RESUMEN
Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.
Asunto(s)
Enfermedades de la Corteza Suprarrenal , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico , Mutación , Humanos , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Enfermedades de la Corteza Suprarrenal/genética , Enfermedades de la Corteza Suprarrenal/patología , Femenino , Adulto , Masculino , Síndrome de Cushing/genética , Síndrome de Cushing/cirugía , Síndrome de Cushing/diagnóstico , Complejo de Carney/genética , Complejo de Carney/diagnóstico , Adulto Joven , Osteoporosis/genéticaRESUMEN
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.
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Enfermedades de la Corteza Suprarrenal , Síndrome de Cushing , Humanos , Niño , Femenino , Enfermedades de la Corteza Suprarrenal/genética , Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/patología , Síndrome de Cushing/genética , Adrenalectomía/efectos adversos , Hidrocortisona , Hormona Adrenocorticotrópica , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP CíclicoRESUMEN
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.
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Enfermedades de la Corteza Suprarrenal , Síndrome de Cushing , Niño , Adulto Joven , Humanos , Síndrome de Cushing/tratamiento farmacológico , Síndrome de Cushing/complicaciones , Adrenalectomía , Hormona Adrenocorticotrópica , Mitotano , Resultado del Tratamiento , Enfermedades de la Corteza Suprarrenal/terapia , Enfermedades de la Corteza Suprarrenal/etiologíaRESUMEN
Cushing´s syndrome (CS) secondary to bilateral adrenal cortical disease may be caused by bilateral macronodular adrenal cortical disease (BMACD) or by bilateral micronodular adrenal cortical disease (miBACD). The size of adrenal nodules is a key factor for the differentiation between these two entities (>1cm, BMACD and <1cm; miBACD). BMACD can be associated with overt CS, but more commonly it presents with autonomous cortisol secretion (ACS). Surgical treatment of BMACD presenting with CS or with ACS and associated cardiometabolic comorbidities should be the resection of the largest adrenal gland, since it leads to hypercortisolism remission in up to 95% of the cases. Medical treatment focused on the blockade of aberrant receptors may lead to hypercortisolism control, although cortisol response is frequently transient. miBACD is mainly divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). miBACD can present at an early age, representing one of the main causes of CS at a young age. The high-dose dexamethasone suppression test can be useful in identifying a paradoxical increase in 24h-urinary free cortisol, that is a quite specific in PPNAD. Bilateral adrenalectomy is generally the treatment of choice in patients with overt CS in miBACD, but unilateral adrenalectomy could be considered in cases with asymmetric disease and mild hypercortisolism. This article will discuss the clinical presentation, genetic background, hormonal and imaging features and treatment of the main causes of primary bilateral adrenal hyperplasia associated with hypercortisolism.
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Enfermedades de la Corteza Suprarrenal , Hiperplasia Suprarrenal Congénita , Síndrome de Cushing , Enfermedades de la Corteza Suprarrenal/complicaciones , Adrenalectomía , Síndrome de Cushing/complicaciones , Síndrome de Cushing/diagnóstico , Humanos , HidrocortisonaRESUMEN
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.
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Enfermedades de la Corteza Suprarrenal , Corteza Suprarrenal , Hiperplasia Suprarrenal Congénita , Síndrome de Cushing , Corteza Suprarrenal/metabolismo , Enfermedades de la Corteza Suprarrenal/complicaciones , Enfermedades de la Corteza Suprarrenal/genética , Hiperplasia Suprarrenal Congénita/patología , Niño , Síndrome de Cushing/genética , Humanos , Hiperplasia/complicacionesRESUMEN
The most frequent endocrine Carney complex manifestation is a bilateral primary pigmented nodular adrenocortical disease and bilateral adrenalectomy (BA) is therefore its main treatment. In this study, a 40 years follow-up of six members of the same family with heterozygous PRKAR1A germline mutation, is reported over two generations. The first cases, two sisters with severe hyperandrogenism and Cushing syndrome (CS) diagnosed in 1972 at age 14 and 25, were successfully treated with unilateral adrenalectomy (UA). Their two brothers were then diagnosed, one with a CS-related severe osteoporosis treated with BA and the other with CS treated with UA. The second generation was diagnosed with CS signs at 7 and 21 years of age and were treated with BA and UA respectively. Out of the four patients treated with UA, the only event possibly related to CS was spontaneous episode of pulmonary embolism, 30 years after surgery. Hormonal evaluation revealed either eucortisolism in one patient or partial adrenal deficiency in two and mild hypercortisolism in one patient. For the two patients with BA, one of them accidentally died. The second one, surprisingly, recovered progressively normal cortisol secretion and circadian variation. Steroid substitution was stopped 6 years after her surgery and we demonstrated by iodocholesterol scintigraphy the presence of bilateral adrenal remnants. In conclusion, our results of long term evolution of PPNAD patients show that UA in this subset of patients could be considered to treat CS.
