Abstract
Context:
Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal hyperplasia (MAH).
Objective:
We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.
Methods:
Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed.
Results:
Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002).
Conclusions:
ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
Macronodular adrenal hyperplasia (MAH)- or ACTH-independent macronodular adrenal hyperplasia (AIMAH), also known as massive macronodular adrenal disease (MMAD), is a bilateral adrenocortical disorder that leads to Cushing's syndrome (CS). MAH is believed to be most commonly a sporadic disease, unlike the frequently inherited form of micronodular adrenocortical hyperplasia known as primary pigmented nodular adrenocortical disease (PPNAD) (1). PPNAD is caused mostly by mutations of the PRKAR1A gene (2, 3), which is also mutated in Carney complex, an autosomal dominant condition. MAH is a rare disease accounting for up to 1% of adrenal causes of CS (4, 5), although its true frequency is likely to be higher. Contributing to the underestimation of this disease's prevalence are the various names by which it is known; for example, in addition to MAH, AIMAH, and MMAD, it has also been called huge or giant macronodular disease (6). In addition, patients usually develop hypercortisolism slowly and/or even in an atypical or cyclical pattern, and CS is established insidiously in most cases. Finally, cortisol levels may even respond with suppression to dexamethasone, and the disease may be picked up only by the concurrent measurement of 17-hydroxycorticosteroids (17OHS) (7). In contrast, in MAH, urinary free cortisol, and some other measures of the adrenal axis could be surprisingly normal, whereas 17OHS production may be increased (2).
Although MAH is seen most commonly in a sporadic setting, a few familial cases have been described (8). We and others have proposed that the disease is most likely genetic in origin (1, 2). Indeed, bilateral adrenal nodules have also been described in conjunction with a number of autosomal dominant conditions, including familial adenomatous polyposis, multiple endocrine neoplasia type 1, and the hereditary leiomyomatosis and renal carcinoma syndrome (2, 9–12). But until recently no clear genetic cause for most cases of MAH was known. In 2013, Assie et al (13) described frequent mutations in a cohort of patients from France in the armadillo repeat-containing 5 (ARMC5) gene, located at 16p11.2. Both alleles of ARMC5 contained mutations, one in the germline and the other at the somatic level, in the tumors, suggesting that the gene acts as a tumor-suppressor gene. Although the exact function of the gene remains under investigation, Assie et al found that ARMC5 inactivation affects steroid production and cell survival in vitro and is associated with more severe CS. One of the most important implications of the study by Assie et al was that MAH is frequently genetic in origin, despite the fact that we see it more frequently in sporadic patients, rather than in families. This will change how we care for these patients (and their families) if confirmed in other cohorts. The purpose of this investigation was to search for ARMC5 mutations in the largest cohort of such patients in the United States, the one at the National Institutes of Health.
Materials and Methods
Clinical studies and patient samples
A total of 34 patients were evaluated at the National Institutes of Health Clinical Research Center between 1995 and 2012. None of the study subjects were part of the original cohort as published by Assie et al (13). Patients had varying levels of hypercortisolemia, with different levels of ACTH suppression. All patients underwent adrenal computed tomography (CT) scans to establish the diagnosis of bilateral and macronodular adrenal disease. Leukocyte DNA was obtained from each patient in addition to tumor DNA (see below).
All patients signed an informed consent. The research protocol (00-CH-0160) was approved by the Institutional Review Boards of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (until 2010) and Diabetes and Digestive and Kidney Diseases (2010 through today), National Institutes of Health.
ARMC5 sequencing analysis in peripheral and tumor DNA samples
DNA was extracted from peripheral blood leukocytes and from adrenal nodules according to manufacturer protocols (QIAGEN). ARMC5 was analyzed in 34 patients with MAH who had features of clinical or subclinical CS and from two adrenal nodules of one patient with clinical CS and a pathogenic ARMC5 defect. The complete ARMC5-coding and surrounding intronic sequence of these patients and tumors was analyzed by classical bidirectional Sanger sequencing on germline DNA, as previously described (14), using the primers and conditions described in the Supplemental Table 1, published on the Endocrine Society's Journals Online website at http://jcem.endojournals.org. .
