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Departments of Endocrinology (A.J.L.C.), St. Bartholomew’s and the Royal London School of Medicine and Dentistry, West Smithfield, London EC1A 7BE, United Kingdom; and Children’s Hospital (A.W.), Technical University Dresden, D-01307 Dresden, Germany
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Abstract |
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 Top Abstract I. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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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 (MIM1202200).
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II. Familial Glucocorticoid Deficiency |
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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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, 4, 5, 6, 7, 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 within the first month of life (3, 4, 10), although this phenomenon is usually first noted between 5 and 12 months (1, 3, 6, 11) or even later.
Hypoglycemia, sometimes manifesting as convulsions, is often a presenting feature in infancy and childhood. Alternatively, children may present at this time with a significant infective episode that may be fatal (1). Others will exhibit frequent minor infections, which take an unusually long time to disappear. Another occasional presenting feature of FGD is childhood asthma, which responds to replacement doses of glucocorticoid (e.g., Ref. 7).
At presentation, a history of other features including frequent infective episodes, lethargy and malaise, failure to thrive, and unusual skin pigmentation can often be elicited. Such features would be entirely consistent with a diagnosis of childhood Addison’s disease, and in many patients this is the initial working diagnosis. FGD differs from Addison’s disease in one major respect however: patients with FGD never develop mineralocorticoid deficiency, and thus no disturbance of electrolyte balance, no dehydration, and no salt wasting. This reflects the fact that mineralocorticoid production by the adrenal cortex is primarily under the control of angiotensin II and is relatively independent of ACTH, although ACTH can normally stimulate aldosterone production in the short term.
Other steroid products of the adrenal cortex are under the control of ACTH. In particular, androstenedione and dihydroepiandrosterone are mostly secreted from the zona reticularis cells from around 7 yr of age in the process known as adrenarche (12). Although considerable debate continues to surround the trigger for adrenarche, it is clear that ACTH is required for normal adrenal androgen secretion, since patients with FGD lack any evidence of an adrenarche and often have undetectable adrenal androgens (13).
Several patients with the clinical diagnosis of FGD have been reported to be unusually tall (1, 3, 7, 11, 14, 15, 16, 17). No endocrinological explanation for this has been apparent, and when investigated, there do not appear to have been disturbances of the measurable components of the growth axis (7). Some patients show a marked acceleration of their bone age before puberty despite low or undetectable adrenal androgens or other sex steroids. Patients with adrenal failure resulting from other causes, such as autoimmune Addison’s disease, are not unusually tall (18), and the excessive height usually predates any clinical intervention. Puberty is neither advanced nor delayed in these patients, and the enhanced stature is, in any case, apparent well before puberty begins. This phenomenon may be of significance in understanding the etiology of the disease (see below).
B. Investigation
The symptoms described above should lead to a measurement of an
0800 to 0900 h plasma cortisol, which in the normal child should
exceed the minimum value quoted by the laboratory involved (usually
200–300 nmol/liter), and, especially in a stressed and sick child,
should be significantly greater than this minimum level. The patient
with FGD will almost always have a low or undetectable cortisol
concentration. Occasionally, some patients have low normal
cortisol values.
A plasma ACTH taken at the same time will inevitably be markedly elevated, and values of more than 1000 pg/ml are commonly found. Such findings suggest Addison’s disease as the most likely cause. This diagnosis can often be rendered unlikely by demonstrating a normal electrolyte balance, and in support of this, renin and aldosterone measurements should be near normal in the supine patient with FGD, but will indicate aldosterone deficiency and a high renin in the patient with Addison’s disease. This combination of a high ACTH with cortisol deficiency and a normal renin and aldosterone is indicative of an ACTH insensitivity syndrome, although, as outlined below, there may be some exceptions in the case of the triple A syndrome.
In fact, at initial presentation there may be minor disturbances of the renin-aldosterone axis in patients with FGD that probably result from the varying and opposing influences of 1) the absence of any ACTH stimulation of aldosterone production by the zona glomerulosa (5, 19); and 2) the underlying illness of patients with FGD at presentation as a result of infection or frequent hypoglycemia. As in any other patient, these disturbances may stimulate the renin-aldosterone axis. These influences may therefore result in a broad range of renin and aldosterone levels in patients with ACTH resistance, which may occasionally confuse the diagnosis.
In all patients, including those with less severe cortisol deficiency or in whom the diagnosis is in doubt for other reasons, a standard short ACTH stimulation test is required. Synthetic ACTH[1–24] (250 µg/m2 body surface area; maximum 250 µg) is given intravenously, and plasma cortisol is measured after 30 and 60 min. Normally, cortisol should exceed the upper limit of normal for the laboratory involved (500–580 nmol/liter) in this time but will fail to achieve this level in patients with ACTH insensitivity, Addison’s disease, or other adrenal disorders.
A number of other investigations may be used in excluding other
diagnoses at this time. Although the clinical history and physical
signs are not usually suggestive, it may be helpful to exclude
congenital adrenal hyperplasia by measurement of plasma
17
-hydroxyprogesterone. Likewise, adrenoleukodystrophy could be
excluded by measurement of very-long-chain fatty acids. Distinction
between a diagnosis of FGD and the triple A syndrome may be more
difficult, and this is discussed in more detail later. However, a
Schirmer test of tear production and a barium swallow may make the
diagnosis of the latter syndrome in this situation.
