ACTH Insensitivity Research Articles

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity.

Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.

The "double a" phenotype: Portending allgrove′s syndrome and averting adrenal crisis

Introduction:Allgrove's syndrome is a rare autosomal-recessive disorder with only about 70 cases reported thus far and is characterized by alacrima, achalasia, and ACTH insensitivity among other clinical features. However, it has a widely variable clinical presentation, which may result in such cases remaining undiagnosed.Objective:To report a patient with impending Allgrove's syndrome and to highlight the importance of clinical suspicion in diagnosing the same.Materials and Methods:A 2.5-year-old girl was diagnosed with impending Allgrove's syndrome on the basis of clinical presentation, barium swallow study, Schirmer's test, and hormonal evaluation.Results:A 2.5-year-old girl, born of non-consanguineous marriage, presented with failure to thrive and developmental delay with occasional vomiting on taking solid or semi-solid food for past 6 months. Examination revealed stunted weight (SDS of -4.4) and height (SDS of -4.76), and barium swallow showed presence of achalasia. On direct questioning, her mother mentioned presence of decreased tears on crying since birth, and Schirmer's test confirmed the presence of dry eyes. Baseline ACTH was slightly elevated with normal basal and post-ACTH stimulation serum cortisol. Based on these findings, impending Allgrove's syndrome was diagnosed with a plan for follow-up study of adrenal function. Conclusions: Allgrove's syndrome may be an under diagnosed disorder as aclarima is often overlooked. However, a high index of clinical suspicion may help in avoiding adrenal crisis by diagnosing the condition early.

Loss of the C Terminus of Melanocortin Receptor 2 (MC2R) Results in Impaired Cell Surface Expression and ACTH Insensitivity

Objective Mutations in melanocortin receptor 2 (MC2R) and its related melanocortin receptor accessory protein (MRAP) cause familial glucocorticoid deficiency. We identified a novel MC2R mutation, K289fs. This unique mutation in the C terminus of MC2R is located in the intracellular part of the protein for which the exact function is unknown. Setting A 6-wk-old boy presented with severe hypoglycemia, unmeasurable cortisol, and grossly elevated ACTH but normal electrolytes. Genetic analysis revealed homozygote K289fs mutation in MC2R. His parents and siblings were heterozygous but phenotypically normal. Intervention and Results The role of the C terminus of MC2R was studied in two cell systems. Because the K289fs mutant changes the last eight amino acids of the protein and leads to protein elongation, wild-type MC2R and C-terminally mutated constructs were tested for activity to respond to ACTH in an OS3 cell-based reporter assay. Wild-type and alanine-substituted constructs responded normally to ACTH. By contrast K289fs and M290X had a total loss of activity. Cell surface assays and confocal localization studies revealed that K289fs and M290X receptors were not found at the cell surface, indicating that their transport from the endoplasmic reticulum to the cell membrane is disrupted. Interestingly, coimmunoprecipitation experiments showed no alteration in the interaction of mutant MC2R with MRAP, suggesting that interaction between these two proteins does not guarantee normal localization. Conclusions Loss of the C terminus of MC2R impairs cell surface expression and ACTH sensitivity but does not disrupt interaction of MC2R with MRAP. These findings highlight the extreme sensitivity of MC2R to structural disruption.

Loss of the C Terminus of Melanocortin Receptor 2 (MC2R) Results in Impaired Cell Surface Expression and ACTH Insensitivity

Objective: Mutations in melanocortin receptor 2 (MC2R) and its related melanocortin receptor accessory protein (MRAP) cause familial glucocorticoid deficiency. We identified a novel MC2R mutation, K289fs. This unique mutation in the C terminus of MC2R is located in the intracellular part of the protein for which the exact function is unknown. Setting: A 6-wk-old boy presented with severe hypoglycemia, unmeasurable cortisol, and grossly elevated ACTH but normal electrolytes. Genetic analysis revealed homozygote K289fs mutation in MC2R. His parents and siblings were heterozygous but phenotypically normal. Intervention and Results: The role of the C terminus of MC2R was studied in two cell systems. Because the K289fs mutant changes the last eight amino acids of the protein and leads to protein elongation, wild-type MC2R and C-terminally mutated constructs were tested for activity to respond to ACTH in an OS3 cell-based reporter assay. Wild-type and alanine-substituted constructs responded normally to ACTH. By contrast K289fs and M290X had a total loss of activity. Cell surface assays and confocal localization studies revealed that K289fs and M290X receptors were not found at the cell surface, indicating that their transport from the endoplasmic reticulum to the cell membrane is disrupted. Interestingly, coimmunoprecipitation experiments showed no alteration in the interaction of mutant MC2R with MRAP, suggesting that interaction between these two proteins does not guarantee normal localization. Conclusions: Loss of the C terminus of MC2R impairs cell surface expression and ACTH sensitivity but does not disrupt interaction of MC2R with MRAP. These findings highlight the extreme sensitivity of MC2R to structural disruption.

