Clinical Features and Genetic Analysis of Pediatric Patients with Alagille Syndrome Presenting Initially with Liver Function Abnormalities

Alagille syndrome （AGS） is a multisystem disorder and caused by mutations in JAG1 or NOTCH2 gene. The diagnosis of AGS is hampered by its highly variable clinical manifestations. We performed a retrospective analysis on 16 children diagnosed as having AGS in recent five years in our hospital. Cholestasis was seen in 15 patients （93.8%）, heart disease in 12 （75%）, characteristic facies in 7 （43.8%）, and butterfly vertebrae in 7 （43.8%）. Ophthalmology examination was not performed on all the patients. Further, serum biochemical parameters were compared between AGS and 16 biliary atresia （BA） patients who were confirmed by surgery. Elevated liver enzymes were seen in all the patients. Serum total cholesterol （TC） （P=0.0007）, alanine aminotransferase （ALT） （P=0.0056）, aspartate aminotransferase （AST） （P=0.0114）, gamma-glutamyl transferase （GGT） （P=0.035） and total bile acid （TBA） levels （P=0.042） were significantly elevated in AGS patients compared to those in BA cases. However, there were no significant differences in serum total bilirubin （TB）, conjugated bilirubin （CB） and albumin （ALB） between the two groups. We identified 14 different JAG1 gene variations and 1 NOTCH2 gene mutation in 16 Chinese AGS patients. Our study suggested clinical features of AGS are highly variable and not all patients meet the classical diagnostic criteria. It was suggested that hypercholesterolaemia and significantly elevated GGT, TBA and ALT may be helpful to diagnose AGS. Genetic testing is integral in the diagnosis of AGS.

Autosomal dominant osteopetrosis typeⅡresulting from a de novo mutation in the CLCN7 gene:A case report

BACKGROUND Osteopetrosis is a family of extremely rare diseases caused by failure of osteoclasts and impaired bone resorption. Among them, autosomal dominant osteopetrosis type Ⅱ(ADO Ⅱ), related to the chloride channel 7(CLCN7) gene, is the most frequent form of osteopetrosis. In this study, we report a de novo mutation of CLCN7 in a patient without the family history of ADO Ⅱ.CASE SUMMARY A 5-year-old Chinese boy with ADO Ⅱ was found to have a de novo mutation in the CLCN7 gene [c.746 C>T(p.P249 L)]. Typical clinical manifestations, including thickening of the cortex of spinal bones and long bones, non-traumatic fracture of the femoral neck, and femoral head necrosis, were found in this patient. The patient is the first reported case of ADO Ⅱ with the missense mutation c.746 C>T(p.P249 L) of the CLCN7 gene reported in China. We also review the available literature on ADO Ⅱ-related CLCN7 mutations, including baseline patient clinical features, special clinical significance, and common mutations.CONCLUSION Our report will enrich the understanding of mutations in ADO Ⅱ patients. The possibility of a de novo mutation should be considered in individuals who have no family history of osteopetrosis.

Novel Mutations in the 3β-hydroxy-A5-C27-steroid Dehydrogenase Gene （HSD3B7）in a Patient with Neonatal Cholestasis

Bile acid synthetic defect （BASD） is a rare category of genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants. Until date, four enzynles responsible for congenital defects of bile acid synthesis （CBAS） have been identified. 313-hydroxy-A5-C27-steroid dehydrogenase （3β-HSD）, the deficiency of which can cause CBAS 1 （OMIM No. 607765）, is encoded by the gene HSD3B7 and works in the second step of transforming the steroid into primary bile acids.