Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness.

BACKGROUND: Bartter syndrome (BS) is a genetic disorder accompanied by hypokalaemic metabolic alkalosis. BS with sensorineural deafness (SND, OMIM602522) is a newly identified phenotype caused by mutations in the BSND gene that encodes barttin, a beta-subunit for chloride channel ClC-Ka and ClC-Kb and classified as type IV BS. Type IV BS features the most severe phenotype entailing life-threatening neonatal volume depletion and chronic renal failure developing during infancy. A recent report described a case of BS with SND from a consanguineous family who showed homozygous mutations in the CLCNKA and CLCNKB genes. This case indicated the possibility of the occurrence of digenic inheritance in BS with SND resulting from double mutations in the CLCNKA and CLCNKB genes. SUBJECT AND RESULTS: The current report concerns a 2-year-old girl from a non-consanguineous family with BS accompanied by SND. In our case, four loss-of-function mutations, consisting of mutations in both parental alleles in both CLCNKA and CLCNKB, were identified. The paternal allele had a nonsense mutation (Q260X) in CLCNKA and a splicing site mutation (IVS17+1 g>a) in CLCNKB. The maternal allele had a large deletion mutation (about 12 kbp) extending from CLCNKA to CLCNKB. Our case provides clear evidence that loss-of-function alleles in both alleles of both CLCNKA and CLCNKB results in a phenotype indistinguishable from that of mutations in BSND (type IV BS). CONCLUSIONS: Recent advances in genetics have resulted in a better understanding of many human inherited diseases, but most of them are monogenic disorders and more complex inheritance patterns remain unresolved. Our case provides clear evidence of digenic inheritance outside the scope of Mendelian inheritance disorders.

ABCVEP (I) treatment for advanced intermediate grade and high grade non-Hodgkin's lymphoma.

With the intent to improve the cure rate for non-Hodgkin's lymphoma (NHL), a prospective single-arm trial named ABCVEP (I) was initiated in April 1989. ABCVEP (I) was consisted of 6 drugs: adriamycin (ADM); bleomycin (BLM); cyclophosphamide (CPM); vincristine (VCR); and prednisolone (PDN) with or without granulocyte colony-stimulating factor (G-CSF) to rescue the neutropenia. As of March 1991, 31 patients with intermediate- and high-grade NHL were entered in the trial and all the patients were evaluable with median age of 56 years. Twenty-five out of 31 patients were D. large; 2 were F. large, 2 D. small cleaved; and 2 D. mixed: 9 were in stage II, 6 in stage III and 16 in stage IV. Twenty-five patients achieved complete response and 6 partial response (response rate was 100%). The median follow-up period was 50 months, the actual over all survival rate for the entire group was 59.3%. The relapse-free survival for complete responders was 63.8%. Administration of G-CSF was required for 20 patients. Relative dose intensity (RDI) in patients required G-CSF was maintained at more than 80% of the RDI in patients not requiring G-CSF. Although severe pulmonary toxicity due to bleomycin was found in 4 patients, ABCVEP (I) is a feasible treatment regimen for aggressive NHL.

Ectopic ACTH-MSH producing carcinoid tumor with multiple endocrine hyperplasia in a child.

An autopsy case of a 9-year-old Japanese girl revealed a carcinoid tumor originating in the duodenum and hyperplasia of the multiple endocrine organs as manifested by ectopic ACTH syndrome, carcinoid syndrome and giantism. The tumor cells were positive for histochemical argyrophile reaction and two types of secretory granules were identified by electron microscopy. Biochemical assay revealed the production of ACTH and beta-MSH by the tumor cells. Other changes of multiple endocrine organs included acidophil dominant hyperplasia of the pituitary, diffuse hyperplasia of the thyroid, chief cell hyperplasia of the parathyroid, hyperplasia of the islets of Langerhans and the adrenal cortex. This case was considered to be a type of multiple endocrine adenomatosis including carcinoid tumor. The relationship between the carcinoid tumor and multiple endocrine adenomatosis was discussed.

The "bronze baby" syndrome: postmortem data.

The case history and autopsy findings of an infant with the "bronze baby" syndrome are presented. These findings substantiate that kernicterus occurs in term infants receiving phototherapy for concentrations of serum indirect bilirubin below 20 mg/dl. The findings at autopsy suggest that the photodecomposed pigmented products of bilirubin are unable to pass the blood-brain barrier. The need for establishing the cause of jaundice prior to initiation of phototherapy is stressed.