AHC is a special type of primary adrenal insufficiency (PAI), which was first documented by the pathologist Sikl in 1948. In 1994, Muscatelli et al. found the candidate gene was localized at the Xp21.3 region, whose mutation or deletion results in AHC. The NR0B1 gene consists of 2 exons separated by a 3385bp intron and encodes a 470 amino acid DAX-1 protein, an unusual member of the nuclear hormone-receptor superfamily. The N-terminal of DAX-1 is absence of highly conserved zinc finger DNA binding domain (DBD) of the classical nuclear receptor, replaced by a 65–70 amino acid motif consisting of 3.5 alanine/glycine-rich repeats, which plays a vital role in the transcription regulation of NR0B1 [11,12]. The C-terminal domain of DAX-1 protein is similar to the Ligand-binding Domain (LBD) of the nuclear receptor superfamily, which successfully applies to selectivity and specificity ability of physiological activities.
Over 300 individuals and families with XL-AHC had been reported previously, most of which were frameshift or nonsense mutations[14–18]. It is speculated that the hot spot mutation of NR0B1 located in the putative LBD[2,18], causing premature truncation of the DAX1 protein.
It has been described that the age of onset and clinical features caused by the same NR0B1 mutation are different , and the phenotype of patients with AHC was variable. In the present pedigree, affected individuals manifested various clinical phenotypes from the detailed history, which is concordant with previous studies[19,20]. This phenomenon suggested genetic heterogeneity and epigenetic factors were paramount in prognosis of AHC. However, it's a pity we were unable to obtain detailed data of the other patients from the extended family. In the near future, studies were required to reveal the complex genotype-phenotype correlation.
The patient reported here presented with the classical, late-onset clinical and endocrine characteristics, subsequent direct DNA sequencing supported the diagnosis with XL-AHC. In addition, the constructed family tree was consistent with X-linked recessive inheritance, accordingly we speculated that female was the heterozygous carrier of this mutation and male was the patient with XL-AHC. We hypothesized that undiagnosed adrenal crisis was the cause of early death in these male patients. Furthermore, severe osteoporosis was induced by the lack of multitude of hormones, especially androgen. Long term corticosteroid replacement therapy may also have an adverse impact on BMD. Previous studies had described HH patients accompanied with osteoporosis or osteopenia[21,7], yet even sufficient androgen substitution didn’t reverse bone loss. However, there is a shortage of follow-up data of osteoporosis treatment. Our study was the first follow-up study of osteoporosis in AHC patients.
Interestingly, Most of osteoporosis patients responded well to alendronate or zoledronate. In contract, long-term high bone turnover marker concentrations (OC and β-CTX) in the subject with AHC indicating that bisphosphonates treatment either in oral or intravenous routes failed to suppress bone resorption. More seriously, AFF occurred during the treatment, which was is extremely rare in Asian patients with osteoporosis[24,25]. There were several speculations behind the above-mentioned phenomenon. In the first place, the patient himself was resistance to bisphosphonates. Secondly, the mutation site c.572_575dup in NR0B1 gene had a certain effect on bone metabolism, which may promote osteoclast activity and enhance bone resorption through unknown mechanism. Thirdly, bone metabolic markers can not evaluate the effectiveness of bisphosphonates properly. With regard to the above assumptions, we need to perform pharmacogenomics analysis and functional research both in vitro and in vivo in the near future.
The therapies for AHC were mainly maintenance of hormone replacement and symptomatic treatment, affected boys with HHG required androgen replacement therapy before pubertal to develop secondary sexual characteristics and improve the quality of life. Since previous studies demonstrated that sufficient testosterone replacement did not reverse the decreased bone mass associated with hypogonadism after adolescence [22,26], we harbored the idea that bone health of AHC patients should be paid attention to before skeletal maturation. Owing to the long-term low bone mass, it is necessary to monitor the course of treatment, dosage and drug type when using anti-osteoporotic drugs (especially bisphosphonates) to avoid side effects such as AFF and osteonecrosis of the jaw (ONJ).
In conclusion, the present study summarized clinical features of the patient suffered AHC and bone complications, followed him up for two years by regular visits. From our part, clinicians should not only focus on the treatment of typical clinical manifestations, but also pay attention to the skeletal complications in clinical practice. Besides, we emphasized the importance of an assessment of bone mass, treatment with replacement therapy or a specific treatment for osteoporosis at an earlier age should be considered, also, dosage and course of treatment should be monitored in time. In other words, anabolic agent may be a better choice.