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Service des Maladies Endocriniennes et Métaboliques (L.G., J.P.L., X.B., J.B.), Service Central d’Anatomie Pathologique (A.L.), Centre Hospitalier Universitaire (CHU) Cochin, Paris 75014, France; Service de Médecine Infantile III et Génétique Clinique (B.L.), CHU de Nancy, Nancy 54505, France; and Département d’Endocrinologie (L.G., E.J., K.P., X.B., J.B.), Institut Cochin, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique UMR8104, IFR 116, Université Paris V-René Descartes, Paris 75014, France
Address all correspondence and requests for reprints to: Dr. Jérôme Bertherat, Service des Maladies Endocriniennes et Métaboliques, Hôpital Cochin, 27 rue du Fg-St-Jacques, 75014, Paris, France. E-mail: . jerome.bertherat{at}cch.ap-hop-paris.fr
Abstract
Primary pigmented nodular adrenocortical disease (PPNAD) is a cause of ACTH-independent Cushing’s syndrome. This condition can be difficult to diagnose because hypercortisolism may be periodic and adrenal imaging may not demonstrate an adrenal tumor. PPNAD can be part of the Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome. Germline mutations of the regulatory subunit R1A of PKA (PRKAR1A) have been observed in about 45% of CNC kindreds. To improve our understanding of sporadic PPNAD and develop a potential diagnostic tool, we investigated the genetics of patients with sporadic and isolated PPNAD.
Patients undergoing surgery for bilateral ACTH-independent Cushing’s syndrome in whom pathological examination revealed PPNAD were subjected to endocrinological investigations and a systematic search for other manifestations of CNC. The PRKAR1A gene was sequenced using DNA from frozen adrenal tissues and leukocytes from three patients with sporadic isolated PPNAD and using leukocyte DNA from two additional patients.
Different inactivating germline mutations of the PRKAR1A gene were found in the five patients. For three cases, study of the parents’ DNA demonstrated a de novo mutation. One patient presented with an unusual 2.5-cm macronodule of the right adrenal mimicking an adrenal adenoma. A somatic 16-bp deletion of PRKAR1A gene was also found in this macronodule.
Inactivating germline mutations of PRKAR1A are frequent in sporadic and isolated cases of PPNAD. The wild-type allele can be inactivated by somatic mutations, consistent with the hypothesis of the gene being a tumor suppressor gene. Thus, genetic analysis can be of help to the clinician in the diagnosis of this difficult form of adrenal Cushing’s syndrome.
ADRENAL CUSHING’S SYNDROME (ACS) is a consequence of one or both adrenal glands secreting excess cortisol in an ACTH-independent manner. In most cases, a unilateral tumor, either an adenoma or a carcinoma, allows straightforward diagnosis and an adequate treatment.
In rare cases, ACS is secondary to a primary bilateral adrenal dysfunction and may be difficult to diagnose. However, this is a condition that has recently been elegantly described at the molecular level (1). In the McCune-Albright syndrome, ACS results from autonomous activation of the cAMP pathway in the adrenal nodules due to somatic activating mutations of the Gs
subunit (2). ACTH-independent macronodular adrenal hyperplasia is another form of ACS in which bilateral macronodules cause large increases in the size and weight of the two glands. Since the original work by Lacroix et al. (3) and Reznik et al. (4), it was shown that most of these cases display illegitimate expression of membrane G protein-coupled receptors (5). Primary pigmented nodular adrenocortical disease (PPNAD) is the last form of ACS for which a molecular description has been reported. However, it was probably the first to be described as a peculiar pathological entity (6); the adrenal weight and size are most often normal, but there are numerous typical pigmented micronodules scattered within both glands (7). Most patients with PPNAD are children or young adults (8).
The diagnosis of Cushing’s syndrome in PPNAD can be difficult; hypercortisolism usually progresses only slowly and in some cases periodically, and the clinical and laboratory features can be normal during nonhypersecretory periods. The typical growth failure observed in children with Cushing’s syndrome is therefore not constant. Plasma ACTH levels are not fully suppressed in all cases in which hypercortisolism is mild or periodic (8). Furthermore, adrenal imaging can be normal or show only minor alterations with minimal adrenal nodularity that cannot always be distinguished from Cushing’s disease or normal glands. In some instances, the diagnosis may be confused with factitious exogenous glucocorticoid excess.
