Adrenocorticotropic Hormone-independent Cushing's Syndrome Research Articles

Role of adrenal venous sampling in the differential diagnosis and treatment protocol of ACTH-independent Cushing's syndrome with bilateral adrenal lesions.

The diagnosis and management of adrenocorticotropic hormone-independent Cushing's syndrome (AICS) with bilateral adrenal lesions remain challenging. Some studies have explored the value of adrenal vein sampling (AVS) in patients with AICS; however, more investigations are needed to assess its benefits for diagnosis and treatment planning in this population. Thirteen patients with clinical, biochemical and imaging evidence of AICS with bilateral adrenal lesions underwent AVS in our department from 2017-2022 were recruited. Only the data from nine patients for whom AVS succeeded were finally included in this study and further analyzed. Blood samples were successfully collected from both adrenal veins (AV) and inferior vena cava (IVC) in these nine patients, and the levels of plasma total cortisol (PTC) and plasma aldosterone concentrations (PAC) were measured. The ratio of the PAC of the AV to the IVC was calculated, and the PTC to PAC ratios were compared between AV. The surgical strategy was chosen according to the results of AVS. Postoperative histology and immunohistochemistry of the adrenal tissues were performed. The prognosis was evaluated based on the improvement of clinical symptoms and biochemical parameters (including PTC and ACTH measurements). Patients with AICS were clinically diagnosed based on clinical signs, results of functional tests and the presence of bilateral adrenal lesions as observed on computed tomography imaging. An AV to IVC PAC ratio greater than 2 confirmed successful AVS. The PTC to PAC ratio (high side to low side) was greater than 2 in four patients, and less than 2 in five patients. The postoperative pathological results were consistent with clinical diagnosis and AVS. During the mean follow-up of 33 months, all nine patients achieved varying degrees of clinical improvement. Our study showed that AVS helped to distinguish unilateral and bilateral lesions, identify the laterality of the autonomous hypercortisolism, and improve therapeutic strategy selection in patients with AICS and bilateral adrenal lesions.

Eleven-Year Experience with Selective Adrenal Vein Sampling in Management of Primary Adrenal Hormonal Hypersecretion.

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions: Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Recent Advances in the Clinical Application of Adrenal Vein Sampling.

We reviewed clinical research investigating the applications of adrenal vein sampling (AVS). AVS could be applied not only to primary aldosteronism (PA) but also to other endocrine diseases, such as adrenocorticotropic hormone (ACTH) independent Cushing syndrome (AICS) and hyperandrogenemia (HA). However, the AVS protocol requires improvements to increase its success rate. Using the computed tomography image fusion, coaxial guidewire technique, and fast intraprocedural cortisol testing (CCF) technique could improve the success rate of catheterization in AVS for PA. ACTH loading could be considered in medical centers with a low selectivity of AVS for PA but is not essential in those with mature AVS technology. The continuous infusion method should be recommended for ACTH stimulation in AVS for PA to reduce adverse events. AVS has not been routinely recommended before management decisions in AICS, but several studies verified that AVS was useful in finding out the source of excess cortisol, especially for distinguishing unilateral from bilateral disease. However, it is necessary to reassess the results of AVS in AICS with the use of reference hormones to fully normalize cortisol levels. In addition, it is essential to determine the optimal model that combines AVS results and mass size to guide the selection of surgical plans, including identifying the dominant gland and presenting the option of staged adrenalectomy, to minimize the impact of bilateral resection. For HA, AVS combined with ovarian intravenous sampling to locate excess androgens could be considered when imaging results are equivocal.

Cushing Syndrome Due to Pigmented Nodular Adrenal Hyperplasia in an Iranian Patient: A Case Report and Review of the Literature

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Adrenocorticotropic hormone-independent Cushing syndrome. In this case, we present a case of PPNAD in 25 y/o women who presented with a 3 years history of weight gain, hirsutism, and abnormal menstruation. Our findings were suggestive of PPNAD in the pathological study of adrenal biopsy.

