X-linked congenital adrenal hypoplasia: a case presentation.

BACKGROUND: Most patients with congenital adrenal hypoplasia (AHC) develop symptoms during infantile and juvenile periods, with varying clinical manifestations. AHC is a disease that is easily misdiagnosed as Addison's disease or congenital adrenal hyperplasia (CAH). There was also a significant time difference between the age at which patients developed symptoms and the age at which they were diagnosed with AHC. Most patients showed early symptoms during infantile and juvenile periods, but were diagnosed with AHC many years later. CASE PRESENTATION: We are currently reporting a male patient who developed systemic pigmentation at age 2 and was initially diagnosed with Addison's disease. At 22 years of age, he experienced a slipped capital femoral epiphysis (SCFE), a disease mostly seen in adolescents aged 8-15 years, an important cause of which is endocrine disorder. Testes evaluated using color Doppler Ultrasonography suggested microcalcifications. Further genetic testing and auxiliary examinations revealed that the patient had hypogonadotropic hypogonadism (HH) and DAX-1 gene disorders, at which time he was diagnosed with AHC complicated by HH. He was given hormone replacement therapy, followed by regular outpatient review to adjust the medication. CONCLUSIONS: The typical early symptoms of AHC are hyperpigmentation and ion disturbance during infantile and juvenile periods, while few patients with AHC develop puberty disorders as early symptoms. AHC is prone to being misdiagnosed as Addison's disease, and then gradually develops the symptoms of HH in adolescence. The definitive diagnosis of AHC ultimately is based on the patient's clinical presentation, laboratory results and genetic testing results.

A novel stop-loss DAX1 variant affecting its protein-interaction with SF1 precedes the adrenal hypoplasia congenital with rare spontaneous precocious puberty and elevated hypothalamic-pituitary-gonadal/adrenal axis responses.

The case study unveils the likely mechanism of a novel stop-loss DAX1 variant preceding the prolonged precocious puberty in the adrenal hypoplasia congenital (AHC) boy. A boy aged five years and nine months initially examined for the primary adrenal insufficiency symptoms. Next-generation sequencing confirmed the X-linked inheritance of a novel stop-loss DAX1 variant: c.1411T>C/p.Ter471Gln associated with AHC in the patient. The patient was subjected to a brief clinical follow-up from 11 to 15.1 years of age. The effect of the mutant-DAX1 variant (p.Ter471Gln) on DAX1-steroidogenic factor 1 (SF1) (protein-protein) interaction was studied by protein-protein docking using the ClusPro-online tool. At 5.9 yrs of age, the patient exhibited precocious puberty with the secondary sexual characteristics of Tanner 2 stage (of 9-14 yrs of age). The patient showed primary adrenal insufficiency with diminished cortisol concentrations at blood serum (25 ng/ml) and urine (3.55 µg/24 h) levels. Upon steroidal exposure, the patient showed normalized serum cortisol levels of 45-61 ng/ml. However, the precocious puberty got prolonged with the increased penis length of 8.5 cm and the bone age of 18 yrs old during the follow-up. The patient showed increased basal serum adrenocorticotropic hormone (110->2000 pg/ml) and follicle-stimulating hormone (18.4-22.3 mIU/ml) concentrations. Following an elevated hypothalamic-pituitary-gonadal axis activity witnessed upon gonarellin stimulation. Protein-protein docking confirmed a weaker interaction between the mutant-DAX1 (p.Ter471Gln) protein and the wild-SF1 protein. Overall, we hypothesize the weakened mutant-DAX1-SF1 (protein-protein) interaction could govern the prolonged precocious puberty augmented with the elevated hypothalamic-pituitary-gonadal/adrenal axis responses via SF1-induced neuronal nitric oxide synthetase activation in the patient.

Evaluation of the genetic basis of primary hypoadrenocorticism in Standard Poodles using SNP array genotyping and whole-genome sequencing.

Primary hypoadrenocorticism, also known as Addison's disease, is an autoimmune disorder leading to the destruction of the adrenal cortex and subsequent loss of glucocorticoid and mineralocorticoid hormones. The disease is prevalent in Standard Poodles and is believed to be highly heritable in the breed. Using genotypes derived from the Illumina Canine HD SNP array, we performed a genome-wide association study of 133 carefully phenotyped Standard Poodles (61 affected, 72 unaffected) and found no markers significantly associated with the disease. We also sequenced the entire genomes of 20 Standard Poodles (13 affected, 7 unaffected) and analyzed the data to identify common variants (including SNPs, indels, structural variants, and copy number variants) across affected dogs and variants segregating within a single pedigree of highly affected dogs. We identified several candidate genes that may be fixed in both Standard Poodles and a small population of dogs of related breeds. Further studies are required to confirm these findings more broadly, as well as additional gene-mapping efforts aimed at fully understanding the genetic basis of what is likely a complex inherited disorder.