In silico analyses
Two independent in silico software tools were used to predict the pathogenic potential of the identified missense variants in ARMC5: polymorphism phenotyping version 2 (PolyPhen-2) (15) and sorting tolerant from intolerant algorithm (16).
Western blot analysis
Tumor tissue was obtained during surgery and was immediately frozen in liquid nitrogen and stored until protein extraction. Tissue lysates were studied for the amount of ARMC5 protein by Western blotting using a specific ARMC5 antibody (rabbit antihuman NBP1–94024; Novus Biologicals), actin antibody (sc-1615; Santa Cruz Biotechnology), and suitable secondary antibodies (Santa Cruz Biotechnology).
Immunostaining
Deparaffinized sections of adrenal tissue were immunostained using antibodies against the following: 1) synaptophysin (mouse antihuman A0010; Dako Corp), a neuroendocrine marker that does not normally stain cortical cells but is a marker for adrenocortical tumors; and 2) ARMC5 (rabbit antihuman NBP1–94024; Novus Biologicals). Routine staining was performed at Histoserv Inc.
Hormone measurements
Plasma ACTH and serum cortisol were measured using a chemiluminescent enzyme immunoassay on a Siemens Immulite 2500 analyzer. Cortisol levels were tested during the morning (7:30 and 08:00 am) as well as late night (11:30 pm and 12:00 am). Averages of morning and late-night cortisol levels were used in all analysis (17). Measurements of 17OHS and 24-hour urine free cortisol (UFC) have been previously described by our group (2).
Dexamethasone tests
The 6-day Liddle's test was performed as described in detail elsewhere (7, 18, 19). Briefly, urine was collected from each patient for 2 days prior to treatment with dexamethasone, measuring baseline 17OHS and UFC, as well as urine creatinine excretion and urine volume. Dexamethasone 0.5 mg was given by mouth every 6 hours for 2 consecutive days. Dexamethasone dose was increased to 2 mg every 6 hours for another 2 consecutive days. Throughout the test, UFC and 17OHS were measured and the percentage of suppression documented. 17OHS was corrected by urine creatinine (17OHS/Cr, per day per gram creatinine), whereas UFC was corrected by body surface area (BSA) (UFC/BSA). Suppression of UFC greater than 90% and/or 17OHS greater than 69% was considered diagnostic for CS (20). Definition of subclinical CS is somewhat vague; we defined it as late-night cortisol levels being marginally elevated, partially suppressed ACTH, and/or normal UFC in the absence of classical clinical signs of CS.
Statistical analysis
Data are described as frequencies and percentages, and mean ± SD or median (interquartile range), as appropriate, and were analyzed using SAS version 9.1 (SAS Inc). Continuous data were compared between the patients with an ARMC5 mutation predicted as damaging and those without and/or with nonpathogenic mutations using two-sample Student's t tests, or nonparametric tests, as appropriate. The categorical data were compared using the Fisher's exact test. Mixed models were used for a repeated-measures analysis of 17OHS/Cr and UFC/BSA data between the mutation groups. A value of P ≤ .05 was considered statistically significant.
Results
ARMC5 mutations
We identified 11 ARMC5 coding sequence alterations in 13 unrelated and in two related individuals from our cohort of 34 patients; all mutations were found in a heterozygote state on germline DNA (Table 1). Two of the variations were frame-shift mutations: p.G57GfsX45 (c.171insG) and p.C579SfsX49 (c.1735–1738delTGCC); one was a nonsense mutation [p.R364X (c.1090C>T)], and the other eight were missense and resulted in amino acid substitutions. Five of eight missense variants were previously described in public databases (21): p.F14Y c.41T>A (rs151069962), p.S115P (c.343T>C, rs199693319), p.L156F (c.466C>T, rs114930262), p.I170V (c.508A>G, rs35923277), and p.G798A (c.2393G>C, rs115611533). The other three were novel: p.R315Q (c.944G>A), p.R593W (c.1777C>T), and p.R898W (c.2692C>T). Figure 1 shows the schematic representation of the ARMC5 gene with the detected mutations and the associated phenotype. To confirm these results, we sequenced tumor of one of the patients from whom tissue was available (ADT36.01) with a damaging ARMC5 mutation and found two mutations in both tumors. One was c.171insG, corresponding to our findings in leukocyte DNA of the patient. The other, c.583+26 G>T (rs9921490), was a new mutation. This may indicate that adrenal tumors in MAH are polyclonal, and individual nodules bear different mutations, consistent with the findings by Assie et al (13), and as suggested by Almeida et al (22).
