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Adrenal hypoplasia congenita (AHC) constitutes a rare disorder of adrenal gland development inherited either in an autosomal recessive or in an X-linked manner. The two forms differ with respect to the histological appearance of the adrenal gland as well as the accompanying comorbitities. Autosomal
The autosomal recessive form of AHC, also called the miniature adult form, is characterized by small adrenal glands with permanent adult cortex zone and absent or minimal fetal cortex. The permanent zone is smaller than normal and has well defined structural zonation. This form of AHC may also occur sporadically and has been associated with congenital abnormalities of central nervous system and pituitary-hypothalamic development and function. In the X-linked form of AHC, also called the cytomegalic form, the mature adult permanent zone fails to develop resulting in dysfunctional adrenal glands. The residual adrenal cortex
The autosomal recessive form of AHC, also called the miniature adult form, is characterized by small adrenal glands with permanent adult cortex zone which has well defined structural zonation but is smaller than normal. This form of AHC may also occur sporadically and has been associated with abnormalities of the central nervous system. In the X-linked form of AHC, also called the cytomegalic form, the mature adult permanent zone fails to develop, resulting in dysfunctional adrenal glands. The residual adrenal cortex is structurally disorganized with large vacuolated 'cytomegalic' cells that resemble the cells of fetal adrenal cortex.
Adrenal hypoplasia congenita (AHC) constitutes a rare disorder of adrenal gland development with an estimated incidence of approximately 1:12,500 live births (1). The condition is inherited either in an autosomal recessive or in an X-linked manner, with the two forms differing with respect to the histological appearance of the adrenal gland.
The gene responsible for the X-linked AHC was initially identified as part of a contiguous gene deletion syndrome characterized by AHC, glycerol kinase deficiency and Duchenne muscular dystrophy (2, 3). The gene was initially designated as DAX1 [Dosage Sensitive Sex-reversal (DSS), Adrenal Hypoplasia Congenita (AHC), critical region on the X chromosome, gene 1], and later renamed to NR0B1 in accordance with the nomenclature system for nuclear receptors. DAX1/NR0B1 gene is mapped to the Xp21.3 region of the X chromosome (4, 5) and encodes an orphan nuclear receptor that is expressed in the developing as well as adult adrenal cortex, ventromedial hypothalamus, gonads and pituitary gonadotrope cells (6-8). This pattern of expression highlights a crucial role of DAX1 receptor in the development and function of the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis. In particular, DAX1 appears to function primarily as a transcriptional repressor that interacts with steroidogenic factor 1 (SF1) and inhibits SF1-mediated transactivation of genes involved in the biosynthesis of steroid hormones and the development of the HPAG axis (9).
It is now well established that duplications of DAX1/NR0B1 region on the X chromosome are associated with dosage-sensitive XY sex-reversed female phenotype (10), whereas mutations in this gene result in the X-linked form of AHC (11, 4, 5). To date, in accordance with the Human Gene Mutation Database (HGMB), mutations in DAX1/NR0B1 gene have been identified in patients with the X-linked form of AHC. These are mainly frameshift and nonsense mutations, whereas missense mutations in NR0B1 are rarely reported in patients with the X-linked form of AHC.
Due to the X-linked pattern of inheritance, this form of AHC primarily affects males, presenting with adrenal insufficiency early in childhood. A bimodal distribution regarding the age of onset has been reported with the majority of cases presenting with severe salt wasting shortly after birth and others presenting with insidious adrenal failure between the ages of 2-9 years (a). Commonly, most patients with X-linked AHC who survive past childhood develop hypogonadotropic hypogonadism (HH) which is usually detected because of pubertal development disturbance. The condition is the result of mixed hypothalamic and pituitary defects in the secretion of gonadotropins (b).
However, a considerable phenotypic variability among patients with X-linked AHC is recognized and genotype-phenotype correlations are elusive in the majority of cases reported (c). In particular, female carriers developing adrenal insufficiency (Bernard 2006) or hypogonadotropic hypogonadism (Seminara 1999) have been reported. In addition, phenotypic variability may occur with the same mutation within the same family (Bernard 2006). Also variable is the degree of gonadotropin deficiency (). These observations suggest the existence of modifier genes as well as environmental factors that impact on DAX1/NR0B1 function () and illustrate the importance of genetic counseling for known carrier females.
We report a novel missense DAX1/NR0B1 mutation in a male patient presenting with AHC and hypogonadotropic hypogonadism.