Abstract No. 191 Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with adrenocorticotropic hormone–independent Cushing syndrome and bilateral adrenal masses

To evaluate adrenal venous sampling (AVS) in guiding surgical management of patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS) and bilateral adrenal masses 28 patients with bilateral adrenal masses and ACTH independent autonomous cortisol secretion who underwent AVS from January 1, 2008, to August 1, 2020, were identified. Methodology and data interpretation were performed as previously described. Cortisol and epinephrine levels were measured from each adrenal vein (AV) and the inferior vena cava (IVC). AVS was technically successful if plasma epinephrine concentration in AV-IVC was > 100 pg/mL. AV/IVC cortisol ratio for each adrenal gland and cortisol lateralization ratio (CLR) were calculated. Previously described parameters were utilized for interpretation: AV/IVC cortisol ratio of > 6.5 on one side and ≤3.3 on the contralateral side with CLR ≥ 2.3 was consistent with a unilateral cortisol-secreting adenoma whereas bilateral AV/IVC cortisol ≥ 4.1 with CLR < 2 was consistent with bilateral cortisol hypersecretion. Clinical, imaging, laboratory, pathology and follow-up data were collected. Primary outcome measure was hypercortisolism recurrence. 28 patients underwent AVS. Patients underwent subsequent right (n = 12) or left (n = 9) total, right total and left partial (n = 1) or bilateral total (n = 3) adrenalectomy. 3 patients were recommended adrenalectomy but were lost to follow up and not included in outcome analysis. Initial presentation included incidental adrenal masses (12%), subclinical CS (64%), overt CS (24%). Sequela included hypertension (88%), osteoporosis/osteopenia (38%), diabetes mellitus (36%), hyperlipidemia (56%), weight gain (76%), depression (52%). AVS was successful in all 28 patients. Data were interpreted as described above to guide laterality of adrenalectomy. Mean AV/IVC cortisol for unilateral adrenalectomies was 12 with mean CLR 3.7. Mean AV/IVC for bilateral adrenalectomies was 8.67 right and 6.33 left with CLR 0.76. Among 29 resected adrenal glands, pathology demonstrated benign adrenocortical adenomas (52%) and macronodular hyperplasia (48%) and mean dominant nodule maximum diameter of 2.7cm and mean weight of 18.2g. At a mean follow-up of 21.8 months, there was no clinical or biochemical recurrence of ACTH-independent hypercortisolism with most recent cortisol of 12.8 ± 7.5 mcg/dL and ACTH of 19.7 ± 13.1 pg/mL. AVS can be used to guide surgical management in patients with ACTH independent Cushing syndrome and bilateral adrenal masses, with favorable midterm outcomes.

The occurrence of Adrenocorticotropic hormone-independent Cushing's syndrome in a woman with the history of papillary thyroid carcinoma: a case report

BackgroundThyroid papillary carcinoma is one of the most common endocrine tumors, and it accounts for 85% of thyroid tumors. Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome is a rare disease. In this case report, we discuss a very rare case of coexistence of papillary thyroid carcinoma and Cushing's syndrome with an adrenal origin.Case presentationThe patient was a 33-year-old Iranian/Persian woman with a history of papillary thyroid carcinoma treated with iodine 131 three years ago. She presented with weight gain, amenorrhea, and mood disorders in the last six months. She was diagnosed with an ACTH-independent Cushing's syndrome due to benign adrenal adenoma and underwent laparoscopic adrenalectomy surgery. The symptoms of the syndrome were disappeared after the surgery.ConclusionsACTH-independent Cushing's syndrome due to adrenal tumor and papillary thyroid cancer occurs sporadically. The co-occurrence of two endocrine tumors with different origins is rare. It is recommended that the occurrence of other endocrine neoplasms be considered when an endocrine tumor is diagnosed.

A Case Report of Cortisol-Secreating Adrenal Adenoma Causing Cushing Syndrome

Cushing syndrome is a state of prolonged exposure to excess cortisol production. Causes can be varied ranging from exogenous intake or endogenous production from a pituitary source due to overproduction of adrenocorticotropic hormone (ACTH) or due to over secretion from unilateral or bilateral adrenal glands. Cushing syndrome in an adult can present with proximal muscle weakness, facial plethora, wasting of the extremities with increased fat in the abdomen and face, wide purplish striae, bruising with no obvious trauma, and supraclavicular fat pads. Here, we report a 38 year old male who presented with suspicion of having Cushing syndrome due to his clinical manifestations and high cortisol levels. He presented to the clinic with new onset diabetes, severe hypertension, chronic abdominal pain and distension which was being investigating by different specialties. The patient underwent CT scan of the abdomen which show right adrenal adenoma and on examination, he was found to have proximal weakness and purple striae. Laboratory data showed high morning cortisol, 24 urine free cortisol and ACTH levels which were strongly suggestive of ACTH independent Cushing syndrome.

