Adrenocorticotropin Insensitivity Syndromes

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 should the by the in a and should be significantly this The with FGD will almost always have a or cortisol some patients have cortisol A ACTH at the will be and of more are Addison’s as the most This be by a and in of and should be in the with FGD, will deficiency and a high in the with Addison’s This of a high ACTH with cortisol deficiency and a and is of an ACTH insensitivity as may be some in the case of the triple A In at presentation may be of the in patients with FGD that result from the and of the of ACTH of by the and the of patients with FGD at presentation as a result of or frequent As in other these may the may result in a of and in patients with ACTH which may occasionally the In patients, with cortisol deficiency or in the is in for other a ACTH is is and cortisol is and cortisol should the of for the in this will to this in patients with ACTH Addison’s or other adrenal A of other may be used in other at this Although the clinical and are not usually it may be to adrenal by of be by of a of FGD and the triple A syndrome may be more and this is in more a of and a may the of the syndrome in this the of ACTH insensitivity is in that only glucocorticoid with is has in of its As with the to be increased in of or is are of patients who have been for Addison’s with glucocorticoid and who of it to continue with the and who to have For this it may be for patients with childhood Addison’s and cases in a is to the since of a of FGD will the to the to In with may be more only one to be The first of FGD the that the had been in two and that the was to be inherited In other cases described the familial nature of the disorder and the of in the neonatal this The that the of these patients and had adrenal with of was of an et al. patients with this and that it may be although recognized that the of not by many have the that this is an disorder of in A of have been to the of which are as 1. A in the adrenal receptor for ACTH. This is the most frequent by the of who have this The to this have been that since these patients become ACTH is to the the adrenal (see a of the adrenal which may a cell to this evidence this from et al. who ACTH binding to in a with FGD, in to binding in from a This is a result in since is evidence that the receptor is in and it may have been the result of binding A in the response to ACTH receptor is an to a receptor although it from the that many or most are to many other cell and receptor that not to in these some was to this by the of et al. in who cell ACTH binding and cAMP a to cortisol cAMP was the that this that the from a to cAMP A in was by who had the to examine the adrenal or from patients Since in most cases these to a of of the fasciculata and it was that this was the primary of the This of be with the of The of adrenal is later in more (see of the adrenal was originally by et al. in of the that some patients have to deficiency, the reported by and As will be later in this this adrenal is frequently seen in patients with the triple A and it is that may be some in the of FGD and the triple A 1. ACTH receptor in The ACTH receptor was originally in by et al. who in the paper reported the of a receptor for which was in three other distinct of this of which are and comprise the receptor The principal features of of these are in 1. appears that although ACTH is an for of these the receptor that is in and that is for the steroidogenic of ACTH is the which is with the ACTH of the as an this receptor In is evidence that the receptor is also in the adrenal its is of the features of the receptor and some of of the features of the receptor and some of In the of the receptor was we had the of this gene in a with a typical of FGD, which had with neonatal by frequent and in childhood. to a in the and This which in the to and with the in the and have subsequently reported a of different and in this gene that in or forms in patients with the disorder In cases these with the in the The current of these is summarized in and Fig. In some cases the nature of the will to of the receptor and it is to be expected that the receptor will be In other cases it is the should to the Investigation of these cases a for of the in a cell that of with of the such a has been of the ACTH receptor the of the and to in patients with and for of and some ACTH receptor and of and some ACTH receptor and had some in the and receptor a in This only of that by an receptor in these to that the receptor to ACTH, for an This is with the clinical in some patients with this that by the ACTH an of cortisol be by the adrenal to the that with some other et al. used a different in which the ACTH in the cell which has that the and in this in to the these results are by the response from the is to the cell a of the cell that to the ACTH receptor This to be of ACTH in the of background and is results and A. D. A. and A. This that an adrenal is for receptor that of the ACTH receptor for some cases of FGD, the nature of the This also these patients become since this results from excessive ACTH of the receptor ACTH is an at this receptor with only is that although have been described in the case of a of other G have not been described in the case of the ACTH have the ACTH receptor in from a of adrenal and reported This not