RESUMEN
Cortisol is central to several homeostatic mechanisms including the stress and immune response. Adrenal insufficiency and impaired cortisol production leads to severe, potentially fatal disorders. Several fundamental stages of steroidogenesis occur within the mitochondria. These dynamic organelles not only contribute ATP for steroidogenesis, but also detoxify harmful by-products generated during cortisol synthesis (reactive oxygen species). Mutations in nuclear or mitochondrial DNA that impair mitochondrial function lead to debilitating multi-system diseases. Recently, genetic variants that impair mitochondrial function have been identified in people with isolated cortisol insufficiency. This review aimed to clarify the association between mitochondrial diseases and adrenal insufficiency to produce cortisol. Mitochondrial diseases are rare and mitochondrial diseases that feature adrenal insufficiency are even rarer. We identified only 14 cases of adrenal insufficiency in people with confirmed mitochondrial diseases globally. In line with previous reviews, adrenal dysfunction was most prevalent in mitochondrial deletion syndromes (particularly Pearson syndrome and Kearns-Sayre syndrome) and with point mutations that compromised oxidative phosphorylation. Although adrenal insufficiency has been reported with mitochondrial diseases, the incidence reflects that expected in the general population. Thus, it is unlikely that mitochondrial mutations alone are responsible for an insufficiency to produce cortisol. More research is needed into the pathogenesis of adrenal disease in these individuals.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales , Insuficiencia Suprarrenal , Enfermedades Mitocondriales , Humanos , Hidrocortisona , Enfermedades Mitocondriales/genética , Enfermedades de las Glándulas Suprarrenales/genética , Mitocondrias/genética , Insuficiencia Suprarrenal/genéticaRESUMEN
Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11% of cancer deaths. It originates from highly migratory progenitor cells that leave the dorsal neural tube and contribute neurons and glial cells to sympathetic ganglia, and chromaffin and supportive cells to the adrenal medulla and paraganglia. Clinically, histologically and molecularly, NBs present as extremely heterogeneous, ranging from very good to very poor prognosis. The etiology of NB still remains unclear and needs to be elucidated, however, aberrant auto- and paracrine embryonic cell communications seem to be likely candidates to initiate or facilitate the emergence, progression and regression of NB. The wingless-type MMTV integration site (WNT) family of proteins represents an evolutionary highly conserved signaling system that orchestrates embryogenesis. At least 19 ligands in the human, numerous receptors and co-receptors are known, which control not only proliferation, but also cell polarity, migration and differentiation. Here we seek to interconnect aspects of WNT signaling with sympathoadrenal and paraganglionic development to define new WNT signaling cues in the etiology and progression of NB.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Regulación Neoplásica de la Expresión Génica , Neuroblastoma/genética , Paraganglioma/genética , Proteínas Wnt/genética , Vía de Señalización Wnt/genética , Adolescente , Enfermedades de las Glándulas Suprarrenales/metabolismo , Enfermedades de las Glándulas Suprarrenales/mortalidad , Enfermedades de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/crecimiento & desarrollo , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Niño , Preescolar , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Cresta Neural/crecimiento & desarrollo , Cresta Neural/metabolismo , Cresta Neural/patología , Neuroblastoma/metabolismo , Neuroblastoma/mortalidad , Neuroblastoma/patología , Neuronas/metabolismo , Neuronas/patología , Paraganglioma/metabolismo , Paraganglioma/mortalidad , Paraganglioma/patología , Células Madre/metabolismo , Células Madre/patología , Análisis de Supervivencia , Sistema Nervioso Simpático/crecimiento & desarrollo , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/patología , Proteínas Wnt/metabolismoRESUMEN
We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary S1P, the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient's renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with CNS, adrenal calcifications, and hypogonadism.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Aldehído-Liasas/genética , Calcinosis/genética , Mutación , Síndrome Nefrótico/genética , Enfermedades de las Glándulas Suprarrenales/congénito , Enfermedades de las Glándulas Suprarrenales/enzimología , Adulto , Aldehído-Liasas/deficiencia , Animales , Secuencia de Bases , Calcinosis/enzimología , Consanguinidad , Femenino , Humanos , Lactante , Lisofosfolípidos/sangre , Lisofosfolípidos/metabolismo , Masculino , Ratones Noqueados , Síndrome Nefrótico/congénito , Síndrome Nefrótico/enzimología , Linaje , Análisis de Secuencia de ADN/métodos , Esfingosina/análogos & derivados , Esfingosina/sangre , Esfingosina/metabolismoRESUMEN