Table 1.
Allele Frequency (Minor Allele) of Sequence Variations in ARMC5 in MAH Patients and 1000 Genomes Control Individuals
| DNA Change | Protein Change | SNP Identification | MAH Patients (n = 68) | Controls (1000 Genomes Database) |
MAH Patients vs Controlsa |
|||
|---|---|---|---|---|---|---|---|---|
| ALL (n = 2184) | AMR (n = 362) | EUR (n = 758) | χ2 | P Value | ||||
| c.41T>A | p.F14Y | rs151069962 | 2 (0.029) | 63 (0.029) | 2 (0.041) | 45 (0.047) | 0.01 | Ns |
| c.171insGa | p.G57GfsX45 | - x - | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| c.343T>C | p.S115P | rs199693319 | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| c.466C>T | p.L156F | rs114930262 | 1 (0.015) | 17 (0.008) | 0 (0) | 0 (0) | 0.4 | Ns |
| c.508A>G | p.I170V | rs35923277 | 6 (0.088) | 54 (0.025) | 5 (0.014) | 45 (0.059) | 10.26 | .019 |
| c.944G>Ab | p.R315Q | - x - | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| c.1090C>Tb | p.R364X | - x - | 2 (0.029) | 0 (0) | 0 (0) | 0 (0) | 35.42 | <.001 |
| c.1735–1738delTGCCb | p.C579SfsX49 | - x - | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| c.1777C>Tb | p.R593W | - x - | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| c.2393G>C | p.G798A | rs115611533 | 2 (0.029) | 17 (0.008) | 1 (0.003) | 0 (0) | 2.71 | Ns |
| c.2692C>Tb | p.R898W | - x - | 1 (0.015) | 0 (0) | 0 (0) | 0 (0) | 7.54 | .006 |
| Total | 19 (0.279) | 151 (0.069) | 8 (0.022) | 29 (0.119) | 38.82 | <.001 | ||
Abbreviations: ALL, all individuals from 1000 genomes database are being considered; AMR, Mixed American; EUR, European; Ns, nonsignificant; SNP, single-nucleotide polymorphism.
A χ2 test was performed using the ALL population as a general control. χ2 is calculated after Yates correction for continuity (Yates correction was applied for all calculations having number < 10 in any cell of the contingency table).
Variations newly identified in the MAH patients, comparing it with the database.
Figure 1.
Structure of the ARMC5 gene with all detected mutations and the respective phenotype. aa, amino acids; BTB, blood-testis barrier; UTR, untranslated region.
ARMC5 in silico analysis
Two independent in silico models (PolyPhen-2, sorting tolerant from intolerant, and SeattleSeq Annotation) predicted a likely benign effect on the ARMC5 protein function for the four (of five) previously described variants (p.F14Y, p.S115P, p.I170V, and p.G798A) found in our cohort. The mutations p.R315Q and p.R898W (seen only in the patient group), and the mutation p.L156F (previously described) were predicted to significantly impair the protein function (Table 2). Based on predicted phenotypes, we defined the patient cohort with ARMC5 mutations as limited to the seven patients with likely pathogenic mutations (ie, nonsense mutations, frameshift mutations, or codon changes predicted to be functionally significant).
Table 2.
