DIJAGNOSTIČKI I TERAPIJSKI PRISTUPI KOD KLINIČKE SUMNJE NA POREMEĆAJ GENETIČKE ETIOLOGIJE

Cilj: Poznavanje genetičke osnove nekog poremećaja je važno jer omogućava razumijevanje patogeneze, postavljanje točne dijagnoze, prognoze bolesti te planiranje potencijalne terapije. Genetičke bolesti predstavljaju važan dio patologije u pedijatriji, a značajan broj genetičkih bolesti svoj početak ima u pedijatrijskoj dobi. Genetičke bolesti su rijetke ili pak iznimno rijetke, stoga često i u tercijarnim centrima liječnici tek ponekad tijekom svoga radnog razdoblja imaju priliku vidjeti rijetki poremećaj, što otežava stjecanje iskustva. Problem predstavlja klinička heterogenost genetičkih bolesti, jer ista bolest u podlozi može biti povezana s patogenim varijantama u više različitih gena, a fenotip, simptomi i znakovi ovise o starosnoj dobi djeteta i vrsti varijante. Postupci: U kliničkom pristupu kod sumnje na genetički poremećaj važno je postaviti dijagnostičku hipotezu, odabrati i kombinirati dijagnostičke metode, slikovne obrade te genetičke testove koji će se primijeniti, a pretrage su nerijetko dugotrajne i skupe. Kariotipizacija ili aCGH (engl. Array Comparative Genomic Hybridization) postale su rutinske metode u medicinskoj genetici i pedijatriji, a primjenjuju se kao početni testovi u slučajevima vidljivih višestrukih razvojnih nepravilnosti ili razvojnog zaostajanja koje ne možemo jasno povezati s određenim sindromom. Metoda masivnog paralelnog sekvenciranja je omogućila sekvenciranje neograničenog broja gena u jednom genetičkom testu. Sekvenciranje nove generacije (engl. Next Generation Sequencing - NGS) omogućava pregled cjelokupnog ljudskog genoma te specifi čne gene od interesa. Danas se u kliničkoj praksi uglavnom koriste četiri vrste genskog testiranja: genski paneli ili testiranje jednog gena podrazumijeva ispitivanje samo jednog gena ili seta (panela) gena koji se povezuju sa specifi čnim poremećajem. Ovo je najisplativija upotreba NGS-a koja uskom selekcijom gena postiže izvrsnu dubinu čitanja. Sekvenciranje kliničkog egzoma (CES – engl. Clinical Exome Sequencing) istovremeno sekvencira 4813 klinički relevantnih gena. Sekvenciranje cijelog egzoma (WES - engl. Whole Exome Sequencing) analizira dijelove koji kodiraju proteine u približno 20 500 poznatih gena. Sekvenciranje cijelog genoma (WGS - engl. Whole Genome Sequencing) analizira 95% - 98% cjelokupne ljudske DNA. Time pokriva intronske regije čije mutacije zauzimaju sve veće mjesto na popisu uzroka genskih bolesti. Velika prednost WGS-a je pristup bez hipoteze koji nam omogućuje da otkrijemo patološki uzrok nastanka bolesti bez prethodne radne dijagnoze. Zaključak: Genetički poremećaji rezultat su promjene gena ili dijela genoma. Većina se ne može ciljano izliječiti, no dostupno je liječenje znakova i simptoma. Za genetičke bolesti iz skupine nasljednih metaboličkih poremećaja, a koje su rezultat genetičkih promjena koje ometaju proizvodnju specifi čnih enzima, tretmani uključuju promjene u prehrani ili zamjenu određenog enzima koji nedostaje. Većina strategija liječenja genetičkih poremećaja ne mijenja temeljnu gensku mutaciju, no danas se nekoliko poremećaja liječi genskom terapijom. Ova eksperimentalna tehnika uključuje promjenu gena osobe kako bi se spriječila ili liječila bolest. Genska terapija, zajedno s mnogim drugim pristupima liječenju genetičkih bolesti danas je predmet brojnih kliničkih studija

New Variant of Unknown Significance found in ERCC6 gene -Cerebro-oculo-facio-skeletal syndrome

INTRODUCTION/OBJECTIVES: Cerebro-oculo-facio-skel- etal syndrome (COFS) is a genetic disorder caused by a mutation of the DNA repair genes presenting with severe sensorineural involvement. The aim was to present a possible new pathogen mutation in the ERCC6 gene responsible for the clinical presentation of COFS

