Novel frameshift mutation of the NR0B1(DAX1) in two tall adult brothers

Abstract

NR0B1 (nuclear receptor subfamily 0, group B, member 1) is a transcription factor encoded by DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) responsible for the development and maintenance of the steroidogenic tissues. In humans the DAX1 mutations cause congenital adrenal hypoplasia (AHC) and hypogonadotropic hypogonadism (HHG) in boys. Here we report two brothers who were assessed by endocrinologist at the age of 51 and 43 because of their serious osteoporosis. They had been substituted with prednisolone since the age of 4 and 9 years because of their primary adrenal insufficiency (PAI). Due to their late puberty caused by HHG at the age of 16 and 17 years their heights were − 3.1 and − 3.3 SD, but then they had a significant growth during their adulthood and reached the + 1.85 SD and + 3.78 SD respectively. During this period, they received glucocorticoid supplementation, but the treatment of their HHG was inadequate. At the age of 51 and 43 years insulin tolerance test (ITT) and gonadotropin releasing hormone (GnRH) test confirmed their PAI and HHG. Genetic test performed at this time revealed a novel, four nucleotides deletion (del.586-571c.GGGC or 572-575c.GGGC) of DAX1 gene. The two brothers with AHC and HHG caused by a novel DAX1 mutation, reached tall final heights, despite of the disadvantageous prednisolone treatment during their childhood. We assume that the long-term lack of the sexual hormone substitution was a significant reason of their above average height as well as their serious osteoporosis.

Case report: Clinical characteristics and treatment of secondary osteoporosis induced by X-linked congenital adrenal dysplasia

“…Bertalan reported two brothers with serious osteoporosis secondary to AHC at the ages of 51 and 43 and revealed two novel NR0B1 mutations (c.568-571del and c.572-575del). However, the treatment method was not mentioned ( 25 ). Previous studies did not focus on osteoporosis secondary to AHC.…”

X-linked congenital adrenal hypoplasia: a case presentation

“…Finally, we reviewed 21 pieces of literature [ 15 – 35 ] which included a total of 26 cases of AHC and is stratified by the patients’ age of onset and early symptoms, as well as the age at which they were diagnosed with AHC (Table 5 ). Of the 26 cases collected, 8 had hyperpigmentation complicated by ion disturbances [ 15 , 16 , 19 , 20 , 25 , 27 , 29 , 31 ], 4 had hyperpigmentation [ 17 , 18 , 22 , 32 ], 10 had ion disturbances [ 24 – 26 , 28 , 29 , 31 , 33 , 34 ], 3 had puberty disorders [ 21 , 23 , 35 ]. Most AHC patients developed early symptoms of hyperpigmentation, ion disturbances, and few developed puberty disorders as early symptoms.…”

The importance of genetic research in cases of severe male factor infertility: A case of 46,XX testicular disorder of sex development

“…In situations where the SRY gene is not present in individuals with 46,XX testicular DSD, patients present varying degrees of masculinization. Mechanisms that might explain this phenotype include changes in genes related to sexual development (e.g., SOX9 and DAX1) or the activation of testicular differentiation cascades, occult Y-chromosome mosaicism limited to gonadal tissue or eliminated during development ( Bianco et al ., 2011 ; De La Chapelle, 1987 ; Croft et al, 2018 ; Bertalan et al ., 2019 ; Rizvi, 2008 ).…”