Hypercortisolism in children - a difficult, interdisciplinary diagnostic and therapeutic problem

WSTĘP. Endogenny zespół Cushinga (CS) występuje rzadko u dzieci i młodzieży, a różnorodny obraz kliniczny utrudnia jego rozpoznanie i leczenie. MATERIAŁ I METODY. Analizie poddano 10 chorych z endogennym CS w wieku od 1 miesiąca do 16 lat, leczonych w klinice w okresie ostatnich 25 lat - 4 raki kory nadnerczy (AC), 2 gruczolaki, 3 mikrogruczolaki przysadki (choroba Cushinga [CD]), 1 mikroguzkowy rozrost nadnerczy (PPNAD) - w celu wykazania typowych dla różnych postaci CS problemów diagnostyczno-leczniczych. Przedstawiono je na przykładzie 6-miesięcznego chorego z AC, 7-letniej chorej z PPNAD oraz 16-letniej chorej z CD. WYNIKI. Wspólną cechą była otyłość o typie cushingoidalnym, nadciśnienie tętnicze, różnego stopnia androgenizacja oraz kolejno: zahamowanie wzrastania, przedwczesne dojrzewanie (AC, PPNAD) lub wtórny brak miesiączki (CD), plethora (AC) oraz rozstępy skórne (CD). W całej grupie 10 chorych rodzaj i nasilenie objawów zależały od wartości stężeń hormonów, czasu trwania oraz postaci CS. U wszystkich stwierdzono zaburzenie rytmu kortyzolemii, i kolejno: hiperkortyzolemię wraz ze zwiększonym wydalaniem kortyzolu z moczem (AC), zwiększone wydalanie kortyzolu (CD, PPNAD) o typie cyklicznym w PPNAD. Zmiany organiczne uwidoczniono za pomocą badań CT i MRI w AC, a nie uwidoczniono w PPNAD i CD. Pomocny był test z CRH w rozpoznaniu CD oraz profil steroidowy GC-MS w przypadku PPNAD. W wyrównywaniu nadciśnienia chory na AC (200/140 mm Hg) wymagał zahamowania syntezy mineralokortykoidów i kortyzolu (ketokonazol, mitotan). Po leczeniu operacyjnym, po którym u wszystkich ustąpiły objawy CS, włączono substytucję hydrokortyzonem (u chorej z PPNAD, u której wykonano jednostronną adrenalektomię dopiero po przełomie nadnerczowym). W przypadku chorego na AC, u którego stosowano mitotan przez 7 miesięcy po operacji, wznowę w badaniach MRI i GC-MS stwierdzono po 4 latach. WNIOSKI. Hiperkortyzolemia u dzieci może stanowić zagrożenie życia, a ustalenie jej przyczyn oraz sposobu leczenia wymaga indywidualnego postępowania.INTRODUCTION. Endogenous Cushing’s syndrome (CS) is rare in children and adolescents and its diversified clinical presentation hinders diagnosis and treatment. MATERIAL AND METHODS. The analysis included 10 patients aged 1 month to 16 years of life with endogenous CS, who were treated at the Department within the past 30 years: 4 adrenal carcinomas (AC), 2 adenomas, 3 pituitary microadenomas (Cushing’s disease [CD]), 1 primary pigmented nodular adrenocortical disease (PPNAD), to demonstrate diagnostic and therapeutic problems typical of various CS forms. The problems were exemplified by a 6-month old boy with AC, a 7-year old girl with PPNAD and a 16-year old girl with CD. RESULTS. Common properties included cushingoid obesity, hypertension, a variable degree of androgenization and delay in growth velocity, precocious puberty (AC, PPNAD) or secondary amenorrhea (CD), plethora (AC) and striae (CD). In all 10 analyzed patients, the presence and intensity of clinical signs of CS depended on age, intensity of hormonal abnormalieties, duration of disease and its form. All the patients demonstrated abnormal 24 hour rhythm of cortisolemia and in AC hypercortisolemia with increased urinary cortisol excretion, increased cortisol excretion (CD, PPNAD), which was cyclic in character in PPNAD. Organic lesions were visualized by CT and MRI in AC, but not seen in PPNAD and CD. In diagnosing CD, CRH test was helpful; while diagnosing PPNAD was facilitated by steroid profiling by GC-MS. Controlling hypertension in a patient with AC (200/140 mm Hg) required inhibition of mineralocorticoids and cortisol synthesis (ketoconazole, mitotane). Following surgical treatment, all the patients showed resolution of Cushing’s symptoms. Hydrocortisone substitution was introduced in all the patients (in a PPNAD girl subjected to a unilateral adrenalectomy, after an adrenal crisis). An AC patient administered mitotane for 7 months postoperatively, showed carcinoma recurrence after 4 years in MRI an GC-MS examinations. CONCLUSIONS. Hypercortisolemia in children may be life threatening and determination of its causes and treatment modality requires an individualized approach

Comparative two time-point proteome analysis of the plasma from preterm infants with and without bronchopulmonary dysplasia

Background: In this study, we aimed to analyze differences in plasma protein abundances between infants with and without bronchopulmonary dysplasia (BPD), to add new insights into a better understanding of the pathogenesis of this disease. Methods: Cord and peripheral blood of neonates (≤ 30 weeks gestational age) was drawn at birth and at the 36th postmenstrual week (36 PMA), respectively. Blood samples were retrospectively subdivided into BPD(+) and BPD(−) groups, according to the development of BPD. Results: Children with BPD were characterized by decreased afamin, gelsolin and carboxypeptidase N subunit 2 levels in cord blood, and decreased galectin-3 binding protein and hemoglobin subunit gamma-1 levels, as well as an increased serotransferrin abundance in plasma at the 36 PMA. Conclusions: BPD development is associated with the plasma proteome changes in preterm infants, adding further evidence for the possible involvement of disturbances in vitamin E availability and impaired immunological processes in the progression of prematurity pulmonary complications. Moreover, it also points to the differences in proteins related to infection resistance and maintaining an adequate level of hematocrit in infants diagnosed with BPD

