OBJECTIVE: To report on the clinical pictures of 7 patients from a pedigree affected with X-linked adrenal hypoplasia congenita (XL-AHC) and hypogonadotropic hypogonadism (HH) and the underlying mutations. METHODS: Seven patients were identified from a four-generation pedigree affected with XL-AHC and HH. Their clinical features, endocrinological changes, treatment and drug response were recorded. The patients were subjected to next-generation sequencing, and the result was verified by Sanger sequencing. PolyPhen-2 was used for predicting the influence of the mutation on protein production. RESULTS: Three deceased patients had manifested adrenal insufficiency (AI) within one year after birth. Two died at 6 and one died at 12. The four survivors presented with salient clinical and endocrinological features of AHC and HH, adrenal and testicular atrophy, and renin-angiotensin compensation. Two adult patients had testicular micro-stone detected by ultrasound.One of them also had remarkable seminiferous tubule degeneration by biopsy. The patients were followed up for 0.5 to 10 years. All required hyper-physiological dose of hydrocortisone to stabilize their clinical condition. In three patients, gonadotropic or androgen replacement induced cardinal masculine development but with unsatisfactory testis growth and sperm production.Genetic analysis revealed a novel missense c.827A>C (p.Q276P) mutation in a hotspot region within a highly conserved domain. PolyPhen-2 predicted the mutation to be highly hazardous. CONCLUSION The novel p.Q276P mutation of the DAX1 gene probably underlies the XL-AHC and HH in this pedigree with variable clinical presentations in the patients.
Adrenal Insufficiency ; DAX-1 Orphan Nuclear Receptor ; genetics ; Humans ; Hypoadrenocorticism, Familial ; genetics ; Male ; Mutation ; Mutation, Missense ; Pedigree ; Repressor Proteins

OBJECTIVE: To explore the pathogenesis of a 46,XY female with sex reversal. METHODS: Peripheral blood lymphocytes of the patient were subjected to G-banding karyotype analysis. Sex chromosomes were analyzed with fluorescence in situ hybridization (FISH). SRY gene was analyzed by Sanger sequencing. The whole exome of the patient was subjected to next generation sequencing. Copy number variations (CNVs) of the NR0B1, SF1, SRY, SOX9 and WNT4 genes were validated by multiplex ligation-dependent probe amplification (MLPA). RESULTS: The patient had a 46,XY karyotype. FISH analysis showed that her sex chromosomes were X and Y. No mutation was found in the SRY gene, and no pathogenic mutation was detected in her exome. However, a duplication spanning approximately 67.31 kb encompassing the MAGEB1, MAGEB3, MAGEB4 and NR0B1 genes at Xp21, was predicted by software analysis. MLPA confirmed duplication of the NR0B1 gene in the patient and her mother. CONCLUSION A duplication fragment of Xp21 encompassing the NR0B1 gene in the 46,XY female with sex reversal is transmitted from her asymptomatic carrier mother. Attention should be paid towards the insidious nature and high morbidity of this duplication.
DAX-1 Orphan Nuclear Receptor ; genetics ; DNA Copy Number Variations ; Female ; Gene Duplication ; Genes, sry ; Gonadal Dysgenesis, 46,XY ; genetics ; Humans ; In Situ Hybridization, Fluorescence

OBJECTIVEInactivating mutations of DAX-1 give rise to the X-linked form of adrenal hypoplasia congenita (AHC). Affected individuals are at risk of early postnatal Addisonian crisis, but the variable phenotypic expression of DAX-1 insufficiency renders this diagnosis challenging. This study aimed to understand the clinical features and identify DAX-1 gene mutation of the affected individuals and their relatives in a Chinese adrenal hypoplasia congenita kindred.

METHODSThe proband was diagnosed as adrenal insufficiency shortly after birth and his elder cousin was also diagnosed as having this disease at the age of about 8 years. Clinical data were obtained from 2 affected individuals when they were hospitalized into the department of pediatrics, Ruijin Hospital in 2006; 20 peripheral blood samples were obtained from the affected individuals and their relatives; exons in DAX-1 gene were amplified, and PCR product was purified and sequenced directly for analyzing mutation.

RESULTSA novel hemizygous mutation (T785C) was found in DAX-1 gene in both patients. Some clinical features such as the age of onset were different although these 2 patients carried the same mutation. There were 5 carriers of this mutation in the patients' maternal pedigree.

CONCLUSIONThe results suggested that adrenal hypoplasia congenita in this kindred was caused by a novel mutation (T785C) in DAX-1 gene, and the same mutation can give rise to the variable phenotype.

