Adrenocorticotropin Insensitivity Syndromes

Abstract

I. Introduction II. Familial Glucocorticoid Deficiency A. Clinical presentation B. Investigation C. Treatment D. Pathogenesis III. Triple A Syndrome A. Clinical features B. Treatment C. Pathogenesis D. Mapping of triple A syndrome gene E. Candidate genes IV. Acquired ACTH Resistance V. Conclusions ACTH INSENSITIVITY syndromes comprise an uncommon group of disorders that, current evidence suggests, have at least three different molecular etiologies. The aim of this review is to examine the various forms of clinical presentation in conjunction with the current knowledge of the molecular and genetic background of these diseases, which as will be seen, reveals some interesting and unexpected physiological and anatomical relationships. The principal pathways by which ACTH stimulates adrenal steroidogenesis are summarized in Fig. 1. The syndrome of ACTH insensitivity was originally described by Shepard et al. (1) in 1959 in a paper entitled “Familial Addison’s Disease,” which reported the case of two sisters who had what has subsequently become known most frequently as familial glucocorticoid deficiency, isolated glucocorticoid deficiency, adrenal unresponsiveness to ACTH, or hereditary unresponsiveness to ACTH. For uniformity, and since it was the first of these terms to be coined and has been most frequently used in the literature, we continue to refer to this disorder as familial glucocorticoid deficiency (FGD), although the other terms are equally descriptive (MIM*202200). Essential features of the mechanism of action of ACTH in stimulating steroidogenesis in the adrenal fasciculata cell. ACTH binds to and activates its cognate seven-transmembrane domain receptor at the cell surface, resulting in activation of the heterotrimeric G protein by exchange of GTP for GDP and dissociation of the α-subunit from the βγ-subunits. Gsα then stimulates membrane-associated adenylate cyclase to synthesize cAMP, which in turn activates protein kinase A (PKA) in the cytosol. The catalytic subunits of PKA dissociate and phosphorylate target factors, which include the cAMP response element binding protein (CREB). CREB and other unidentified factors which may also be substrates for PKA then activate the steroidogenic acute regulatory protein (StAR) protein and induce the transcription of the steroidogenic enzymes CYP11A (P450 scc), CYP17 (17α-hydroxylase), CYP21 (21-hydroxylase), and CYP11B1 (11β-hydroxylase), which ultimately results in an increased rate of cortisol synthesis. Although it had been recognized previously as a variant of FGD, the other distinct syndrome of ACTH insensitivity that we shall discuss was identified as such in a paper by Allgrove et al. in 1978 (2). This syndrome became known as Allgrove syndrome or, more recently, as the triple A syndrome for reasons that will be described. As we shall show, this is a distinct clinical and genetic entity that shares with FGD only the feature of ACTH insensitivity. The typical presentation of patients with ACTH insensitivity is almost always as a consequence of glucocorticoid deficiency. Excessive skin pigmentation as a result of high circulating ACTH is occasionally reported as one of the primary complaints. Since these disorders are inherited diseases (see below), it might be expected that glucocorticoid deficiency should be manifest in the neonatal period. Although this is true for some patients, many are not diagnosed until infancy or later childhood. The nature of the clinical presentation in the neonate differs from that in later childhood and in most patients takes the form of hypoglycemia (3–8). This may not be profound and usually responds to more frequent feeding. Often these patients are significantly jaundiced and may require phototherapy (4, 5, 7, 8). In some cases this appears to result from a transient hepatitis, which may be glucocorticoid dependent (9). Perhaps surprisingly, excessive pigmentation of the skin is occasionally seen the first of although this is usually first and or as is a feature in infancy and childhood. may at this with a that may be will frequent which an to feature of FGD is childhood which responds to of glucocorticoid a of other features frequent and to and skin pigmentation be features be with a of childhood Addison’s and in many patients this is the FGD differs from Addison’s in one patients with FGD deficiency, and of and This the that by the adrenal is the of and is of ACTH, although ACTH in the of the adrenal are the of ACTH. In and are from the from of in the known as Although to the for it is that ACTH is for adrenal since patients with FGD evidence of an and have adrenal patients with the clinical of FGD have been reported to be 7, for this has been and not to have been of the of the patients a of or adrenal or other with adrenal resulting from other such as Addison’s are not and the excessive usually clinical is in these patients, and the in This may be of in the of the (see The described should to a of an to which in the