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Enfermedades de la Corteza Suprarrenal , Hiperplasia Suprarrenal Congénita , Complejo de Carney , Síndrome de Cushing , Adolescente , Enfermedades de la Corteza Suprarrenal/diagnóstico , Hiperplasia Suprarrenal Congénita/cirugía , Adrenalectomía , Adulto , Complejo de Carney/genética , Complejo de Carney/cirugía , Síndrome de Cushing/diagnóstico , Femenino , Humanos , Masculino , Cintigrafía , Adulto JovenRESUMEN
We herein report a case of Carney complex (CNC) complicated with primary pigmented nodular adrenocortical disease (PPNAD) after unilateral adrenalectomy. A 44-year-old woman was admitted to our hospital for PPNAD surgery. She had previously undergone surgery for cardiac myxoma and had a PRKAR1A mutation with no family history of CNC. She had Cushing's signs, but her metabolic abnormalities were mild. Adrenal insufficiency due to poor medication adherence was a concern, so she underwent unilateral adrenalectomy. Cushing's signs improved postoperatively and without recurrence for five years. Treatment plans for PPNAD should be determined based on the patient's condition, medication adherence, and wishes.
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Enfermedades de la Corteza Suprarrenal , Complejo de Carney , Síndrome de Cushing , Enfermedades de la Corteza Suprarrenal/genética , Enfermedades de la Corteza Suprarrenal/cirugía , Adrenalectomía , Adulto , Complejo de Carney/genética , Complejo de Carney/cirugía , Síndrome de Cushing/etiología , Síndrome de Cushing/cirugía , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Femenino , HumanosRESUMEN
The adrenal cortex plays pivotal roles in the maintenance of blood volume, responsiveness to stress and the development of gender characteristics. Gender differences of human adrenal cortex have been recently reported and attracted increasing interests. Gender differences occur from the developing stage of the adrenal, in which female subjects had more activated stem cells with higher renewal capacity resulting in gender-associated divergent structures and functions of cortical zonations of human adrenal. Female subjects generally have the lower blood pressure with the lower renin levels and ACE activities than male subjects. In addition, HPA axis was more activated in female than male, which could possibly contribute to gender differences in coping with various stressful events in our life. Of particular interest, estrogens were reported to suppress RAAS but activate HPA axis, whereas androgens had opposite effects. In addition, adrenocortical disorders in general occur more frequently in female with more pronounced adrenocortical hormonal abnormalities possibly due to their more activated WNT and PRK signaling pathways with more abundant activated adrenocortical stem cells present in female adrenal glands. Therefore, it has become pivotal to clarify the gender influence on both clinical and biological features of adrenocortical disorders. We herein reviewed recent advances in these fields.
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Enfermedades de la Corteza Suprarrenal/patología , Corteza Suprarrenal/patología , Caracteres Sexuales , Corteza Suprarrenal/embriología , Femenino , Humanos , Sistema Hipotálamo-Hipofisario/patología , Masculino , Sistema Hipófiso-Suprarrenal/patología , Sistema Renina-AngiotensinaRESUMEN
Primary bilateral adrenocortical hyperplasias are rare forms of pituitary ACTH-independent Cushing's syndrome (CS). They are divided between primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia (MiBAH), which is subdivided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). One of the most debated aspects surrounding these entities is their most appropriate therapy. Although bilateral adrenalectomy (BA) has previously been the most utilized therapy for patients with overt CS, recent studies have indicated that unilateral adrenalectomy (UA) can be effective in patients with PBMAH and some with MiBAH with fewer long-term side effects. Medical therapies can also be used for bridging to surgery or rarely in the long-term for these patients. We review the various degrees of CS resulting from PBMAH and MiBAH, with a special focus on their respective therapies including UA, taking into account the recent pathophysiological and genetics findings.