In Silico Modeling of the Effect of ARMC5 Missense Substitution on the Protein Function
| Protein Change | Domains | In Silico Modeling |
Interspecies Alignment |
||||
|---|---|---|---|---|---|---|---|
| Prediction | Scorea | Mus musculus | Dasypus novemcinctus | Xenopus tropicalis | Petromyzon marinus | ||
| p.F14Y | - x - | Likely benign | 0.255 | F | D | A | |
| p.S115P | - x - | Likely benign | 0.378 | S | L | ||
| p.L156F | Armadillo | Possible damaging | 0.527 | L | |||
| p.I170V | Armadillo | Likely benign | 0.311 | I | I | I | I |
| p.R315Q | Armadillo | Probably damaging | 1 | R | R | R | R |
| p.R593W | - x - | Probably damaging | 0.999 | S | S | S | S |
| p.G798A | BTB/POZ-like | Likely benign | 0.015 | G | S | C | A |
| p.R898W | - x - | Probably damaging | 1 | R | R | R | |
PolyPhen-2 was used as standard. Scores goes from 0 to 1. Greater score indicates higher probability to impair the protein function. The main factors taken into account for the calculation of the score are as follows: 1) difference in the thermo-physical properties of the wild-type and mutant protein; and 2) evolutionary preservation of the residue in the corresponding position.The letters in the topic “Interspecies Alignment” are relative to the amino acid present in the position and the absence of a letter means there is no amino acid at that specific position: F, Phenylalanine; S, Serine; L, Leucine; I, Isoleucine; R, Arginine; G, Glycine; D, Aspartic Acid; C, Cysteine; A, Alanine.
Immunostaining and protein level expression
Representative images are shown in Figure 2. Immunostaining was performed on three cohorts of patients: those with PPNAD (CAR01.05) and another form of nonpigmented micronodular adrenal hyperplasia known as isolated micronodular adrenocortical disease (iMAD) (CAR54.03) and MAH (ADT053.01 and ADT06.01). Immunostaining with synaptophysin (a cytoplasmic stain) was used to identify neuroendocrine nodules. Intense synaptophysin staining was observed in PPNAD and iMAD tissue, with less intense staining in MAH tissue. ARMC5 immunostaining (also localized to the cell cytoplasm) was identified in PPNAD and to a lesser intensity in iMAD tissue; no or limited staining was identified in MAH tissue. Western blot analysis of adrenal tumor samples from both patient and a control indicated a decrease in ARMC5 expression, in patient vs control adrenal. Relative band intensities from three separate analyses were used to determine whether there was in fact a decrease in ARMC5 protein expression. Indeed, adrenal sample from ADT36.01 exhibited a decrease, compared with control adrenal tissue.
Figure 2.
A, Immunostaining of adrenocortical nodules stained for synaptophysin and ARMC5. B, Western blot analysis of ARMC5 protein in an adrenal gland with MAH from one patient. SYN, synaptophysin.
Correlation of the molecular genetic data with the clinical features of the cohort
The mean age of our patient cohort at the time of the robust clinical and biochemical investigation was 50.4 years (±12.0 y) (Supplemental Table 2). A female sex predominance of 79.4% was observed, which is consistent with other reports of adrenal tumors (2). A total of 71.9% of the patients were Caucasians (Table 3).
Table 3.
Demographic Characteristics of Subjects With ARMC5-Damaging Mutations Compared With Those Without and/or With Nonpathogenic Mutations
| ARMC5 (n = 7) | No ARMC5 (n = 27) | P Value | |
|---|---|---|---|
| Females, %/males, % | 5 (71.4)/2 (28.6) | 22 (81.5)/5 (18.5) | .61 |
| Race, % | |||
| Asian | 0 (0) | 3 (11.1) | .024 |
| Black | 4 (57.1) | 2 (07.4) | |
| White | 3 (42.9) | 20 (74.1) | |
| Other/unknown | 0 (0) | 2 (07.4) | |
| Ethnicity, % | |||
| Latino or Hispanic | 0 | 1 (3.7) | 1 |
| Not Latino or Hispanic | 7 (100) | 26 (96.3) | |
Clinical characteristics are presented in Table 4. Characteristics were compared between the group carrying pathogenic ARMC5-damaging mutations and the group with benign and/or with nonpathogenic mutations. There was no statistically significant difference in body mass index between the two groups. ACTH was significantly more suppressed in patients with the ARMC5-damaging mutation group (5.6 ± 3.6 pg/mL vs 12.2 ± 10.0 pg/mL, P = .031). Late-night cortisol levels were higher in the ARMC5-damaging mutation cohort (14.5 ± 5.6 vs 6.7 ± 4.3; P < .001). There was no difference in adrenal gland weight between the groups.
