Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.

OBJECTIVE: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort. METHODS: Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded. RESULTS: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset. CONCLUSIONS: Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.

Hemofiltration in myoglobinuric acute renal failure.

The frequency of myoglobinuric renal failure is estimated between 8 and 20%. Despite early onset of therapy often the use of renal substitution by hemodialysis or hemofiltration is required. This study of the clinical course of nine patients with myoglobinuric acute renal failure reveals continuous arterio-venous hemofiltration (CAVH) to have an effective clearance for myoglobin. Thus, the time until recovery of renal function as well as the frequency of secondary complications in rhabdomyolysis induced acute renal failure can be distinctly reduced.

[Dermatofibrosis lenticularis disseminata with osteopoikilosis. Buschke-Olldendorff syndrome]. / Dermatofibrosis lenticularis disseminata mit Osteopoikilie. Buschke-Ollendorff-Syndrom.

Buschke-Ollendorff syndrome is characterized by the coincidence of dermato-fibrosis lenticularis disseminata and focal sclerotic bone dysplasia (osteopoikilosis). The case of a 39-year-old female is presented and the characteristic clinical, histopathological and radiological manifestations of this rare disease are reviewed. As focal bone lesions in Buschke-Ollendorff's syndrome are mostly asymptomatic, the rate of diagnosis could be increased if locations of predilection were subjected to X-ray examinations on clinical observation of the typical cutaneous manifestations.