An interesting feature is that PPNAD is frequently part of a wider clinical spectrum, the Carney complex (CNC; Ref. 9). In this autosomal dominant multiple neoplasia syndrome (MIM 160980), affected patients have, in addition to PPNAD, other endocrine tumors (GH-secreting adenomas, thyroid adenomas or carcinomas, ovarian cysts, large-cell calicifying Sertoli cell tumors, etc.), as well as cardiac myxomas and spotty skin pigmentation (10). Thus, diagnosis is facilitated when PPNAD occurs in a patient with full blown CNC. Inactivating germline mutations of the regulatory subunit type I- of the protein kinase A (PRKAR1A) have recently been observed in about 40–50% of CNC families (11, 12, 13). PRKAR1A has therefore been proposed to be a tumor suppressor gene (12). According to the Knudson hypothesis (14), somatic mutations of the PRKAR1A gene should be observed in sporadic isolated PPNAD. Alternatively, a clinically apparently isolated and sporadic PPNAD might be the result of a germline PRKAR1A mutation with incomplete clinical expression and low penetrance. In such cases, molecular analysis might help diagnose this difficult form of ACS.
We screened patients with well documented, isolated, and sporadic PPNAD for mutations of the PRKAR1A gene. A somatic mutation was found in a unique PPNAD macronodule, but de novo germline mutations were found consistently. This emphasizes the need for genetic screening in difficult cases of bilateral ACS.
Patients and Methods
Medical records of all the patients who were either followed in the Endocrine Department of Hospital Cochin and had adrenalectomy for PPNAD between 1991 and 2001 or were referred to our laboratory for PRKAR1A gene mutation analysis were reviewed. For PPNAD, 21 patients from 15 kindreds were identified. Seven of these patients had apparently isolated PPNAD with no familial history suggestive of CNC. The familial medical histories of these patients were investigated, and the patients were studied for clinical signs of CNC, including dermatological examination and thyroid palpation. Ovarian or testicular, thyroid, and cardiac ultrasound scans and pituitary magnetic resonance imaging were performed to exclude other features of CNC. Plasma concentrations of GH, PRL, and IGF-I were determined as previously described (15). Informed consent was obtained for genetic analysis of PRKAR1A and adrenal tissue collection as part of a protocol approved by the Institutional Review Board of the Cochin Hospital. If investigations revealed any other manifestation suggestive of CNC (as defined by Stratakis et al., Ref. 10), the patient was excluded. Two of these seven patients were thus excluded after diagnosis of ovarian cyst and pigmented skin lesions.
Three of the five remaining patients (patients 1–3) were investigated before adrenalectomy in our department. Endocrinological investigations were performed as part of the routine standard procedure for Cushing’s syndrome diagnosis as previously reported (16, 17).
Adrenal tissue collection and DNA and total RNA extraction were performed as previously described (18). The cDNA Cycle kit (Invitrogen, Groningen, The Netherlands) was used for RT. For mutation analysis, the 12 exons and the flanking intronic sequences of the PRKAR1A gene were separately amplified by PCR as described by Kirschner et al. (11) and Casey et al. (13). Both strands of the amplified products were directly sequenced on an automated sequencer (ABI 3700; Perkin-Elmer Corp., Wellsley, MA). Nucleotides were numbered in accordance with the reference sequence for PRKAR1A (GenBank accession no. NM_002734) used by Kirschner et al. (11, 12).
Case records
Patient 1.
An 18-yr-old woman of African origin was referred for Cushing’s syndrome. She presented with growth failure at age 15, secondary amenorhea at age 17, and central obesity. Investigations (Table 1
) demonstrated ACTH-independent Cushing’s syndrome. Computed tomography (CT) scan showed a right adrenal mass 2.5 cm across, suggestive of an adrenal adenoma, but the left adrenal appeared nonatrophic (Fig. 1). Laparoscopic adrenalectomy was performed. The right adrenal weighed 8.3 g, and pathological examination revealed a 2.5-cm pigmented nodule surrounded by small (0.2 cm) micronodules. The left adrenal weighed 4.2 g and displayed multiple small pigmented nodules (0.2–0.6 cm). Adjacent adrenal was normal or slightly atrophic. At age 18, investigations did not reveal any alteration suggestive of CNC.
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), associated with increased testosterone. Daily salivary cortisol and testosterone measurements over 6 wk showed variable but simultaneous oversecretion of both steroids. Both adrenals appeared normal on CT scan, and iodocholestrol scintigraphy revealed bilateral uptake. Bilateral adrenalectomy was performed, and pathological analysis revealed diffuse pigmented nodules (0.1–0.3 cm) with apparently normal adjacent adrenal cortex. The right adrenal weighed 7 g, and the left adrenal weighed 9 g. Cortisol and testosterone were undetectable in plasma after surgery. At age 20, investigations did not reveal any alteration suggestive of CNC.