Validity of Neuroimaging in Juvenile Headaches

Aim: The objectives of this study are to evaluate the incidence of headache considering the type of headache, to define the types of headaches, to determine the difference in the status of diagnostic scanning in children with headaches, to establish a correlation between the psychological profile of the child and the incidence of headache, and to establish a correlation between socio-demographic characteristics and the type of headache. Patients and Methods: The study included 139 patients with headache symptoms up to the age of 18, hospitalized at the Pediatric Clinic of the University Hospital Center Osijek from 1/1/2017 to 31/12/2018. The data included demographic data, diagnosis, environmental factors, EEG findings, neuroimaging data processing and other indicated medical tests. Results: A headache usually occurs between the ages of 12 and 18 (69.8%). It is more common in girls (70.5%). The common localizations are frontal and occipital. Altered standard EEG findings were reported in 26.7% of patients. Additional neuroradiological processing (brain MRI) was indicated in 98 patients (70.5%), with changes found in 56 patients (57.1%). Psychological assessment indicated that patients with functional headaches predominantly suffer from anxiety, emotional instability and somatization, while patients with organic headaches reported high stress levels (82%). Conclusion: Headaches occur more frequently in pubescent girls. The most common concomitant symptoms include nausea and vomiting, while the most common localization is frontal. Patients also report emotional instability, cognitive deficits and somatization, as well as high stress levels. Headache as a result of psychological tension is the most common diagnosis in the observed group of patients. (Serdarušić I, Pušeljić S, Tomac V, Romić M. Validity of Neuroimaging in Juvenile Headaches. SEEMEDJ 2020; 4(2); 69-76

Partial Monosomy 2p and Partial Trisomy 4q due to Paternal Translocation t(2;4)(p25.1;q31.3)

Clinical features in patients with segmental aneuploidy often vary depending on the size of the chromosomal segment involved. Monosomy 2p is usually observed as a part of more complex syndromes among probands of balanced reciprocal translocation carriers. Patients with dup4q syndrome have variable clinical features, which are both related to the size of duplicated segment of the 4q and specific associated monosomy. Clinical findings of our patient were compatible with those previously reported in dup4q and del2p patients. Herein are presented the clinical and cytogenetic findings in a 4-year-old female with an unbalanced karyotype 46,XX,der(2)t(2;4)(p25.1;q31.3)pat. Clinical phenotypes of 2p;4q translocation cases are variable, because the involved breakpoints vary case-by-case. We also compare similarity of the clinical features of our proband and other patients carrying either duplication of the distal part of 4q and patients carrying a deletion of distal part of 2p as described in the literature. To our knowledge, this is the first case of partial trisomy 4q accompanied with partial monosomy 2p

Environmental effects on changes in gene expression

Posljednjih 10 do 15 godina ubrzani razvoj novih spoznaja u genetici ukazao je na potpuno nove mehanizme nastanka pojedinih bolesti, a posebno razvoja pojedinih kliničkih fenotipova. Promjene u epigenetskome profilu stanice mogu biti pozitivne i pogodovati izražavanju povoljnih gena, kao što su geni koji sudjeluju u staničnoj signalizaciji i suzbijanju onkogeneze. Međutim, promjene također mogu biti štetne i mijenjati funkcije važnih gena, što dovodi do bolesti. Nedavno je dokazano da se neki epigenetski biljezi mogu zadržavati tijekom mejoze i tako prenositi transgeneracijski. Najveći broj publiciranih radova odnosi se na mehanizme autoimunosti i karcinogenezu, no u zadnjih pet godina pojavljuju se i radovi koji se bave fenomenom međureakcije čimbenika okoliša i ekspresije bolesti za brojna druga stanja. U radu su analizirane dosadašnje spoznaje te njihov klinički značaj.In the last 10-15 years the rapid development of new knowledge in genetics pointed out entirely new mechanisms of development of certain diseases, in particular the development of some clinical phenotypes. Changes in the epigenetic profile of a cell can be positive and favor the expression of advantageus genes such as those linked to cell signaling and tumor suppression. However, they can also be detrimental and alter the functions of important genes, thereby leading to disease. Recent evidence has further highlighted that some epigenetic marks can be maintained across meiosis and be transmitted to the subsequent generation to reprogram developmental and cellular features. The largest number of published works refers to the mechanisms of carcinogenesis and autoimmunity, but in the last five years, there are also works that deal with the phenomenon of interplay of environmental factors and the expression of the disease for many other conditions. The article analyzes recent findings and their clinical significance

