Diagnosis, Genetics, and Management of 24 Patients With Cardiac Paragangliomas: Experience From a Single Center.

Context: Paragangliomas located within the pericardium represent a rare yet challenging clinical situation. Objective: The current analysis aimed to describe the clinical characteristics of cardiac paragangliomas, with emphasis on the diagnostic approach, genetic background, and multidisciplinary management. Methods: Twenty-four patients diagnosed with cardiac paraganglioma (PGL) in Peking Union Medical College Hospital, Beijing, China, between 2003 and 2021 were identified. Clinical data was collected from medical record. Genetic screening and succinate dehydrogenase subunit B immunohistochemistry were performed in 22 patients. Results: The median age at diagnosis was 38 years (range 11-51 years), 8 patients (33%) were females, and 4 (17%) had familial history. Hypertension and/or symptoms related to catecholamine secretion were present in 22 (92%) patients. Excess levels of catecholamines and/or metanephrines were detected in 22 (96%) of the 23 patients who have completed biochemical testing. Cardiac PGLs were localized with 131I-metaiodobenzylguanidine scintigraphy in 11/22 (50%), and 99mTc-hydrazinonicotinyl-tyr3-octreotide scintigraphy in 24/24 (100%) patients. Genetic testing identified germline SDHx mutations in 13/22 (59%) patients, while immunohistochemistry revealed succinate dehydrogenase (SDH) deficiency in tumors from 17/22 (77%) patients. All patients were managed by a multidisciplinary team through medical preparation, surgery, and follow-up. Twenty-three patients received surgical treatment and perioperative death occurred in 2 cases. Overall, 21 patients were alive at follow-up (median 7.0 years, range 0.6-18 years). Local recurrence or metastasis developed in 3 patients, all of whom had SDH-deficient tumors. Conclusion: Cardiac PGLs can be diagnosed based on clinical manifestations, biochemical tests, and appropriate imaging studies. Genetic screening, multidisciplinary approach, and long-term follow-up are crucial in the management of this disease.

Subclinical left ventricular systolic dysfunction detected by two-dimensional speckle tracking echocardiography in patients with pheochromocytoma and paraganglioma and preserved ejection fraction.

BACKGROUND: Excessive catecholamine leads to pressure overload and left ventricular (LV) remodeling. The goal of this study was to explore subclinical LV systolic dysfunction and the mechanism of preserved left ventricular ejection fraction (LVEF) in patients with pheochromocytoma and paraganglioma using two-dimensional speckle tracking echocardiography. METHODS: A total of 48 patients with pheochromocytoma and paraganglioma and preserved LVEF and 38 age- and gender-matched volunteers were studied. Echocardiographic parameters including LVEF, and global peak longitudinal and circumferential strains were measured. The correlation between echocardiographic parameters and blood pressure as well as biochemical parameters was analyzed. RESULTS: LVEF was similar between patients with pheochromocytoma and paraganglioma and controls. The amplitude of LV longitudinal strain was decreased, and the amplitude of LV circumferential strain was increased in the pheochromocytoma and paraganglioma group (P = .003 and P = .009). LV mass index and blood pressure were positively correlated with 24-hour urinary norepinephrine (r = .696, P < .0001; r = .470, P = .0007). The amplitude of LV longitudinal strain reduced with increase in blood pressure, 24-hour urinary norepinephrine and LV mass index (r = -.305, P = .035; r = -.506, P = .0002; r = -.680, P < .0001). CONCLUSIONS: This study revealed that excessive norepinephrine in pheochromocytoma and paraganglioma was associated with increased blood pressure and LV mass. The LV longitudinal strain was decreasing with increase in blood pressure and LV mass index. The enhanced LV circumferential strain might be the mechanism of compensation to maintain the normal LVEF in these patients.