Development and Maturation of the Immune System in Preterm Neonates: Results from a Whole Genome Expression Study

To expand the knowledge about the consecutive expression of genes involved in the immune system development in preterm neonates and to verify if the environment changes the gene expression after birth we conducted a prospective study that included three cohorts: (A) extremely (gestational age (GA): 23–26 weeks; n=41), (B) very (GA: 27–29 weeks; n=39), and (C) moderately preterm infants (GA: 30–32 weeks; n=33). Blood samples were drawn from the study participants on the 5th and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of GeneChip Human Gene 1.0ST microarrays. Differential expression analysis revealed small subsets of genes that presented positive or negative monotone trends in both the 5th (138 genes) and 28th DOL (308 genes) in the three subgroups of patients. Based on pathway enrichment analysis, we found that most of the pathways that revealed a positive monotone trend were involved in host immunity. The most significantly GA dependent pathways were T-cell receptor signaling pathway and intestinal immune network for IgA production. Overall 4431 genes were differentially expressed between the 5th and 28th DOL. Despite differences in gestational age, patients with the same postconceptional age have a very similar expression of genes

An iTRAQ-based quantitative proteomic analysis of plasma proteins in preterm newborns with retinopathy of prematurity

Purpose: Retinopathy of prematurity (ROP) is a vision-threatening complication of a premature birth, in which the etiology still remains unclear. Importantly, the molecular processes that govern these effects can be investigated in a perturbed plasma proteome composition. Thus, plasma proteomics may add new insights into a better understanding of the pathogenesis of this disease. Methods: The cord and peripheral blood of neonates (≤30 weeks gestational age) was drawn at birth and at the 36th postmenstrual week (PMA), respectively. Blood samples were retrospectively subdivided into ROP(+) and ROP(−) groups, according to the development of ROP. Results: The quantitative analysis of plasma proteome at both time points revealed 30 protein abundance changes between ROP(+) and ROP(−) groups. After standardization to gestational age, children who developed ROP were characterized by an increased C3 complement component and fibrinogen level at both analyzed time points. Conclusions: Higher levels of the complement C3 component and fibrinogen, present in the cord blood and persistent to 36 PMA, may indicate a chronic low-grade systemic inflammation and hypercoagulable state that may play a role in the development of ROP

Short- and long-term impact of hyperoxia on the blood and retinal cells' transcriptome in a mouse model of oxygen-induced retinopathy

Background We aimed to identify global blood and retinal gene expression patterns in murine oxygen-induced retinopathy (OIR), a common model of retinopathy of prematurity, which may allow better understanding of the pathogenesis of this severe ocular prematurity complication and identification of potential blood biomarkers. Methods A total of 120 C57BL/6J mice were randomly divided into an OIR group, in which 7-day-old pups were maintained in 75% oxygen for 5 days, or a control group. RNA was extracted from the whole-blood mononuclear cells and retinal cells on days 12, 17, and 28. Gene expression in the RNA samples was evaluated with mouse gene expression microarrays. Results There were 38, 1370 and 111 genes, the expression of which differed between the OIR and control retinas on days 12, 17, and 28, respectively. Gene expression in the blood mononuclear cells was significantly altered only on day 17. Deptor and Nol4 genes showed reduced expression both in the blood and retinal cells on day 17. Conclusion There are sustained marked changes in the global pattern of gene expression in the OIR mice retinas. An altered expression of Deptor and Nol4 genes in the blood mononuclear cells requires further investigation as they may indicate retinal neovascularization

Pulmonary vascular disease is evident in gene regulation of experimental bronchopulmonary dysplasia

Objective: To examine the gene expression regarding pulmonary vascular disease in experimental bronchopulmonary dysplasia in young mice. Premature delivery puts babies at risk of severe complications. Bronchopulmonary dysplasia (BPD) is a common complication of premature birth leading to lifelong affection of pulmonary function. BPD is recognized as a disease of arrested alveolar development. The disease process is not fully described and no complete cure or prevention is known. The focus of interest in the search for treatment and prevention of BPD has traditionally been at airspace level; however, the pulmonary vasculature is increasingly acknowledged in the pathology of BPD. The aim of the investigation was to study the gene expression in lungs with BPD with regards to pulmonary vascular disease (PVD). Methods: We employed a murine model of hyperoxia-induced BPD and gene expression microarray technique to determine the mRNA expression in lung tissue from young mice. We combined gene expression pathway analysis and analyzed the biological function of multiple single gene transcripts from lung homogenate to study the PVD relevant gene expression. Results: There were n = 117 significantly differentially regulated genes related to PVD through down-regulation of contractile elements, up- and down-regulation of factors involved in vascular tone and tissue-specific genes. Several genes also allowed for pinpointing gene expression differences to the pulmonary vasculature. The gene Nppa coding for a natriuretic peptide, a potent vasodilator, was significantly down-regulated and there was a significant up-regulation of Pde1a (phosphodiesterase 1A), Ptger3 (prostaglandin e receptor 3), and Ptgs1 (prostaglandin-endoperoxide synthase one). Conclusion: The pulmonary vasculature is affected by the arrest of secondary alveolarization as seen by differentially regulated genes involved in vascular tone and pulmonary vasculature suggesting BPD is not purely an airspace disease. Clues to prevention and treatment may lie in the pulmonary vascular system