The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

Background Patients with severe combined immunodeficiency disease (SCID) who have matched sibling donors (MSD) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective To determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URD), either from volunteer adults or umbilical cord blood, are comparable to those from matched sibling donors (MSD). Methods A multicenter survey of SCID transplant centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT, from either URDs (n = 37) or MSDs (n = 66). Results Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment, compared to 97% for MSDs, however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively), compared to MSD recipients (92% and 89%, respectively; P <0.01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year OS (100%) to MSD recipients. The incidences of Grade II-IV acute and chronic GVHD were higher in URD (50% and 39%, respectively), compared to MSD recipients (22% and 5%, respectively; P <0.01 for both). In the surviving patients, there was no difference in T-cell reconstitution at last follow-up between the URD recipients and MSD recipients, however MSD recipients were more likely to achieve B-cell reconstitution (72% vs. 17%; P <0.001). Conclusion Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to MSD recipients, and reconstitution rates are adequate. However, only a minority will develop myeloid and B cell reconstitution and attention must be paid to GVHD prophylaxis. This approach may be safer in children ineligible for intense regimens to spare potential complications of chemotherapy.

BackgroundOver the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.ProcedureA retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009).ResultsDespite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time.ConclusionEFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post-HSCT are unchanged, and remain the focus for improvement.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.