Exome sequencing identifies compound heterozygous PKHD1 mutations as a cause of autosomal recessive polycystic kidney disease.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disease, which is a disorder with multiple organ involvement, mainly the kidney and liver. It is caused by mutations in the PKHD1 gene. Here, we reported the clinical characteristics of a case with ARPKD and analyze the genetic features of this patient as well as of his father using targeted exome sequencing and Sanger sequencing. METHODS: Genomic DNA was extracted from peripheral blood leukocytes obtained from a patient with ARPKD. The mutations were identified using exome sequencing and confirmed by Sanger sequencing. RESULTS: The patient was diagnosed as ARPKD based on ultrasonography and abdominal computed tomography which showed polycystic changes, multiple calcinosis of both kidneys, and multiple dilated bile ducts of the liver. Compound heterozygous PKHD1 gene mutations A979G and G5935A, which lead to substitution of an asparagine for an aspartate at amino acid 327 (N327D) and a glycine for an arginine at amino acid 1979 (G1979R) respectively, were identified using targeted exome sequencing and confirmed by Sanger sequencing for the patient. In addition, the father of the patient was identified to be a carrier of heterozygous A979G mutation of this gene. CONCLUSIONS: We identified that the compound heterozygous PKHD1 gene mutations are the molecular basis of the patient with ARPKD. Targeted exome sequencing is suitable for genetic diagnosis of single-gene inherited diseases like ARPKD in which the pathogenic gene is a large.

[Differences of blood plasma renin activity, angiotensin II and aldosterone levels in essential or secondary hypertension].

OBJECTIVE: To study on the difference of plasma renin activity (PRA), angiotensin II (Ang II), and aldosterone levels in patients with essential hypertension (EH) or primary aldosteronism (PA) or pheochromocytoma (PHEO), and to analyze the sensitivity and specificity on the diagnosis of PA among patients with hypertension with aldosterone/PRA ratio (ARR). METHODS: The plasma aldosterone, Ang II and PRA concentrations in supine and upright positions were measured by radioimmunoassay from 413 patients including idiopathic hyperaldosteronism (IHA, n = 111), aldosterone-producing adenoma (APA, n = 118), PHEO (n = 98) and EH (n = 86). ARR was calculated. RESULTS: Plasma aldosterone concentrations in both of supine and upright positions in PHEO group [374 (294, 465) pmol/L and 629 (449, 997) pmol/L] and PA group [471 (346, 632) pmol/L and 673 (499, 825) pmol/L] were higher than those in EH group [277 (224, 332) pmol/L and 427 (341, 501) pmol/L] (P < 0.01). They were also higher in APA group [576 (416, 731) pmol/L and 726 (554, 906) pmol/L] than those in IHA group [399 (313, 504) pmol/L and 609 (485, 776) pmol/L] (P < 0.01). Ang II levels in both positions were lower in PA group [43.2 (26.4, 74.4) ng/L and 60.1 (38.5, 103.6) ng/L] than in EH group [56.7 (43.3, 78.9) ng/L and 84.3 (61.3, 108.4) ng/L] or PHEO group [54.3 (29.9, 101.5) ng/L and 102.8 (49.9, 167.0) ng/L] (all P values < 0.01), and there was no difference between IHA and APA group (P > 0.05). The PRA level in both positions of each group were PHEO group [0.3 (0.2, 1.0) µg · L(-1) · h(-1) and 1.4 (0.6, 3.4) µg · L(-1) · h(-1)] > EH group [0.2 (0.1, 0.4) µg · L(-1) · h(-1) and 0.6 (0.4, 1.0) µg · L(-1) · h(-1)] (P < 0.01) > PA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (P < 0.01), and APA group [0.1 (0.1, 0.1) µg · L(-1) · h(-1) and 0.1 (0.1, 0.3) µg · L(-1) · h(-1)] < IHA group [0.1 (0.1, 0.2) µg · L(-1) · h(-1) and 0.2 (0.1, 0.3) µg · L(-1) · h(-1)] (supine P < 0.01; upright P < 0.05). APA was divided into 2 types with renin-Ang II-responsive APA (n = 26) and unresponsive APA (n = 92). The plasma aldosterone concentration was lower in supine position but higher in upright position in renin-Ang II-responsive APA than in unresponsive APA patients. ARR in upright was higher in PA group (P < 0.01) but lower in PHEO group (P < 0.05) compared with EH. ARR was higher in APA than in IHA (P < 0.01). The sensitivity and specificity of ARR as 40 (aldosterone unit: ng/dl; PRA unit: µg · L(-1) · h(-1); its value should multiply 27.7 when transferred to pmol/L, simili) were 93% and 76%, respectively. CONCLUSION: The levels of PRA, Ang II and aldosterone from patients with EH, PA and PHEO are significant different. ARR as 40 in upright position could be used for PA screening cutoff point.