Limitations of Basal Cortisol in the Diagnosis of Cushing Syndrome

Cushing syndrome (CS) is one of the most challenging diseases to diagnose due to the difficulties that may arise during laboratory test interpretations. A random serum cortisol level is often obtained by a general practitioner as a first step in the work-up of suspected CS patients. In this respect, it is rarely useful and has limitations. We report an extremely unusual case of a female patient who presented with adrenocorticotropic hormone-independent CS and corticosteroid-binding globulin (CBG) deficiency. The patient was initially misdiagnosed with and treated for adrenal insufficiency because of persistently low basal cortisol levels, in detriment of her exacerbated Cushing features and symptoms. We describe the limitations of using basal cortisol in the diagnosis of CS and review the differential diagnosis of patients with CS who have low basal cortisol. CBG variants may explain the findings of high urinary and salivary cortisol, in the absence of increased serum cortisol.

RELIABILITY OF THE CORTICOTROPIN RELEASING HORMONE STIMULATION TEST FOR DIFFERENTIATING BETWEEN ACTH DEPENDENT AND INDEPENDENT CUSHING SYNDROME.

It is a challenge to determine the origin of Cushing syndrome (CS), especially in patients with low-normal adrenocorticotropic hormone (ACTH) concentrations. To evaluate the reliability of the corticotropin-releasing hormone (CRH) stimulation test in patients with CS whose origin of disease was not clearly identified using ACTH values, the high-dose dexamethasone suppression test (HDDST), and imaging in a single tertiary referral center. Twenty-one patients with CS who were admitted to the endocrinology-metabolism clinic between 2004 and 2016 whose ACTH concentrations were 5-20 pg/mL and needed CRH stimulation test were retrospectively assessed. Nine out of 21 patients were diagnosed as having Cushing's disease (CD) and 12/21 had adrenal CS. The CRH stimulation test had a sensitivity and specificity of 100% and 8%, and positive and negative predictive values of 100% and 45% according to the current diagnostic criteria, respectively. An increase in ACTH ≥115% at 15 minutes and cortisol ≥86% at 60 minutes after CRH were associated with the highest likelihood ratio. The sensitivity and specificity of ACTH was 67% and 83% (AUC=0.75±0.12, 95% CI: [0.5-0.9]; p=0.03), and for cortisol it was 75% and 78% (AUC=0.71±0.15, 95% CI: [0.5-0.9]; p=0.03). Cortisol suppression of more than 64% from basal level in the HDDST suggested CD with the highest likelihood ratio. When these cut-off values were used together, both tests were negative in the patients with CD. The CRH stimulation test has low specificity to localize CS in patients with ACTH concentrations of 5-20 pg/mL according to the current diagnostic criteria. Different diagnostic criteria may be used in the CRH stimulation test and also in the HDDST in this group of patients.

Multiple myeloma concealed by adrenal Cushing syndrome: a case report and review of the literature

BackgroundCushing syndrome coexisting with multiple myeloma has been previously described in a few reports. Overlapping clinical manifestations can lead to misdiagnoses.Case presentationWe presented an extremely rare case of a 33-year-old Thai woman with concomitant kappa light chain myeloma with adrenal Cushing syndrome, both of which were related to skeletal manifestations. A precedence report indicated that treatment of the Cushing syndrome could exacerbate the myeloma symptoms. Therefore, we were faced with the dilemma of which disease should be addressed first. We decided to treat our patient with a combination chemotherapy followed by an autologous stem cell transplant. Subsequently, a left laparoscopic adrenalectomy was successfully undertaken.ConclusionWe have reported the first association between adrenocorticotropic hormone-independent Cushing syndrome resulting from a left autonomous cortisol-secreting adrenal adenoma, and multiple myeloma.

Efficacy of dexamethasone suppression test during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome