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Enfermedades de la Corteza Suprarrenal , Síndrome de Cushing , Enfermedades de la Corteza Suprarrenal/patología , Enfermedades de la Corteza Suprarrenal/cirugía , Glándulas Suprarrenales/cirugía , Adrenalectomía , Síndrome de Cushing/patología , Síndrome de Cushing/cirugía , Humanos , Hidrocortisona , HiperplasiaRESUMEN
PURPOSE: Insulin-like growth factor-II (IGF2), a key regulator of cell growth and development, is tightly regulated in its expression by epigenetic control that maintains its monoallelic expression in most tissues. Biallelic expression of IGF2 resulting from loss of imprinting (LOI) has been reported in adrenocortical tumors. In this study, we wanted to check whether adrenocortical lesions due to PRKAR1A mutations lead to increased IGF2 expression from LOI and compare these findings to those in other benign adrenal lesions. METHODS: We compared the expression of IGF2 by RNA and protein studies in primary pigmented nodular adrenocortical disease (PPNAD) caused by PRKAR1A gene mutations to that in primary macronodular adrenocortical hyperplasia (PMAH) and cortisol-producing adenomas (CPA) that did not have any mutations in known genes. We also checked LOI in all lesions by DNA allelic studies and the expression of other components of IGF2 signaling at the RNA and protein level. RESULTS: We identified cell clusters overexpressing IGF2 in PPNAD; although immunostaining was patchy, overall, by RNA and immunoblotting PPNAD expressed high IGF2 message and protein. However, this was not due to LOI, as there was no correlation between IGF2 expression and the presence of LOI. CONCLUSIONS: Our data pointed to over-expression of IGF2 protein in PPNAD compared to other benign adrenocortical lesions, such as PMAH and CPA. However, there was no correlation of IGF2 mRNA levels with LOI of IGF2/H19. The discrepancy between mRNA and protein levels with regards to LOI points, perhaps, to different control of IGF2 gene expression in PPNAD.
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Enfermedades de la Corteza Suprarrenal , Neoplasias de la Corteza Suprarrenal , Neoplasias de la Corteza Suprarrenal/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Mutación , ARN Mensajero , Factores de TranscripciónRESUMEN
Endogenous Cushing's syndrome (CS) is rare in infancy. Bilateral micronodular adrenocortical disease (BMAD), either primary pigmented nodular adrenocortical disease or the non-pigmented isolated micronodular adrenocortical disease is an important aetiology of CS in this age group, which requires bilateral adrenalectomy for cure. BMAD may be isolated, or a component of Carney complex. Isolated sporadic BMAD without other systemic manifestations poses a diagnostic challenge. Paradoxical cortisol response to dexamethasone suggests, while adrenal histopathology and mutational analysis of the culprit genes confirm BMAD. BMAD was suspected in 6-year-old infant with midnormal adrenocorticotrophic hormone, inconclusive adrenal and pituitary imaging and paradoxical increase in cortisol following high dose of dexamethasone. Exome sequencing revealed heterozygous c.354+1G>C (5' splice site) variant in the myosin heavy chain gene (MYH8), located in chromosome 17. This particular variant has not been reported in the literature. In view of suspected phenotype and its absence in the population databases, the variant was classified as pathogenic.
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Enfermedades de la Corteza Suprarrenal/complicaciones , Síndrome de Cushing/genética , ADN/genética , Mutación , Cadenas Pesadas de Miosina/genética , Enfermedades de la Corteza Suprarrenal/diagnóstico , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Adrenal lesions diagnosed during pregnancy remain rare, and their management is challenging because of maternal physiologic modifications, restricted imaging investigations, and contraindications to several treatments. Surgical issues of adrenalectomy during pregnancy and consequences on perinatal outcomes are poorly described. We therefore aimed to report maternal and fetal outcomes after adrenalectomy during pregnancy. METHODS: All pregnant women who underwent adrenalectomy over a 15-year inclusion period were identified from a prospectively maintained database. Surgical management and maternal and fetal outcomes were reviewed. RESULTS: From January 2003 to July 2018, a total of 12 women underwent adrenalectomy at a median gestation of 20 weeks. Of these women, 11 had hyper-secreting lesions, including 8 with cortisol oversecretion, and 11 had benign lesions, including cortisol-secreting adenoma (n = 5), pheochromocytoma (n = 2), primary pigmented, nodular adrenal disease (n = 1), severe Cushing's disease (n = 2), and hematoma (n = 1). A total of 3 patients with severe Cushing's disease (n = 2) and primary pigmented, nodular adrenal disease (n = 1) required bilateral adrenalectomy. One patient presented with a malignant adrenal Ewing sarcoma. Adrenalectomy during pregnancy was performed by the lateral laparoscopic transabdominal laparoscopic route in 9 patients. Postoperative morbidity occurred in 3 women. Maternal mortality was nil, but preterm birth occurred in 7 cases and intrauterine growth retardation was observed in 3 cases. Finally, among the 12 women, 10 had a child in good health. CONCLUSION: During pregnancy, a lateral laparoscopic transabdominal approach is a feasible procedure. Maternal outcome is acceptable but fetal outcome is determined by the underlying disease, with a worse outcome when the adrenalectomy is indicated for malignant lesions or Cushing's syndrome.