Loss of the C Terminus of Melanocortin Receptor 2 (MC2R) Results in Impaired Cell Surface Expression and ACTH Insensitivity

Mutations in melanocortin receptor 2 (MC2R) and its related melanocortin receptor accessory protein (MRAP) cause familial glucocorticoid deficiency. We identified a novel MC2R mutation, K289fs. This unique mutation in the C terminus of MC2R is located in the intracellular part of the protein for which the exact function is unknown. A 6-wk-old boy presented with severe hypoglycemia, unmeasurable cortisol, and grossly elevated ACTH but normal electrolytes. Genetic analysis revealed homozygote K289fs mutation in MC2R. His parents and siblings were heterozygous but phenotypically normal. The role of the C terminus of MC2R was studied in two cell systems. Because the K289fs mutant changes the last eight amino acids of the protein and leads to protein elongation, wild-type MC2R and C-terminally mutated constructs were tested for activity to respond to ACTH in an OS3 cell-based reporter assay. Wild-type and alanine-substituted constructs responded normally to ACTH. By contrast K289fs and M290X had a total loss of activity. Cell surface assays and confocal localization studies revealed that K289fs and M290X receptors were not found at the cell surface, indicating that their transport from the endoplasmic reticulum to the cell membrane is disrupted. Interestingly, coimmunoprecipitation experiments showed no alteration in the interaction of mutant MC2R with MRAP, suggesting that interaction between these two proteins does not guarantee normal localization. Loss of the C terminus of MC2R impairs cell surface expression and ACTH sensitivity but does not disrupt interaction of MC2R with MRAP. These findings highlight the extreme sensitivity of MC2R to structural disruption.

Two Patients with an Identical Novel Mutation in the AAAS Gene and Similar Phenotype of Triple A (Allgrove) Syndrome

Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by three cardinal symptoms: adrenal insufficiency due to ACTH insensitivity, achalasia and alacrima. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. AAAS encodes a protein named ALADIN which is part of the nuclear pore complex (NPC). The mislocalization of mutated ALADIN proteins in the cytoplasm and/or the nucleus results in an impaired protein function. Phenotypes of previously reported patients with triple A syndrome varied within and between affected families so that no genotype-phenotype could be established. Genetic analysis was performed in two unrelated patients, their parents and one sister. AAAS coding sequences including exon-intron boundaries were amplified and sequenced using an ABI 3100 sequencing machine. We present two unrelated Swiss patients with triple A syndrome demonstrating similar phenotypic characteristics. Both showed a progression of the disease presenting with adrenal insufficiency and alacrima in early childhood. At the age between 30-40 years they developed symptomatic achalasia. The pattern and severity of progressive neurological and autonomic dysfunction was comparable. In both patients molecular genetic analysis revealed an identical novel homozygous mutation (c.618delC, p.Ser207fs) in the AAAS gene. Recent genotype/phenotype studies showed a marked inter- and intrafamiliar variability in triple A syndrome. Here we present a rather tight genotype/phenotype correlation in two unrelated patients carrying the identical novel p.Ser207fs mutation in the AAAS gene.

Genetics of ACTH insensitivity syndromes

The last decade has seen remarkable progress in our understanding of the genetic causes of these potentially lethal conditions. Clearly, other genes that cause FGD remain to be discovered, and further work is required on the functions of MRAP and ALADIN in the expectation that they will provide insights into essential biological processes and perhaps identify key therapeutic strategies and targets for these diseases.

Mutations in a Novel Gene, Encoding a Single Transmembrane Domain Protein Are Associated with Familial Glucocorticoid Deficiency Type 2

Familial Glucocorticoid Deficiency (FGD) is a rare autosomal recessive disorder characterized by ACTH insensitivity with glucocorticoid but not mineralocorticoid deficiency and high circulating ACT...

Proopiomelanocortin and the immune-neuroendocrine connection.