Table 4.
Clinical Characteristics of Subjects With ARMC5-Damaging Mutations Compared With Those Without and/or With Nonpathogenic Mutations
| ARMC5 (n = 7) |
No ARMC5 (n = 27) |
P Value | |
|---|---|---|---|
| Mean (±SD) | Mean (±SD) | ||
| Age at the time of biochemical testing (Liddle's), y | 48.7 ± 7.6 | 50.8 ± 12.9 | .69 |
| SBP, mm Hg | 152.4 ± 17.9 | 135.2 ± 20.7 | .053 |
| BMI, kg/m2 | 39.2 ± 12.4 | 34.1 ± 7.3 | .16 |
| 17OHS/Cr, mg/d·g Cr (average 1–2 d) | 11.5 ± 7.9 | 7.3 ± 3.5 | .22 |
| 17OHS/Cr, mg/d·g Cr (after dexamethasone) | 10.5 ± 5.7 | 5.1 ± 4.6 | .014a |
| 17OHS suppression, % | −0.7 ± 41.1 | −22.1 ± 80.2 | .5 |
| UFC/BSA, μg/d·m2 (average 1–2 d) | 51.4 ± 62.6 | 31 ± 36.7 | .33 |
| UFC/BSA, μg/d·m2 (after dexamethasone) | 55.7 ± 83.1 | 20.5 ± 41.4 | .4 |
| UFC suppression, % | −12.4 ± 48 | −39 ± 75.1 | .46 |
| ACTH, pg/mL | 5.6 ± 3.6 | 12.2 ± 10 | .031a |
| Morning cortisol, μg/dL (average) | 15.5 ± 7.8 | 13.5 ± 3.7 | .53 |
| Late-night cortisol, μg/dL (average) | 14.5 ± 5.6 | 6.7 ± 4.3 | <.001a |
| Left adrenal weight, g | 80 ± 47.3 | 40.4 ± 30.1 | .066 |
| Right adrenal weight, g | 84.3 ± 81.1 | 47 ± 28 | .32 |
Abbreviations: BMI, body mass index; SBP, systolic blood pressure.
Statistically significant.
Dexamethasone testing and ARMC5 mutations
All patients with ARMC5-damaging mutations failed to suppress 17OHS during the Liddle's test, whereas 10 of the 24 patients without ARMC5 mutations and/or with nonpathogenic mutations (41.7%) did suppress 17OHS to greater than 69% (P = .067); data were not available in three patients. Data were available on UFC levels during the Liddle's test for five of the seven patients with ARMC5-damaging mutations; all of these individuals failed to suppress UFC during the Liddle's test. Data were available on UFC levels in the Liddle's test for 22 of the patients without ARMC5 pathogenic mutations; of those individuals, 6 of 22 patients (27.3%) suppressed UFC levels during the Liddle's test greater than 90% (P = .56). Repeated-measures analysis showed a statistically significant difference overall from baseline to the sixth-day 17OHS values between the two mutation groups (P = .0002). The patients with ARMC5 pathogenic mutation had consistently higher 17OHS values throughout the Liddle's test compared with those without/benign mutations. Similarly, UFC values by repeated-measures analysis showed the individuals with ARMC5 damaging mutations had consistently higher UFC values throughout the Liddle's test compared with individuals without/benign mutations and a statistically significant overall difference (P = .038).
