Disorders of Adrenal Development

Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, University College London, London, UK.
Endocrine development 02/2008; 13:19-32. DOI: 10.1159/000134753
Source: PubMed


Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected.

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    • "The differential diagnosis of hypoglycaemia in childhood should include adrenal cortical insufficiency. This can be due to congenital adrenal hypoplasia (33) due to a primary defect in adrenal development or defects in ACTH synthesis, processing, release and response (familial glucocorticoid deficiency) (34). "
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    ABSTRACT: Biochemical tests have been the basis for investigations of disorders affecting steroid hormones. In recent years it has been possible however to study the genes that determine functional enzymes, cofactors, receptors, transcription factors and signaling systems that are involved in the process. Analyses of mutations are available as a diagnostic service for only a few of these genes although research laboratories may be able to provide a service. Both biochemical and genetic research have brought to light new disorders. Some genes for transcription factors involved in the development of the endocrine organs have also been identified and patients with defects in these processes have been found. This paper will review general aspects of adrenal disorders with emphasis on clinical and laboratory findings. As with all endocrine investigations there are few single measurements that provide a definitive answer to a diagnosis. Timing of samples in relation to age, gender and time of day needs to be considered. Conflict of interest:None declared.
    Journal of Clinical Research in Pediatric Endocrinology 09/2009; 1(5):209-26. DOI:10.4274/jcrpe.v1i5.209
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    ABSTRACT: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood. We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease. CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders. CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders. CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process.
    Journal of Clinical Endocrinology &amp Metabolism 12/2008; 94(2):678-83. DOI:10.1210/jc.2008-1064 · 6.21 Impact Factor
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in the maintenance of basal and stress-related homeostasis. The hypothalamus controls the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which in turn stimulates the secretion of glucocorticoids from the adrenal cortex. Glucocorticoids, the final effectors of the HPA axis, regulate a broad spectrum of physiologic functions essential for life and exert their effects through their ubiquitously distributed intracellular receptors. Alterations in the activity of the HPA axis may present with symptoms and signs of glucocorticoid deficiency or excess. Detailed endocrinologic evaluation is of primary importance in determining the diagnosis and/or etiology of the underlying condition. We review the most common endocrinologic investigations used in the evaluation of the HPA axis integrity and function.
    NeuroImmunoModulation 02/2009; 16(5):272-83. DOI:10.1159/000216185 · 1.88 Impact Factor
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