Alternative titles; symbols
ORPHA: 189427; DO: 0111623;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | ACTH-independent macronodular adrenal hyperplasia 1, somatic | 219080 | 3 | GNAS | 139320 |
A number sign (#) is used with this entry because ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be caused by somatic mutation in the GNAS1 gene (139320) on chromosome 20q13. Bilateral adrenocortical nodular hyperplasia can also be found in McCune-Albright syndrome (174800), which is also caused by mutation in the GNAS1 gene.
ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an endogenous form of adrenal Cushing syndrome characterized by multiple bilateral adrenocortical nodules that cause a striking enlargement of the adrenal glands. Although some familial cases have been reported, the vast majority of AIMAH cases are sporadic. Patients typically present in the fifth or sixth decade of life, approximately 10 years later than most patients with other causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005).
Approximately 10 to 15% of adrenal Cushing syndrome is due to primary bilateral ACTH-independent adrenocortical pathology. The 2 main subtypes are AIMAH and primary pigmented nodular adrenocortical disease (PPNAD; see 610489), which is often a component of the Carney complex (160980) and associated with mutations in the PRKAR1A gene (188830). AIMAH is rare, representing less than 1% of endogenous causes of Cushing syndrome (Swain et al., 1998; Christopoulos et al., 2005).
See also ACTH-independent Cushing syndrome (615830) due to somatic mutation in the PRKACA gene (601639).
Cushing 'disease' (219090) is an ACTH-dependent disorder caused in most cases by pituitary adenomas that secrete excessive ACTH.
Genetic Heterogeneity of ACTH-Independent Macronodular Adrenal Hyperplasia
AIMAH2 (615954) is caused by germline mutation on 1 allele of the ARMC5 gene (615549) coupled with a somatic mutation in the other allele. AIMAH3 (620990) is caused by germline mutation on 1 allele of the KDM1A gene (609132) coupled with a somatic mutation in the other allele.
Kirschner et al. (1964) first reported AIMAH in a 40-year-old woman with long-standing Cushing syndrome (Christopoulos et al., 2005).
Findlay et al. (1993) reported a mother and daughter who each presented with clinical features of Cushing syndrome at age 38 years and were found to have AIMAH.
Minami et al. (1996) reported 2 Japanese sibs with Cushing syndrome due to AIMAH. The proband was a 69-year-old woman who presented with easy bruising, fatigability, muscle weakness, hypertension, and cognitive decline. She had truncal obesity, 'moon facies,' muscle wasting, and pretibial edema. Serum cortisol was elevated and did not respond to dexamethasone; CT scan showed bilateral adrenal enlargement. The patient died of subarachnoid hemorrhage and postmortem examination confirmed AIMAH. Family history revealed an older brother with AIMAH who had died postoperatively. Two additional sibs showed bilateral enlargement of the adrenal glands as well as impaired response to dexamethasone, although they were not clinically Cushingoid.
Swain et al. (1998) reported 9 unrelated patients with AIMAH who underwent curative bilateral adrenalectomy. The mean age was 56 years. All patients had increased serum cortisol, decreased serum ACTH, and failed to show suppression of cortisol excretion following dexamethasone administration. All patients except 1 had hypertension; subtle signs or symptoms consistent with Cushing syndrome were noted in patients' histories dating back up to 20 years. Pathologic examination showed bilateral adrenal cortical nodules that were yellow and ranged in size from 1 to 4.2 cm within enlarged adrenal glands weighing from 16.7 to 218 g combined. Microscopic analysis showed hyperplastic nodules composed of clear cells in cord-like arrangements and compact eosinophilic cells occasionally interspersed with atrophic nonnodular cortex. Swain et al. (1998) cited studies (Aiba et al., 1991; Sasano et al., 1994; Morioka et al., 1997; Koizumi et al., 1994) indicating that AIMAH nodules show impaired steroidogenesis, suggesting a primary intrinsic alteration in the adrenal cells. Importantly, none of the patients developed Nelson syndrome (pituitary tumor) after adrenalectomy and none showed any sign of malignancy. Swain et al. (1998) concluded that AIMAH is a distinct and legitimate disease entity.
Doppman et al. (2000) reported the radiographic findings of 11 patients with AIMAH and noted that the adrenal glands are often massive with combined weights up to 300 g and individual nodules up to 5 cm in diameter. One male patient reportedly had a brother with surgically-proven AIMAH. The authors commented that the clinical manifestations of Cushing syndrome are mild in many patients with AIMAH.
Nies et al. (2002) reported a family in which 3 female members had clinically symptomatic AIMAH. Three deceased female family members were reportedly affected. Although the father, who was determined to be an obligate carrier, had no overt symptoms, his adrenal glands showed nodular hyperplasia and he had impaired cortisol suppression on dexamethasone administration. Nies et al. (2002) suggested autosomal dominant inheritance.
Lee et al. (2005) reported 2 Asian sisters who developed AIMAH at ages 46 and 58 years, respectively. Both patients had typical Cushingoid features, including 'moon facies,' dorsocervical fat pad ('buffalo hump'), and central obesity; 1 had purple striae. Both had increased serum cortisol and bilateral adrenal masses, and both had meningiomas, which may or may not have been related. Pituitary tumors were not present.