Clinical vs subclinical CS and ARMC5 mutations
All patients with ARMC5-damaging mutations had clinical CS (seven of seven, 100%) compared with 14 of 27 of those without and/or with nonpathogenic mutations (52%) (P = .029). All patients with an ARMC5-damaging mutation had bilateral adrenal hyperplasia on CT compared with 16 of 27 of those without and/or with nonpathogenic mutations (59%) (P = .069).
Discussion
In our cohort, we identified a possible genetic cause of MAH in seven patients (25.9%) who had an ARMC5- damaging mutation. These results confirm findings published recently by Assie et al (13) in a US cohort of patients. All our patients with the novel mutations had CS. Additionally, these patients presented with higher late-night cortisol and consistently higher urinary glucocorticoids during the Liddle's test and severely suppressed ACTH levels, suggesting a more severe disease. In contrast, Assie et al (13) found that cortisol and ACTH levels did not differ between their groups.
Limited information about ARMC5 mutations is available in the public domain (13). ARMC5 may promote tumor suppression by regulating the production of steroids and disrupting adrenal cell apoptosis. Accordingly, ARMC5 expression in adrenal nodules was not detected or resulted in very scant staining in MAH tissue samples. Nodules from PPNAD and iMAD patients that stained positively for synaptophysin also stained for ARMC5, yet nodules from MAH patients exhibiting less intense staining showed a decrease or no staining at all for ARMC5. Protein levels, as determined by Western blot, showed a decrease in ARMC5 expression. Together these results indicate ARMC5 inactivation in MAH. Patients with the ARMC5-damaging mutation had a greater degree of clinical CS, with suppressed ACTH, higher late-night cortisol values, and failure to suppress urinary 17OHS and UFC during the Liddle's test. Our data support the hypothesis that the presence of an ARMC5-damaging mutation is associated with a more severe clinical phenotype as well as with the presence of bilateral disease.
It is often challenging to decide on a correct surgical approach in patients with MAH, based only on results of the CT imaging. Our team is often debating, deciding on unilateral vs bilateral adrenalectomy in MAH. Patients with ARMC5 mutation may benefit from a more aggressive management of MAH, such as bilateral adrenalectomy.
In conclusion, MAH (also known as AIMAH or MMAD) is a cause of CS that was previously thought to be rarely genetic. A mutation in ARMC5 is a novel genetic defect that apparently can be found in many patients with MAH. Mutations are spread in the coding region of the ARMC5 gene, and in the absence of information on the gene's function, a genotype-phenotype correlation is not apparent at this point. However, knowledge of a patient's ARMC5 status will assist with diagnosis of MAH. Moreover, screening family members of affected patients may enable clinicians to accomplish early identification and prevention of morbidity and even mortality caused by CS and possibly other endocrinopathies that may be associated with ARMC5 mutations.
Acknowledgments
The supporting organizations had no further role in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication. The principal investigator had full access to all the data in the case and takes responsibility for the integrity of the data and the accuracy of the data interpretation.
We thank Diane Cooper, MSLS, National Institutes of Health Library, for providing assistance in writing this manuscript. We also thank Aaron Hodes, BS, for providing assistance with the data collection.
The study had a clinical trial registration number of NCT00005927.
This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development, protocol 00-CH-0160 (Clinical and Molecular Analysis of ACTH-Independent Steroid Hormone Production in Adrenocortical Tissue); and in part, by a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Process: 311166/2011–3 - PQ-2 (to F.R.F.).
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- AIMAH
- ACTH-independent macronodular adrenal hyperplasia
- ARMC5
- armadillo repeat-containing 5
- BSA
- body surface area
- Cr
- creatinine
- CS
- Cushing's syndrome
- CT
- computed tomography
- iMAD
- isolated micronodular adrenocortical disease
- MAH
- macronodular adrenal hyperplasia
- MMAD
- massive macronodular adrenal disease
- 17OHS
- 17-hydroxycorticosteroids
- PolyPhen-2
- polymorphism phenotyping version 2
- PPNAD
- primary pigmented nodular adrenocortical disease
- UFC
- urine free cortisol.
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