this it be an uncommon of and As these different are to the receptor to different the that we originally described has to be the most of these and we have identified it in from in a form and as a with a more in more of these patients have a and it that the in this in the ACTH receptor some interesting physiological Since a in of this gene result in to be that the gene originally by et al. the ACTH and that it is the only ACTH is evidence that also the which has been to in to ACTH at high it appears that the high of ACTH in FGD are not high to this receptor for of cortisol and is that the ACTH receptor has an in the and of the of the adrenal and that the receptor is to steroidogenesis are this receptor and the steroidogenic genes in these has been a the of ACTH, other and other factors in adrenal Since the ACTH receptor is for ACTH it that patients with FGD an with which the of ACTH be patients have adrenal an for ACTH. of these have become for adrenal from a who from FGD by an are and with from a of the of A and The the of a adrenal with evidence of fasciculata or This is typical of of the other of adrenal in FGD of the adrenal in a who had of a who had in FGD resulting from a of the ACTH receptor and two who had as a result of the triple A syndrome the of the in and by the with of the fasciculata and and in the with in are with the of of and of The for these ACTH receptor is not with disorder of the of circulating ACTH or cortisol have been reported in it may be that a more is to and for this the has been et al. reported that the of a with the and had to in a this may be by in the response reported the to in who for a different ACTH receptor had a appears that the results of are and may not be for this receptor cases of FGD are with the of the ACTH that we have to in only are cases with or is that are in of the gene from the as the it is true that in are not a of genetic As a result of the it is to at in the The ACTH receptor was to the of we the of a of in this by in the with ACTH receptor This that the and of the ACTH receptor gene at of and and a although in is for the The results of this that, in the case of of the FGD ACTH receptor the was not with an for the ACTH receptor gene This result is since it it that the clinical of FGD be by at least one other genetic For of we have the FGD for the syndrome that is not to the ACTH receptor in to the FGD for the by of the ACTH For the of this we also the FGD for patients who have a ACTH and in is that ultimately the gene for this syndrome will be which may a more descriptive the of this have the clinical features of the two of FGD in the of that may the nature of the in FGD in ACTH, ACTH or other the clinical presentation not these disorders an unexpected was in the patients with FGD have that the patients with ACTH receptor have a that is This is are summarized in Fig. as in patients with FGD with and patients ACTH receptor by of Although it has not been in or have been identified in of these patients to In some patients, it has been that the rate of is it is to a of excessive glucocorticoid that this the of FGD as as unexpected of ACTH A the two of FGD may be by the adrenal et al. described the adrenal from a who a and who was this had a in a of FGD had been and who had to glucocorticoid from the first are different from of other FGD patients from patients with the triple A and with of and with and is distinct from the seen in are of from a that we have who had a ACTH receptor not In the molecular of FGD has not only the of in the ACTH receptor in some has it in has unexpected the of ACTH and and has with the for ACTH in and it has the of at least one other gene that, to an almost syndrome from that by ACTH receptor The of this gene in ACTH and adrenal 1. In and described a who with isolated glucocorticoid deficiency of the with as the result of and of the with is one other of a with FGD in was as an This later In 1978 Allgrove et al. first described two of with the of the of adrenal of the and which has become known as Allgrove the a of with patients with the of adrenal and have been and the triple A syndrome became This syndrome be from FGD by the of the the first of with that as in of the described patients Although in most cases hypoglycemia and to the or is the and most which be by and or in one in this was The of patients have isolated glucocorticoid deficiency, in may also become at a later not results from a disorder to of the adrenal at a has been by of the adrenal of the in of the of from to This may adrenal by In and to or as a result of may be the feature that the to and is the most to with the of and adrenal have been described. This was as a distinct entity the syndrome the of the primary features of the triple A Since the of the it has become that many patients also in to the three which result in a that the of and may be of the may be to the of to and of the has been seen in the form of that be and have been described as may be to in patients is although in two cases of the was seen In the case of have been in one and which and binding in the these results not an for the in may and a that is typical of a and is by of the and In many patients a is reported which is to an of the and The may also be of the seen in patients with hereditary such as of and other and of and with with with and The of and are summarized (see of patients