (Gestblom et al, 1997(Gestblom et al, , 1999Hoehner et al, 1996a;Påhlman and Hedborg, 2000). Such progenitor cells give rise to three major closely related, sympathetic cell lineages: the neuronal/ganglionic, the small intensely fluorescent, and the chromaffin cell lineages (Patterson, 1990). The hormones and growth factors determining rat sympathetic progenitor cell lineage selection are grossly understood and involve glucocorticoids, classical growth factors, and neurotrophins (Anderson, 1993(Anderson, , 1997. For example, development into and along the neuronal lineage requires sequential exposure to insulin-like growth factors, basic fibroblast growth factor, and the neurotrophins nerve growth factor (NGF) and neurotrophin(NT)-...

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