Purpose To determine if adrenal calcifications seen at computed tomography (CT) are associated with familial cerebral cavernous malformations (fCCMs) in carriers of the CCM1 Common Hispanic Mutation. Materials and Methods This study was approved by the institutional review board. The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease. © RSNA, 2017.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/diagnóstico por imagen , Enfermedades de las Glándulas Suprarrenales/etiología , Enfermedades de las Glándulas Suprarrenales/genética , Calcinosis/diagnóstico por imagen , Calcinosis/etiología , Calcinosis/genética , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Proto-Oncogénicas/genética , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Biomarcadores/análisis , Estudios de Casos y Controles , Niño , Medios de Contraste , Diagnóstico Diferencial , Femenino , Humanos , Proteína KRIT1 , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Discuss exciting new research in the area of adrenal disorders that has emerged in the last few years. Advances in genetics, biochemical diagnosis, and imaging modalities that have set new standards for diagnosis and treatment are described. METHODS: A literature review was conducted on adrenal disorders using PubMed. RESULTS: We highlight new developments in adrenal diseases from new genes discovered in aldosterone-producing adenomas, cortisol-producing tumors to pheochromocytomas/paragangliomas. In addition, we discuss new information regarding the question of whether nonfunctional adrenal adenomas are really functional or not. In congenital adrenal hyperplasia, emerging steroids that might be helpful in the near future for diagnostic purposes are discussed. New types of imaging are now available to identify endocrine neoplasms to help clinicians find lesions after biochemical confirmation. CONCLUSION: The tremendous knowledge gained thus far in adrenal diseases sets the stage for not only new precision treatment modalities for individualized care but also for prevention. ABBREVIATIONS: ACC = adrenal cortical carcinoma; APA = aldosterone-producing adenoma; APCC = aldosterone-producing cell cluster; CAH = congenital adrenal hyperplasia; CT = computed tomography; DOTATATE = [68Ga]-DOTA(0)-Tyr(3)-octreotate; FDG = fluorodeoxyglucose; FH = fumarate hydratase; MR = miner-alocorticoid; MDH2 = malate dehydrogenase 2; PCC = pheochromocytoma; PET = positron emission tomography; PGL = paraganglioma; SCS = subclinical cortisol-secreting; SDHB = succinate dehydrogenase subunit B; TCGA = The Cancer Genome Atlas.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/terapia , Medicina de Precisión , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/terapia , Enfermedades de las Glándulas Suprarrenales/diagnóstico por imagen , Enfermedades de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/terapia , Hiperplasia Suprarrenal Congénita/diagnóstico por imagen , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/terapia , Carcinoma Corticosuprarrenal/diagnóstico por imagen , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/terapia , Humanos , Hiperaldosteronismo/diagnóstico por imagen , Hiperaldosteronismo/genética , Hiperaldosteronismo/terapia , Paraganglioma/diagnóstico por imagen , Paraganglioma/genética , Paraganglioma/terapia , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/genética , Feocromocitoma/terapiaRESUMEN
Timothy syndrome (TS) is a congenital long QT syndrome that is associated with syndactyly and mutations in CACNA1C, encoding an L-type voltage-dependent calcium channel, Cav1.2. Recently, TS has been associated with autism and other psychological disorders. This case indicated bradycardia by prenatal screening and was diagnosed as TS by the occurrence of syndactyly and QT prolongation at birth. Despite therapy with anti-arrhythmia reagents and a pacemaker, the patient died 2 months after birth and was autopsied. The heart showed mild dilation and mild hypertrophy with a focal disarray pattern, which may be inconsistent with typical cardiomyopathy. Unexpectedly, bilateral adrenal glands showed marked shrinkage and severe fibrosis of the medulla with a small number of single-strand DNA positive medullary cells and accumulation of hemosiderin-containing macrophages. This finding suggests that CACNA1C mutation may induce drop-out of medulla cells via apoptosis. This may be due to increased concentration of calcium ions consistent with Cav1.2 expression in adrenal glands as well as in the brain and the heart. This is the first report describing a systemic autopsy of TS with adrenal medullary dystrophy.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/patología , Médula Suprarrenal/patología , Trastorno Autístico/patología , Síndrome de QT Prolongado/patología , Sindactilia/patología , Enfermedades de las Glándulas Suprarrenales/genética , Trastorno Autístico/complicaciones , Autopsia , Femenino , Humanos , Recién Nacido , Síndrome de QT Prolongado/complicaciones , Sindactilia/complicacionesRESUMEN