from which may be manifest by of the and of or to and et al. have the syndrome to the of these that the of one should a for other In of patients, skin are of and with which may only be in the of of the and The clinical is by a of that have been described in a of these are of the triple A or are features as a result of distinct or, in the case of as a consequence of glucocorticoid is not include of with and syndrome and features that we have include one who with high with and patients have with and a with resulting in a of In to the in the of of the is a and of the a gene or, more of the gene The triple A syndrome an of The evidence for this is that the with a patients are to and is an increased of is that the triple A syndrome is a as is genetic are of of the with are reported from of the that this is to have a Glucocorticoid deficiency be by with and of is with may that require or In cases it may be to to feeding. Glucocorticoid to have the and of are for the and or for the other The molecular of the triple A syndrome is The and of clinical features in this a and in to its The evidence from the of other gene and are 1. of other of patients with triple A syndrome has the disorders with or the Addison’s adrenal deficiency, of the adrenal from patients who have from this are in are in adrenal with an almost of the fasciculata and of the and adrenal In this are to the adrenal of many patients with adrenal from two patients with the triple A syndrome are in Fig. features include and of the with primary adrenal of patients who have features of the are a and a of the with of and only a in to from the with and seen (2). the of of patients with triple A syndrome not in and reported a who with glucocorticoid deficiency with and As in triple A syndrome patients, ACTH In this from which was with the was the and the a as by This to patients in the features and not glucocorticoid the not or of this who might have been of for genetic The that this syndrome may have had a genetic from of two of in which primary adrenal has been reported In these two more a genetic or that this syndrome has to ACTH insensitivity The is a disorder by of the with of and The of this disorder is later in this (see In one not described in patients with triple A syndrome have a of in the of in include and C. A. D. 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The from the of the triple A syndrome of this are from A. et by of the triple A gene and and The the genetic to the the is at the of this are from A. et by of the the triple A gene we a and identified the and as the of the triple A The genetic these two is from the with three at least at the and at the triple A gene In we a with from this a of at and the triple A in the and et al. have the triple A gene by in genetic in a we one with the clinical of triple A and one with only and of This was the first that the syndrome and the triple A syndrome may be one by in the gene it will be with the syndrome in in the known genes are to the triple A are genes the gene a gene the genes for receptor the transcription the the protein kinase and A receptor and and of these genes appears as a that the triple A The uncommon of the triple A a gene The of the and as as the adrenal and the of the in some patients a or and of A or a transcription for genes in the as the for the gene action The of the triple A syndrome in the of the gene and the in some triple A patients an of one or more genes in the of this the of a gene is by the of this the of the genes at least in the of the in the triple A syndrome The gene genes 5, and in genes of the gene have been described in form of of and and with resulting in a of primary and was seen in some triple A patients (see A and is described for the syndrome and the syndrome et al. to the and genes and et al. of syndrome to a a gene for This the the and in some triple A patients are to in should be in the known other unidentified genes in this be as has been by et al. the of the a was to by in in have been to be for various of the by with of the and et al. that an gene be a for a In to the that some features of the of some in these should this feature is to adrenal of is to this gene the triple A The of the gene triple A syndrome may of cell and as as of the of the molecular of this disorder may of in and may the of at the of the ACTH is almost always an inherited the only patients with Addison’s in which the ACTH This is a et al. reported a of isolated from a with Addison’s with the syndrome and that this cortisol by adrenal was to this and this was seen as evidence for the of receptor In a more et al. the of Addison’s in the of Although cortisol only of these be by was that ACTH receptor not a of Addison’s ACTH insensitivity syndromes are a group of diseases that result from three or more are glucocorticoid in FGD is In the current of the of the triple A is that be and the and of the only be by at diseases are in of what adrenal and ACTH receptor in patients with FGD have a the of this such as the of these patients to be that the will the of the gene FGD and the triple A which will and to this review to the to who to these diseases and in many the of FGD and triple A and the by have from with most and and the of and also the of and the of and in of the adrenal and A. and for of and of for and of are to of for with the of the ACTH receptor in the triple A