ObjectiveTo evaluate the cut-off value of the ratio of 24 h urinary free cortisol (24 h UFC) levels post-dexamethasone to prior-dexamethasone in dexamethasone suppression test (DST) during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome.DesignRetrospective study.ParticipantsThe patients diagnosed with primary pigmented nodular adrenocortical disease (PPNAD, n = 25), bilateral macronodular adrenal hyperplasia (BMAH, n = 27), and adrenocortical adenoma (ADA, n = 84) were admitted to the Peking Union Medical College Hospital from 2001 to 2016.EstimationsSerum cortisol, adrenocorticotropic hormone (ACTH), and 24 h UFC were measured before and after low-dose dexamethasone suppression test (LDDST) and high-dose dexamethasone suppression test (HDDST).ResultsAfter LDDST and HDDST, 24 h UFC elevated in patients with PPNAD (paired t-test, P = 0.007 and P = 0.001), while it remained unchanged in the BMAH group (paired t-test, P = 0.471 and P = 0.414) and decreased in the ADA group (paired t-test, P = 0.002 and P = 0.004). The 24 h UFC level after LDDST was higher in PPNAD and BMAH as compared to ADA (P < 0.017), while no significant difference was observed between PPNAD and BMAH. After HDDST, 24 h UFC was higher in patients with PPNAD as compared to that of ADA and BMAH (P < 0.017). The cut-off value of 24 h UFC (Post-L-Dex)/(Pre-L-Dex) was 1.16 with 64.0% sensitivity and 77.9% specificity, and the cut-off value of 24 h UFC (Post-H-Dex)/(Pre-H-Dex) was 1.08 with 84.0% sensitivity and 75.6% specificity.ConclusionThe ratio of post-dexamethasone to prior-dexamethasone had a unique advantage in distinguishing PPNAD from BMAH and ADA.

Etiology analysis of 522 hospitalized cases with Cushing syndrome

To summarize the characteristics of the etiology distribution of Cushing syndrome (CS) patients in Chinese PLA general hospital during the past 20 years. All data of CS patients admitted to Chinese PLA General Hospital between 1995 and 2014 were collected. The sex ratio of patients, visiting age, final diagnosis were retrospectively analyzed. From January 1995 to December 2014, 522 patients with CS were admitted, of which, 134 (25.67%) were males and 388(74.33%) were females. The overall mean age was (42±13) years old. 46.36% of the cases were adrenocorticotropic hormone (ACTH) dependent, and ACTH independent CS accounted for 53.64%. At the 41-60 age group, the proportion of ACTH independent CS was higher than that of ACTH independent CS.The proportions of ACTH-independent macronodular adrenal hyperplasia (AIMAH), ectopic ACTH syndrome and adrenal cortical carcinoma were higher in male group than in female group. The number of CS patients was gradually increased during the past 20 years. The proportion of ACTH independent CS was increased (from 32.8% to 60.4%). The proportion of ACTH dependent CS was declined (from 67.2% to 39.6%). The etiology spectrum of CS has changed. There was significant gender-related, age-related difference of etiology distribution in patients with CS.

Carney complex presenting with a unilateral adrenocortical nodule: a case report

IntroductionCarney complex is an autosomal dominant syndrome with multiple neoplasms in different sites, including myxomas, endocrine tumors and lentigines lesions. To the best of our knowledge, this is the first report of Carney complex presenting with a unilateral adrenal adenoma associated with a pituitary incidentaloma.Case presentationA 27-year-old Iranian woman was referred to our endocrinology clinic with amenorrhea and hirsutism, further confirming a diagnosis of adrenocorticotropic hormone-independent Cushing’s syndrome. The cause was believed to be a right adrenocortical adenoma based on a computed tomography scan. Our patient underwent a right laparoscopic adrenalectomy and pathological examination revealed pigmented micronodular adrenal hyperplasia. Pituitary magnetic resonance imaging also documented a microadenoma that was considered to be an incidentaloma based on normal pituitary function tests. Recurrence of hypercortisolism led to a left laparoscopic adrenalectomy, providing further evidence for the diagnosis of primary pigmented nodular adrenocortical disease. Carney complex was established in light of her history of cardiac myxomas.ConclusionWe present what we believe to be the first case of Carney complex presenting with a unilateral adrenocortical adenoma in association with a pituitary incidentaloma. Although primary pigmented nodular adrenocortical disease is rare as a component of Carney complex, it should be considered in the differential diagnosis of Cushing's syndrome. Rarely, adrenal and pituitary imaging can be misleading.

Skeletal Maturation in Children with Cushing Syndrome Is Not Consistently Delayed: The Role of Corticotropin, Obesity, and Steroid Hormones, and the Effect of Surgical Cure

To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA. Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P=.8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001). Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Luteinizing hormone correlates with adrenal function in postmenopausal women

In postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone-independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). Participants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women's Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson's correlation coefficient. Serum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = -0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. In postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion.