C. Treatment
After initial resuscitation, the treatment of ACTH insensitivity
is relatively simple in that only glucocorticoid replacement with oral
hydrocortisone is required. Occasionally oral dexamethasone has
advantages in view of its longer action. As with any patient taking
glucocorticoids, the dose needs to be increased in times of stress or
injury. No mineralocorticoid replacement is needed.
We are aware anecdotally of patients who have been started on treatment for Addison’s disease with glucocorticoid and mineralocorticoid replacement, who have, of their own accord, found it unnecessary to continue with the mineralocorticoid component, and who on reinvestigation were found to have FGD. For this reason it may be valuable for clinicians managing patients with childhood Addison’s disease, and especially those cases in whom a sibling is affected, to reconsider the initial diagnostic criteria, since establishment of a diagnosis of FGD will alter the advice given to parents over the risk to further offspring. In addition, compliance with steroid replacement may be more effective if only one steroid needs to be replaced rather than two.
D. Pathogenesis
The first description of FGD highlighted the point that the
diagnosis had been made in two sisters, and that therefore the disease
was likely to be inherited (1). In other cases described shortly
afterward, the familial nature of the disorder and the appearance of
symptoms in the neonatal period supported this notion (15). The
demonstration that the parents of these patients were healthy and had
no adrenal abnormality, combined with reports of parental consanguinity
(20), was suggestive of an autosomal recessive inheritance. However,
Migeon et al. (3) reviewed six male patients with this
disease and concluded that it may be X-linked, although they recognized
that the data of others did not necessarily support this.
Subsequent reports by many authors have supported the view that this is
an autosomal recessive disorder of greater prevalence in consanguineous
families (14).
A number of hypotheses have been put forward to explain the origin of FGD. These fall into four groups which are as follows:
1. A defect in the adrenal receptor for ACTH. This is the most frequent proposal made by the majority of authors who have speculated on this question (e.g., Refs. 3, 14) The main drawbacks to this proposal have been that since these patients become pigmented, their ACTH is able to act on the melanocyte. Second, the adrenal histology (see below) suggests a developmental failure of the adrenal gland, which may argue against a simple cell surface resistance to this hormone. Nevertheless, evidence favoring this hypothesis came from Smith et al. (21) who demonstrated defective ACTH binding to peripheral blood mononuclear cells in a patient with FGD, in contrast to normal binding characteristics in cells from a control subject (21). This is a somewhat surprising result in retrospect, since there is little evidence that the MC2 (ACTH) receptor is expressed in leukocytes, and it may have been the result of undertaking nonsaturated binding studies.
2. A defect in the intracellular signaling response to ACTH receptor stimulation is an obvious alternative to a receptor defect, although it suffers from the disadvantage that many or most intracellular signaling components are common to many other cell types and receptor systems that do not appear to function abnormally in these patients. However, some weight was given to this hypothesis by the findings of Yamaoka et al. (22) in 1992 who demonstrated normal peripheral blood mononuclear cell ACTH binding and cAMP generation, yet a failure to generate cortisol when cAMP was infused into the patient. They argued that this indicated that the disease resulted from a postreceptor defect lying distal to cAMP generation.
3. A defect in adrenocortical development was proposed by those who had the opportunity to examine the adrenal glands removed pre- or postmortem from affected patients (11, 16). Since in most cases these glands seemed to show a failure of development of the zona fasciculata and reticularis, it was argued that this was the likely primary cause of the disorder. This proposal would of course be compatible with the inevitable hyperpigmentation of patients. The question of adrenal histology is discussed later in more depth (see Section II.D.2).
4. Degeneration of the adrenal gland was originally proposed by Moshang et al. (23) in view of the observation that some patients have progressed to develop mineralocorticoid deficiency, including the patient reported by Stempfel and Engel (15). As will be discussed later in this review, this progressive adrenal failure is frequently seen in patients with the triple A syndrome, and it is conceivable that there may be some error in the diagnosis of FGD and the triple A syndrome.
1. ACTH receptor defects in FGD. The human ACTH receptor was
originally cloned in 1992 by Mountjoy et al. (24), who in
the same paper reported the cloning of a second receptor for -MSH,
which was expressed in melanocytes. Shortly thereafter, three other
distinct members of this family of receptors were cloned, which are
named MC1, MC2, etc, and together they comprise the melanocortin
receptor family (25, 26, 27, 28, 29). The principal biological features of each of
these are listed in Table 1. It appears
that although ACTH is an agonist for all of these receptors, the
receptor that is expressed in adrenocortical cells and that is
responsible for the steroidogenic actions of ACTH is the MC2 receptor,
which is synonymous with the term ACTH receptor. None of the MSH
peptides acts as an agonist on this receptor (30). In fact, there is
good evidence that the MC5 receptor is also expressed in the adrenal
cortex (31, 32), but its functional role there is currently obscure.
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and Fig. 2. In some cases the nature of the
mutation will clearly lead to significant structural disruption of the
receptor molecule, and it is to be expected that the receptor will be
nonfunctional. In other cases it is less obvious why the mutation
should lead to the disease. Investigation of these cases requires a
system for expression of the mutant receptors in a cell type that
allows proper comparison of their functional characteristics with those
of the normal MC2 receptor. Achieving such a test system has been
difficult.
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Naville et al. (8) used a different system in which the
mutant ACTH receptors were expressed in the M3 melanoma cell line,
which has endogenous MC1 (-MSH) receptors. They showed that the
D107N, C251F, and 1347insA mutations lacked all cAMP-generating
function in this system in contrast to the normal sequence receptor.
