Three cases of congenital adrenal hypoplasia with hypogonadotropic hypogonadism due to novel NR0B1 mutation / 中华内分泌代谢杂志

Objective:To advance the understanding of X-linked adrenal hypoplasia congenita(XL-AHC)through genetic analysis.Methods:Genomic DNA was extracted from peripheral blood of three patients with XL-AHC and their family members as well. Pathogenic genes were screened with whole exome sequencing followed by Sanger sequencing and pedigree verification.Results:All three probands were diagnosed as primary adrenal insufficiency at early age and developed hypogonadotropic hypogonadism in adolescence. The proband 1 was hemizygous for c. 420delG(p.R141Gfs*123)mutation in exon 1 of NR0B1 gene. His mother was a heterozygous mutation carrier while his brother did not carry the mutation, which was consistent with the X-linked recessive inheritance. A hemizygous mutation c. 212_213delAA(p.K71Rfs*41)of NR0B1 gene was detected in both proband 2 and proband 3. These two novel mutations were not reported in HGMD database.Conclusions:In this study, two novel NR0B1 mutations, c. 420delG and c. 212_213delAA were identified in 3 patients with XL-AHC. For men with early onset of adrenocortical hypofunction, XL-AHC should be considered. Early genetic screening of NR0B1 gene is helpful for early diagnosis.

A novel mutation in the DAX1 gene in a newborn with adrenal hypoplasia congenita in Korea

Adrenal hypoplasia congenita (AHC) is a rare cause of adrenal insufficiency during neonatal period. Mutations in the gene coding for DAX1 cause X-linked adrenal hypoplasia. Most affected patients are shown to have salt wasting and hyperpigmentation on the skin during the neonatal period and require intensive medical care. In addition, it is usually associated with hypogonadotropic hypogonadism in adolescence. The DAX1 gene is expressed in the adrenal cortex, pituitary gland, hypothalamus, testis, and ovary. We report on a patient with genetically confirmed AHC whose initial clinical presentations were consistent with congenital adrenal hyperplasia. A point mutation in the DAX1 gene identified in this report resulted in a truncated DAX1 protein. Our patient was diagnosed with AHC.

Progress in diagnosis and treatment of adrenal hypoplasia congenita with hypogonadotropic hypogonadism caused by DAX-1 gene mutation / 中华内分泌代谢杂志

[Summary] With the improvement of current medical diagnosis and treatment technology, more and more patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism have been diagnosed. DAX-1 gene mutation has been accounted for one of the most important reasons. Clinical manifestations include adrenocortical hypofunction such as loss of salt, dehydration, nausea and vomiting, as well as gonad dysplasia of male patients in puberty. The disease can be diagnosed by blood biochemical and hormonal level testings, imaging tests and gene sequencing. Patients can be treated by glucocorticoid, mineralocorticoid, and male sex hormone. The review will expand the diagnosis and treatment of adrenal hypoplasia congenita with hypogonadotropic hypogonadism caused by DAX-1 gene mutation.

Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome

X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.

Central precocious puberty in a patient with X-linked adrenal hypoplasia congenita and Xp21 contiguous gene deletion syndrome

X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.

Expression of steroidogenic factor-1 and DAX-1 in human adrenocortical tumours / 中华内分泌代谢杂志

ObjectiveTo detect mRNA and protein expression of steroidogenic factor-1 ( SF-1 ) and DAX-1 in human adrenocortical tumors and normal adrenal cortex,and to investigate the effect of SF-1 and DAX-1 on the steroidogenesis and development of adrenocortical tumors.Methods Total RNA and protein was extracted from angiotensin Ⅱ unresponsive aldoterone-producing adenomas ( A Ⅱ -U-APA,n =12 ),angiotensin Ⅱ responsive aldoterone-producing adenomas ( AⅡ -R-APA,n =5 ),cortisol-producing adenomas ( CPA,n =10 ),adrenal nonfunctional adenomas ( NFA,n =10 ),aldosterone-producing carcinoma ( APC,n =2 ) and normal adrenal cortex ( NAC,n =8).To analyze gene expression of SF-1,DAX-1,ACTH receptor(ACTHR),and β-actin by real-time quantitative PCR in different tissues.The protein expression of SF-1,DAX-1,and β-actin in the same tissues by Western blot.To study the relationship of ACTHR,SF-1,and DAX-1 with clinical data in adrenocortical tumors.ResultsThe expression of SF-1,DAX-1 mRNA and protein was different in NAC,AⅡ -U-APA,A Ⅱ -R- APA,APC,CPA,and NFA tissues [ relative expression of SF-1 mRNA:24.58±2.45,23.89±3.17,21.59±3.00,(38.75,44.16),14.17±2.80,and 36.38±3.50; DAX-1 mRNA:0.57±0.06,0.37±0.05,0.43±0.05,( 1.52,1.21 ),0.39 ±0.04,and 0.83 ±0.08 ; SF-1 protein:0.76 ±0.11,0.76 ±0.10,0.73 ±0.07,(1.24,1.40),0.55±0.04,and0.98±0.10; DAX-1 protein:0.65±0.14,0.39±0.13,0.43±0.14,(1.18,1.02),0.56±0.04,and 1.03±0.13 ; all P＜0.05 or P＜0.01 ].There was negative correlation by higher SF-1/DAX-1 ratio and tumor size in AⅡ -U-APA tissues.The mRNA and protein expression of SF-1 was lower in CPA and there was the positive correlation with tumor size.Conclusion SF-1 and DAX-1 might play a key role in the development of the adrenocortical tumorigenesis and steroidogenic tissues.

