DOI 10.1515/jpem-2013-0260 J Pediatr Endocr Met 2014; 27(3-4): 343–347
Chun Lin Wang, Zhu Wei Fen and Li Liang*
A de novo mutation of DAX1 in a boy with congenital adrenal hypoplasia without hypogonadotropic hypogonadism Abstract: We report the case of a 12-year-old boy with a de novo mutation in the DAX1 gene (for dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1; also called NROB1). He was born at term, Addison’s disease was diagnosed at 8 years with a salt-wasting syndrome, and then hydrocortisone substitution was taken; the child continued to develop normally. A reoccurrence of salt-wasting syndrome usually happened after an episode of an abrupt withdrawal of hydrocortisone substitution. Because of adrenal insufficiency without hypogonadotropic hypogonadism, he came to the clinic at 12 years of age and hypoplasia of adrenal glands was found by MRI scans. We proposed the diagnosis of congenital adrenal hypoplasia in this patient and identified a hemizygous mutation (c.999_1000insCTCA, p.Leu335ThrfsX389) in exon 1 of the DAX1 gene. To our knowledge, it is a de novo mutation that leads to a frameshift, a premature stop codon. In conclusion, it is very important to identify mutation in the DAX1 gene for a boy with adrenal insufficiency of unknown etiology. Keywords: adrenal insufficiency; DAX1; gene; hypogonadotropic hypogonadism. *Corresponding author: Li Liang, Department of Pediatrics, The First Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China, Fax: +86-571-87235128, E-mail: [email protected] Chun Lin Wang and Zhu Wei Fen: Department of Pediatrics, The First Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
Introduction Congenital adrenal hypoplasia (AHC) is a rare inherited disorder of adrenal gland development, characterized by the absence or near absence of the permanent zone of the adrenal cortex (1). AHC has an estimated incidence of 1 in 12,500 live births and can be inherited in an X-linked manner or as an autosomal-recessive disease (2, 3). Affected boys usually have primary adrenal failure
in infancy or early in childhood, including salt-wasting, hyperpigmentation, hyperkalemia, hyponatremia, reduction of serum glucocorticoid and aldosterone, and increase in plasma adrenocorticotropic hormone (ACTH). The typical adolescent presentation of AHC is hypogonadotropic hypogonadism (HH), characterized by puberty delay and, sometimes, by cryptorchidism (4). Mutations in the DAX1 gene (for dosage-sensitive sex reversal, AHC critical region on the X chromosome, gene 1; also called NROB1) in Xp21 are responsible for the AHC/HHG (OMIM 300200) (5, 6). An autosomal-recessive form of AHC is due to a mutation or deletion of the NR5A1 gene that codes for steroidogenic factor 1 (SF-1) on chromosome 9q33 (OMIM 184757) and also associated with HH. The DAX1 gene is composed of two exons of 1168 and 245 bp, respectively, separated by a 3385-kb intron and codes for an atypical, 470 amino acid that belongs to the orphan nuclear receptor superfamily that is structurally related to the ligand binding domain localized in the carboxyl terminus of other nuclear receptors but lacks the typical zinc finger DNA-binding domain in the amino terminus. DAX1, as a transcriptional repressor, plays a predominant role in gonadal and adrenal development and regulation of gonadotropin production. To date, more than 100 mutations in DAX1 have been reported, most of which are nonsense or frame-shift mutations that cause premature truncation of the protein. Most missense mutations clustered at the carboxyl terminus, and only a few were reported at the amino terminus (7, 8). In this study, we report a boy who presented with AHC with a de novo missense mutation (c.G379A, p.Ala127Thr) and a frame-shift mutation (c.999_1000insCTCA, p.Leu335ThrfsX54) of the DAX1 gene.
Materials and methods Case A 12-year-old boy was admitted to our department with a 2-day history of vomiting, diarrhea, and fatigue. The patient was born at term with weight appropriate for dates and with an Apgar score of 10 (at birth).
