Pheochromocytoma Masked by Mutation in the TH Gene
Karim AbidKatayoun AfsharEnzo FontanaJulien DucrySamuel RotmanEdouard StaufferFlorence FellmannOliver TschoppZahurul A. BhuiyanEric Grouzmann
1
Citation
12
Reference
10
Related Paper
Citation Trend
Abstract:
A 51-year-old woman consulting within the framework of investigation for abdominal discomfort, nausea, and vomiting underwent a computed tomography examination that revealed a well-delimited right adrenal heterogeneous mass measuring 8.2 × 8.3 cm with a native density of 40 Hounsfield units (HU)8. An 18F-deoxyglucose positron emission tomography scan showed a hypercaptation on the adrenal tumor of 7.4 SUVmax. Apart from these symptoms, the patient had no other complaint. Familial history was unremarkable. On examination, the patient was in good physical condition, arterial blood pressure was 136/85 mmHg, heart rate at 74 bpm.
The measurement of plasma renin activity and aldosterone and the results of a 1-mg overnight dexamethasone suppression test ruled out primary hyperaldosteronism and Cushing syndrome. Catecholamine and metanephrine concentrations in multiple blood and urine samples were consistently within the reference interval and not compatible with the diagnosis of a pheochromocytoma (Table 1).
View this table:
Table 1.
Concentrations of renin, aldosterone, cortisol, catecholamine, and their metabolites in urine and plasma found in the patient.a
Because the adrenal mass was not hormonally active, its surgical resection was performed without preoperative care. The removal of a mass weighing 356 g in the right adrenal gland was performed by open laparotomy.
Histopathological analysis of tissue sections of the adrenal mass yielded an unexpected result: a pheochromocytoma was diagnosed on the basis of typical well-arranged nests called zellballen. This encapsulated adrenal tumor exhibits a low proliferation index (MIB-1, 1%–2%; 1 mitosis/high power field) without vascular invasion. Immunohistochemistry of the tumor sections revealed its neuroendocrine feature, with cells highly expressing CD56, chromogranin A, NSE, synaptophysin, and vimentin. Unfortunately, blood samples obtained before surgery were collected on heparin-coated tubes precluding serum chromogranin A assay. Because the unusual presentation of a “non–catecholamine-secreting pheochromocytoma” was in complete contradiction with the biochemical feature expected for these tumors, we …Keywords:
Dexamethasone suppression test
Plasma renin activity
Metanephrines
Aldosterone synthase
Medullary Thyroid Cancer
Hyperaldosteronism
Primary aldosteronism (PA) is one of the most frequent curable forms of secondary hypertension. It can be caused by the overproduction of aldosterone in one or both adrenal glands. The most common subtypes of PA are unilateral aldosterone over-production due to aldosterone-producing adenomas (APA) or bilateral aldosterone over-production due to bilateral hyperaldosteronism (BHA). Utilizing the immunohistochemical (IHC) detection of aldosterone synthase (CYP11B2) has allowed the identification of aldosterone-producing cell clusters (APCCs) with unique focal localization positive for CYP11B2 expression in the subcapsular portion of the human adult adrenal cortex. The presence of CYP11B2 supports that synthesis of aldosterone can occur in these cell clusters and therefore might contribute to hyperaldosteronism. However, the significance of the steroidogenic properties of APCCs especially in regards to PA remains unclear. Herein, we review the available evidence on the presence of APCCs in normal adrenals and adrenal tissues adjacent to APAs, their aldosterone-stimulating somatic gene mutations, and their accumulation during the ageing process; raising the possibility that APCCs may play a role in the development of PA and age-related hypertension.
Primary Aldosteronism
Hyperaldosteronism
Aldosterone synthase
Secondary hypertension
Cite
Citations (8)
Hyperaldosteronism
Aldosterone synthase
Steroid 11-beta-hydroxylase
Mineralocorticoid
Cite
Citations (6)
s: Friday, June 2, 2000: ORAL SESSIONS: ORAL SESSION 5B: ENDOCRINE SYSTEM/GROWTH FACTORS/METABOLISM
Aldosterone synthase
Hyperaldosteronism
Cite
Citations (3)
Aldosterone synthase
Hyperaldosteronism
Steroid 11-beta-hydroxylase
Primary Aldosteronism
Secondary hypertension
Cite
Citations (6)
Background: Primary aldosteronism is caused by aldosterone overproduction. While conventional hematoxylin-eosin staining can demonstrate morphological abnormality, it cannot provide any functional histopathological information. We aimed to identify the diagnostic, functional and prognostic value of CYP11B2, CYP11B1, and β-catenin immunostaining in unilateral hyperaldosteronism. Method: A total of 134 patients with unilateral hyperaldosteronism were recruited in our study. The expression of CYP11B2, CYP11B1, and β-catenin was evaluated semiquantitatively on 134 patients’ sections using immunohistochemistry technology and the relationship with clinical data was assessed. Results: Patients were classified into four subtypes based on CYP11B2 staining as below: (1)118 patients with unilateral single aldosterone-producing adenoma (APA), (2)11 with unilateral multiple APA, (3)four with aldosterone-producing cell cluster (APCC), and (4)one with an undefined source. Adjusted CYP11B2 H-score was correlated with serum aldosterone, aldosterone to renin ratio (ARR), and serum potassium. In the abnormal β-catenin staining group, hypertension duration, aldosterone, ARR, cortisol, tumor diameter, tumor area, and CYP11B2 H-score were significantly higher than those of the wild-type group. Serum potassium level was significantly lower in the abnormal β-catenin staining group. Age, gender, BMI, family history of hypertension, adjusted CYP11B2 and CYP11B1 H-scores differed significantly between complete clinical success and incomplete clinical success groups. Age, gender and family history of hypertension were independently associated with complete clinical success based on multivariate logistic regression analysis. Conclusion: CYP11B2 immunostaining could improve the differential diagnosis of unilateral hyperaldosteronism. Adjusted CYP11B2 H-score could be used as a histopathological marker to reflect the severity of unilateral APA. Dysregulation of Wnt/β-catenin signaling and impaired β-catenin degradation may provoke the proliferation and enhance the steroidogenic ability of APA tumor cells, indicating that the Wnt pathway might be a potential, actionable, therapeutic target in the treatment of hyperaldosteronism. Age, sex and family history of hypertension were independent predictors of clinical outcome after adrenalectomy for unilateral hyperaldosteronism.