Mutations within ion-transporting proteins may severely affect their ability to traffic ions properly and thus perturb the delicate balance of ion gradients. Somatic gain-of-function mutations of the Na(+),K(+)-ATPase α1-subunit have been found in aldosterone-producing adenomas that are among the causes of hypertension. We used molecular dynamics simulations to investigate the structural consequences of these mutations, namely, Leu97 substitution by Arg (L97R), Val325 substitution by Gly (V325G), deletion of residues 93-97 (Del93-97), and deletion-substitution of residues 953-956 by Ser (EETA956S), which shows inward leak currents under physiological conditions. The first three mutations affect the structural context of the key ion-binding residue Glu327 at binding site II, which leads to the loss of the ability to bind ions correctly and to occlude the pump. The mutated residue in L97R is more hydrated, which ultimately leads to the observed proton leak. V325G mimics the structural behavior of L97R; however, it does not promote the hydration of surrounding residues. In Del93-97, a broader opening is observed because of the rearrangement of the kinked transmembrane helix 1, M1, which may explain the sodium leak measured with the mutant. The last mutant, EETA956S, opens an additional water pathway near the C-terminus, affecting the III sodium-specific binding site. The results are in excellent agreement with recent electrophysiology measurements and suggest how three mutations prevent the occlusion of the Na(+),K(+)-ATPase, with the possibility of transforming the pump into a passive ion channel, whereas the fourth mutation provides insight into the sodium binding in the E1 state.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Hipertensión/genética , ATPasa Intercambiadora de Sodio-Potasio/química , Enfermedades de las Glándulas Suprarrenales/complicaciones , Sitios de Unión , Cationes Monovalentes , Humanos , Hipertensión/etiología , Simulación de Dinámica Molecular , Mutación , Ouabaína/química , Unión Proteica , Sodio/química , ATPasa Intercambiadora de Sodio-Potasio/genética , Electricidad Estática , Agua/químicaRESUMEN
Significant progress has been made in the understand-ing of many human diseases, especially cancers, which has contributed to improved and increased survival. The Human Genome Project and The Cancer Genome Atlas project brought about a new era, with an understanding of inherited diseases at a molecular level, which subsequently facilitated the option of precision medicine. Precision medicine has helped tailor treatment decisions at an individual level, for instance in terms of surgical treatments or targeted therapies in advanced diseases. Despite the increasing advances in genetic-lead precision medicine, this has not translated into increasing uptake among patients. Reasons for this may be potential knowledge gaps among clinicians; on reasons for poor uptake of genetic testing such as for cultural, religious or personal beliefs; and on financial implications such as lack of support from insurance companies. In this review, we look at the current scenario of genetic screening for common inherited endocrine conditions affecting the thyroid, parathyroid and adrenal glands in Singapore, and the implications associated with it.
Asunto(s)
Pruebas Genéticas , Humanos , Singapur , Pruebas Genéticas/métodos , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/diagnóstico , Enfermedades del Sistema Endocrino/genética , Enfermedades del Sistema Endocrino/diagnóstico , Enfermedades de las Paratiroides/genética , Enfermedades de las Paratiroides/diagnóstico , Enfermedades de las Glándulas Suprarrenales/genética , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Medicina de Precisión/métodosRESUMEN
Background: Some observational studies and clinical experiments suggest a close association between gut microbiota and metabolic diseases. However, the causal effects of gut microbiota on adrenal diseases, including Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism, remain unclear. Methods: This study conducted a two-sample Mendelian randomization analysis using summary statistics data of gut microbiota from a large-scale genome-wide association study conducted by the MiBioGen Consortium. Summary statistics data for the three adrenal diseases were obtained from the FinnGen study. The study employed Inverse variance weighting, MR-Egger, and MR-PRESSO methods to assess the causal relationship between gut microbiota and these three adrenal diseases. Additionally, a reverse Mendelian randomization analysis was performed for bacteria found to have a causal relationship with these three adrenal diseases in the forward Mendelian randomization analysis. Cochran's Q statistic was used to test for heterogeneity of instrumental variables. Results: The IVW test results demonstrate that class Deltaproteobacteria, Family Desulfovibrionaceae, and Order Desulfovibrionales exhibit protective effects against adrenocortical insufficiency. Conversely, Family Porphyromonadaceae, Genus Lachnoclostridium, and Order MollicutesRF9 are associated with an increased risk of adrenocortical insufficiency. Additionally, Family Acidaminococcaceae confers a certain level of protection against Cushing syndrome. In contrast, Class Methanobacteria, Family Lactobacillaceae, Family Methanobacteriaceae, Genus. Lactobacillus and Order Methanobacteriales are protective against Hyperaldosteronism. Conversely, Genus Parasutterella, Genus Peptococcus, and Genus Veillonella are identified as risk factors for Hyperaldosteronism. Conclusions: This two-sample Mendelian randomization analysis revealed a causal relationship between microbial taxa such as Deltaproteobacteria and Desulfovibrionaceae and Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism. These findings offer new avenues for comprehending the development of adrenal diseases mediated by gut microbiota.