Again, however, these results are confounded by the endogenous response
derived from the MC1 receptor. Currently, our own strategy is to use
the mouse Y6 cell line, a mutant derivative of the mouse Y1
adrenocortical cell line that fails to express the endogenous ACTH
receptor (36). This line seems to be capable of expressing transfected
ACTH receptors in the absence of any background and is providing
promising results (Ref. 37 and L. L. K. Elias, A. Weber,
G. D. Pullinger, A. Mirtella, and A. J. L. Clark,
manuscript submitted). This suggests that an adrenal component is
required for normal efficient MC2 receptor expression.
These studies indicate that mutations of the ACTH receptor can account
for some cases of FGD, explaining the autosomal recessive nature of the
disease. This also explains why these patients become pigmented, since
this results from excessive ACTH stimulation of the MC1 receptor on
cutaneous melanocytes. ACTH is an effective agonist at this
receptor with only slightly greater EC50 values than
-MSH (24, 25).
It is notable that although activating mutations have been described in the case of a number of other G protein-coupled receptors, they have not been described in the case of the ACTH receptor. Two studies have examined the ACTH receptor sequence in DNA obtained from a variety of adrenal tumors, and both reported no abnormalities (38, 39). This does not completely exclude this occurrence, but it must be an uncommon cause of adrenocortical hyperfunction and hyperplasia.
2. Genotype-phenotype correlations. As these expression studies suggest, different mutations are likely to disable the receptor to different degrees, making genotype-phenotype comparisons difficult. However, the S74I mutation that we originally described has proved to be the most prevalent of these mutations and we have now identified it in 10 individuals from 6 families in a homozygous form and as a compound heterozygote with a more severe mutation in 2 more unrelated cases. Many of these patients have a Scottish family background, and it seems highly likely that the founder mutation occurred in this region, probably in the past few centuries.
ACTH receptor mutations provide some interesting physiological points. Since a point mutation in both alleles of this gene can result in complete failure to secrete cortisol, there can be little doubt that the gene originally cloned by Mountjoy et al. (24) encodes the ACTH receptor, and that it is the only ACTH receptor. There is good evidence that adrenocortical cells also express the MC5 (MSH) receptor, which has been shown to respond in vitro to ACTH at high concentrations (31, 32). However, it appears that the high concentrations of ACTH found in untreated FGD are not sufficiently high to recruit this receptor for stimulation of cortisol production. An alternative and very probable explanation, however, is that the ACTH receptor has an essential role in the growth and development of the inner zones of the adrenal cortex, and that the MC5 receptor is unable to stimulate steroidogenesis simply because there are insufficient cells expressing this receptor and the steroidogenic enzyme genes in these patients.
There has long been a debate on the relative contributions of ACTH,
other POMC-derived peptides, and other factors in adrenal growth. Since
the ACTH receptor is highly specific for ACTH (30), it would seem that
patients with FGD would provide an excellent model with which the role
of ACTH could be defined. These patients consistently have small
adrenal glands, suggesting an important role for ACTH. Few of these
glands have become available for histological examination. However,
adrenal sections obtained from a 3-yr-old girl who died from FGD caused
by an S74I mutation are shown and compared with those from a child of
the same age dying of nonadrenal disease (Fig. 3, A and B). The histological appearance
suggests the presence of disorganized glomerulosa cells surrounding a
normal adrenal medulla with no evidence of fasciculata or reticularis
cells. This appearance is typical of several of the other examples of
adrenal histology in FGD (1, 3, 11).
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3. Normal receptor FGD. Not all cases of FGD are associated with mutations within the coding region of the ACTH receptor. Of 37 families that we have studied to date, in only 14 families are affected cases associated with homozygous or compound heterozygous mutations. One possibility is that there are mutations in regions of the gene apart from the coding exon (such as the promoter). However, it is generally true that mutations in promoters are not a common cause of genetic disease.
As a result of the human genome-mapping project it is now relatively straightforward to identify highly polymorphic microsatellite repeat sequences at given locations in the genome. The ACTH receptor was mapped to the short arm of chromosome 18 (18p11.2) (41, 42); therefore, we investigated the proximity of a number of repeats in this region by performing linkage analysis in the families with ACTH receptor mutations. This approach revealed that the markers D18S40 and D18S44 were positioned on either side of the ACTH receptor gene at distances of 3 and 4 centimorgans, respectively (Ref. 43 and our unpublished observations). Such a distance, although large in physical terms, is satisfactory for the segregation studies proposed.
The results of this analysis indicate that, in the case of several of the FGD families without ACTH receptor mutations, the segregation analysis was not compatible with an etiological role for the ACTH receptor gene (43). This result is important since it makes it clear that the identical clinical phenotype of FGD can be caused by at least one other genetic defect. For ease of reference we have adopted the term FGD type 2 for the syndrome that is not linked to the ACTH receptor locus, in contrast to the term FGD type 1 for the disease caused by mutation of the ACTH receptor. For the remainder of this discussion we also use the term FGD type 2 for those patients who have a normal ACTH receptor-coding sequence and in whom linkage markers were uninformative. It is hoped that ultimately the causative gene for this syndrome will be identified, which may allow a more descriptive distinction between the etiologies of this disease.
4. Phenotypic distinctions. We have examined the clinical
features of the two types of FGD in the hope of identifying
distinctions between them that may help elucidate the nature of the
defect in FGD type 2. No differences in ACTH, cortisol, ACTH
stimulation tests, or other biochemical aspects were apparent.
