Familial cases of pseudohypoaldosteronism type II harboring a novel mutation in the Cullin 3 gene.

Pseudohypoaldosteronism type II (PHA II) is inherited in an autosomal dominant manner and is characterized by hypertension, hyperkalemia, and hyperchloremic metabolic acidosis. The enhancement of with-no-lysine kinase (WNK) functions is correlated to the pathogenesis of the condition. Cullin 3 (CUL3) forms an E3 ubiquitin ligase complex, and it can ubiquitinate WNK. Most CUL3 gene mutations are distributed in sites, such as intron 8 splice acceptor, intron 9 splice donor, and putative intron 8 splice branch sites, which are involved in the splicing of exon 9. These mutations result in the deletion of exon 9, which reduces the activity of ubiquitination against WNK and inhibits the degradation of WNK. In this report, we identified a novel CUL3 c.1312A>G mutation in familial cases. A mutation prediction software showed that the significance of these mutations was not clear. However, using the Human Splicing Finder 3.1 software, in silico analyses revealed that these mutations induced splicing alterations, which affected the sites of exon 9, altered the balance between predicted exonic splicing enhancers and silencers, and led to the deletions of exon 9. This study presented a novel pathogenic splicing variant to the CUL3 mutation and provided a reference for further research about the mechanisms of splicing. Moreover, it showed that not only amino acid substitution caused by nonsynonymous mutations but also splicing motif changes due to base substitutions have important roles in the pathogenesis of PHA II.

Targeted use of prednisolone with the second IVIG dose for refractory Kawasaki disease.

BACKGROUND: Prednisolone (PSL) has been suggested to be useful for the treatment of Kawasaki disease (KD) resistant to i.v. immunoglobulin (IVIG), but much remains to be elucidated regarding its use. METHODS: A total of 1087 subjects were involved in a two-study multicenter prospective investigation of the effects of acute phase therapy on IVIG-resistant KD. Subjects resistant to the first dose of IVIG were classified into high (≥10 mg/dL) and low (<10 mg/dL) serum C-reactive protein (CRP) groups after the first dose of IVIG. RESULTS: In the first study, the efficacy of the second dose of IVIG in the high CRP group was significantly lower than in the low CRP group (47.8% vs 76.8%, P < 0.005). In the second study, PSL was co-administered with the second dose of IVIG to the high CRP patients (intensified regimen). The efficacy of the intensified regimen was similar to that of the second dose of IVIG in the low CRP group (79.4% vs 83.3%). Although the difference in the incidence of persistent coronary artery lesions (CAL) between the high and low CRP groups was significant in the first study (19.6% vs 3.0%, P < 0.005), it was not significant in the second study (8.8% vs 2.4%). CONCLUSIONS: The targeted use of PSL with the second dose of IVIG in KD patients resistant to the first dose of IVIG and who are predicted to be resistant to the second dose of IVIG, appears to be effective.

The long-term effect of replacement therapy in a short girl with autoimmune atrophic thyroiditis of prepubertal onset.

A 9 yr 11 mo old girl was admitted to our hospital because of short stature. Her growth rate gradually decreased and her height was 120 cm (-2.5 SD) on admission. The mother's and father's heights were 157 cm (-0.2 SD) and 163 cm (-1.3 SD), respectively. Her bone age was retarded (6 yr 10 mo). An MRI indicated pituitary enlargement, which mimicked adenoma. Evaluation of the pituitary-thyroid axis and thyroid function proved she had primary hypothyroidism (T3 0.5 ng/ml, T4 1.0 µg/dl, TSH 1,030 µU/ml). These findings, thyroid autoantibody (anti-microsome antibody 400 xs) and histopathology (moderate fibrosis and mild lymphocytic infiltration) suggested acquired hypothyroidism due to autoimmune atrophic thyroiditis of prepubertal onset. Since the evaluation, she has been treated with levothyroxine. The pituitary enlargement disappeared within 3 mo after levothyroxine replacement. The growth rate increased and her height reached 153.2 cm (-1.0 SD) during 10 yr replacement (at 19 yr 11 mo of age). An improvement in her final height was obtained by long-term thyroid hormone replacement therapy. Enough endocrinological study and repeated MRI evaluation are necessary in cases of pituitary enlargement which mimics adenoma before considering surgery.