Asunto(s)
Microbioma Gastrointestinal , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Microbioma Gastrointestinal/genética , Enfermedades de las Glándulas Suprarrenales/microbiología , Enfermedades de las Glándulas Suprarrenales/genética , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Hiperaldosteronismo/genética , Hiperaldosteronismo/microbiología , Síndrome de Cushing/microbiología , Síndrome de Cushing/genética , Insuficiencia Suprarrenal/microbiologíaRESUMEN
The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3ß-hydroxysteroid dehydrogenase, 11ß-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales , Investigación Biomédica , Humanos , Hiperplasia Suprarrenal Congénita/genética , Hormonas , Oxigenasas de Función Mixta , Biología Molecular , Esteroides , Enfermedades de las Glándulas Suprarrenales/genética , Enfermedades de las Glándulas Suprarrenales/historia , Enfermedades de las Glándulas Suprarrenales/patología , Enfermedades de las Glándulas Suprarrenales/terapia , Glándulas Suprarrenales/anatomía & histología , Investigación Biomédica/historiaAsunto(s)
Enfermedades de las Glándulas Suprarrenales , Enfermedades de las Glándulas Suprarrenales/complicaciones , Enfermedades de las Glándulas Suprarrenales/diagnóstico , Enfermedades de las Glándulas Suprarrenales/tratamiento farmacológico , Enfermedades de las Glándulas Suprarrenales/genética , Predisposición Genética a la Enfermedad , Humanos , Medicina Interna , Japón , Sociedades MédicasRESUMEN
Introduction: Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to adrenal hypoplasia (syndromic/non-syndromic) is a rare disorder. MIRAGE is a recently described syndrome with PAI and multisystem involvement. Case Presentation: A preterm female neonate presenting with PAI and persistent severe thrombocytopenia was diagnosed to have MIRAGE syndrome due to a de novo pathogenic variant c.3406G>C (p. Glu1136Gln) in the SAMD9 gene. In the first year of life, she had recurrent respiratory and gastrointestinal infection causing failure to thrive. At 17 months, she suffered recurrent intussusception requiring treatment with parenteral nutrition and high-dose steroids. Subsequently, she established oral feeds with hydrolysed formula and demonstrated good weight gain. Conclusion: In neonates presenting with PAI and associated multisystem involvement, a thoughtful approach and genetic testing is valuable in discerning an etiological diagnosis. This case of MIRAGE adds to the spectrum of reported cases and is the first to report on recurrent intussusception and its management with high-dose steroids.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Intususcepción/genética , Enfermedades de las Glándulas Suprarrenales/genética , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Intususcepción/congénito , Mutación , Nutrición Parenteral , Recurrencia , Esteroides/uso terapéutico , Síndrome , Trombocitopenia/complicacionesRESUMEN
OBJECTIVE: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone-producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. DESIGN AND METHODS: Clinical data of 12 patients with partial and absent biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological, and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. RESULTS: Patients with absent hormonal cure displayed a longer duration of arterial hypertension and lower lateralization index of aldosterone production. In ten patients, APAs expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with or without a hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APAs; CACNA1D mutations were the most frequent genetic abnormality. CONCLUSIONS: Patients with partial and absent biochemical cure were diagnosed later and exhibited a lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Enfermedades de las Glándulas Suprarrenales/patología , Adrenalectomía , Hiperaldosteronismo/genética , Hiperaldosteronismo/patología , Enfermedades de las Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/cirugía , Adulto , Femenino , Humanos , Hiperaldosteronismo/cirugía , Masculino , Persona de Mediana Edad , Mutación , Resultado del TratamientoRESUMEN