Rare case of reninoma with double inferior vena cava.

A 16-year-old boy suffered from headaches and dizziness for 2 years. He was found to have remarkably elevated blood pressure (BP) of 180/110 mmHg. Laboratory findings showed a low level of serum potassium and markedly increased plasma renin activity. A solid mass at the periphery of the right kidney and double inferior vena cava (IVC) were detected by abdominal computer tomography (CT). Right partial nephrectomy via laparoscopy was performed on the patient. The histologic and electron microscopic findings comfirmed a diagnosis of juxtaglomerlar cell tumor. The patient had no headache or dizziness with normal BP after surgery.

[An analysis of hyperinsulinemia in Bartter syndrome].

OBJECTIVE: To analyse hyperinsulinemia in Bartter syndrome. METHODS: Twenty-three cases of Bartter syndrome [age (27 ± 9) years; fasting serum potassium (2.8 ± 0.5) mmol/L], 20 patients of aldosterone-producing adenoma [APA, age (45 ± 11)years, fasting serum potassium (3.0 ± 0.4) mmol/L], 20 patients of idiopathic hyperaldosteronism [IHA, age (51 ± 11) years, fasting serum potassium (3.4 ± 0.2) mmol/L] were diagnosed in Peking Union Medical College Hospital from September 2003 to May 2008. All patients underwent 3-hours oral glucose tolerance test (3hOGTT), postural stimulation test and calculated HOMA-insulin resistance (HOMA-IR) and HOMA-insulin sensitivity (HOMA-IS) by Homeostasis model. RESULTS: The insulin area under curve[(229.0 ± 162.4) mIU×L(-1)×h] was significantly higher than APA group [(121.2 ± 81.1) mIU×L(-1)×h, P < 0.05] and were similar to the aged-matched patients with IHA [(227.7 ± 158.6) mIU×L(-1)×h]. But HOMA-IR in Bartter group were similar to APA group (1.96 ± 1.14 vs 1.41 ± 0.91), and HOMA-IR in APA group was lower than IHA group (1.96 ± 1.14 vs 2.40 ± 1.60, P < 0.05). There was no deference in HOMA-IS among three groups, but APA group had lower level. In all three groups, the peak of insulin secretion was delayed. CONCLUSION: Bartter syndrome patients commonly present with hyperinsulinemia.

[Relationship between plasma level of leptin and the expression of leptin receptor in human adrenal tissues and tumors].

OBJECTIVE: To compare the mRNA, protein expression of long leptin receptor (Ob-Rb) in human adrenal tissues and tumors and observe the plasma level of leptin in primary aldosteronism (PA), cortisol-secreting tumors (CS) and pheochromocytomas (PHEO). METHODS: Total RNA and protein were extracted from 6 normal human adrenal glands, 10 CS, 20 PHEO; and 14 aldosterone-producing adenomas (APA) (RNA), 10 APA (protein); plasma samples were drawn from 20 controls, 15 PHEO, 29 PA and 11 CS. RESULTS: The mRNA and protein of Ob-Rb were widely expressed in human adrenal glands and tumors. The mRNA (0.32±0.12) and protein (1.31±0.26) expressions of Ob-Rb were higher in normal human adrenal cortex (C) than all other tissues (P<0.05) while the mRNA expression of Ob-Rb in APA (0.15±0.10) was higher than CS (0.05±0.02) (P<0.05). The mRNA expression of Ob-Rb in APA was positively correlated with plasma supine aldosterone level (r=0.670, P=0.024). The mRNA expression of Ob-Rb in CS was positively correlated with 24-hour urinary free cortisol level (r=0.870, P=0.005). The plasma level of leptin was higher in CS than in non-CS groups (P=0.001). CONCLUSIONS: Ob-Rb is widely expressed in adrenal tissues and tumors. There is a differential expression in various tissues. Further studies are warranted to understand the relationship between leptin and adrenal gland.

Clinical and pathological features of Riedel's thyroiditis.

