ACTH-dependent precocious pseudopuberty in an infant with DAX1 gene mutation

Abstract

DAX1 gene (Xp21) expression is involved in the development of the hypothalamo-pituitary-gonadal and adrenal axes, and acts as a negative regulator of steroidogenesis. Mutations of this gene determine adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. We report the case of a 9-month-old boy referred for the study of macrogenitosomia and pubic hair development. He had presented acute adrenal crises in the neonatal period and, later, a clinical picture of peripheral precocious puberty. A mutation in the DAX1 gene was found (Trp291Arg) and a diagnosis of AHC was made. Replacement doses of hydrocortisone (HC) (10 mg/m2/day) failed to produce a feedback inhibition of adrenocorticotropic hormone (ACTH), and testosterone levels remained high. Testosterone and ACTH values normalized after HC was progressively increased to 18 mg/m2/day. In conclusion, peripheral precocious puberty in patients with DAX1 gene mutations appears to be secondary to the stimulus exerted by ACTH on melanocortin receptors in Leydig cells and to the overexpression of testicular steroidogenesis activators by the loss of transcriptional repression.

<b><i>NR0B1</i></b> Frameshift Mutation in a Boy with Idiopathic Central Precocious Puberty

“…Indeed, GnRH analog treatment ameliorated the physical symptoms and laboratory findings in 3 cases [Darcan et al, 2011;Durmaz et al, 2013;Koh et al, 2013]. Alternatively, adrenocorticotropic hormone (ACTH) overproduction secondary to adrenal insufficiency may underlie PP in AHC patients, because it was reported that the clinical features of 2 patients were lessened during glucocorticoid supplementation therapy [Domenice et al, 2001;Yeste et al, 2009]. Consistent with this, ACTH was suggested to exert a stimulatory effect on steroid biosynthesis in the testis [O'Shaughnessy et al, 2003].…”

“…Previous studies have shown that patients with AHC occasionally manifest early sexual maturation ( table 1 ) [Takahashi et al, 1997;Domenice et al, 2001;Argente et al, 2003;Ahmad et al, 2007;Loke et al, 2009;Yeste et al, 2009;Landau et al, 2010;Darcan et al, 2011;Durmaz et al, 2013;Koh et al, 2013]. Phenotypic severities of these patients vary from PP with pubic hair and advanced bone age to transient testicular/penile enlargement without additional symptoms.…”

A novel DAX-1 (NR0B1) mutation in a boy with X-linked adrenal hypoplasia congenita

“…However, some affected boys might develop pubertal sign up to Tanner stage 3, when puberty stops due to disrupted hypothalamic and pituitary release of gonadotropin-releasing hormone and gonadotropins, respectively (6). Similarly, a few patients with DAX-1 mutation were reported to develop ACTH-dependent transient precocious pseudopuberty during infancy/childhood (7,8).…”

A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita

“…To date, hundreds of different mutations in NR0B1 have been reported, including deletions, frameshift, and point mutations, with variable onsets of presentation, different degrees of mineralocorticoid and glucocorticoid insufficiency, hypogonadism, and in some instances precocious puberty. A clear genotype–phenotype correlation is yet to be defined …”