A Novel NR0B1 Gene Mutation Causes Different Phenotypes in Two Male Patients with Congenital Adrenal Hypoplasia

X-linked congenital adrenal hypoplasia is characterised by the acute onset of primary adrenal insufficiency in infancy or early childhood and hypogonadotropic hypogonadism(HH)at puberty,arising from mutations of the nuclear receptor subfamily 0 group B member 1(NR0B1)gene.This study investigated an extended family with two affected males(patient A:23 years and patient B:2 months old)and three carrier females.Sequencing analysis of the NR0B1 gene coding region from the family revealed a novel hemizygous deletion[c.604delT;p.(C202Afs*62)]in the two male patients.Furthermore,the patients'respective mothers and their common grandmother had this heterozygous mutation,but it was not present in the Human Gene Mutation Database.The two male patients showed inconsistent clinical features at onset,particularly in early childhood;however,it is possible that the younger patient will eventually show a delay of puberty,feminisation,and nonspermatogenesis in adulthood,similar to that in the older patient.Identification of a novel NR0BI mutation in this family is important for the diagnosis and genetic counselling of children with primary adrenal insufficiency and HH,and will be helpful for predicting long-term clinical symptoms.

Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner

Background and objective:Acute liver failure(ALF)is a type of disease with high mortality and rapid progression with no specific treatment methods currently available.Glucocorticoids exert beneficial clinical effects on therapy for ALF.However,the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to determine.The purpose of this study was to investigate the specific immunological mechanism of dexamethasone(Dex)on treatment of ALF induced by lipopolysaccharide(LPS)/D-galactosamine(D-Ga IN)in mice.Methods:Male C57 BL/6 mice were given LPS and D-Ga IN by intraperitoneal injection to establish an animal model of ALF.Dex was administrated to these mice and its therapeutic effect was observed.Hematoxylin and eosin(H&E)staining was used to determine liver pathology.Multicolor flow cytometry,cytometric bead array(CBA)method,and next-generation sequencing were performed to detect changes of messenger RNA(m RNA)in immune cells,cytokines,and Kupffer cells,respectively.Results:A mouse model of ALF can be constructed successfully using LPS/D-Ga IN,which causes a cytokine storm in early disease progression.Innate immune cells change markedly with progression of liver failure.Earlier use of Dex,at 0 h rather than 1 h,could significantly improve the progression of ALF induced by LPS/D-Ga IN in mice.Numbers of innate immune cells,especially Kupffer cells and neutrophils,increased significantly in the Dex-treated group.In vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor(Gr).Sequencing of Kupffer cells revealed that Dex could increase m RNA transcription level of nuclear receptor subfamily 4 group A member 1(Nr4 a1),and that this effect disappeared after Gr inhibition.Conclusions:In LPS/D-Ga IN-induced ALF mice,early administration of Dex improved ALF by increasing the numbers of innate immune cells,especially Kupffer cells and neutrophils.Gr-dependent Nr4 a1 upregulation in Kupffer cells may be an important ALF effect regulated by Dex in this process.