OBJECTIVE: To evaluate the clinical and pathological features of Riedel's thyroiditis (RT), and current diagnostic and treatment methods for that disease. METHODS: Five RT cases identified by surgery and pathological examinations at Peking Union Medical College Hospital from 1985 to 2009 were analyzed and compared with the cases reported in the literature in terms of clinical and pathological features. Immunohistochemical staining of kappa and lambda light chains was carried out for RT tissues from all the five patients. RESULTS: All the five cases were females, aged 45-55 years. Elevation of serum thyroid autoantibodies was found in only one patient, who had longer disease duration than the others. Pathological examination revealed invasive fibrosclerosis of the thyroid follicles, thyroid capsule, and the surrounding tissues. In RT tissues, the number of cells containing lambda chains was a little higher than those containing kappa chains. CONCLUSIONS: RT is a rare disease which might be more common in middle-aged females than in other populations. Pathological features include the destruction of thyroid follicle, extension into surrounding tissues by inflammatory cells and fibrous tissues. Immunohistochemical staining of kappa and lambda chains could help diagnose RT.

Sulfated tyrosines 27 and 29 in the N-terminus of human CXCR3 participate in binding native IP-10.

AIM: Human CXCR3, a seven-transmembrane segment (7TMS), is predominantly expressed in Th1-mediated responses. Interferon-gamma-inducible protein 10 (IP-10) is an important ligand for CXCR3. Their interaction is pivotal for leukocyte migration and activation. Tyrosine sulfation in 7TMS is a posttranslational modification that contributes substantially to ligand binding. We aimed to study the role of tyrosine sulfation of CXCR3 in the protein's binding to IP-10. METHODS: Plasmids encoding CXCR3 and its mutants were prepared by PCR and site-directed mutagenesis. HEK 293T cells were transfected with plasmids encoding CXCR3 or its variants using calcium phosphate. Transfected cells were labeled with [(35)S]-cysteine and methionine or [(35)S]-Na(2)SO(3) and then analyzed by immunoprecipitation to measure sulfation. Experiments with (125)I-labeled IP-10 were carried out to evaluate the affinity of CXCR3 for its ligand. Calcium influx assays were used to measure intercellular signal transduction. RESULTS: Our data show that sulfate moieties are added to tyrosines 27 and 29 of CXCR3. Mutation of these two tyrosines to phenylalanines substantially decreases binding of CXCR3 to IP-10 and appears to eliminate the associated signal transduction. Tyrosine sulfation of CXCR3 is enhanced by tyrosyl protein sulfotransferases (TPSTs), and it is weakened by shRNA constructs. The binding ability of CXCR3 to IP-10 is increased by TPSTs and decreased by shRNAs. CONCLUSIONS: This study identifies two sulfated tyrosines in the N-terminus of CXCR3 as part of the binding site for IP-10, and it underscores the fact that tyrosine sulfation in the N-termini of 7TMS receptors is functionally important for ligand interactions. Our study suggests a molecular target for inhibiting this ligand-receptor interaction.

Bilateral pheochromocytoma as first presentation of von Hippel-Lindau disease in a Chinese family.

OBJECTIVE: To investigate the clinical and genetic features of a Chinese family with von Hippel-Lindau (VHL) disease revealed by bilateral pheochromocytoma. METHODS: The proband and other members in a Chinese family with familial pheochromocytoma were clinically evaluated and followed up. Genomic DNA extracted from the peripheral blood of 8 family members (including 3 patients) was amplified by polymerase chain reaction (PCR) and the PCR products were directly sequenced. RESULTS: The first presentation in the proband, his mother, and his sister was bilateral pheochromocytoma, and the missense mutation of 695G-A (Arg161Gln) in exon 3 of VHL gene was detected in the three patients. In the follow-up study, the proband and his mother were found to have other VHL tumors, induding retinal and cerebellar hemangioblastomas and pancreatic tumor. Neither clinical presentation of VHL disease nor gene mutation was found in other family members. CONCLUSION: VHL disease should be suspected in some patients with familial pheochromocytoma, and VHL gene screening helps to achieve early diagnosis of the disease.

[Perioperative hemodynamics in pheochromocytoma secreting different types of catecholamine].