Likewise, the clinical presentation did not distinguish these disorders
(44). However, an unexpected difference was found in the patients’
heights. Thus whereas those patients with FGD type 2 have heights that
fall within the normal distribution (±2 SD), patients with
ACTH receptor mutations have a mean height that is about 2
SDs greater than normal. This difference is statistically
significant (44). These findings are summarized in Fig. 4.
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A further possible distinction between the two types of FGD may be revealed by the adrenal histology. Kelch et al. (11) described the adrenal histology from a child who died after a 6-day coma and who was pigmented; this patient had a brother in whom a diagnosis of FGD had been made and who had responded well to glucocorticoid replacement. Adrenal sections from the first sibling are clearly different from those of other FGD patients (and from patients with the triple A syndrome) and show multinodular hyperplasia, with areas of focal calcification and lipid congestion with cholesterol-like clefts. (This implies extracellular lipid deposition and is distinct from the intracellular deposition seen in certain diseases.) We are aware of somewhat similar sections obtained from a patient that we have studied who had a normal sequence ACTH receptor (data not shown).
In summary, the molecular analysis of FGD has not only confirmed the etiological role of defects in the ACTH receptor in some cases, but has excluded it in others. It has revealed unexpected connections between the actions of ACTH and linear growth and has demonstrated with great clarity the essential need for ACTH in adrenocortical growth and development. Furthermore, it has indicated the existence of at least one other gene that, when defective, leads to an almost indistinguishable syndrome from that caused by ACTH receptor defects. The identification of this gene will, in turn, reveal much about ACTH and adrenal physiology.
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III. Triple A Syndrome |
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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This syndrome can be clearly distinguished from FGD by the presence of the additional features. It manifests itself during the first decade of life with severe hypoglycemic episodes that can cause sudden death as in 17 of the 97 described patients (2, 46, 47, 48, 49, 50, 51, 52, 53, 54). Although in most cases hypoglycemia and hyperpigmentation lead to the diagnosis, alacrima or hypolacrima is probably the earliest and most consistent sign, which can easily be overlooked by parents and physicians (55). Orbital computerized tomography revealed absent or very small lacrimal glands in one patient in whom this was studied (48). The majority of patients have isolated glucocorticoid deficiency, but in about 15% mineralocorticoid production may also become impaired at a later time (47, 49, 50, 56, 57, 58, 59, 60, 61). Adrenal insufficiency does not occur immediately postnatally but results from a progressive disorder leading to hypofunction of the adrenal gland at a variable time after birth (56, 60). Adrenal hypoplasia has been demonstrated by computerized tomography of the adrenal gland (62).
Achalasia of the cardia occurs in about 75% of all cases, the times of onset ranging from 0.5 to 16 yr. This symptom may precede adrenal insufficiency by about 1–4 yr (55, 60, 63). In fact, achalasia and gastric atonia (our unpublished observation) leading to recurrent or chronic pulmonary disease as a result of aspiration (64) may be the feature that causes the greatest threat to patient well being and is the most difficult to treat.
Patients presenting with the combination of achalasia and alacrima without adrenal failure have been described. This condition was defined as a distinct entity (MIM200440) named the achalasia-alacrima syndrome (65, 66, 67, 68, 69, 70, 71, 72), but probably reflects the delayed penetrance of all the primary features of the triple A syndrome.
2. Associated features.
a. Neurological features.
Since the original description of
the disease, it has become apparent that many patients also suffer
from, in addition to the three main features, progressive neurological
symptoms, which often result in a disabling disease that considerably
impairs the quality of life (60). Central, peripheral, and autonomic
nervous systems may be involved. Some of the neurological symptoms may
be partly attributable to the complications of hypoglycemic episodes
leading to microcephaly, seizures, intellectual deterioration, and
developmental delay (61).
Impairment of the central nervous system has been seen in the form of mental retardation (48, 51, 52, 57, 60, 61, 73, 74, 75) that can be progressive (48, 75), optic atrophy (47, 57), clumsiness, ataxia (55, 57, 61, 76), Parkinsonism (75), and hyperreflexia (46, 47, 52, 55, 60, 61, 74, 75, 76, 77, 78). Recurrent seizures have been described but, as stated above, may be due to hypoglycemic episodes in untreated patients (46, 49, 51, 56, 60, 61). Electroencephalography is normal (57, 75, 79), although in two cases mild dilation of the ventricles was seen on computed tomography scanning (75). In the case of Parkinsonian features, positron emission photometry scans have been performed in one subject using methyl spiperone and 18-F-L-flurodopa, which demonstrated diminished dopamine metabolism, storage, and binding in the striatum. However, these results do not provide an explanation for the mechanisms involved in neurological damage (75).
Sensorineural deafness may occur and brainstem auditory-evoked responses show a bilateral Stockard type II abnormality that is typical of a sensineural deficit and is characterized by amplitude reduction, elevation of the threshold intensity, and normal latencies (57, 60). In many patients a characteristic hypernasal speech is reported (2, 46, 47, 48, 52, 60, 74, 76, 77), which is due to an abnormally diminished motion of the lateral pharyngeal walls and incomplete velopharyngeal closure during plosive formation reflecting palatopharyngeal incompetence (48, 80).
