Cushing syndrome: Old and new genes Tatsi, Christina; Flippo, Chelsi; Stratakis, Constantine A.
Baillière's best practice & research. Clinical endocrinology & metabolism,
March 2020, 2020-03-00, 20200301, Letnik:
34, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Cushing syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ...ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.
Abstract
Context:
Pheochromocytomas and paragangliomas (PPGLs) in children are often hereditary and may present with different characteristics compared with adults. Hereditary PPGLs can be separated ...into cluster 1 and cluster 2 tumors due to mutations impacting hypoxia and kinase receptor signaling pathways, respectively.
Objective:
To identify differences in presentation of PPGLs between children and adults.
Design:
A retrospective cross-sectional clinical study.
Setting:
Seven tertiary medical centers.
Patients:
The study included 748 patients with PPGLs, including 95 with a first presentation during childhood. Genetic testing was available in 611 patients. Other data included locations of primary tumors, presence of recurrent or metastatic disease, and plasma concentrations of metanephrines and 3-methoxytyramine.
Results:
Children showed higher (P < 0.0001) prevalence than adults of hereditary (80.4% vs 52.6%), extra-adrenal (66.3% vs 35.1%), multifocal (32.6% vs 13.5%), metastatic (49.5% vs 29.1%), and recurrent (29.5% vs 14.2%) PPGLs. Tumors due to cluster 1 mutations were more prevalent among children than adults (76.1% vs 39.3%; P < 0.0001), and this paralleled a higher prevalence of noradrenergic tumors, characterized by relative lack of increased plasma metanephrine, in children than in adults (93.2% vs 57.3%; P < 0.0001).
Conclusions:
The higher prevalence of hereditary, extra-adrenal, multifocal, and metastatic PPGLs in children than adults represents interrelated features that, in part, reflect the lower age of disease presentation of noradrenergic cluster 1 than adrenergic cluster 2 tumors. The differences in disease presentation are important to consider in children at risk for PPGLs due to a known mutation or previous history of tumor.
This study establishes the link between extraadrenal, multifocal, metastatic, reccurent, hereditary PPGLs to a higher prevalence of noradrenergic and cluster 1 tumors in pediatric than adults.
Endogenous Cushing syndrome (CS) in pediatrics is rare; it may be caused by tumors that produce corticotropin in the pituitary gland or elsewhere, tumors that produce corticotropin-releasing hormone ...anywhere, and adrenocortical masses that produce cortisol. Adrenocortical cancer is a rare cause of CS in children but should be excluded first. CS in children is often caused by germline or somatic mutations with implications for patient prognosis and for their families. CS should be recognized early in children; otherwise, it can lead to significant morbidity and mortality. Patients with suspected CS should be referred to specialized clinical centers for workup.
"
" 1 Was Hippocrates talking about patients with pheochromocytomas and their classic triad of paroxysmal symptomatology of palpitations, diaphoresis, and headaches? We will never know….
The Genetics of Pituitary Adenomas Tatsi, Christina; Stratakis, Constantine A
Journal of clinical medicine,
12/2019, Letnik:
9, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all ...patients and may present in the context of relevant family history. Defects in
(mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA),
(coding for
, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1),
(mutated in Carney complex),
(involved in X-Linked Acrogigantism or X-LAG), and
(mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in
,
,
and
are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.
Skin manifestations of Cushing’s syndrome Stratakis, Constantine A.
Reviews in Endocrine & Metabolic Disorders,
09/2016, Letnik:
17, Številka:
3
Journal Article, Book Review
Recenzirano
Odprti dostop
Among the most common diagnostic manifestations of Cushing’s syndrome (CS) are those involving the skin; they include violaceous striae, facial acne, hirsutism, acanthosis nigricans (AN), fungal ...infections, hyperpigmentation (Hp) and easy bruisability. Fortunately, most resolve within a year or two after cure of CS, although light-colored striae can persist for years depending on the age of the patients. AN, Hp, and bruisability usually resolve within months after cure in almost all ages. Facial plethora (along with acne and other facial skin changes) is a typical sign of CS that is due to increased perfusion. It resolves immediately after curative therapy of CS. Typically, the severity of the manifestations does not correlate with the biochemical indices of the disease, pointing to age, gender, genetic and skin-type differences that determine the cutaneous manifestations of CS.