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Adrenalectomía , Complicaciones del Embarazo/cirugía , Adenoma/cirugía , Enfermedades de la Corteza Suprarrenal/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugía , Adulto , Estudios de Casos y Controles , Síndrome de Cushing/cirugía , Femenino , Retardo del Crecimiento Fetal/epidemiología , Francia/epidemiología , Humanos , Laparoscopía , Tiempo de Internación , Feocromocitoma/cirugía , Embarazo , Nacimiento Prematuro/epidemiología , Estudios Retrospectivos , Sarcoma de Ewing/cirugía , Centros de Atención TerciariaRESUMEN
Not required for Clinical Vignette.
Asunto(s)
Adenoma/diagnóstico , Síndrome de Cushing/diagnóstico , Neoplasias Hipofisarias/diagnóstico , Adenoma/complicaciones , Adenoma/diagnóstico por imagen , Adenoma/patología , Enfermedades de la Corteza Suprarrenal/diagnóstico , Adulto , Síndrome de Cushing/diagnóstico por imagen , Síndrome de Cushing/etiología , Síndrome de Cushing/patología , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/patologíaRESUMEN
PURPOSE OF REVIEW: Primary micronodular bilateral adrenocortical hyperplasias (MiBAH) are rare challenging diseases. Important progress in understanding its pathophysiology and genetics occurred in the last two decades. We summarize those progress and recent data on investigation and therapy of MiBAH focusing on primary pigmented nodular adrenocortical disease (PPNAD). RECENT FINDINGS: Larger recent cohorts of PPNAD patients from various countries have confirmed their variable Cushing's syndrome phenotypes. Age of onset is earlier than other ACTH-independent Cushing's syndrome causes and the youngest case have now occurred at 15 months. Two retrospective studies identified an increased risk of osteoporotic fractures in PPNAD as compared with other Cushing's syndrome causes. The utility of 6-day oral dexamethasone test to produce a paradoxical increase of urinary-free cortisol in PPNAD was confirmed but the mean fold of increase was of 48%, less than previously suggested. Several new genetic variants of the PRKAR1A gene have been reported in PPNAD or Carney complex (CNC). Remission of Cushing's syndrome with unilateral adrenalectomy was reported in a few patients with PPNAD. SUMMARY: MiBAH, PPNAD and CNC are rare challenging diseases, but with combined expert clinical and genetic approaches a comprehensive investigation and prevention strategy can be offered to affected patients and families.
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Enfermedades de la Corteza Suprarrenal , Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/epidemiología , Enfermedades de la Corteza Suprarrenal/etiología , Enfermedades de la Corteza Suprarrenal/terapia , Adrenalectomía/efectos adversos , Adrenalectomía/métodos , Edad de Inicio , Humanos , Lactante , Factores de RiesgoRESUMEN
Adrenocortical hyperplasia may develop in different contexts. Primary adrenal hyperplasia may be secondary to primary bilateral macronodular adrenocortical hyperplasia (PBMAH) or micronodular bilateral adrenal hyperplasia (MiBAH) which may be divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). Both lead to oversecretion of cortisol and potentially to Cushing's syndrome. Moreover, adrenocortical hyperplasia may be secondary to longstanding ACTH stimulation in ACTH oversecretion as in Cushing's disease, ectopic ACTH secretion or glucocorticoid resistance syndrome and congenital adrenal hyperplasia secondary to various enzymatic defects within the cortex. Finally, idiopathic bilateral adrenal hyperplasia is the most common cause of primary aldosteronism. We will discuss recent findings on the multifaceted forms of adrenocortical hyperplasia.
