Novas perspectivas no diagnóstico do hipogonadismo pediátrico masculino: a importância do AMH como marcador de células de Sertoli

Sertoli cells are the most active cell population in the testis during infancy and childhood. In these periods of life, hypogonadism can only be evidenced without stimulation tests, if Sertoli cell function is assessed. AMH is a useful marker of prepubertal Sertoli cell activity and number. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Serum AMH is undetectable in anorchidic patients. In primary or central hypogonadism affecting the whole gonad and established in fetal life or childhood, serum AMH is low. Conversely, when hypogonadism affects only Leydig cells (e.g. LHb mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.b mutations, LH/CG receptor or steroidogenic enzyme defects), serum AMH is normal or high. In pubertal males with central hypogonadism, AMH is low for Tanner stage (reflecting lack of FSH stimulus), but high for the age (indicating lack of testosterone inhibitory effect). Treatment with FSH provokes an increase in serum AMH, whereas hCG administration increases testosterone levels, which downregulate AMH. In conclusion, assessment of serum AMH is helpful to evaluate gonadal function, without the need for stimulation tests, and guides etiological diagnosis of pediatric male hypogonadism. Furthermore, serum AMH is an excellent marker of FSH and androgen action on the testis.As células de Sertoli são a população de células mais ativa nos testículos durante a primeira e segunda infância. Neste período, o hipogonadismo só pode ser evidenciado sem o uso de testes estimulatórios se a função das células de Sertoli for avaliada. O AMH é um marcador útil do número e da atividade das células de Sertoli no período pré-puberal. A concentração sérica de AMH é alta da metade da vida fetal até a metade da puberdade. A produção de AMH pelos testículos aumenta em resposta ao FSH e é potencialmente inibida por androgênios. O AMH sérico não é detectável em pacientes anorquídicos. No hipogonadismo central ou primário afetando a gônada inteira, ou estabelecido na vida fetal ou infância, a concentração de AMH sérica é baixa. Por outro lado, quando o hipogonadismo afeta apenas as células de Leydig (por exemplo, nas mutações, LHb, defeitos do receptor de LH/CG ou das enzimas esteroidogênicas), a concentração de AMH sérico é normal ou alta. Em meninos púberes com hipogonadismo central, a concentração de AMH é baixa para o estágio na escala de Tanner (refletindo a falta de estímulo pelo FSH), mas alta para a idade (indicando a falta do efeito inibidor da testosterona). O tratamento com FSH provoca um aumento do AMH sérico, enquanto a administração de hCG aumenta os níveis de testosterona, que fazem a downregulation do AMH. Em conclusão, a concentração sérica de AMH é útil na avaliação da função gonadal, excluindo a necessidade de testes estimulatórios, e direciona o diagnóstico etiológico do hipogonadismo pediátrico masculino. Além disso, o AMH sérico é um marcador excelente da ação do FSH e dos androgênios nos testículosFil: Grinspon, Romina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rey, Rodolfo Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Biología Celular e Histología; Argentin

The Molecular Genetics of Wilms Tumour And The Wilms Tumour Predisposition Syndromes

A molecular genetic analysis of Wilms tumour and the Wilms tumour predisposition syndromes. Genetic analysis of Wilms tumour (WT) and WT predisposition syndromes has revealed that a complex set of genetic events are associated with the development of this tumour. This thesis analyses specific genetic loci in a series of patients and tumours in order to gain a greater understanding of the molecular aetiology of this tumour. Sporadic Wilms tumours are the most common type and constitute the bulk of the analysis presented. The WT1 gene in 11p13 was analysed using SSCP and DNA sequencing in 36 tumours. Mutations were only found in 1 of 32 sporadic Wilms tumours, strongly suggesting that WT1 has only a limited role to play in the development of sporadic WT. Karyotypic analysis and Loss of Heterozygosity (LOH) studies have implicated loci on chromosome arms 7p and 16q in Wilms tumourigenesis. Paired constitutional and tumour DNA from sporadic WT were studied for LOH using polymorphic microsatellite repeats from both these chromosomes. 15% showed LOH for 16q and there was evidence for a worse outcome in this small group. LOH for 7p was found in 10% of cases and in one tumour a homozygous deletion was detected, this finding suggests the locaton of a tumour suppressor gene on 7p. Previous analysis of Beckwith-Wiedemann syndrome (BWS) patients has suggested another WT predisposition gene lies in 11p15. Two patients with constitutional translocations were analysed using fluoresence in situ hybridisation (FISH) and trisomy for the 11p15 region was identified. Analysis of the extent of the triplication was studied using 11p15-specific cosmids. The importance of these observations in the development of WT are discussed. Perlman syndrome (PS) is another WT predisposition syndrome and cytogenetic analysis in two patients with this syndrome suggested rearrangements of 11p15. Detailed FISH and molecular analysis has been used to characterise the nature of these rearrangments. The data presented in this thesis adds to the body of evidence demonstrating the complex nature of the molecular mechanisms underlying Wilms tumorigenesis

LABRAD : Vol 41, Issue 3 - December 2015

Overview on Approach to Inherited Bleeding Disorders Diagnostic Approach to Haemoglobinopathies Transient Abnormal Myelopoiesis Urinary Tract Infections (UTI) in Children Role of Histopathology in the Diagnosis of Paediatric Renal Tumours Role of Histopathology in the Diagnosis of Paediatric Bone and Soft Tissue Small Round Cell Tumours Evaluation of Inborn Errors of Metabolism (IEM) In a Nutshell An Update on Blood Lead Levels in Children Clinical Utility of Immature Platelet Fraction – An advanced 25 Parameter in Laboratory Hematology Meeting Report: “Les Confluences” The Society for the Study 30 of Inborn errors of Metabolism (SSIEM) Annual Symposium 2015 in Lyon, Francehttps://ecommons.aku.edu/labrad/1000/thumbnail.jp

Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]

peer-reviewedIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie) (MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www. gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R)

Genetics of Wilms' tumor: A blend of aberrant development and genomic imprinting

Wilms' tumor or nephroblastoma (WT), one of the most common childhood solid tumors (1:10,000, 8% of childhood tumors), is probably the one that best deserves the designation of embryonal tumor. Wilms' tumors are composed of three major elements in variable proportions: compact areas of blastemal cells, tubular structures of various sizes and fibrous or mixoid stroma containing elongated stellate-shaped large round cells. These components are reminiscent of normal human nephrogenesis, known to be initiated by the ingrowth of the ureteral bud into the metanephrogenic mesenchyma which then condenses and forms the different portions of the nephron. These tumors thus show a remarkable mimicry of the normal nephrogenic processes, although in an extravagant mode leading to incompletely differentiated structures with as many dead ends as a labyrinth [1]. These structures are accompanied, in a minority of cases, by heterologous ectopic tissues of mesodermal origin including bone, cartilage and skeletal muscle [2]

Contributions of Cytogenetics and Molecular Cytogenetics to the Diagnosis of Adipocytic Tumors

Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13–15 involving the MDM2, CDK4, and CPM genes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors