Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Recent data implicate locally produced steroids, termed neurosteroids, as regulators of neuronal function. Adrenal and gonadal steroidogenesis is controlled by changes in the steroidogenic acute regulatory protein (StAR); however, little is known about the regulation of neurosteroid production. We now demonstrate unequivocally that StAR mRNA and protein are expressed within glia and neurons in discrete regions of the mouse brain, and that glial StAR expression is inducible. Consistent with a role in de novo neurosteroidogenesis, StAR colocalizes with the cholesterol side-chain cleavage enzyme P450 scc in both mouse and human brains. These data support a role for StAR in the production of neurosteroids and identify potential sites of active de novo steroid synthesis in the brain.

The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.

Increasing shortage of cadaveric grafts demands the utilization of living donor and split liver grafts. The purpose of this study was to 1) define the "small-for-size" graft in a pig liver transplant model 2) evaluate pathological changes associated with small-for-size liver transplantation. Pigs were divided into four groups based on the volume of transplanted liver: (a) control group (n‫,)4؍‬ 100% liver volume (LV) (b) group I (n‫,)8؍‬ 60% LV (c) group II (n‫,)8؍‬ 30% LV (d) group III (n‫,)51؍‬ 20% LV. Tacrolimus and methyl prednisone were administered as immunosuppression. Animals were followed for 5 days with daily serum biochemistry, liver biopsies on day 3 and 5 for light microscopy, and tissue levels of thymidine kinase (TK) and ornithine decarboxylase (ODC). Liver grafts were weighed pretransplant and at sacrifice. All the recipients of 100%, 60%, and 30% grafts survived. Transplantation of 20% grafts (group III) resulted in a 47% mortality rate. Group III animals showed significantly prolonged prothrombin times (p<0.05), elevated bilirubin levels (p<0.05), and ascites. The rate of regeneration, as indicated by TK activity and graft weight was inversely proportional to the size of the transplanted graft. The severity of the microvascular injury was inversely proportional to graft size and appeared to be the survival-limiting injury. Frank rupture of the sinusoidal lining, parenchymal hemorrhage, and portal vein injury were prominent in group III animals 1 hour following reperfusion. This study established a reproducible large animal model of partial liver grafting; it defined the small-for-size syndrome in this model and described the associated microvascular injury. (Liver Transpl 2004;10:253-263.) R ecent technical innovations in the field of liver transplantation have been driven by the critical shortage of cadaveric organs. [1][2][3] It is hoped that the increasing number of adult living donor liver transplants (LDLT) and split liver transplants being performed annually will significantly reduce the number of deaths on the liver transplant waiting list. However, split liver transplantation for adults is hindered by the logistics of dividing a perfect donor liver to provide grafts of sufficient size for two small adult recipients of the same blood group. The split technique has the additional problem of prolonged cold ischemia times unless the liver is split in-situ. Currently LDLT is the technique with the greatest potential to address the organ shortage crisis but its widespread application is limited by the volume of liver that can be safely resected from a living donor, while at the same time providing a graft of sufficient size for the recipient. The size of graft required for successful liver transplantation is 30 -40% of the expected liver volume for the recipient or 0.8 -1.0% of the body weight. 4 For most adult recipients of an LDLT graft, this will require a right lobe graft from another adult. Given the smaller volume of the left lobe graft it is most suitable for small adults or larger ped...

Donor hypernatremia was reported to cause postoperative graft dysfunction in human orthotopic liver transplantation (OLT). However, the effects of the correction of donor hypernatremia before organ procurement have not been confirmed. The aim of this study is to determine whether donor hypernatremia is associated with early graft dysfunction after OLT and to determine the effect of the correction of donor hypernatremia. One hundred eighty-one consecutive OLTs performed between May 1997 and July 1998 were entered onto this study. The cases were divided into three groups according to the donor serum sodium concentration: group A, serum sodium of 155 mEq/L or less before organ procurement (n ‫؍‬ 118); group B, peak sodium greater than 155 mEq/L and final sodium 155 mEq/L or less (n ‫؍‬ 36); and group C, final sodium greater than 155 mEq/L (n ‫؍‬ 27). Graft survival within 90 days after OLT and early postoperative graft function were analyzed. There were no significant differences in donor and recipient variables among the three groups. The frequencies of graft loss were 15 of 118 grafts (12.7%) in group A, 4 of 36 grafts (11.1%) in group B, and 9 of 27 grafts (33.3%; P F .05 v groups A and B) in group C. The liver enzyme values in groups B and C were significantly greater than those in group A postoperatively. The prothrombin times of group C were significantly longer than those of group A for the first 4 postoperative days. Recipients of hepatic allografts from donors with uncorrected hypernatremia had a significantly greater incidence of graft loss compared with recipients of hepatic allografts from normonatremic donors. However, the differences in graft survival were abrogated by the correction of donor hypernatremia before procurement. Copyright 1999 by the American Association for the Study of Liver DiseasesS everal retrospective analyses of donor and recipient variables have attempted to identify risk factors predictive of both patient and graft survival after orthotopic liver transplantation (OLT). To date, the following donor-associated risk factors have been shown to adversely affect patient or graft survival: donor age, 1,2 sex, 3,4 liver function test results, 5 cytotoxic cross-match, 6 length of intensive care unit (ICU) stay, 1 use of vasopressors, 7 and preservation time. 2,8,9 Previously, all these risk factors were considered static and not subject to manipulation by the procurement team, primarily because of time constraints. However, recent legislation requiring earlier notification of potential organ donors and earlier turnaround time for serum chemistries have provided additional time to manage brain-dead donors before organ procurement and correct such abnormalities as hypernatremia that may adversely impact on both graft and recipient survival.Uncorrected hypernatremia in organ donors has been associated with poor graft or patient survival in at least four studies. 7,9-11 These retrospective analyses suggested donor hypernatremia resulted in a greater incidence of early postoperative graft dys...