De Novo Case of a Partial Trisomy 4p and a Partial Monosomy 8p

The extent of clinical expression in cases of segmental aneuploidy often varies depending on the size of the chromosomal region involved. Here we present clinical and cytogenetic findings in a 5-month old boy with a duplication of a chromosomal segment 4p16.1→4pter and a deletion of a chromosomal segment 8p23.1→8pter. His karyotype was determined by applying classical GTG banding and FISH method (WHCR region, centromere 4, centromere 8, telomere 8p) as 46,XY,der(8)t(4;8)(p16.1;p23.1).ish der(8)t(4;8)(D8S504-,WHCR+,D8Z2+)dn. Parents are not related and have normal karyotypes, indicating de novo origin. We have compared similarity of the clinical features in our proband to other patients carrying only a duplication of the distal part of 4p or a deletion of distal part of 8p or similar combination described in the literature

Environmental effects on changes in gene expression

Posljednjih 10 do 15 godina ubrzani razvoj novih spoznaja u genetici ukazao je na potpuno nove mehanizme nastanka pojedinih bolesti, a posebno razvoja pojedinih kliničkih fenotipova. Promjene u epigenetskome profilu stanice mogu biti pozitivne i pogodovati izražavanju povoljnih gena, kao što su geni koji sudjeluju u staničnoj signalizaciji i suzbijanju onkogeneze. Međutim, promjene također mogu biti štetne i mijenjati funkcije važnih gena, što dovodi do bolesti. Nedavno je dokazano da se neki epigenetski biljezi mogu zadržavati tijekom mejoze i tako prenositi transgeneracijski. Najveći broj publiciranih radova odnosi se na mehanizme autoimunosti i karcinogenezu, no u zadnjih pet godina pojavljuju se i radovi koji se bave fenomenom međureakcije čimbenika okoliša i ekspresije bolesti za brojna druga stanja. U radu su analizirane dosadašnje spoznaje te njihov klinički značaj.In the last 10-15 years the rapid development of new knowledge in genetics pointed out entirely new mechanisms of development of certain diseases, in particular the development of some clinical phenotypes. Changes in the epigenetic profile of a cell can be positive and favor the expression of advantageus genes such as those linked to cell signaling and tumor suppression. However, they can also be detrimental and alter the functions of important genes, thereby leading to disease. Recent evidence has further highlighted that some epigenetic marks can be maintained across meiosis and be transmitted to the subsequent generation to reprogram developmental and cellular features. The largest number of published works refers to the mechanisms of carcinogenesis and autoimmunity, but in the last five years, there are also works that deal with the phenomenon of interplay of environmental factors and the expression of the disease for many other conditions. The article analyzes recent findings and their clinical significance

Autism spectrum disorder – what are the relations with inherited metabolic diseases?