Primary pigmented nodular adrenocortical disease presenting with a unilateral adrenocortical nodule treated with bilateral laparoscopic adrenalectomy: a case report

IntroductionPrimary pigmented nodular adrenocortical disease is a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome. We report an uncommon primary pigmented nodular adrenocortical disease case presenting with a unilateral adrenocortical nodule and provide a brief overview of the existing literature.Case presentationA 27-year-old Caucasian woman was admitted to our Department with adrenocorticotropic hormone-independent Cushing's syndrome. Its cause was initially considered a left adrenocortical adenoma based on computer tomography imaging. The patient underwent left laparoscopic adrenalectomy and histological examination revealed pigmented micronodular adrenal hyperplasia. Evaluation for the presence of Carney complex was negative. Six months later recurrence of hypercortisolism was documented and a right laparoscopic adrenalectomy was performed further establishing the diagnosis of primary pigmented nodular adrenocortical disease. After a nine-year follow-up there is no evidence of residual disease.ConclusionsEven though primary pigmented nodular adrenocortical disease is a rare cause of Cushing's syndrome, it should be included in the differential diagnosis of adrenocorticotropic hormone-independent Cushing's syndrome, especially because adrenal imaging can be misleading mimicking other adrenocortical diseases. Bilateral laparoscopic adrenalectomy is the preferred treatment in these subjects.

Adrenocorticotropic hormone-independent Cushing's syndrome

Endogenous Cushing's syndrome is adrenocorticotropic hormone (or corticotropin)-independent in 15-20% of cases. Primary Cushing's syndrome is most often secondary to adrenocortical adenomas or carcinomas, and more rarely to bilateral adrenal hyperplasias. Corticotropin-independent cortisol-producing hyperplasia is caused by micronodular diseases, including primary pigmented nodular adrenocortical disease and nonpigmented micronodular hyperplasia and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. Primary pigmented nodular adrenocortical disease can be found either alone or in the context of Carney complex, a multiple endocrine neoplasia syndrome. In recent years, the pathophysiology of adrenocortical tumors and hyperplasias became better understood following the identification of genes responsible for syndromes associated with corticotropin-independent Cushing's syndrome and the demonstration of aberrant expression and function of various hormone receptors in adrenocortical adenomas and adrenocorticotropic hormone-independent macronodular adrenal hyperplasia. This article reviews findings on the molecular and genetic aspects of corticotropin-independent Cushing's syndrome including recent gene expression profiling studies of adrenocortical tumors and hyperplasias and animal models that provided clues on the pathogenesis of primary Cushing's syndrome. A better understanding of molecular mechanisms involved in adrenocortical tumors and hyperplasias may lead to improved diagnostic and prognostic markers and treatment strategies to assist clinicians in the management of corticotropin-independent Cushing's syndrome.

Primary pigmented nodular adrenocortical disease associated with Carney complex: case report and literature review

Carney complex (CNC), a familial multiple neoplasm syndrome with dominant autosomal transmission, is characterized by tumors of the heart, skin, endocrine and peripheral nervous system, and also cutaneous lentiginosis. This is a rare syndrome and its main endocrine manifestation, primary pigmented nodular adrenal disease (PPNAD), is an uncommon cause of adrenocorticotropic hormone-independent Cushing's syndrome. We report the case of a 20-year-old patient with a history of weight gain, hirsutism, acne, secondary amenorrhea and facial lentiginosis. Following the diagnosing of CNC and PPNAD, the patient underwent laparoscopic bilateral adrenalectomy, and she evolved with decreasing hypercortisolism. Screening was also performed for other tumors related to this syndrome. The diagnostic criteria, screening and follow-up for patients and affected family members are discussed.

Ligand-independent hormone secretion.

The secretion of many hormones is regulated by extracellular signals, such as hormones, growth factors, neurotransmitters, and ions, that mediate signal transduction via a G protein-coupled pathway. Three components comprise the G protein-coupled pathway: the G protein-coupled receptor, the G protein, and the effector. G protein-coupled receptors allow cells to respond to external stimuli and comprise a large superfamily with hundreds of members. G proteins function as signal transducers between ligand-bound receptors and intracellular effectors. G protein-regulated effectors include enzymes of second messenger metabolism, such as adenylyl cyclase, phospholipase C, cyclic GMP phosphodiesterase, and ion channels. Abnormalities in any of these three components alter signal transduction and can lead to human disease. For example, mutations of G protein-coupled receptors that promote G protein activation in the absence of an agonist cause retinitis pigmentosa, hyperthyroidism due to hyperfunctioning thyroid adenomas and thyroid hyperplasia, male-limited precocious puberty, and hypocalcemia. Human disorders attributed to constitutively activating mutations of the alpha subunit of Gs include the McCune-Albright syndrome, adrenocorticotropic hormone-independent Cushing's syndrome, and functional endocrine tumors.