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Enfermedades de la Corteza Suprarrenal , Glándulas Suprarrenales/patología , Enfermedades de la Corteza Suprarrenal/clasificación , Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/etiología , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/etiología , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/etiología , Humanos , Hidrocortisona/metabolismo , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/diagnóstico , Hiperplasia/diagnóstico , Hiperplasia/etiología , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Receptores de Glucocorticoides/deficienciaRESUMEN
Primary or adrenocorticotropin-independent adrenocortical tumors and hyperplasias represent a heterogeneous group of adrenocortical neoplasms that arise from various genetic defects, either in isolation or familial. The traditional classification as adenomas, hyperplasias, and carcinomas is non-specific. The recent identification of various germline and somatic genes in the development of primary adrenocortical hyperplasias has provided important new insights into the molecular pathogenesis of adrenal diseases. In this new era of personalized care and genetics, a gene-based classification that is more specific is required to assist in the understanding of their disease processes, hormonal functionality and signaling pathways. Additionally, a gene-based classification carries implications for treatment, genetic counseling and screening of asymptomatic family members. In this review, we discuss the genetics of benign adrenocorticotropin-independent adrenocortical hyperplasias, and propose a new gene-based classification system and diagnostic algorithm that may aid the clinician in prioritizing genetic testing, screening and counseling of affected, at risk individuals and their relatives.
Asunto(s)
Enfermedades de la Corteza Suprarrenal/genética , Hiperplasia/genética , Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/tratamiento farmacológico , Enfermedades de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Asesoramiento Genético , Humanos , Hiperplasia/diagnóstico , Hiperplasia/tratamiento farmacológico , Hiperplasia/metabolismoRESUMEN
Bilateral hyperplasias of the adrenal cortex are rare causes of chronic endogenous hypercortisolemia also called Cushing syndrome. These hyperplasias have been classified in two categories based on the adrenal nodule size: the micronodular types include Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) and the macronodular also named Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). This review discusses the genetic and molecular causes of these different forms of hyperplasia that involve mutations and dysregulation of various regulators of the cAMP/protein kinase A (PKA) pathway. PKA signaling is the main pathway controlling cortisol secretion in adrenocortical cells under ACTH stimulation. Although mutations of the regulatory subunit R1α of PKA (PRKAR1A) is the main cause of familial and sporadic PPNAD, inactivation of two cAMP-binding phosphodiesterases (PDE11A and PDE8B) are associated with iMAD even if they are also found in PPNAD and PBMAH cases. Interestingly, PBMAH that is observed in multiple familial syndrome such as APC, menin, fumarate hydratase genes, has initially been associated with the aberrant expression of G-protein coupled receptors (GPCR) leading to an activation of cAMP/PKA pathway. However, more recently, the discovery of germline mutations in Armadillo repeat containing protein 5 (ARMC5) gene in 25-50% of PBMAH patients highlights its importance in the development of PBMAH. The potential relationship between ARMC5 mutations and aberrant GPCR expression is discussed as well as the potential other causes of PBMAH.
Asunto(s)
Enfermedades de la Corteza Suprarrenal/patología , Biomarcadores de Tumor/genética , Síndrome de Cushing/patología , Predisposición Genética a la Enfermedad , Hiperplasia/patología , Mutación , Enfermedades de la Corteza Suprarrenal/complicaciones , Enfermedades de la Corteza Suprarrenal/genética , Síndrome de Cushing/etiología , Síndrome de Cushing/genética , Humanos , Hiperplasia/complicaciones , Hiperplasia/genética , PronósticoRESUMEN
Background: The majority of the critically ill patients may have critical illness-related corticosteroid insufficiency (CIRCI). The therapeutic effect of dexamethasone may be related to its ability to improve cortical function. Recent study showed that dexamethasone can reduce COVID-19 deaths by up to one third in critically ill patients. The aim of this article is to investigate whether SARS-CoV-2 can attack the adrenal cortex to aggravate the relative adrenal insufficiency. Methods: We summarized the clinical features of COVID-19 reported in currently available observational studies. ACE2 and TMPRSS2 expression was examined in human adrenal glands by immunohistochemical staining. We retrospectively analyzed serum cortisol levels in critically ill patients with or without COVID-19. Results: High percentage of critically ill patients with SARS-COV-2 infection in the study were treated with vasopressors. ACE2 receptor and TMPRSS2 serine protease were colocalized in adrenocortical cells in zona fasciculata and zona reticularis. We collected plasma cortisol concentrations in nine critically ill patients with COVID-19. The cortisol levels of critically ill patients with COVID-19 were lower than those in non-COVID-19 critically ill group. Six of the nine COVID-19 critically ill patients had random plasma cortisol concentrations below 10 µg/dl, which met the criteria for the diagnosis of CIRCI. Conclusion: We demonstrate that ACE2 and TMPRSS2 are colocalized in adrenocortical cells, and that the cortisol levels are lower in critically ill patients with COVID-19 as compared to those of non-COVID-19 critically ill patients. Based on our findings, we recommend measuring plasma cortisol level to guide hormonal therapy.