The peripheral nervous system may also be affected. Some of the symptoms resemble those seen in patients with hereditary sensorimotor neuropathy such as muscle hypotonia, muscle weakness, progressive distal muscular atrophy, pes cavus, loss of deep sensibility, and other sensory impairment (48, 50, 52, 57, 60, 61, 74, 75, 76, 77, 78, 81). Electrophysiological investigation including nerve conduction studies and electromyography reveal slow conduction velocities of motor and sensory nerves consistent with mixed sensorimotor polyneuropathy with predominant axonal involvement with fibrillation potentials, motor unit drop-out, and enlarged motor unit potentials (48, 49, 52, 61, 75, 77, 78, 79). The histological appearances of muscle biopsy and sural nerve biopsy are summarized below (see Section III.C.2.).
About 30% of all patients suffer from autonomic impairment, which may be manifest by any of the following symptoms and signs: postural hypotension, impaired cardiovascular reflexes, cardiac dysrhythmias, unequal pupils, abnormal miosis after instillation of metacholine eye drops, absent or reduced sweating, abnormal responses to intradermal histamine, and impotence (48, 56, 60, 61, 74, 76, 77, 78, 82, 83). Gazarian et al. (61) have proposed the name "4A" syndrome to describe the appearance of these features. They suggested that the finding of one main symptom should prompt a search for other associated features.
b. Dermatological features.
In about 20% of all patients,
skin abnormalities are present comprising hyperkeratosis of palms and
soles with fine palmar creases, which may only be present in the early
years of life (2, 49, 77), incompletely developed dermatoglyphs,
fungiform papillae of the tongue, and cutis anserina ("gooseflesh")
(45, 49, 55, 60, 61, 74, 79).
c. Other features.
The clinical variability is reflected by a
variety of associated symptoms that have been described in a minority
of patients. Whether these are truly part of the triple A syndrome, or
are features arising as a result of distinct etiological processes, or,
in the case of osteoporosis, as a consequence of glucocorticoid
replacement, is not clear. They include 1) significant short stature
(47, 57, 60, 74); 2) microcephaly (52, 57); 3) osteoporosis (49); 4)
lack of eye lashes (74); 5) dysmorphic facies with long narrow face,
long philtrum, down-turned mouth, and thin upper lip (48, 55, 61); 6)
poor wound healing (2, 61); 7) cleft palate (60); 8) multiple nasal
polyps (60); 9) scoliosis (60); 10) long QT syndrome (62); and 11)
hyperlipoproteinemia type IIb (62).
Other features that we have observed include one patient who presented with Noonan’s syndrome-like symptoms including short stature, high arched palate, ptosis, hypertelorism, epicanthus, broad chest, short neck with pterygium colli, and low posterior hairline. Other patients have presented with hyperextensible joints, kyphosis, and a marked dental caries with periodontitis resulting in a nearly complete loss of secondary dentition (our unpublished observations).
In addition to the variability in the age of onset of the main features, there is a considerable inter- and intrafamilial variability of the associated symptoms suggesting either a contiguous gene defect, or, more probably, variable expression of the impaired gene (48, 50).
3. Inheritance. The triple A syndrome shows an autosomal recessive mode of inheritance. The evidence for this conclusion is that 1) the disease affects either sex with a relatively even sex ratio (48, 60); 2) patients are born to unaffected parents; and 3) there is an increased incidence of parental consanguinity (48, 50, 60, 61). There is no indication that the triple A syndrome is a mitochondrially encoded disease as there is no matrilineal inheritance. Preliminary genetic studies are suggestive of full penetrance of the disease with variable expression (84, 85). Affected children are reported from all continents of the world indicating that this rare disease is unlikely to have a single founder.
B. Treatment
Glucocorticoid and, if present, mineralocorticoid deficiency can
easily be treated by replacement with hydrocortisone and
fludrocortisone (9--fluoro-hydrocortisone), respectively.
Symptomatic treatment of alacrima is possible with artificial tears
(52). Achalasia may provide significant management problems that often
require esophageal dilatation or Heller’s cardiomyotomy (51). In
severe cases it may be necessary to resort to gastrostomy feeding.
Glucocorticoid replacement therapy seems to have no influence on the
development and progression of neurological symptoms (80). Hence, no
treatment strategies are available either for the variable and
progressive neurological damage or for the other associated features.
C. Pathogenesis
The molecular cause of the triple A syndrome is still unknown. The
unusual and varied combination of clinical features found in this
disease provide a compelling and complex problem in attempting to
understand its etiology. The evidence accumulated from the exclusion of
other disease processes, histopathological studies, animal models,
cytogenetics, candidate gene studies, and genome search strategies are
reviewed below.
1. Exclusion of other disease processes. Thorough investigation of patients with triple A syndrome has ruled out the following disorders associated with or causing the disease: 1) autoimmune Addison’s disease (no adrenal autoantibodies) (2, 57); 2) adrenoleukodystrophy (normal very-long-chain fatty acids) (52, 57, 75, 77, 86); 3) organic aciduria, carnitine deficiency, Refsum’s disease (52); 4) thyroid dysfunction (normal thyroid hormones, no antithyroid antibodies) (47, 57, 62, 77).
2. Histological studies. Histological examination of the
adrenal glands removed from patients who have died from this condition
are few in number, but are consistent in revealing relative adrenal
atrophy with an almost complete loss of the zona fasciculata and
reticularis despite preservation of the zona glomerulosa and adrenal
medulla (2, 46, 47). In this regard, there are considerable
similarities to the adrenal histology of many patients with FGD.