Adrenal Hyperplasia, Congenital ; genetics ; Asian Continental Ancestry Group ; genetics ; Child ; DAX-1 Orphan Nuclear Receptor ; genetics ; Genetic Diseases, X-Linked ; genetics ; Humans ; Male ; Mutation ; Pedigree ; Receptors, Retinoic Acid ; genetics ; Repressor Proteins ; genetics

Adolescent ; Adrenal Hyperplasia, Congenital ; diagnosis ; genetics ; Adrenal Insufficiency ; Child ; Child, Preschool ; DAX-1 Orphan Nuclear Receptor ; genetics ; Female ; Genetic Diseases, X-Linked ; diagnosis ; genetics ; Humans ; Hypoadrenocorticism, Familial ; Male ; Mutation ; Pedigree ; Phenotype ; Young Adult

Gene expressions are sex-specific in the sex development of mammals. Different genes express in different phases and tend to change with the time. The functions of some genes, such as SRY, SOX9, SOX8, DAX1, and FGF9, have already been defined in male gonadal morphogenesis. This paper presents a review of the genes involved in the formation of the male gonad in mammals.
Animals ; DAX-1 Orphan Nuclear Receptor ; DNA-Binding Proteins ; genetics ; Gene Expression Regulation, Developmental ; Genitalia, Male ; embryology ; growth & development ; metabolism ; High Mobility Group Proteins ; genetics ; Male ; Mammals ; embryology ; genetics ; growth & development ; Morphogenesis ; genetics ; Receptors, Retinoic Acid ; genetics ; Repressor Proteins ; genetics ; SOX9 Transcription Factor ; Sex-Determining Region Y Protein ; genetics ; Transcription Factors ; genetics

OBJECTIVETo investigate the clinical features and to identify the DAX-1 gene mutation in a Chinese kindred with X-linked adrenal hypoplasia congenital(AHC).

METHODSClinical data and peripheral blood samples were obtained from the affected individuals and their relatives. The genomic DNA was isolated from whole blood. Four pairs of primers were used to amplify the two exons of the DAX-1 gene, and PCR products were purified and sequenced directly. Sequencing results were compared to the human DAX-1 sequence in the public database.

RESULTSA novel hemizygous frameshift mutation (428delG) in exon 1 of the DAX-1 gene was found in both patients (the index case and his cousin). Some clinical features such as the age of onset were different although these 2 patients carried the same mutation. Three females in the family, including the mothers of the 2 patients and their grandmother were carriers of this mutation. No such mutation was detected in other healthy persons in the family.

CONCLUSIONThe result suggested that X-linked AHC in the kindred was caused by a novel mutation of 428delG in the DAX-1 gene, and the same mutation can give rise to variable phenotypes.

Adolescent ; Adrenal Hyperplasia, Congenital ; genetics ; pathology ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Child ; DAX-1 Orphan Nuclear Receptor ; DNA-Binding Proteins ; genetics ; Female ; Genetic Diseases, X-Linked ; genetics ; pathology ; Humans ; Male ; Mutation ; Pedigree ; Phenotype ; Receptors, Retinoic Acid ; genetics ; Repressor Proteins ; genetics ; Sequence Analysis, DNA

Congenital adrenal insufficiency is caused by specific genetic mutations. Early suspicion and definite diagnosis are crucial because the disease can precipitate a life-threatening hypovolemic shock without prompt treatment. This study was designed to understand the clinical manifestations including growth patterns and to find the usefulness of ACTH stimulation test. Sixteen patients with confirmed genotyping were subdivided into three groups according to the genetic study results: congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH, n=11), congenital lipoid adrenal hyperplasia (n=3) and X-linked adrenal hypoplasia congenita (n=2). Bone age advancement was prominent in patients with CAH especially after 60 months of chronologic age (n=6, 67%). They were diagnosed in older ages in group with bone age advancement (P<0.05). Comorbid conditions such as obesity, mental retardation, and central precocious puberty were also prominent in this group. In conclusion, this study showed the importance of understanding the clinical symptoms as well as genetic analysis for early diagnosis and management of congenital adrenal insufficiency. ACTH stimulation test played an important role to support the diagnosis and serum 17-hydroxyprogesterone levels were significantly elevated in all of the CAH patients. The test will be important for monitoring growth and puberty during follow up of patients with congenital adrenal insufficiency.
17-alpha-Hydroxyprogesterone/blood ; 46, XY Disorders of Sex Development/drug therapy/*genetics ; Adolescent ; Adrenal Hyperplasia, Congenital/drug therapy/*genetics ; Adrenal Insufficiency/*congenital/diagnosis/drug therapy/genetics ; Adrenocorticotropic Hormone/*metabolism ; Bone Development/genetics ; Child ; Child, Preschool ; DAX-1 Orphan Nuclear Receptor/genetics ; Female ; Genetic Diseases, X-Linked/drug therapy/*genetics ; Genotype ; Glucocorticoids/therapeutic use ; Humans ; Intellectual Disability/complications ; Male ; Mineralocorticoids/therapeutic use ; Obesity/complications ; Phosphoproteins/genetics ; Puberty, Precocious/complications ; Retrospective Studies ; Steroid 21-Hydroxylase/genetics