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Frontiers in Endocrinology 2022Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.
Topics: Adult; Humans; Child; Young Adult; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Li-Fraumeni Syndrome
PubMed: 36387865
DOI: 10.3389/fendo.2022.961650 -
Pediatrics in Review Nov 2019
Review
Topics: Adolescent; Adrenal Cortex Hormones; Asthma; Child; Diagnosis, Differential; Disease Progression; Emergency Service, Hospital; Healthcare Disparities; Humans; Infant; Practice Guidelines as Topic; Prevalence; Severity of Illness Index; United States
PubMed: 31676529
DOI: 10.1542/pir.2018-0282 -
Developmental Cell Nov 2022The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we...
The mechanisms leading to adrenal cortex development and steroid synthesis in humans remain poorly understood due to the paucity of model systems. Herein, we recapitulate human fetal adrenal cortex specification processes through stepwise induction of human-induced pluripotent stem cells through posterior intermediate mesoderm-like and adrenocortical progenitor-like states to ultimately generate fetal zone adrenal-cortex-like cells (FZLCs), as evidenced by histomorphological, ultrastructural, and transcriptome features and adrenocorticotropic hormone (ACTH)-independent Δ5 steroid biosynthesis. Furthermore, FZLC generation is promoted by SHH and inhibited by NOTCH, ACTIVIN, and WNT signaling, and steroid synthesis is amplified by ACTH/PKA signaling and blocked by inhibitors of Δ5 steroid synthesis enzymes. Finally, NR5A1 promotes FZLC survival and steroidogenesis. Together, these findings provide a framework for understanding and reconstituting human adrenocortical development in vitro, paving the way for cell-based therapies of adrenal insufficiency.
Topics: Humans; Induced Pluripotent Stem Cells; Adrenal Cortex; Wnt Signaling Pathway; Adrenocorticotropic Hormone; Steroids
PubMed: 36413950
DOI: 10.1016/j.devcel.2022.10.010 -
Best Practice & Research. Clinical... May 2020Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and... (Review)
Review
Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, mitotane is used in association with chemotherapy to treat the more aggressive forms, while mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Endocrinology; Humans; Mitotane
PubMed: 32179008
DOI: 10.1016/j.beem.2020.101415 -
Current Opinion in Pediatrics Aug 2020Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when... (Review)
Review
PURPOSE OF REVIEW
Adrenarche is the pubertal maturation of the innermost zone of the adrenal cortex, the zona reticularis. The onset of adrenarche occurs between 6 and 8 years of age when dehydroepiandrosterone sulfate (DHEAS) concentrations increase. This review provides an update on adrenal steroidogenesis and the differential diagnosis of premature development of pubic hair.
RECENT FINDINGS
The complexity of adrenal steroidogenesis has increased with recognition of the alternative 'backdoor pathway' and the 11-oxo-androgens pathways. Traditionally, sulfated steroids such as DHEAS have been considered to be inactive metabolites. Recent data suggest that intracellular sulfated steroids may function as tissue-specific intracrine hormones particularly in the tissues expressing steroid sulfatases such as ovaries, testes, and placenta.
SUMMARY
The physiologic mechanisms governing the onset of adrenarche remain unclear. To date, no validated regulatory feedback mechanism has been identified for adrenal C19 steroid secretion. Available data indicate that for most children, premature adrenarche is a benign variation of development and a diagnosis of exclusion. Patients with premature adrenarche tend to have higher BMI values. Yet, despite greater knowledge about C19 steroids and zona reticularis function, much remains to be learned about adrenarche.
Topics: Adrenal Glands; Adrenarche; Androgens; Child; Child Development; Dehydroepiandrosterone Sulfate; Female; Humans; Pregnancy; Puberty; Puberty, Precocious; Steroids; Zona Reticularis
PubMed: 32692055
DOI: 10.1097/MOP.0000000000000928 -
Neuromuscular Disorders : NMD Feb 2020Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic... (Review)
Review
Myasthenia gravis is an autoimmune disease characterized by dysfunction of the neuromuscular junction. Current treatment is based on lifestyle advice, symptomatic treatment, immunosuppressive drugs and thymectomy. Corticosteroids remain the cornerstone of treatment beside symptomatic medication due to their low cost, wide availability and fast mode of action. However, long term steroid use carries substantial risks of severe adverse side effects. Therefore, non-steroidal immunosuppressive drugs are commonly added to the treatment. Unfortunately, they have a delayed-onset effect and evidence of their efficacy appears to be difficult to obtain. Several trials using drugs that have had clear positive results in other immunological disorders have failed in myasthenia. This failure may in part be related to difficulties in the design of clinical trial for myasthenia, which has a fluctuating disease course involving weakness that may be difficult to assess quantitively. This problem is exacerbated by the tendency of most clinical trials to select patients with a stable, but severe disease. Future trials should: select patients with weakness and fatigability that is completely explained by their myasthenia gravis, use a design that avoids the exclusion of patients with recent changes in medication, and explore the possibilities to completely avoid the use of corticosteroids.
Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Exercise Therapy; Humans; Immunosuppressive Agents; Myasthenia Gravis; Proteasome Inhibitors; Thymectomy
PubMed: 32007304
DOI: 10.1016/j.nmd.2019.12.003 -
Frontiers in Endocrinology 2023X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters... (Review)
Review
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
Topics: Adult; Humans; Male; Female; Child; Adrenoleukodystrophy; ATP-Binding Cassette Transporters; Addison Disease; Fatty Acids; Adrenal Cortex; Glucocorticoids
PubMed: 38034003
DOI: 10.3389/fendo.2023.1309053 -
Archivos de Bronconeumologia Mar 2021
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Bacterial Infections; COVID-19; Disease Progression; Humans; Pandemics; Pulmonary Disease, Chronic Obstructive; Remote Consultation; Spirometry; Venous Thromboembolism
PubMed: 33551276
DOI: 10.1016/j.arbres.2021.01.001 -
Frontiers in Endocrinology 2022Pediatric adrenocortical hyperplasias are rare; they usually present with Cushing syndrome (CS); of them, isolated micronodular adrenal disease and its variant, primary... (Review)
Review
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.
Topics: Adrenal Cortex; Adrenal Cortex Diseases; Adrenal Hyperplasia, Congenital; Child; Cushing Syndrome; Humans; Hyperplasia
PubMed: 35992119
DOI: 10.3389/fendo.2022.937793