Representative adrenal sections from two patients with the triple A
syndrome are shown in Fig. 3C
. Other histopathological features include
pituitary gland hyperplasia and hypertrophy of the corticotroph cells,
consistent with primary adrenal failure (46).
Detailed neuropathological studies of patients who have developed neurological features of the disease are unfortunately lacking. Muscle biopsy indicates a denervation atrophy (77, 78), and sural nerve biopsy suggested a predominant axonal degeneration (52, 61, 77). Histology of the lower esophagus showed muscle hypertrophy with absence of ganglionic cells and only a few small nerve fibers on routine staining, in contrast to sections from the midesophagus where ganglion cells with large and small nerve fibers were seen (2).
3. Animal models. Animals exhibiting the complete combination of symptoms (adrenal insufficiency, achalasia, alacrima, neurological disorders) resembling those of patients with triple A syndrome do not exist. However, in 1992 Bartges and Nielson reported a 5-yr-old female standard poodle who presented with ACTH-resistant glucocorticoid deficiency with normal mineralocorticoid production and generalized intrathoracic megaesophagus (87). As in triple A syndrome patients, endogenous ACTH concentrations were markedly elevated. In addition this dog suffered from hypothyroidism, which was treated with L-T4. After the dog was started on prednisolone treatment, the regurgitation ceased within 3 days and the megaesophagus resolved completely after a 3-month period, as indicated by thoracic radiography. This contrasts to human patients in whom the neurological features and achalasia do not improve on glucocorticoid replacement (80). Unfortunately, the authors could not locate any littermates or ancestors of this dog who might have been of great value for genetic studies.
The view that this canine syndrome may have had a genetic basis comes from reports of two ‘families’ of standard poodles in which primary adrenal failure has been reported (88, 89). In these two pedigrees, female members were affected 4 times more often than males, suggesting a genetic or hormonal influence. It remains doubtful that this syndrome has any relevance to human ACTH insensitivity syndromes.
The mouse neurological mutant ‘motor endplate disease’ (med) is a neurological disorder characterized by early-onset progressive paralysis of the hind limbs, severe muscle atrophy, mild ataxia with degeneration of Purkinje cells, and juvenile lethality (90). The etiology of this disorder is discussed later in this article (see Section III.E).
4. Cytogenetic studies. In one early study, chromosomal abnormalities were not described in patients with triple A syndrome (57). However, recent studies using high-resolution banding techniques have revealed a variety of abnormalities in the heterochromatic region of chromosome 9q12 in affected patients. These include chromatid breaks, chromosome breaks, deletions, and marker chromosomes (S. C. Reshini, A. Weber, D. N. Finegold, A. J. L. Clark, and S. M. Gollin, in preparation). Precisely how this finding relates to the triple A locus on chromosome 12 (see below) is not clear. Linkage studies clearly exclude chromosome 9q12 as a potential triple A locus (see Section III.D).
5. Candidate gene studies. Several candidate genes have been proposed for the triple A syndrome. In view of the similarities between the endocrine and histological features of FGD and the triple A syndrome, it has long been proposed that defects in or near the ACTH receptor gene might also be responsible for the triple A syndrome (48, 60, 73, 77). This hypothesis is supported by numerous in vitro studies with ACTH and related peptides that identified it as having neuroactive, neurotrophic, and neurodevelopmental activity (91). Furthermore, there is evidence for an action of ACTH on the lacrimal gland leading to activation of a cAMP-dependent pathway that results in stimulation of protein phosphorylation and tear production (92, 93). Moore et al. (48) were unable to demonstrate any difference in either the affinity or capacity of lymphocyte ACTH binding between triple A patients, their siblings, and controls, using a conventional saturation assay and Scatchard analysis. It is possible, especially in view of the large affinity constants obtained, that this assay was measuring other melanocortin receptor subtypes.
Sequence analysis of the ACTH receptor gene was undertaken by ourselves
in four unrelated patients and shown to be normal (94). Similar results
have been reported by other groups (33, 50, 52, 53). This result does
not rule out the possibility of mutations in flanking regions of the
gene (e.g., the promoter), and therefore we undertook a
linkage study using two highly polymorphic dinucleotide repeat markers,
D18S40 and D18S44, which lie on chromosome
18p11.2 flanking the ACTH receptor locus at a genetic distance of 4 and
3 centimorgans (cM), respectively. Two-point linkage analysis
was performed in 12 triple A syndrome families, which included 22
affected patients, and indicated log of the odds (lod) scores of
less than -2 at a recombination fraction of 0.05 for both markers. The
lod scores remained negative up to a recombination fraction of 0.30.
Figure 5 shows a multipoint exclusion map
of the region around the gene and provides conclusive evidence for the
exclusion of the ACTH receptor as a candidate gene for the triple A
syndrome.
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SG protein subunit. This work, however, did not exclude
the possibility of the presence of more subtle mutations in the
S subunit that would impair the transmission of the ACTH
signal from receptor to effector. The weakness of the candidacy of any
component of this system is that cAMP signaling is a widespread
activity, and it may be difficult to explain the specificity of any
defect primarily for adrenal, neuronal, and lacrimal tissue. Tsao et al. (52) raised the question of whether mitochondrial respiratory chain enzymes could be involved in the pathogenesis of the disease. They demonstrated normal enzyme activities and no mitochondrial abnormalities, such as red ragged fibers, in a skeletal muscle biopsy, making a mitochondiopathy unlikely.
