Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity.

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.

Aminoterminal brain-type natriuretic peptide levels correlate with heart failure in patients with bidirectional Glenn anastomosis and with morbidity after the Fontan operation.

OBJECTIVE: The aims of this study were to generate normal values of aminoterminal pro-brain natriuretic peptide in children with a bidirectional Glenn anastomosis without congestive heart failure and to test the hypothesis that plasma levels of aminoterminal pro-brain natriuretic peptide correlate with the clinical severity of congestive heart failure and morbidity after the Fontan operation. METHODS: Aminoterminal pro-brain natriuretic peptide plasma levels of 78 patients after the bidirectional Glenn operation with a median age of 3.2 years and a median follow-up time of 3 years were measured by using an automated enzyme immunoassay. The severity of heart failure was quantified by using the New York University Pediatric Heart Failure Index. RESULTS: The 97.5th percentile of aminoterminal pro-brain natriuretic peptide level in patients without congestive heart failure was 339 pg/mL. Aminoterminal pro-brain natriuretic peptide levels strongly correlated with the New York University Pediatric Heart Failure Index score (P < .001). In patients with congestive heart failure (31/78), the aminoterminal pro-brain natriuretic peptide levels were significantly higher (median, 670 pg/mL) than in patients without congestive heart failure (median, 171 pg/mL). In 41 patients who underwent the Fontan operation, the time to removal of chest tubes and the length of hospital stay positively correlated with the preoperative value of aminoterminal pro-brain natriuretic peptide. CONCLUSIONS: In children with a bidirectional Glenn anastomosis without signs of heart failure, aminoterminal pro-brain natriuretic peptide levels were within the normal range and correlated with the severity of congestive heart failure. Further studies are needed to determine whether aminoterminal pro-brain natriuretic peptide levels can aide clinicians in the early detection of congestive heart failure in this patient group.

Fatal Epstein-Barr virus encephalitis in a 12-year-old child: an underappreciated neurological complication?

BACKGROUND: A 12-year-old boy presented to a community hospital with fever, malaise and fatigue. A polymerase chain reaction test of the cerebrospinal fluid was positive for Epstein-Barr virus. Despite intensive care treatment and antiviral drugs, the patient died 1 month after his initial presentation. INVESTIGATIONS: Physical examination, polymerase chain reaction analysis of the cerebrospinal fluid, brain MRI, immunohistochemistry and molecular biological investigations of postmortem brain samples. DIAGNOSIS: Epstein-Barr Virus encephalitis. MANAGEMENT: Aciclovir, intensive care treatment with intubation, sedation, antiepileptic drugs.