OBJECTIVE: To analyze the characteristics of perioperative hemodynamics in pheochromocytoma secreting different types of catecholamine, and to discuss how to improve the hemodynamics. METHODS: The clinical data of 202 patients with pheochromocytoma who had received operation were analyzed. Three classification systems were used to divided the patients: they were, firstly, divided into high and low epinephrine secreting groups (E(high) and E(low)) according to the 24 hours urine catecholamine quantitation; secondly, into high and low norepinephrine secreting groups (NE(high) and NE(low)) according to 24-h urine norepinephrine quantitation; and thirdly, into high and low dopamine secreting groups (DA(high) and DA(low)) according to the 24 hours urine dopamine quantitation. Relationship between the characteristics of perioperative hemodynamics and catecholamine secreting types were analyzed. RESULTS: The highest preoperative systolic blood pressure values of E(high) and NE(high) groups were (201 +/- 40) mm Hg and (205 +/- 38) mm Hg, both significantly higher than those of the E(low) and NE(low) groups [(183 +/- 43) mm Hg, P = 0.003 and (181 +/- 43) mm Hg, P = 0.000]. The range of systolic blood pressure fluctuation during the operation of the E(high) group was 108 +/- 39 mm Hg, significantly larger than that of the E(low) group (91 +/- 33 mm Hg, P = 0.001). The incidence rates of persisting postoperative hypotension of the NE(high) and DA(high) groups were 23.3% (20/86) and 32.7% (17/52) respectively, both higher than those of the NE(low) and DA(low) groups [2.6% (3/116) and 4.0% (6/150) respectively, P = 0.000 and P = 0.000]. CONCLUSION: Different characteristics of perioperative hemodynamics are present in pheochromocytoma secreting different types of catecholamines. Patients with highly epinephrine secreting pheochromocytoma are apt to have larger blood fluctuation during the operation. Patients with highly norepinephrine and dopamine secreting pheochromocytoma are apt to suffer from persisting postoperative hypotension.

[Retroperitoneal laparoscopic resection for pheochromocytoma (experience of 107 cases)].

OBJECTIVE: To evaluate the safety and efficacy of retroperitoneal laparoscopic resection for pheochromocytoma. METHODS: The clinical data of 107 cases of pheochromocytoma in PUMCH from 2003 to 2008 were analyzed retrospectively. There were 58 males and 49 females with an age range from 8 to 77 years (mean 44 years) in this cohort. One hundred and two cases were intra-adrenal and 5 extra-adrenal. Of the 102 intra-adrenal tumors, 43 tumors were located in left adrenal, 51 in right adrenal and 8 in both sides. All of the 5 extra-adrenal tumors were at para-abdominal aorta. Retroperitoneal laparoscopic resection was performed for the 107 cases. This period was separated to 3 stages based on the degrees of the practical ability for retroperitoneal laparoscopic resection, such as tentative and exploratory stage, accumulative stage, and mature stage. RESULTS: At tentative and exploratory stage from June 2003 to December 2003, 10 cases underwent retroperitoneal laparoscopic surgery, of which 3 cases were converted to open surgery. The mean diameter was 4.2 cm (range in diameter from 2.5 cm to 6.0 cm). The mean operation time was 105 min (range from 60 min to 230 min). The mean volume of blood loss during operation was 620 ml (range from 150 ml to 1800 ml). At accumulative stage from January 2004 to December 2006, 66 cases underwent retroperitoneal laparoscopic surgery with none converted to open surgery. The mean diameter was 5.7 cm (range in diameter from 2.1 cm to 8.7 cm), and the diameter was above 6.0 cm in 19 cases. The mean operation time was 95 min (range from 40 min to 210 min). The mean volume of blood loss during operation was 350 ml (range from 50 ml to 1800 ml). At mature stage from January 2007 to June 2008, 31 cases, including 5 extra-adrenal pheochromocytomas, underwent retroperitoneal laparoscopic surgery. The mean diameter was 6.5 (range in diameter from 1.5 cm to 12.3 cm). The mean operation time was 75 min (range from 40 min to 160 min). The mean volume of blood loss during operation was 180 ml (range from 50 ml to 800 ml). No peri-operative death occurred. Follow up period was ranging from 1 to 62 months (the mean was 34 months), and 7 failed to be followed up, 3 cases recurred. And there was no distant metastases and death case. CONCLUSIONS: Retroperitoneal laparoscopic surgery for pheochromocytoma is feasible and safe. This procedure will be more and more performed as the advancement of the skill and accumulation of experience. The dimension, recurrence and location of tumor are not the absolute contraindication of retroperitoneal laparoscopic surgery for pheochromocytoma.

[Early changes in function of hypothalamic-pituitary-target gland axis in patients with severe sepsis and septic shock].