Geffner et al. pointed out the similarities to familial dysautonomia (Riley-Day syndrome, MIM1223900) and proposed a defect of the autonomic, or specifically the parasympathetic, nervous system or its transmitter(s) as the underlying mechanism to account for the diverse manifestations of the disorder (73). This hypothesis was taken up by several authors who claimed that many features of the triple A syndrome could be explained by a primary degeneration of cholinergic neurons resulting in a progressive loss of cholinergic function (48, 51, 60, 61, 77, 78, 80, 83). Support for this hypothesis comes from studies demonstrating that adrenal growth may be dependent on afferent neurons originating in the adrenal cortex and that the autonomic nervous system may play a role in regulating the growth and development of the adrenal cortex (95). The adrenal gland receives significant vagal (96) and thoracic splanchnic efferent innervation, which may serve to regulate function of both the adrenal medulla and cortex (97). Results from animal models underline the involvement of the autonomic nervous system in adrenal growth and corticosteroid release (98, 99).
Based on pathological studies in patients with classical achalasia, which show neuronal degeneration and reduction in neuron counts in the vagal nuclei of the brainstem, as well as in myenteric neurons of the esophageal body and lower esophageal sphincter (100), it was proposed that the primary lesion for achalasia in the triple A syndrome is extraesophageal, caused by either extrinsic neural structure changes or by defects in sympathetic or neuromuscular transmission due to defective transmitter synthesis, release, or metabolism (48, 51, 61, 73, 80). Although alacrima may occur as a consequence of absence or hypoplasia of the lacrimal gland (48), it has been shown that the lacrimal gland has autonomic nervous input (101), and so it is conceivable that a disruption of these pathways by a progressive, degenerative, neuropathic process would result in deficient tear production (61, 80). A similar neuropathic process presumably underlies the velo-pharyngeal incompetence (80).
In addition to the ACTH receptor gene, we have excluded several other genes that have been shown to influence adrenocortical function, lacrimal gland function, and esophageal motility, or which exert diverse functions as a neurotransmitter, neuromodulator, or neurotropic factor. Thus we were able to exclude vasoactive intestinal peptide (VIP), the type 1 VIP receptor (VIPR1), pituitary adenylate cyclase activating polypeptide (PACAP), the type 1 PACAP receptor (ADCYAP1R1), and neurotropin 3 (NT3) (84).
In view of the exclusion of these candidate genes and the absence of other obvious candidates, we reasoned that a genome-wide search for the triple A syndrome gene was warranted.
D. Mapping of the triple A syndrome gene
Moore et al. (48) described a large and highly inbred
Métis Canadian family with triple A syndrome comprising eight
affected members (48). This family has an explicit genealogy extending
over six generations with multiple consanguinity loops, and as a first
step we used only this family to screen for linkage. For this, we
combined three microsatellite marker screening sets [UK MRC Human
Genome Mapping Project primer set; Généthon, France (102);
Microsatellite Center Berlin, Germany] comprising in total 345 mostly
dinucleotide repeat markers spaced at approximately 10 cM intervals.
Only markers from the pericentromeric region of the long arm of
chromosome 12 suggested linkage to the triple A phenotype; a maximum
pairwise lod score of 2.13 was obtained with marker D12S355
at a recombination fraction of 
= 0.05.
We then selected 7 additional families out of a series of 28 triple A families to test for linkage with additional closely spaced markers from this region. These families were of white European, Australian, Northern American, and Moroccan origin. Two families were consanguineous, and 4 families had two affected members. Investigating all 8 families together (19 patients, 25 unaffected siblings), we obtained a maximum lod score of 10.81 at a recombination fraction of zero with marker D12S368 (84). Marker loci showing no recombination with the triple A trait represent the cosegregating segment. This was defined by the two markers, D12S368 and D12S1586, which are approximately 4 cM apart.
The cosegregating segment maps to chromosome 12q13, which is shown in
Fig. 6A (103). All patients deriving from
consanguineous familes were found to be homozygous for all tested
markers in this region. There was no evidence for locus heterogeneity;
all families tested showed significant linkage only with markers from
this segment of chromosome 12q13.
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) (84). Apart
from the families with explicit consanguinity, three families
apparently represented compound heterozygotes, at least at the marker
level, and presumably at the triple A gene also. In addition, we
performed a multipoint linkage analysis with nine markers from this
region, revealing a maximum multipoint lod score of 13.18 at
D12S368, and placing the triple A locus in the 6-cM interval
between D12S1629 and D12S312 (Fig. 6B). Stratakis
et al. (53) have confirmed the triple A gene locus on
chromosome 12q13 by linkage analysis in four families. By genetic analysis in a consanguineous Moroccan family, we recently revealed one sibling presenting with the full clinical picture of triple A syndrome, and one sibling aged 12 yr with only alacrima and mild signs of achalasia. This was the first indication that the achalasia-alacrima syndrome and the triple A syndrome may be one disease caused by mutations in the same gene (85). Hence, it will be worth studying families with the achalasia-alacrima syndrome in parallel in the future.
E. Candidate genes
To date, several known genes are mapped to the triple A critical
region on chromosome 12q13. These are eight keratin genes forming the
type II keratin gene cluster, a type I keratin gene (KRT18),
the genes for ß-7 integrin (ITGB7), retinoic acid receptor
gamma (RARG), the trans-acting transcription
factor (SP1), the homeobox C5 (HOXC5), the zipper
protein kinase (ZPK), and activin A receptor type II-like
kinases 1 and 4 (ACVRL1 and ACVRL4) (104, 105, 106).