Aldosterone synthase
Hyperaldosteronism
Primary Aldosteronism
Steroid 11-beta-hydroxylase
Immunostaining
Cite
Citations (6)
Primary aldosteronism is a disorder characterized by hypertension and hypokalemia due to aldosterone secretion out of renin-angiotensin control. It is generally caused by aldosterone-producing adenoma or adrenocortical hyperplasia but, in some cases, it is due to genetic alterations. Familial type I hyperaldosteronism is the result of anomalous regulation of aldosterone secretion from ACTH (which normally regulates cortisol synthesis). Aldosterone hypersecretion can be suppressed by exogenous glucocortcoids such as dexamethasone. This autosomal dominant disorder is caused by unequal cross-over between two genes with wide sequence homology: CYP11B1 and CYP11B2. The hybrid gene is the product of fusion between the ACTH-responsive regulatory portion of the 11b-hydroxylase gene (CYP11B1) and the coding region of the aldosterone synthase gene (CYP11B2). Familial type I hyperaldosteronism is a disease with incomplete penetration and variable expressivity, especially in relation to hypertension. The marked variability in hypertension severity can mirror an interaction between the hybrid gene and other hereditary factors involved in the regulation of blood pressure. Familial type II hyperaldosteronism is another autosomal dominant form of hyperaldosteronism due to aldosterone hyper-secretion not suppressible by dexamethasone. This disorder is unrelated to mutation of the hybrid gene. The genetic cause of type II hyperaldosteronism is presently unknown, but a genome-wide search has revealed that the disorder is linked with a locus on chromosome 7 in a region that corresponds to cytogenetic band 7p22.
Hyperaldosteronism
Aldosterone synthase
Steroid 11-beta-hydroxylase
Primary Aldosteronism
Cite
Citations (1)
Aldosterone synthase
Steroid 11-beta-hydroxylase
Hyperaldosteronism
CYP17A1
Cite
Citations (27)
Glucocorticoid remediable hyperaldosteronism (GRA), a monogenic form of inherited hypertension, is characterised by high plasma levels of aldosterone (regulated by ACTH) in the face of a suppressed plasma renin activity (PRA) and the production of two normally rare steroids, 18hydroxycortisol (18OHF) and 18oxocortisol (18oxoF). The GRA is caused by the presence of a chimeric gene originated from an unequal cross-over between CYP11B1 and CYP11B2 gene. In this work we described (clinically, biochemically and genetically) a large pedigree in which the presence of the chimeric gene is demonstrated in four generations of the family. Arterial blood pressures (BP), GRA screening (by long-PCR), creatinine, urinary kallicrein, 18OHF and 18oxoF, PRA, plasmatic aldosterone and cortisol measurements were detected. After demonstration of the presence of the chimeric gene by long-PCR and Southern blot we detected the site of the crossing-over between CYP11B1 and CYP11B2. Our results demonstrated a significant positive correlation between BP and age, BMI, 18OHF, 18oxoF and plasma aldosterone. Moreover urinary levels of 18OHF and 18oxoF were related with plasma aldosterone levels. No significant correlation was found between kallikrein levels and other variables. This family displays a mild phenotype with an average BP levels for the GRA+ patients of 131/86 mmHg and no subjects with hypokaliemia. Further no patients developed hypertension before the age of 18 and only 3 before the age of 36. Also the occurrence of stroke is very low and could be even not related to the GRA+ genotype. The site of the crossing-over between CYP11B1 and CYP11B2 was located at the end of the intron 3 just before the beginning of exon 4. We described a family originating from Sardinia that displays different characteristics from the published families with the same genetic disorder in fact this kindred shows a phenotype particularly benign with a high number of affected members normotensive or with mild hypertension and a very low frequency of stroke.
Hyperaldosteronism
Aldosterone synthase
Plasma renin activity
Steroid 11-beta-hydroxylase
Cite
Citations (0)
Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
Hyperaldosteronism
TRACER
Aldosterone synthase
PET Imaging
Primary Aldosteronism
Cite
Citations (0)
Objective: The major diagnostic problem in primary aldosteronism is the differentiation between bilateral hyperplasia and aldosterone producing adenoma which is essential for further treatment. Adrenal vein sampling is regarded as the current gold standard; however it is an invasive, highly examiner-dependent method. Molecular imaging targeting the aldosterone synthase (CYP11B2) which is expressed specifically in aldosterone producing adrenal tissue could be a significant improvement. CYP11B2 is highly homologous to 11ß-hydroxylase (CYP11B1) (93%). We, therefore, aimed to develop a PET tracer which binds to CYP11B2 with both high affinity and high selectivity.
Hyperaldosteronism
Aldosterone synthase
Steroid 11-beta-hydroxylase
Primary Aldosteronism
Gold standard (test)
Cite
Citations (0)