Patient 3.
A 28-yr-old woman of African origin was referred for Cushing’s syndrome that had apparently started 1 yr before, during the first trimester of a clomiphene-induced pregnancy. She presented with central obesity, hirsutism, psychiatric manifestations, high blood pressure, and glucose intolerance. Spontaneous abortion occurred after 24 wk of gestation. Hormonal investigations were performed 8 d later and indicated ACTH-independent Cushing’s syndrome with high testosterone (Table 1). CT scan revealed normal adrenals, and iodocholesterol scintigraphy showed bilateral uptake. Bilateral adrenalectomy was performed, and pathological analysis revealed diffuse pigmented nodules (0.1–0.8 cm). The right adrenal weighed 4.5 g, and the left weighed 5.7 g. Plasma cortisol and testosterone levels were very low after surgery. At age 29 yr, investigations did not reveal any evidence of CNC.
Patient 4. A 33-yr-old man of French origin was referred for follow-up after bilateral adrenalectomy. At age 14, he had developed a central obesity. At age 17, he suffered an osteoporotic vertebral fracture, at which time hormonal investigation showed an ACTH-independent Cushing’s syndrome; adrenals appeared normal on CT scan. 2,2-Bis(2-chlorophenyl, 4'-chlorophenyl)1,1-dichloroethane treatment was administered, and the patient then underwent bilateral adrenalectomy at age 18. The adrenals weighed 10 g. Pathological analysis revealed multiple pigmented micronodules (1–4 mm) suggestive of PPNAD. At age 33, investigations revealed no evidence suggestive of CNC.
Patient 5. A 5-yr-old girl of French origin presented with pubic and axillary hair development (Tanner staging P2A2). Hormonal investigations showed that an absence of circadian variations of cortisol and ACTH was undetectable in plasma. Between ages 5 and 10 yr, clinical and endocrinological investigations showed intermittent features of ACTH-independent Cushing’s syndrome that became more severe at age 10 yr. Adrenals were not enlarged on CT scan, and a right adrenalectomy was performed. Pathological analysis revealed pigmented micronodules. After a transient improvement, the ACTH-independent Cushing’s syndrome recurred, so left adrenalectomy was performed at age 11 yr. Pathological analysis revealed pigmented micronodules (1–5 mm). At age 11 yr, clinical examination (skin, thyroid), abdominal CT scan, abdominopelvic ultrasound, pituitary magnetic resonance imaging, and endocrinological investigations did not reveal any evidence suggestive of CNC. At age 12 yr, cardiac ultrasound was normal, and GH under oral glucose load excluded acromegaly.
Results
Patient 1
Two different mutations of the PRKAR1A gene were identified in the 2.5-cm macronodule of the right adrenal (Table 1 and Figs. 1 and 2). One, a 16-bp deletion of the acceptor splice site of exon 4B [exon 4B IVS del (-17
-2)] is predicted to lead to exon skipping and a premature stop codon. This deletion was not detected on the tissue adjacent to this macronodule or in the left adrenal or leukocyte DNA. It was thus a somatic rearrangement.
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A) is a germline mutation of the splice donor site that results in partial exon skipping. This mutation was absent from both parents and is thus a de novo mutation. Study of mRNA from leukocytes and right and left adrenals revealed an abnormally short mRNA. Gel-purified RT-PCR products of exon 1B were sequenced to characterize this mRNA. It appeared to be a splice variant mRNA resulting from the use of a cryptic splice donor site with a deletion of 53 bp in exon 1B (Fig. 2). This mRNA was not detected in controls (leukocytes or adrenal tissues). Patient 2
Sequencing of the PRKAR1A gene in adrenal tissue revealed a single base pair change. An A insertion and thus frameshift in exon 8 (933insA) leads to a premature stop codon. This mutation was also detected in the leukocyte DNA. It was not detected in the parents’ leukocyte DNA. No other mutation was found in micronodules from either adrenal.
Patient 3
The PRKAR1A gene in adrenal tissues had a single base pair mutation (196 CT) creating a stop codon in exon 2. This mutation was also detected in the leukocyte DNA. No other mutation was found in micronodules from either adrenal.
Patient 4
Analysis of leukocyte DNA revealed a 5-bp deletion in the proximal part of intron 6 [exon 7 IVS del (-7 -2)] predicted to lead to exon skipping.
Patient 5
Analysis of leukocyte DNA revealed an 11-bp deletion, and consequently frameshift, in exon 2 (172 del 11 bp) that lead to a premature stop codon. This was not observed in the parents’ leukocyte DNA and was thus a de novo mutation.