This presentation will cover the history, recent developments in, and implications of the ability of both the immune and neuroendocrine systems to produce POMC. The discovery of POMC in immune cells was one of the events that heralded a molecular understanding of neuroimmunomodulation. This, together with the presence of opiate and ACTH receptors on lymphocytes and macrophages, provided the first biochemical circuit for which the same signal molecules and receptors could be used for intrasystem regulation, as well as bidirectional communication between the immune and neuroendocrine systems. Today we have a quite good understanding of the regulation and processing of POMC in immune cells, as well as the interaction of its product peptides with other cytokines. For instance, IL-1 causes POMC production by immune cells, and the POMC product, alpha-MSH, in turn, acts functionally as an IL-1 antagonist. In the past year, the expression of full-length POMC mRNA has been reported and this solved one of the paradoxes with respect to POMC production, processing, and secretion. We provide data on these developments together with quite startling findings on the physiologic function of POMC peptides in the immune system. Among these are the local antinociceptive effects of immune cell-derived beta-endorphin, altered hematopoiesis in opiate receptor-deficient animals, and the diagnosis of ACTH insensitivity by a deficiency of ACTH receptors on lymphocytes.

Myocardiopathie et déficit isolé en glucocorticoïdes par résistance à l'ACTH: une association fortuite?

Hereditary syndrome of unresponsiveness to ACTH is a rare autosomal recessive disorder characterized by an isolated glucocorticoid deficiency which is exceptionally associated to regressive cardiomyopathy. A male newborn had iterative episodes of hypoglycemia since the first hours of life. Acute bronchiolitis at the age of 14 days was associated with transitory dilated cardiomyopathy. Hypoglycemia was due to glucocorticoid deficiency secondary to ACTH insensitivity. Molecular biology showed a composite heterozygotism for the ACTH receptor gene. Any congenital glucocorticoid deficiency should lead to search for cardiomyopathy.

Achalasia of the cardia in childhood and the syndrome of achalasia alacrima and ACTH insensitivity

Achalasia of the cardia is an uncommon condition with an incidence of 0.1 cases per year per 100,000 population under 14 years. A review of experience at Booth Hall Children's Hospital over the past 10 years has revealed six cases of achalasia in children. This includes two cases of the rare syndrome of achalasia, alacrima and ACTH insensitivity (also known as Triple A syndrome) and its variants. There are 23 previously reported cases of Triple A syndrome and a further eight cases of its variants reported in the world literature. One-third of these cases (10 out of 31) have associated neurological abnormalities. The clinical and radiological features of achalasia are reviewed. The importance of barium studies in making the diagnosis is emphasized. However, early cases may show only spasm or incoordination, and manometry is required to confirm the diagnosis in these equivocal cases. In this series only three of the six barium studies were diagnostic and the remainder were diagnosed by manometry; all cases were subsequently confirmed by histology. Delay in diagnosis may result in severe lung damage due to repeated aspiration; this occurred in one of the six cases and was the cause of the child's death.

Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima

Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.

Pediatric case of the day. Triple A syndrome: achalasia, alacrima and ACTH insensitivity.

Pediatric case of the day. Triple A syndrome: achalasia, alacrima and ACTH insensitivity.

165 ADRENOCORTICAL INSUFFICIENCY ASSOCIATED WITH ACHALASIA AND ALACRINA: VARIABILITY OF CLINICAL FINDINGS IN TWO CASES

After the 4 patients reported by Allgrove in 1978, only few cases of the ACTH insensitivity, achalasia and alacrima syndrome have been described. Some clinical aspects of the disorder and its pathogenesis has not yet been clarified. Ne report 2 more patients to confirm the clinical entity of the syndro,e. Case 1 male patient, developed achalasia at age 2.5 yrs (Heller's myotomy was carried out) and after 1.5 yrs glucocorticoid deficiency (skin pigmentation, convulsions uith hypoglycaemia): ACTH>850 pg/ml, no response to ACTH test, normal aldosterone and PRA. Eyes apparently normal, but evidence of impaired tear production after Schiller test. Other features: muscular hypotrophy and hypotonia, foot orthopedic abnormalities. No findings in parents. Case 2 female with alacrima since birth; at age 3.5 diagnosis of adrenal deficiency was made (weakness, skin pigmentation, convulsions uith hypoglycaemia): ACTH levels ranging from 229 to 427 pg/ml, undetectable cortisol levels, urinary aldosterone less than normal. She has sligth dysphagia without radiological signs of achalasia. Isolated findings within faaily: alacrima in maternal grand - mother, elevated ACTH levels in mother's sister.Conclusions: our cases show the clinical variability of this syndrome; the presence of isolated achalasia, adrenocortical insufficiency or alacrima in a child warrants evaluation for the other components.