One case of late-onset adrenal hypoplasia congenita caused by a novel mutation of DAX-1 gene / 中华内分泌代谢杂志

A novel hemizygous frameshift mutation in exon1of DAX-1 gene (993delC) was found in a patient with late-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism.This mutation led the stop codon to appear in advance of 59 amino acids.His mother and two sisters were the carriers of this hemizygous mutation while his father and brother were wild-type.After glucocorticoid hormone replacement therapy, the clinical symptom was improved, but the level of ACTH was not suppressed.

Clinical and epigenetic study of a case with adrenal hypoplasia congenita caused by a novel DAX-1 gene mutation / 中华内分泌代谢杂志

Hormones and epigenetic characteristics in a patient with clinically diagnosed adrenal hypoplasia congenita (AHC) were analyzed. Results indicated that plasma ACTH increased, while cortisol, testosterone, LH and FSH decreased. LH, FSH and testosterone did not sufficiently respond to GnRH or hCG stimulation. Gene analysis indicated that C368F mutation was located in exon 1 of DAX-1 gene.

A novel mutation in DAX1 gene causing different phenotypes in three siblings with adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.

Clinical Significance of DAX-1 Expression using Immunihistochemical Staining in Breast Cancer / 한국유방암학회지

PURPOSE: There have been some reports that DAX-1 (Dosage-sensitive sex reversal, Adrenal hypoplasia critical region, on chromosome X, gene 1) can modify the estrogen receptor-beta and the progesterone and androgen receptors. Therefore, the aims of this work were to evaluate the expression pattern of DAX-1 in human breast cancer and its relationship to the steroid hormone receptors and other prognostic factors. METHODS: A retrospective analysis was performed using the clinical records of 161 patients diagnosed with invasive breast cancer, and who underwent surgical treatment and hormonal therapy between 1994 and 2004. We evaluated the presence and distribution of DAX-1 expressions in breast cancers using immunohistochemical staining. RESULTS: DAX-1 was expressed in 57 (35.4%) of the 161 cases. Also, the DAX-1 expression showed significant correlations with the size and nodal metastasis. In the androgen receptor positive cases (85 cases), the DAX-1 positive cases were statistically younger than the DAX-1 negative cases. In the progesterone receptor positive cases (81 cases), a statistical significance was noted between the DAX-1 expression and nodal metastasis. CONCLUSION: We conclude that DAX-1 can modulate the steroid hormone receptors including the progesterone and androgen receptors, in breast cancer. It could also be assumed that the influence of DAX-1 on the prognosis of breast cancer is different according to the kind of steroid hormonal receptor expressed.

Clinical Significance of DAX-1 Expression using Immunihistochemical Staining in Breast Cancer / 한국유방암학회지

PURPOSE: There have been some reports that DAX-1 (Dosage-sensitive sex reversal, Adrenal hypoplasia critical region, on chromosome X, gene 1) can modify the estrogen receptor-beta and the progesterone and androgen receptors. Therefore, the aims of this work were to evaluate the expression pattern of DAX-1 in human breast cancer and its relationship to the steroid hormone receptors and other prognostic factors. METHODS: A retrospective analysis was performed using the clinical records of 161 patients diagnosed with invasive breast cancer, and who underwent surgical treatment and hormonal therapy between 1994 and 2004. We evaluated the presence and distribution of DAX-1 expressions in breast cancers using immunohistochemical staining. RESULTS: DAX-1 was expressed in 57 (35.4%) of the 161 cases. Also, the DAX-1 expression showed significant correlations with the size and nodal metastasis. In the androgen receptor positive cases (85 cases), the DAX-1 positive cases were statistically younger than the DAX-1 negative cases. In the progesterone receptor positive cases (81 cases), a statistical significance was noted between the DAX-1 expression and nodal metastasis. CONCLUSION: We conclude that DAX-1 can modulate the steroid hormone receptors including the progesterone and androgen receptors, in breast cancer. It could also be assumed that the influence of DAX-1 on the prognosis of breast cancer is different according to the kind of steroid hormonal receptor expressed.