However, none of these genes appears as a strong candidate that could
explain the entire triple A phenotype. The uncommon combination of the
triple A symptoms makes a positional candidate gene approach very
difficult. The involvement of the central, peripheral, and autonomic
nervous systems as well as the adrenal and the progressive course of
the disease in some patients suggest a defective neuromodulator or
neurotrophic factor showing developmental and tissue-specific patterns
of expression. A defective neuromodulator or even a mutant
transcription factor for genes involved in the neuroendocrine system
would serve as the best explanation for the apparent pleiotropic gene
action (84).
The mapping of the triple A syndrome in the close vicinity of the type II keratin gene cluster and the dermatological symptoms in some triple A patients suggest an involvement of one or more keratin genes in the pathogenesis of this disorder. Hence, the hypothesis of a contiguous gene defect is supported by the phenotypic peculiarity of this syndrome. Furthermore, the expression pattern of the type II keratin genes resemble, at least in part, the pattern of the tissues involved in the triple A syndrome (107). The type II keratin gene cluster comprises eight keratin genes (KRT1,-2, -3, -4, -5, -6A, -6B, -7, and -18) (108). Mutations in genes of the type II keratin gene cluster have been described in epidermolytic hyperkeratosis, nonepidermolytic form of palmoplantar keratoderma (KRT1) (109, 110), ichthyosis bullosa of Siemens and exfoliativa (KRT2) (111, 112), epidermolysis bullosa simplex (KRT5) (113), and paronychia congenita (KRT6A) (114).
Marked caries with periodontitis resulting in a premature loss of primary and permanent dentition was seen in some triple A patients (see above). A link between palmoplantar hyperkeratosis and severe periodontitis is described for both the Papillon-Lefèvre syndrome (MIM1245000) and the Haim-Munk syndrome (MIM1245010). Hart et al. (115) demonstrated close linkage to markers near the type I and type II keratin genes on 12q13 and 17q21-q22. Laass et al. (116) demonstrated linkage of Papillon-Lefèvre syndrome to a 9-cM region on chromosome 11q22 containing a gene for ultrahigh sulfur-keratin (KRN1). This raises the question whether the dental and dermatological symptoms in some triple A patients are due to mutations in keratin gene(s) on 12q13. If there should be no mutations in the known keratin genes, other yet unidentified keratin genes in this region could be involved, as has been proposed by Yoon et al. (108).
Furthermore, the human homolog of the mouse Scn8a gene, encoding a voltage-gated sodium channel type VIII, was mapped to chromosome 12q13 by fluorescence in situ hybridization (117). Mutations in Scn8a have been shown to be responsible for various mutants of the med phenotype characterized by severe muscle atrophy with progressive paralysis of preferentially the hind limbs, ataxia, and juvenile lethality (117, 118, 119, 120). Burgess et al. (117) predicted that an impaired human SCN8A gene could be a candidate for a human neurological disease. In addition to the fact that some neurological features resemble those of med mutants, the juvenile lethality of some med mice remain unexplained. Hormone studies in these mice should reveal whether this feature is due to adrenal crisis. Hence, finemapping of human SCN8A is warranted to determine whether this gene lies within the triple A critical region.
The successful identification of the gene causing triple A syndrome may reveal novel aspects of cell signaling and neurodevelopment as well as of the regulation of adrenocortical function. Understanding the molecular defect of this disorder may allow presymptomatic testing of newborns in affected families and may permit the rational design of new therapeutic strategies preferentially aiming at the prevention of the severe neurological symptoms.
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IV. Acquired ACTH Resistance |
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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V. Conclusions |
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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These diseases are fascinating in view of what they tell us about adrenal development and function. ACTH receptor mutations in patients with FGD have provided a unique insight into the role of this receptor. Unexpected effects such as the greater height of these patients remain to be explained. It seems highly probable that the next few years will reveal the identities of the gene (or genes) causing FGD type 2 and the triple A syndrome, which will undoubtedly provide further fascinating and important insights.
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Acknowledgments |
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We gratefully acknowledge the cooperation of all FGD and triple A families involved and the excellent information provided by their physicians. Our studies have benefitted from productive discussions with several endocinologists, most notably Professor Ashley Grossman and Dr. Martin Savage, St Bartholomew’s and the Royal London School of Medicine and Dentistry. We also acknowledge the assistance of Dr. David Lowe, St Bartholomew’s and the Royal London School of Medicine and Dentistry, in interpretation of the adrenal histology, and Dr. A. G. Howatson, Consultant Paediatric and Perinatal Pathologist, Royal Hospital for Sick Children, Glasgow, Professor Boehm, University of Freiburg, and Professor Siebenmann, University of Zurich, for providing histological blocks, slides, and sections of their patients. We are very grateful to Dr. Martin Farrall, Institute of Molecular Medicine, Oxford, for assistance with the exclusion of the ACTH receptor locus in the triple A syndrome.
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Footnotes |
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1 Supported by a UK Wellcome Travelling Research Fellowship, a UK
Wellcome Research Travel Grant, and a Fellowship (We1693/1–1) from the
Deutsche Forschungsgemeinschaft, Germany. We also gratefully
acknowledge the support of the UK Medical Research Council and the
Joint Research Board of St. Bartholomew’s Hospital. 
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TopAbstractI. IntroductionII. Familial Glucocorticoid...III. Triple A SyndromeIV. Acquired ACTH ResistanceV. ConclusionsReferences |
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