Poremećaj iz spektra autizma (PSA) kompleksan je neurobiološki poremećaj koji započinje u ranom djetinjstvu i obilježen je poteškoćama u socijalnoj interakciji, komunikaciji uz ograničene, ponavljajuće obrasce ponašanja. Ima širok spektar različitih simptoma. Epidemiološka istraživanja pokazuju trend snažnog rasta godišnje prevalencije PSA-a. Genetska podloga bolesti definirana je kod oko 10 – 20% pacijenata. Etiološka osnova PSA-a predmet je brojnih istraživanja, a tijekom posljednjih dvadesetak godina fokus mnogih studija usmjeren je na mehanizme epigenetske disregulacije. PSA je prema današnjim spoznajama multifaktorska bolest, a nastaje kao rezultat interakcije različitih genetskih i okolišnih čimbenika. Ovi čimbenici utječu na specifične neuronske krugove, oksidativni stres, neuroinflamaciju i disfunkciju mitohondrija. Time se remeti razvoj živčanog sustava, stvaranje sinapsi, povezanost između regija mozga i veličina mozga. Nesindromska forma PSA-a odnosi se na pojedince koji osim kliničkih elemenata PSA-a nemaju druga pridružena obilježja. Prevalencija nasljednih metaboličkih bolesti povezanih s nesindromskim PSA-om je niska (<0,5%) i stoga ukazuje na slabu isplativost sustavne metaboličke obrade istih. Glavni biokemijski mehanizmi predloženi u PSA-u uključuju disfunkciju mitohondrija, oksidativni stres, oslabljen kapacitet metilacije i promijenjeni metabolizam aminokiselina. Metabolomičkom dijagnostikom mogu se pratiti brze dnevne varijacije u metaboličkim procesima, čime se može procijeniti složen odnos između etiologije bolesti i fiziologije organizma pružajući sveobuhvatan funkcionalni fenotip, no primjena metabolomičkih analiza u kliničkoj praksi još je daleko od primjene u kliničkoj dijagnostičkoj rutini.Autism spectrum disorder (ASD) is a complex neurobiological disorder that begins in early childhood and is characterized by difficulties in social interaction, communication with limited, repetitive patterns of behavior. It has a wide spectrum of different symptoms. Epidemiological studies suggested a trend of strong growth in the annual prevalence of ASD. The genetic basis of the disease is defined in about 10–20% of patients. The etiological basis of ASD is the subject of numerous studies, and during the last twenty years the focus of many studies has been on the mechanisms of epigenetic dysregulation. According to today’s knowledge, ASD is a multifactorial disease, which arises as a result of the interaction of various genetic and environmental factors. These factors affect specific neuronal circuits, oxidative stress, neuroinflammation, mitochondrial dysfunction. This disrupts the development of the nervous system, the formation of synapses, the connection between brain regions and the size of the brain. The non-syndromic form of ASD refers to individuals who, apart from the clinical elements of ASD, have no other associated features. The prevalence of hereditary metabolic diseases associated with nonsyndromic ASD is low (<0.5%) and therefore indicates a low cost-effectiveness of systemic metabolic treatment. The main biochemical mechanisms proposed in ASD include mitochondrial dysfunction, oxidative stress, impaired methylation capacity, and altered amino acid metabolism. Metabolomic diagnostics can monitor rapid daily variations in metabolic processes, which can assess the complex relationship between the etiology of the disease and the physiology of the organism, providing a comprehensive functional phenotype, but the application of metabolomic analyzes in clinical practice is still far from being used in clinical diagnostic routine

Zreli primarni teratom medijastina u novorođenčeta: prikaz slučaja

Primary mediastinal teratomas, whether mature or immature, are very rare. They could cause serious life threatening respiratory obstruction at newborn age. This report presents clinical course, imaging, autopsy and pathohistological findings in a newborn with mature mediastinal teratoma, which led to severe respiratory failure and death. Despite the fact that postnatal respiratory distress was rarely caused by mediastinal tumor, that type of tumor should be taken into consideration in case of severe perinatal asphyxia. The case is therefore worth of presentation.Primarni teratomi medijastina, bez obzira jesu li zreli ili nezreli, rijetkost su i u novorođenačkoj dobi mogu biti uzrokom teške, za život opasne opstrukcije dišnih puteva. U ovom radu prikazan je klinički tijek, pretrage, obdukcijski i patohistološki nalazi u novorođenčeta sa zrelim teratomom medijastina koji je prouzročio težak oblik respiratornog zastoja i smrt. Unatoč činjenici da su postnatalne respiratorne smetnje rijetko prouzročene tumorom medijastina, tu vrstu tumora treba uzeti u obzir u slučaju teške perinatalne asfiksije. Stoga ovaj slučaj vrijedi prikazati

Urinary Tract Infection (UTI) in Newborns: Risk Factors, Identification and Prevention of Consequences

The aim of the study is identification of urinary tract infections (UTI) and urinary tract anomalies (UTA) already in the perinatal period. The authors attempted to prevent serious consequences of the above conditions in the examined chil- dren. Family history data, certain conditions in pregnancy and appertaining symptoms in children were elaborated to specify selective distinctive criteria for children at risk. Newborns (1200) were selected for potential existence of a UTI. All the examined newborns underwent a urinalysis. Those with significant bacteriuria were taken urine specimens, C- reactive protein (RVP), Complete Blood Count (CBC) and bilirubin. The newborns with a UTI and a suspected UTA were sent to ultrasound examination, direct radio nuclide cystography and Tc 99m MAG3 dynamic scanning. The frequency of a UTI in the perinatal period amounted to 4.5%. A UTA was found in 29.6% of the examinees. The infection was more likely to appear among newborns with a UTA in their families, a UTI, pre-eclampsia and a febrile infection in mother, intrauterine growth retardation, premature rupture of membranes (RVP), umbilical cord strangulation, jaundice, cyanosis, breathing difficulties, seizures and asphyxia