MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity.

Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype.

Excellent Outcome Following Liver Transplantation for Hepatoblastoma Using an Extensive En Bloc Hepatectomy Technique.

BACKGROUND: Hepatoblastoma is a rare malignancy but the most common primary hepatic malignancy in childhood. Pediatric liver transplantation (LT) offers the possibility to achieve a complete resection in otherwise unresectable tumors. Almost no data are available regarding specific surgical technique of LT in children with hepatoblastoma. METHODS: We analyzed all children with hepatoblastoma and LT between 2007 and 2012. Special regard was given to the surgical technique and long-term follow-up. RESULTS: Overall 7 children were transplanted with the diagnosis of hepatoblastoma (5 male, 2 female). Thereof, 4 children (median age was 11 months, range, 6-31 months) underwent "primary" LT for hepatoblastoma Pretreatment Extent of Disease III to IV. A 4-year-old boy received "salvage" LT for recurrent hepatoblastoma 2.5 years after successful liver resection. Another 15-year-old boy was transplanted as a prophylactic treatment after repeated liver resection for hepatoblastoma due to the high recurrence risk. A 14-year-old boy underwent LT due to complications following liver resection for hepatoblastoma during infancy. In all children, extensive en bloc hepatectomy was performed together with resection of the adjoining retroperitoneal tissue and regional lymphadenectomy. Actually, all children are alive without tumor recurrence median 7.1 years after LT (range, 5.7-10.7 years). CONCLUSION: Our data show an excellent long-term outcome in selected children with hepatoblastoma undergoing standardized en bloc hepatectomy for "primary" and "rescue" LT with 100% overall and recurrence-free survival.

Alloimmunity and Cholestasis After Liver Transplantation in Children With Progressive Familial Intrahepatic Cholestasis.

OBJECTIVES: Bile salt export pump (BSEP) deficiency is an important reason for chronic cholestasis leading to liver transplantation (LT) in early childhood. The underlying pathology is a dysfunction of BSEP due to various mutations in the ABCB11 gene. Cases of clinical recurrence after LT due to alloantibodies directed against BSEP (antibody-induced BSEP deficiency [AIBD]) have been reported. Most of these patients could be controlled by intensified immunosuppression. METHODS: We here report on 3 children with BSEP-deficiency and end-stage liver disease, which developed AIBD after LT refractory to extensive immunosuppressive and immunomodulatory treatments; retransplantation was necessary in all 3 patients. In 1 patient, a stem cell transplantation was performed successfully. RESULTS: AIBD seems to be induced by triggering factors such as initial impaired graft function or infections after LT. CONCLUSIONS: The underlying mutation may play a role in this process. Intensifying immunosuppression may be able to control AIBD, but some cases seem to be refractory to treatment and require retransplantation. Stem cell transplantation may provide a new therapeutic option for cases refractory to conservative treatment.

Antibiotic prophylaxis in the management of percutaneous endoscopic gastrostomy in infants and children.

BACKGROUND: In randomized controlled trials in adult patients the use of prophylactic broad-spectrum antibiotic reduces the number of insertion site and systemic infections, associated with placement of percutaneous endoscopic gastrostomy (PEG) tubes. For pediatric patients no such trials exist. The aim of this study was to assess the value of antibiotic prophylaxis in PEG placement in pediatric patients. METHODS: In a retrospective chart review PEG placement in infants and children performed in a tertiary care center was analyzed. All PEG procedures were performed by an experienced pediatric gastroenterologist using the pull-through technique under general anesthesia. RESULTS: A total of 103 procedures were analyzed; 33 patients received antibiotic prophylaxis and 70 did not. Two (6%) of the patients receiving prophylaxis developed local or systemic infections after PEG placement, whereas seven (10%) without prophylaxis suffered from a PEG-related infection. This difference was not significant on chi-squared test (P = 0.5). Sixty patients had a body temperature >38°C within the first 3 days after the PEG procedure. A total of 77% of these patients had no antibiotic prophylaxis. Mean body temperature differed significantly between patients with and without prophylaxis (37.9°C vs. 38.3°C, respectively; P = 0.02). CONCLUSIONS: The incidence of PEG-related local or systemic infection after PEG-placement was not significantly different between patients with and without antibiotic prophylaxis, but the latter had a significantly higher mean body temperature after the PEG procedure. Taking elevated mean body temperature as a marker for putative bacteremia it is suggested that antibiotic prophylaxis is indicated in all pediatric patients after PEG placement.