CONTEXT: Aldosterone synthase deficiency (ASD) is an important differential diagnosis of diseases associated with salt wasting in early infancy. OBJECTIVE: The objective of this study was to investigate the molecular basis for the disorder by (1) molecular genetic analysis in the CYP11B2 from patients suffering from ASD type I. (2) Functional characterization of the missense mutant gene products. (3) Structural simulation of the missense mutations. RESULTS: Patient 1 was a homozygous carrier of a novel mutation located in exon 4 causing a premature stop codon (p.W260X). Patient 2 was analyzed to be compound heterozygous for two novel mutations: The first was an insertion mutation (p.G206WfsX51), and the second was a deletion mutation (p.L496SfsX169). Two siblings (patients 3 and 4) were compound heterozygous carriers of two novel missense mutations (p.S315R, p.R374W). The expression studies of the mutant proteins in COS-1 cells showed a complete absence of CYP11B2 activity of p.S315R and p.R374W mutants for the conversion of 11-deoxycorticosterone to aldosterone. A 3-D model of CYP11B2 p.S315R and p.R374W indicated a change of the hydrogen bond network which might explain the cause of the dysfunction. CONCLUSION: We have identified the first CYP11B2 gene defects in two Polish families associated with phenotypes of ASD type I. Analysis of the enzymatic function as a complementary procedure to genotyping revealed data for understanding the clinical phenotype of ASD. Molecular modeling of the mutated enzyme provided a rational basis for understanding the changed activities of the mutant proteins.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/enzimología , Enfermedades de las Glándulas Suprarrenales/genética , Citocromo P-450 CYP11B2/deficiencia , Citocromo P-450 CYP11B2/genética , Mutación/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Western Blotting , Células COS , Preescolar , Chlorocebus aethiops , Citocromo P-450 CYP11B2/química , Análisis Mutacional de ADN , Pruebas de Enzimas , Femenino , Cromatografía de Gases y Espectrometría de Masas , Hormonas/metabolismo , Humanos , Enlace de Hidrógeno , Lactante , Recién Nacido , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Embarazo , Alineación de Secuencia , Esteroides/orinaRESUMEN
X-linked adrenal hypoplasia congenita (AHC) is characterized by primary adrenal insufficiency and is frequently associated with hypogonadotropic hypogonadism (HH). The production of other pituitary hormones (adrenocorticotropic hormone [ACTH], growth hormone [GH], thyroid-stimulating hormone [TSH], and prolactin [PRL]) is usually normal. Mutations of the DAX-1 gene have been reported in patients with AHC and HH. We present a 13-year-old male patient with AHC caused by a nonsense mutation in the DAX-1 gene who developed GH deficiency following head trauma. He showed signs of adrenal insufficiency at the age of 23 months, and glucocorticoid and mineralocorticoid treatment was started. His parents reported head trauma due to a traffic accident at the age of 21 months. Adrenal computed tomography revealed hypoplasia of the left and agenesis of the right adrenal gland. Decreased growth rate was noted at the age of 12.5 years while receiving hydrocortisone 15 mg/m2/day. His height was 139.9 cm (-1.46 SD), body weight was 54.9 kg, pubic hair was Tanner stage 1, and testis size was 3 ml. His bone age was 7 years. His gonadotropin (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and testosterone levels were prepubertal. The evaluation of GH/insulin-like growth factor-1 (IGF-1) secretion at the age of 13 years revealed GH deficiency. Pituitary magnetic resonance imaging demonstrated a hypoplastic hypophysis (< 2.5 mm) and a normal infundibulum. GH treatment (0.73 IU/kg/week) was started. This paper reports a patient with genetically confirmed AHC demonstrating GH deficiency possibly due to a previous head trauma. Complete pituitary evaluation should be performed in any child who has survived severe traumatic brain injury.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/epidemiología , Glándulas Suprarrenales/patología , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/epidemiología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Hormona de Crecimiento Humana/deficiencia , Adolescente , Enfermedades de las Glándulas Suprarrenales/genética , Insuficiencia Suprarrenal/congénito , Insuficiencia Suprarrenal/epidemiología , Comorbilidad , Humanos , MasculinoRESUMEN
Conditions of impaired adrenal function and tissue destruction, such as in Addison's disease, and treatment resistance of adrenocortical carcinoma (ACC) necessitate improved understanding of the pathophysiology of adrenal cell death. Due to relevant oxidative processes in the adrenal cortex, our study investigated the role of ferroptosis, an iron-dependent cell death mechanism and found high adrenocortical expression of glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4) genes, key factors in the initiation of ferroptosis. By applying MALDI mass spectrometry imaging to normal and neoplastic adrenocortical tissue, we detected high abundance of arachidonic and adrenic acid, two long chain polyunsaturated fatty acids which undergo peroxidation during ferroptosis. In three available