Pediatric Adrenal Diseases

Workshop, Turin, May 2010

L. Ghizzoni, M. Cappa, G. P. Chrousos, S. Loche, M. Maghnie, L. Ghizzoni, M. Cappa, G. P. Chrousos, S. Loche, M. Maghnie

• Publisher: S. Karger
• Year: 2010
• Print ISBN:
  9783805596435
• eBook ISBN:
  9783805596442
• Topic: Medicine
• Subtopic: Genetics in Medicine

Written by experts and specialized investigators, this book presents a detailed overview of the recent progress in our understanding of the adrenal cortex and its pivotal roles in homeostasis. Genes, molecules and cell compartments directly or indirectly involved in the complex steroidogenesis pathway as well as the resulting end-hormones glucocorticoids, mineralocorticoids and androgens are analyzed. Furthermore, the defects of the genes responsible both for common and rare adrenal disorders are presented. The interactions of the adrenal cortices with the adrenal medulla and their importance in the integration of adrenocortical and adrenomedullary function are discussed. The complex molecular pathophysiology of congenital adrenal hyperplasia is presented; long-term effects of the disorder and the still controversial antenatal therapy are examined. Finally, expert review chapters discuss autoimmune Addison disease and the adrenoleukodystrophy/adrenomyeloneuropathy syndrome. Presenting novel research findings in adrenal gland physiology and pathophysiology, this book is a useful tool not only for pediatric endocrinologists, but also for clinicians and researchers studying human development, organogenesis, mitochondrial biology, nuclear receptors, stress biology and pharmacology.

Ghizzoni L, Cappa M, Chrousos G, Loche S, Maghnie M (eds): Pediatric Adrenal Diseases.
Endocr Dev. Basel, Karger, 2011, vol 20, pp 38-46

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Role of DAX-1 (NR0B1) and Steroidogenic Factor-1 (NR5A1) in Human Adrenal Function

Ranna El-Khairi · Alejandro Martinez-Aguayo · Bruno Ferraz-de-Souza · Lin Lin · John C. Achermann

Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, University College London, London, UK

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Abstract

The nuclear receptor transcription factors DAX-1 (NR0B1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46,XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46,XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46,XY disorders of sex development phenotypes. These conditions range from 46,XY females with streak gonads and müllerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations.

Copyright © 2011 S. Karger AG, Basel

The human adrenal gland first develops from an area of intermediate mesoderm at around 4 weeks postconception and undergoes rapid growth and differentiation during fetal life into a fully functional organ capable of releasing cortical and medullary hormones. Defects in several different transcriptional, signaling and mitogenic pathways can result in underdevelopment of the adrenal gland, leading to the clinical condition congenital adrenal hypoplasia (or adrenal hypoplasia congenita (AHC)) [1]. Many of these processes also regulate adrenal function postnatally and throughout the lifespan, potentially resulting in primary adrenal insufficiency when disruption occurs.

In this chapter we will focus on the role of the nuclear receptor transcription factors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) in human adrenal development and function. The importance of these factors in human adrenal disease is now well established, but the spectra of phenotypes associated with these conditions continue to expand.

DAX-1 (NR0B1)

DAX-1 (dosage-sensitive sex reversal - AHC critical region on the X chromosome 1) is an atypical nuclear receptor first reported in 1994 to be associated with X-linked AHC (OMIM 300200) [2]. The genetic locus for this transcription factor was mapped to the short arm of the X chromosome (Xp21) as X-linked AHC can occur as part of a contiguous gene deletion syndrome with glycerol kinase deficiency and Duchenne muscular dystrophy. DAX1 (officially called NR0B1) encodes an atypical nuclear receptor with a ligand-like binding domain at the carboxyl-terminus and an unusual amino-terminal region containing 3.5 repeats of an LXXLL motif-containing sequence (fig. 1). DAX-1/NR0B1 is expressed in key areas of the adrenal gland, gonad, and central reproductive axis during development and postnatal life, consistent with its role in the development and function of these endocrine systems.

The ‘classical’ clinical features of X-linked AHC are: (1) primary adrenal failure presenting in early infancy or childhood; (2) hypogonadotropic hypogonadism presenting as absent or arrested puberty, and (3) impaired spermatogenesis [2, 3]. Boys with this condition usually need glucocorticoid and mineralocorticoid replacement throughout life and induction of secondary sex characteristics with testosterone. In general, GnRH pumps or recombinant gonadotropins are not effective at reversing azoospermia [4, 5], although TESE/ICSI following prolonged gonadotropin treatment has been successful [Christin-Maitre, unpubl. data].

Approximately one-third of boys with X-linked AHC have a deletion of DAX1 (NR0B1) [6]. A contiguous gene deletion syndrome affecting another Xp locus gene occurs in about half of these cases. Approximately two-thirds of individuals have point mutations in the DAX1 (NR0B1) gene. These changes can be insertions, deletions or nonsense changes scattered throughout the two exons. The most common point mutations are frameshift changes (approx. 50%) and nonsense mutations (approx. 30%) (fig. 1, upper panel). Missense mutations have been reported in 20% of patients with point mutations and are mostly located within the putative ligand-binding region of DAX-1 (fig. 1, lower panel) [6]. These changes can cause several different defects such as altered protein structure, reduced protein-cofactor interactions, or disrupted nuclear localization [7, 8]. Missense changes in the amino-terminus of DAX-1 are very rare.