Objective Inflammatory biomarkers, such as absolute neutrophil and lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), platelet (PLT)-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio ...(MLR), are associated with the progression and development of several disorders. Although patients with Cushing syndrome (CS) have immunosuppression with altered leucocyte counts, the profile of the inflammatory biomarkers in these patients has not been extensively studied. Design We compared a panel of inflammatory biomarkers in patients with active endogenous CS (n of complete blood count (CBC) reports = 319) and eucortisolemic subjects of similar age, gender and BMI (n of CBC reports = 93). Patients were divided into two age groups (6–12 years at the time of CBC and >12 years at the time of CBC) based on age differences in normal reference ranges. Results Patients with CS had higher NLR vs controls (6–12 years: 2.47 (1.86, 3.32) vs 1.35 (1.11, 2.27), P < 0.0001; >12 years: 3.00 (2.23–4.17) vs 1.80 (1.23–2.31), P < 0.0001). Similarly, absolute neutrophil and lymphocyte counts, MLR and PLR differed between patients with CS and controls. The inflammatory biomarkers correlated with indices of cortisol secretion, such as midnight serum cortisol, 24-h urinary free cortisol and morning cortisol. On receiver operating characteristic analysis, NLR showed high area under the curve (AUC) (6–12 years: cutoff of 1.72 had AUC: 0.77, >12 years: cutoff of 2.35 had AUC: 0.81). Conclusions We conclude that multiple inflammatory biomarkers differed between patients with CS and controls suggesting substantial effects of hypercortisolemia on the immune system.
Pediatric adrenocortical hyperplasias are rare; they usually present with Cushing syndrome (CS); of them, isolated micronodular adrenal disease and its variant, primary pigmented adrenocortical ...disease are the most commonly encountered. Most cases are due to defects in the cyclic AMP/protein kinase A (cAMP/PKA) pathway, although a few cases remain without an identified genetic defect. Another cause of adrenal hyperplasia in childhood is congenital adrenal hyperplasia, a group of autosomal recessive disorders that affect steroidogenic enzymes in the adrenal cortex. Clinical presentation varies and depends on the extent of the underlying enzymatic defect. The most common form is due to 21-hydroxylase deficiency; it accounts for more than 90% of the cases. In this article, we discuss the genetic etiology of adrenal hyperplasias in childhood.
Context:
Inactivating germline mutations of the probable tumor suppressor gene, armadillo repeat containing 5 (ARMC5), have recently been identified as a genetic cause of macronodular adrenal ...hyperplasia (MAH).
Objective:
We searched for ARMC5 mutations in a large cohort of patients with MAH. The clinical phenotype of patients with and without ARMC5 mutations was compared.
Methods:
Blood DNA from 34 MAH patients was genotyped using Sanger sequencing. Diurnal serum cortisol measurements, plasma ACTH levels, urinary steroids, 6-day Liddle's test, adrenal computed tomography, and weight of adrenal glands at adrenalectomy were assessed.
Results:
Germline ARMC5 mutations were found in 15 of 34 patients (44.1%). In silico analysis of the mutations indicated that seven (20.6%) predicted major implications for gene function. Late-night cortisol levels were higher in patients with ARMC5-damaging mutations compared with those without and/or with nonpathogenic mutations (14.5 ± 5.6 vs 6.7 ± 4.3, P < .001). All patients carrying a pathogenic ARMC5 mutation had clinical Cushing's syndrome (seven of seven, 100%) compared with 14 of 27 (52%) of those without or with mutations that were predicted to be benign (P = .029). Repeated-measures analysis showed overall higher urinary 17-hydroxycorticosteroids and free cortisol values in the patients with ARMC5-damaging mutations during the 6-day Liddle's test (P = .0002).
Conclusions:
ARMC5 mutations are implicated in clinically severe Cushing's syndrome associated with MAH. Knowledge of a patient's ARMC5 status has important clinical implications for the diagnosis of Cushing's syndrome and genetic counseling of patients and their families.
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