adrenal cortex cell models (H295R, CU-ACC1 and CU-ACC-2) a high susceptibility to GPX4 inhibition with RSL3 was documented with EC50 values of 5.7 × 10-8, 8.1 × 10-7 and 2.1 × 10-8 M, respectively, while all non-steroidogenic cells were significantly less sensitive. Complete block of GPX4 activity by RSL3 led to ferroptosis which was completely reversed in adrenal cortex cells by inhibition of steroidogenesis with ketoconazole but not by blocking the final step of cortisol synthesis with metyrapone. Mitotane, the only approved drug for ACC did not induce ferroptosis, despite strong induction of lipid peroxidation in ACC cells. Together, this report is the first to demonstrate extraordinary sensitivity of adrenal cortex cells to ferroptosis dependent on their active steroid synthetic pathways. Mitotane does not induce this form of cell death in ACC cells.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Enfermedades de las Glándulas Suprarrenales/genética , Ferroptosis/efectos de los fármacos , Hormonas Esteroides Gonadales/metabolismo , Muerte Celular/efectos de los fármacos , HumanosRESUMEN
Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Proteínas del Dominio Armadillo/genética , Síndrome de Cushing/genética , Polimorfismo de Nucleótido Simple , Enfermedades de las Glándulas Suprarrenales/epidemiología , Enfermedades de las Glándulas Suprarrenales/etiología , Enfermedades de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/epidemiología , Adulto , Alelos , Estudios de Casos y Controles , Síndrome de Cushing/complicaciones , Síndrome de Cushing/epidemiología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
CONTEXT: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood. OBJECTIVES: We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease. DESIGN: CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders. RESULTS: CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders. CONCLUSIONS: CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Glándulas Suprarrenales/embriología , Proteínas de Unión al ADN/fisiología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Represoras/fisiología , Transactivadores/fisiología , Enfermedades de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Células Cultivadas , Receptor Nuclear Huérfano DAX-1 , Análisis Mutacional de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mutación/fisiología , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Ácido Retinoico/metabolismo , Receptores de Ácido Retinoico/fisiología , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor Esteroidogénico 1/metabolismo , Factor Esteroidogénico 1/fisiología , Transactivadores/genética , Transactivadores/metabolismo , TransfecciónRESUMEN
OBJECTIVE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. DESIGN: Clinical review of patients with nonsense MC2R mutations. PATIENTS: Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. RESULTS: Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. CONCLUSION: Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Codón sin Sentido , Mutación del Sistema de Lectura , Glucocorticoides/deficiencia , Mineralocorticoides/deficiencia , Receptores de Corticotropina/genética , Adolescente , Enfermedades de las Glándulas Suprarrenales/metabolismo , Enfermedades de las Glándulas Suprarrenales/terapia , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Receptores de Corticotropina/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND/AIMS: X-linked adrenal hypoplasia congenita (AHC) is typically associated with DAX-1 mutations and hypogonadotropic hypogonadism. However, atypical cases of X-linked AHC in association with central precocious puberty and even normal puberty have rarely been reported, although the mechanism of action remains unknown. CASE REPORT: This is a case report of a boy with X-linked AHC associated with Duchenne muscular dystrophy, whose clinical presentation led to analysis of the DAX-1, glycerol kinase (GK1) and dystrophin genes, which were amplified by polymerase chain reaction, with Southern blot analysis of the AHC locus. RESULTS: There was a non-contiguous deletion of the DAX-1 and GK1 genes, with deletion of the dystrophingene from exons 3 to 79. CONCLUSION: This is the first report of X-linked AHC, central precocious puberty in the absence of the DAX-1 gene. The fact that a 'loss of function' DAX-1 mutation can be associated with hypogonadotropic hypogonadism, precocious and normal puberty, suggests that DAX-1 is but one of several transcription factors which regulate puberty, and provides further evidence that other transcription factors may interact with DAX-1 and influence gonadal regulation in a complex, but hierarchical fashion.