Aberrant Hormone Receptors
Several groups have shown that cortisol hypersecretion in AIMAH can be regulated by hormones other than ACTH via the ectopic expression or the overactive eutopic expression of several membrane-bound hormone receptors in the adrenal cortex. These include gastric inhibitory polypeptide receptor (GIPR; 137241), various vasopressin receptors (AVPR1A, 600821; AVPR1B, 600264; AVPR2; 300538), beta-adrenergic receptors (see, e.g., ADRB1; 109630), the LH/human CG receptor (LHCGR; 152790), the serotonin 5-HT4 receptor (HTR4; 602164), and the angiotensin receptor (AGTR1; 106165) (Christopoulos et al., 2005).
Lacroix et al. (1997) reported a 36-year-old woman with Cushing syndrome due to AIMAH who had orthostatic hypotension. During upright posture, the patient's cortisol and aldosterone levels were stimulated despite suppression of ACTH and renin. Arginine vasopressin (AVP; 192340) was found to increase plasma cortisol, aldosterone, and androgens in this patient but not in controls. Following adrenalectomy, orthostatic hypotension persisted; a prolonged vasoconstrictive response to AVP was found in vitro in the patient's small arteries. Lacroix et al. (1997) suggested altered adrenal and vascular responses of the AVP V1 receptor (see 600821). Mune et al. (2002) found increased levels of AVPR1A mRNA in adrenal tissue from 4 patients with AIMAH, suggesting that eutopic V1A receptor overexpression is involved in the etiology. Miyamura et al. (2002) reported a mother and son with AIMAH in whom AVP and catecholamines promoted cortisol secretion. RT-PCR of adrenal tissue from the mother showed abnormal expression of AVPR1B, AVPR2, and LHCGR, none of which was observed in a normal control. In 2 sisters with AIMAH, Lee et al. (2005) demonstrated that AVP promoted cortisol secretion through overexpression of AVPR1A. In addition, RT-PCR analysis revealed abnormal cDNA expression of AVPR1B and AVPR2, which are normally not expressed in the adrenal gland.
Lacroix et al. (1997) reported a 56-year-old man with AIMAH who showed increased serum cortisol when changing from a supine to upright posture and in response to insulin-induced hypoglycemia, suggesting mediation by a beta-adrenergic receptor. Treatment with propranolol was effective, and the authors suggested that ectopic receptor expression led to catecholamine-induced adrenal hyperplasia in this patient. Lacroix et al. (1999) reported a woman with AIMAH that was clinically manifest transiently during pregnancy. Studies showed that the cortisol secretion was stimulated by luteinizing hormone (LH; 152780), HCG (118850), and by drugs that activated 5HT-4 receptors. Long-term suppression of LH secretion with leuprolide led to reversal of symptoms. Lacroix et al. (1999) noted that the identification of ectopic adrenal receptors could lead to medical treatment for such patients as alternatives to adrenalectomy.
Cartier et al. (2003) reported overexpression of 5HT-4 receptors in adrenal tissue from 4 of 6 patients with cisapride-responsive AIMAH. Sequencing of the 5HT4 receptor gene in 2 patients did not reveal any mutations.
Mircescu et al. (2000) found 1 or 2 abnormal hormone receptors in adrenal tissue from all 6 patients with AIMAH who were studied. The findings suggested that aberrant hormone receptors in adrenal tissue are common in these patients.
In a review, Christopoulos et al. (2005) stated that most patients with AIMAH, when screened, have been shown to have aberrant expression of receptors in the adrenal gland resulting in increased cortisol secretion; many patients show aberrant expression of more than 1 receptor. The authors suggested that dysregulation of tissue-specific receptor expression may indicate a disruption of gene regulatory elements in the early stages of embryogenesis since the pathology involves the entire adrenal cortex.
Fragoso et al. (2003) identified somatic heterozygous mutations in the GNAS1 gene (R201H, 139320.0009 and R201S, 139320.0013) in adrenal tissue from 3 unrelated patients with AIMAH. The mutations resulted in constitutive activation of the G protein. The mutations were not present in peripheral blood, and none of the patients had signs of McCune-Albright syndrome. Fragoso et al. (2003) discussed whether the patients could be considered part of the spectrum of McCune-Albright syndrome or whether they represent isolated cases of AIMAH associated with somatic mutations.
By cDNA microarray analysis of adrenal tissue from 8 AIMAH patients, Bourdeau et al. (2004) found upregulation of several genes involved in transcription, chromatin remodeling, and cell cycle and adhesion. There were differences in gene expression between those with and without GIP-dependent AIMAH, confirming clinical heterogeneity and suggesting distinct diagnostic subgroups.
Sato et al. (2014) identified 2 different somatic heterozygous mutations in the GNAS1 gene, both affecting the codon R201 (R201H, 139320.0009 and R201C, 139320.0008), in 11 (16.9%) of 65 cases of corticotropin-independent adrenal Cushing syndrome. The mutations were confirmed to be somatic in all 6 cases tested. GNAS-positive tumors were smaller (average diameter 31.9 mm) than tumors without GNAS mutations (average diameter 37.7 mm), but additional pathologic findings were not reported.
Bourdeau et al. (2006) did not identify mutations in the PRKAR1A gene in 14 unrelated patients with sporadic AIMAH. However, 91% of the tumor tissue samples showed somatic loss of heterozygosity (LOH) of chromosome 2p16, where Carney complex-2 (CNC2; 605244) has been mapped, and 73% of tissue samples showed somatic LOH of 17q22-q24, where the PRKAR1A gene is located. Total protein kinase A activity was higher in AIMAH tissue compared to normal adrenal glands.
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