Discussion
These cases illustrate various problems that can impede the correct diagnosis of bilateral ACS due to PPNAD.
First, the diagnosis of hypercortisolism itself is often difficult. As shown here in cases 2, 4, and 5, the cyclic variations of cortisol oversecretion resulted in a delay of 2–4 yr before diagnosis of Cushing’s syndrome was established. The concomitant oversecretion of testosterone, with normal dehydroepiandrosterone sulfate (cases 2 and 3), was another unusual biological feature and contributed further confusion. Adrenal imaging may be puzzling because CT scan may find no adrenal tumor, or even normal appearing glands, in ACTH-independent Cushing’s syndrome. The diagnostic difficulty was increased when a unilateral mass was found, as in patient 1, who was initially referred to our department for a classical adrenal adenoma. Accurate diagnosis relies on the fine imaging analysis of the contralateral gland, which may not be atrophic, or on adrenal scintigraphy that shows bilateral, if not symmetrical, tracer uptake. Finally, the PPNAD may present as a sporadic and isolated disease without any familial history or clinical evidence of other features of CNC, as reported by Meador et al. (6) and in the five cases presented here.
We hypothesized that all five of our patients were cases of de novo CNC, in an attenuated form, restricted to the adrenals. Were this to be true, diagnosis would be straightforward by germline DNA analysis. Indeed, the five patients with isolated PPNAD all had a germline mutation of the PRKAR1A gene.
These mutations led to gene inactivation by various mechanisms. They are unique mutations, none of which has been previously reported in CNC kindreds. In patients 2–5, a premature stop codon is predicted to create an unstable mRNA, as observed in more typical familial CNC patients (12). The germline mutation observed in patient 2 leads to a frameshift causing a premature stop codon. The germline nonsense mutation observed in patient 3 directly creates a stop codon. The germline mutation observed in patient 4 alters the predicted splicing site and should lead to exon skipping. This abnormal mRNA was not studied in the present case because mutations leading by the same kind of genetic defect to a premature stop codon have been reported already in Carney complex patients (11, 12). Because the abnormal mRNA is degraded by a nonsense mRNA decay mechanism, the abnormally spliced mRNA is not observed in RNA extracted from leukocytes as well as tumor tissues (11).
The de novo germline mutation in exon 1B of patient 1 led to partial exon skipping, generating a shorter mRNA that is not observed in control subjects. This abnormal mRNA is predicted to impede translation into PRKAR1A protein, although the design of the experiments reported here does not allow us to address this issue directly. Nevertheless, a recent report shows that the exon 1B region is involved in positive postranscriptional regulation of PRKAR1A expression in response to cAMP in Sertoli cells (19). This regulation is mediated by a consensus 6 bp, the MED-1-like element (GCTCGG positions + 45 to + 50). The 102 GA mutation disrupts this conserved element (Fig. 2). Furthermore, this consensus 6-bp element has been deleted from the abnormal mRNA observed in the leukocytes and adrenal tissue from this patient.
Thus, germline mutations of the PRKAR1A gene can be found in PPNAD patients who do not fulfill the proposed criteria for CNC (10). In the McCune-Albright syndrome, ACS is due to Gs mutations occurring exclusively in cortisol hypersecreting adrenocortical macronodules. Similarly, somatic PRKAR1A mutations may be found in the nodular adrenals of these patients with no familial history or other features of CNC. Indeed, the somatic mutation of PRKAR1A might explain PPNAD in patients without germline mutation. However, a recent study of another manifestation of CNC (sporadic cardiac myxomas) does not favor this hypothesis because no evidence of PRKAR1A mutation was found (20).
Patient 1 had a unusual presentation: in contrast to the other patients, she had a macronodule of the right adrenal. Within this nodule, we found a somatic PRKAR1A gene mutation that appeared restricted to the lesion. This somatic mutation also led to loss of gene function due to a premature stop codon. This is an alternative mechanism of inactivation of the wild-type allele, and in agreement with the model of PRKAR1A as a tumor suppressor gene (12). This model was suggested in the first report of PRKAR1A germline mutation in CNC by Kirschner et al. (12) on the basis of allelic loss at 17q22-24 in tumors from CNC patients. However, allelic loss at 17q22-24 was not always reported in such tumors, and haploinsufficiency has been postulated as a mechanism of tumorigenesis in this case (13). The early occurrence of the somatic mutation in the right adrenal of patient 1 might have contributed to greatly inactivating PRKAR1A function at an early stage of tumor development. In this case, the occurrence of this somatic mutation could be linked to the development of this right macronodule mimicking an adrenal adenoma. It would be tempting from this observation to speculate that somatic mutation of PRKAR1A could also be observed in sporadic unilateral adrenocortical tumors.