OBJECTIVE: To investigate the early changes in function of hypothalamic-pituitary-target gland (HPTG) axis in patients with severe sepsis and septic shock, in order to clarify its relationship with severity and prognosis of the patients. METHODS: The serum contents of cortisol (F), triiodothyronine (T(3)), thyroxine (T(4)), thyrotropic-stimulating hormone (TSH), growth hormone (GH), follicle-stimulating hormone (FSH), luteotropic hormone (LH), prolactin (PRL) and plasma concentration of adrenocorticotrophic hormone (ACTH) in 10 severe sepsis and 12 septic shock patients on day 1, 3, 5 after diagnosis was made, and 12 patients with no infection or septic shock served as controls. The hypothalamic-pituitary adrenal gland axis (HPAA) function of the patients with severe sepsis and septic shock were evaluated with 1 microgram ACTH stimulation test given 1 day after the concentrations of the above hormones were determined. RESULTS: Compared with the control patients, ACTH, T(3), T(4), GH, FSH, LH and PRL levels were significantly changed in patients with severe sepsis and septic shock (P<0.05 or P<0.01). The numbers of patients with reaction to 1 microgram ACTH stimulation test were similar between patients with severe sepsis (6 cases non-reaction and 3 cases reaction) and patients with septic shock (9 cases non reaction and 2 cases reaction, P>0.05). According to the acute physiology and chronic health evaluation II (APACHE II) and sepsis-related organ failure assessment (SOFA) score, changes in ACTH, T(3), T(4), GH and PRL levels were closely related to the severity of illness (P<0.05 or P<0.01). Significant differences were found in ACTH, T(3), T(4) levels between survivors and non-survivors (P<0.05 or P<0.01). ACTH, T(4) levels and SOFA score were independent predictors of the 28-day hospital mortality (P<0.05 or P<0.01). CONCLUSION: The early changes in HPTG axis are closely related with the severity and hospital mortality in patients with severe sepsis and septic shock.

von Hippel-Lindau gene mutation in non-syndromic familial pheochromocytomas.

Approximately 50% of patients with non-syndromic familial pheochromocytomas had germline von Hippel-Lindau (VHL) gene mutations, but no reports on the subject were available in China. A total of five unrelated Chinese families with non-syndromic familial pheochromocytomas were screened for VHL gene mutation by polymerase chain reaction (PCR) and subsequent direct sequencing. Missense germline mutations of VHL gene were detected in four of the five families. Arg161Gln (695G-A) mutation was found in two families, and the other two families had Leu163Phe (700C-T) and Arg167Trp (712C-T) mutation, respectively. In conclusion, VHL gene may have frequent mutation in Chinese patients with non-syndromic familial pheochromocytomas.

Expression and effect of transforming growth factor-alpha and tumor necrosis factor-alpha in human pheochromocytoma.

This study observed the expression of transforming growth factor-alpha (TGF-alpha) and tumor necrosis factor-alpha (TNF-alpha) in pheochromocytoma (PHEO) tissue and examined their effects on the proliferation and apoptosis of human PHEO cells. The mRNA and protein expressions of TGF-alpha and TNF-alpha were higher in PHEO tissues than in normal adrenal medullary tissues, and their expressions varied with pathological features. TGF-alpha and TNF-alpha stimulated the proliferation of primary human PHEO cells, but had no effect on the cell apoptosis. Both TGF-alpha and TNF-alpha might be involved in the pathogenesis of human PHEO. TNF-alpha needs to be further investigated before its treatment of PHEO can be realized in clinical practice.

Expression and effect of adrenomedullin in pheochromocytoma.

This study investigates the expression of human adrenomedullin (ADM) and its receptor-receptor activity modifying protein 2/calcitonin receptor-like receptor (RAMP2/CRLR) mRNA in pheochromocytoma by reverse transcriptase polymerase chain reaction (RT-PCR) and its effect on the proliferation of pheochromocytoma cells by MTT. The mRNA expression of ADM and its receptor RAMP2/CRLR was present in normal adrenal medulla and pheochromocytoma tissues. The mRNA expression of ADM, RAMP2, and CRLR is markedly higher in pheochromocytomas than in normal medulla. ADM inhibits the proliferation of human pheochromocytoma cells and exerts a possible autocrine or paracrine effect in the adrenal.