ACTH INSENSITIVITY, AUTONOMIC NERVOUS SYSTEM DISORDERS AND SENSORY POLYNEUROPATHY

A 10 year old boy is described with a syndrome of adrenal insufficiency due to selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy. Production of glucocorticoids and adrenal androgens were insufficient, but there were no signs of even latent mineralocorticoid insufficiency (after 4 days of low sodium dlet-9mEq/L NaCl/day). In addition to achalasia, defective lacrimation, anisocoria and hyperkeratosis of palmes and soles, we also found defective sweating, permanent cutis anserina (impaired function of smooth hair muscles) and electromyographically proved sensory polyneuropathy, which were not previously reported in this rare syndrome.

Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

A 10-year-old boy is described with a syndrome of adrenal insufficiency due to selective ACTH insensitivity associated with autonomic nervous system disorders. In addition to insufficient production of glucocorticoids and adrenal androgens, achalasia, defective lacrimation, anisocoria and hyperkeratosis of palms and soles we also found defective sweating, permanent cutis anserina and sensory polyneuropathy, which have not been reported previously in this rare syndrome.

ACTH RECEPTOR DEFECT IN ADRENOLEUKODYSTROPHY (ALD)

ACTH insensitivity is a cardinal feature of ALD, but the mechanism is unknown. We studied a 10 year old hyperpigmented boy with glucocorticoid insufficiency of 8 years duration and a history of two generalized tonic clonic seizures associated with febrile episodes with normal blood glucose. His neurological exam was normal, EEG showed non-specific slowing with normal auditory evoked responses, and Magnetic Resonance Imaging showed areas of increased signal intensity in the cerebral peduncles and the internal capsule. ALD was documented by increased plasma very long chain fatty acids, i.e., C26/C22 = 0.055 (control = 0.01 ± 0.01); C26= 1.572 μg/ml (control = 0.33 ± 0.18 pg/ml). Basal ACTH was elevated at 1840 pg/ml (normal = <100 pg/ml). Cortisol was 7.0 μg/dl with no response to exogenous ACTH. Basal and stimulated renin and aldosterone were normal. The child's leukocytes had no detectable ACTH binding sites in a radioligand binding study. In contrast, normal mononuclear leukocytes possess high and low affinity receptors for ACTH that appear identical to the prototype adrenal receptors. These studies suggest that the adrenal failure associated with ALD is secondary to an ACTH receptor defect. Whether the ACTH receptor defect is primary or secondary to the long chain lipid abnormality is under investigation.

406 ACTH INSENSITIVITY: A NEW RECEPTOR DEFECT DETECTED BY THEOPHYLLINE STIMULATION

A 2 y/o male was evaluated for hypoglycemia and hyperpigmentation. Studies confirming the diagnosis of ACTH insensitivity were as follows: {cortisol=C, aldosterone (ng/dl)=A, renin (ng/ml)=R, ACTH (pg/ml)=ACTH}: (1) Cortrosyn stimulation: ACTH =2000; C undetectable at 0′ and 30′. (2) Upright posture + furosemide: ACTH=2000; A=4.0 at 0′, 48.2 at 60′; R=60 at 0′, 195 at 60′. (3) Cortrosyn stimulation + high-dose dexamethasone + supine position: ACTH=130; C undetectable at 0′ and 30′; A=9.0 at 0′, 23.7 at 30′; R=48 at 0′, 59 at 30′. Thus ACTH failed to induce glucocorticoid production by the zona fasciculata and reticularis (ZFZR) whereas mineralocorticoid or zona glomerulosa (ZG) response to physiologic stimuli of upright posture and salt-water depletion was preserved. ZG responsiveness to ACTH was also clearly shown for the first time. In an attempt to demonstrate the secretory potential of ZFZR, bypassing the initial interaction of ACTH with the cell, we administered IV theophylline, a cAMP phosphodiesterase inhibitor. After a 120′ infusion C rose from undetectable to 7.5 μg/dl. The defect in this form of ACTH insensitivity appears to be failure to generate intracellular cAMP either because of lack of ACTH-receptor binding or impaired coupling of the ACTH-receptor complex with adenylate cyclase. When cAMP levels are increased by a mechanism that circumvents the receptor-adenylate cyclase complex, C production is stimulated.