The lack of familial history of CNC in our patients suggests a de novo mutation in each case, and this was confirmed by the three younger patients whose parents’ leukocyte DNA was normal. The absence of other features of CNC in our patients is more difficult to explain. The younger patients may have been too young for other manifestations of CNC if they occur later. Possibly, some mutations might have tissue-specific effects. This explanation might apply to patient 1. Indeed it has been shown that the cAMP posttranscriptional regulation of exon 1B 5'UTR is tissue specific (19). Therefore, this mutation might have consequences in only a subset of tissues. It should be noted that mutation in exon 1B has not been reported previously in patients with CNC.
In conclusion, de novo germline mutations of the PRKAR1A gene are frequent in sporadic PPNAD, and somatic mutation of this gene can also be observed. Genetic testing might therefore be of great help in the diagnosis of this difficult form of Cushing’s syndrome. Because the current treatment of choice is total bilateral adrenalectomy, genetic testing might be very helpful in indicating surgical treatment for ACTH-independent Cushing’s syndrome in patients with apparently normal adrenal CT scans. These results also suggest that repeated screening for CNC manifestations, in particular searching for cardiac myxomas that can be life threatening, should be considered in patients presenting with isolated PPNAD.
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We thank F. René-Corail (Institut Cochin) for excellent technical assistance; the staff of the banque de cellules (Prof. M. Delpech, CHU Cochin) for lymphocyte collection; the surgeons (Profs. Y. Chapuis and B. Dousset) and the medical and paramedical staff at the Surgery and Endocrine Departments of the Hôpital Cochin who managed the patients; Dr. F. Tissier (Hôpital Cochin) for collaboration in the pathological examinations; Dr. A. Dugue and the staff of the Laudat Hormone Laboratory for homone assays; Prof. D. Dewailly (CHU Lille) for the initial management of patient 4; and Dr. B. Lebon-Labich (CHU Nancy) for management of patient 5. We also thank Prof. C. Beldjord (Institut Cochin, CHU Cochin), Dr. C. A. Stratakis (National Institutes of Health, Bethesda, MD), and the members of our laboratory for helpful discussions.
Footnotes
This work was supported in part by the Plan Hospitalier de Recherche Clinique (AOM 95201 to the Comete Network coordinated by Prof. P. F. Plouin and dedicated to the study of adrenal tumors) and the Association pour la Recherche sur le Cancer (ARC 4225). L.G. was the recipient of a fellowship from the Association pour la Recherche sur le Cancer.
Abbreviations: ACS, Adrenal Cushing’s syndrome; CNC, Carney complex; CT, computed tomography; PPNAD, primary pigmented nodular adrenocortical disease.
Received April 16, 2002.
Accepted June 14, 2002.
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D. F. Gunther, I. Bourdeau, L. Matyakhina, D. Cassarino, D. E. Kleiner, K. Griffin, N. Courkoutsakis, M. Abu-Asab, M. Tsokos, M. Keil, et al. Cyclical Cushing Syndrome Presenting in Infancy: An Early Form of Primary Pigmented Nodular Adrenocortical Disease, or a New Entity? J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3173 - 3182. [Abstract] [Full Text] [PDF]
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J. Bertherat, L. Groussin, F. Sandrini, L. Matyakhina, T. Bei, S. Stergiopoulos, T. Papageorgiou, I. Bourdeau, L. S. Kirschner, C. Vincent-Dejean, et al. Molecular and Functional Analysis of PRKAR1A and its Locus (17q22-24) in Sporadic Adrenocortical Tumors: 17q Losses, Somatic Mutations, and Protein Kinase A Expression and Activity Cancer Res., September 1, 2003; 63(17): 5308 - 5319. [Abstract] [Full Text] [PDF]
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D. Rosenberg, L. Groussin, E. Jullian, K. Perlemoine, S. Medjane, A. Louvel, X. Bertagna, and J. Bertherat Transcription Factor 3',5'-Cyclic Adenosine 5'-Monophosphate-Responsive Element-Binding Protein (CREB) Is Decreased during Human Adrenal Cortex Tumorigenesis and Fetal Development J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3958 - 3965. [Abstract] [Full Text] [PDF]
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M. C. B. V. Fragoso, S. Domenice, A. C. Latronico, R. M. Martin, M. A. A. Pereira, M. C. N. Zerbini, A. M. Lucon, and B. B. Mendonca Cushing's Syndrome Secondary to Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia due to Activating Mutations of GNAS1 Gene J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2147 - 2151. [Abstract] [Full Text] [PDF]
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