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344 Wang et al.: DAX1 and congenital adrenal hypoplasia His parents are healthy and there was no family h istory of adrenal insufficiency disease. When he was 8 years old, he was initially diagnosed with Addison’s disease, with the symptoms of dehydration, vomiting, abdominal pain, diarrhea, hyperpigmentation (especially in scrotum), hyponatremia (Na+, 24 mEq/L), and hyperkalemia (K+, 5.0 mEq/L). The serum cortisol was undetectable (
Chun Lin Wang, Zhu Wei Fen and Li Liang*
A de novo mutation of DAX1 in a boy with congenital adrenal hypoplasia without hypogonadotropic hypogonadism Abstract: We report the case of a 12-year-old boy with a de novo mutation in the DAX1 gene (for dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1; also called NROB1). He was born at term, Addison’s disease was diagnosed at 8 years with a salt-wasting syndrome, and then hydrocortisone substitution was taken; the child continued to develop normally. A reoccurrence of salt-wasting syndrome usually happened after an episode of an abrupt withdrawal of hydrocortisone substitution. Because of adrenal insufficiency without hypogonadotropic hypogonadism, he came to the clinic at 12 years of age and hypoplasia of adrenal glands was found by MRI scans. We proposed the diagnosis of congenital adrenal hypoplasia in this patient and identified a hemizygous mutation (c.999_1000insCTCA, p.Leu335ThrfsX389) in exon 1 of the DAX1 gene. To our knowledge, it is a de novo mutation that leads to a frameshift, a premature stop codon. In conclusion, it is very important to identify mutation in the DAX1 gene for a boy with adrenal insufficiency of unknown etiology. Keywords: adrenal insufficiency; DAX1; gene; hypogonadotropic hypogonadism. *Corresponding author: Li Liang, Department of Pediatrics, The First Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China, Fax: +86-571-87235128, E-mail: [email protected] Chun Lin Wang and Zhu Wei Fen: Department of Pediatrics, The First Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
Introduction Congenital adrenal hypoplasia (AHC) is a rare inherited disorder of adrenal gland development, characterized by the absence or near absence of the permanent zone of the adrenal cortex (1). AHC has an estimated incidence of 1 in 12,500 live births and can be inherited in an X-linked manner or as an autosomal-recessive disease (2, 3). Affected boys usually have primary adrenal failure
in infancy or early in childhood, including salt-wasting, hyperpigmentation, hyperkalemia, hyponatremia, reduction of serum glucocorticoid and aldosterone, and increase in plasma adrenocorticotropic hormone (ACTH). The typical adolescent presentation of AHC is hypogonadotropic hypogonadism (HH), characterized by puberty delay and, sometimes, by cryptorchidism (4). Mutations in the DAX1 gene (for dosage-sensitive sex reversal, AHC critical region on the X chromosome, gene 1; also called NROB1) in Xp21 are responsible for the AHC/HHG (OMIM 300200) (5, 6). An autosomal-recessive form of AHC is due to a mutation or deletion of the NR5A1 gene that codes for steroidogenic factor 1 (SF-1) on chromosome 9q33 (OMIM 184757) and also associated with HH. The DAX1 gene is composed of two exons of 1168 and 245 bp, respectively, separated by a 3385-kb intron and codes for an atypical, 470 amino acid that belongs to the orphan nuclear receptor superfamily that is structurally related to the ligand binding domain localized in the carboxyl terminus of other nuclear receptors but lacks the typical zinc finger DNA-binding domain in the amino terminus. DAX1, as a transcriptional repressor, plays a predominant role in gonadal and adrenal development and regulation of gonadotropin production. To date, more than 100 mutations in DAX1 have been reported, most of which are nonsense or frame-shift mutations that cause premature truncation of the protein. Most missense mutations clustered at the carboxyl terminus, and only a few were reported at the amino terminus (7, 8). In this study, we report a boy who presented with AHC with a de novo missense mutation (c.G379A, p.Ala127Thr) and a frame-shift mutation (c.999_1000insCTCA, p.Leu335ThrfsX54) of the DAX1 gene.
Materials and methods Case A 12-year-old boy was admitted to our department with a 2-day history of vomiting, diarrhea, and fatigue. The patient was born at term with weight appropriate for dates and with an Apgar score of 10 (at birth).
Brought to you by | University of California - San Francisco Authenticated | 10.248.254.158 Download Date | 9/5/14 2:19 PM
344 Wang et al.: DAX1 and congenital adrenal hypoplasia His parents are healthy and there was no family h istory of adrenal insufficiency disease. When he was 8 years old, he was initially diagnosed with Addison’s disease, with the symptoms of dehydration, vomiting, abdominal pain, diarrhea, hyperpigmentation (especially in scrotum), hyponatremia (Na+, 24 mEq/L), and hyperkalemia (K+, 5.0 mEq/L). The serum cortisol was undetectable (