In addition to the classic phenotype of X-linked AHC described above, several variant or partial phenotypes have now been reported (table 1). These include predominant mineralocorticoid insufficiency [9], hyperandrogenism in early childhood [10], early puberty with later pubertal arrest [11], and adrenal insufficiency in a girl with an Xp deletion and extreme skewed X-inactivation [12]. Furthermore, late-onset X-linked AHC has been described in several men who presented with primary adrenal failure or hypogonadotropic hypogonadism in late adolescence or early adulthood [13, 14]. In some cases, these milder conditions may be due to missense mutations with partial loss-of-function, or to premature stop codons at the amino-terminus of the protein with subsequent translation of an alternative isoform of the DAX-1 protein that retains partial function due to preserved LXXLL domains [13, 14].

Fig. 1. DAX-1 structure and a selection of the nonsense (•), frameshift (O) and missense changes reported. Those changes associated with a milder phenotype (*) or isolated mineralcorticoid deficiency (**) are indicated. The potential LXXLL domains are shown below the protein structure, LBD Ligand-binding domain Modified with permission from Lin et al. [6]. Copyright: The Endocrine Society, 2006.

The precise functional role of DAX-1 in adrenal development and function remains unclear. Many studies have shown that DAX-1 can act as a repressor of gene transcription through its effect on the related nuclear receptor steroidogenic factor-1 (SF-1, NR5A1). Indeed, crystallography of DAX-1 bound to the related receptor LRH-1 (NR5A2) predicts that two DAX-1 proteins bind to the ligand-like binding domain of the partner, thereby potentially altering its activation capacity [15]. However, such a repressor role for DAX-1 is paradoxical given the fact that loss-of-function changes in DAX-1 result in adrenal hypoplasia. Two alternative hypotheses have been suggested. Firstly, DAX-1 may be needed to prevent adrenal stem cell differentiation, so that expansion of a pool of progenitor stem cells can occur before these cells mature into a mature steroidogenic lineage [7]. Loss of DAX-1 repression would result in premature differentiation without prior expansion, so that the total number of cells is reduced and adrenal hypoplasia results. Alternatively, DAX-1 may actually function as an activator of gene transcription in certain cases, such as with the steroid receptor RNA activator or on specific promoters (e.g. pre-B-cell leukemia transcription factor 1). These activator effects may be cell- or time-specific [16, 17].

Table 1. Phenotypes associated with changes in DAX-1 (NR0B1)

Clinical phenotype	Example ref.
Primary adrenal insufficiency, HH, infertility	2, 3
Isolated mineralocorticoid insufficiency	9
Premature sexual development	10, 11
Adrenal insufficiency or delayed puberty in girls with skewed X inactivation or gene conversion	12
Late-onset X-linked AHC or HH in early adulthood	13, 14, 30
Presymptomatic diagnosis	31
AHC = Adrenal hypoplasia congenita, HH = hypogonadotropic hypogonadism

Although the exact mechanisms underlying X-linked AHC and its associated reproductive consequences remain to be fully elucidated, understanding the underlying pathogenic mechanism is important to gain new insight into this condition and if new treatment...

Table of contents

• Cover Page
• Front Matter
• Role of Mitochondria in Steroidogenesis
• The Physiology and Biochemistry of Adrenarche
• Update on the Corticomedullary Interaction in the Adrenal Gland
• Role of DAX-1 (NR0B1) and Steroidogenic Factor-1 (NR5A1) in Human Adrenal Function
• Functional and Physiological Consequences of StAR Deficiency: Role in Lipoid Congenital Adrenal Hyperplasia
• P450 Side-Chain Cleavage Deficiency – A Rare Cause of Congenital Adrenal Hyperplasia
• Clinical and Biochemical Consequences of P450 Oxidoreductase Deficiency
• Molecular Genetics of 21- Hydroxylase Deficiency
• Brain Development and Cognitive, Psychosocial, and Psychiatric Functioning in Classical 21- Hydroxylase Deficiency
• Long-Term Outcome of Prenatal Dexamethasone Treatment of 21-Hydroxylase Deficiency
• Role of Genetic Variation in Regulation of Aldosterone Biosynthesis
• Circadian CLOCK-Mediated Regulation of Target-Tissue Sensitivity to Glucocorticoids: Implications for Cardiometabolic Diseases
• Glucocorticoid Resistance
• Mineralocorticoid Receptor Gene Variants as Determinants of HPA Axis Regulation and Behavior
• Adrenoleukodystrophy
• Autoimmune Addison's Disease
• Optimal Glucocorticoid Therapy
• Modulation of Glucocorticoid Metabolism by the GH-IGF-I Axis
• Effects of Glucocorticoids on the Growth Plate
• Growth Hormone Treatment in Children on Chronic Glucorticoid Therapy
• Ancient History of Congenital Adrenal Hyperplasia
• Author Index
• Subject Index