Development of Genetics in the World and in Croatia – Forty Years of the Croatian Society of Human Genetics of the Croatian Medical Association

Resulting from several basic scientific disciplines, genetics has made impressive progress in the last century by discoveries of the heredity rules and genome structure, and by identification of the genes that determine the occurrence and characteristics of human diseases. In Croatia, the development of genetics began in the middle of the past century by the pioneering work of clinicians and basic scientists, which resulted in significant development of this scientific discipline that has quickly found its practical application in clinical genetics-cytogenetics, molecular genetics and prenatal diagnosis. The rapid advancement of technology and knowledge of genetics in recent decades has led to the development of genomics and related disciplines, entering the revolutionary new era of personalized medicine. Currently, much more data can be collected than interpreted. The data of electronic medical records, genomics, epigenetics, proteomics, metabolomics and microbiomics should be integrated and interpreted at the level of individual genome. Extensive use of new information will open a range of ethical issues that we must face timely. It is expected that in the forthcoming years, we will be able to learn more about genetics than what we have learned throughout the history of medicine. We must be prepared to welcome this new knowledge, reflecting on the positive and negative aspects of the latest achievements in the field of genetics. We hope that the experts dealing with human genetics in Croatia will successfully continue their work to enable practical application of the latest achievements in genetics, expanding our understanding of the concept of health and disease

Electronic databases of human genetic disorders: the fundamentals of differential diagnosis in clinical genetics

Kongenitalne anomalije zahvaćaju 3 – 5 % sve novorođene djece, te čine značajan postotak morbiditeta i mortaliteta u prenatalnom razdoblju i dojenačkoj dobi. Iako bolesnik s multiplim kongenitalnim anomalijama predstavlja dijagnostički izazov za pedijatre i kliničke genetičare, nužno je prepoznati specifične kombinacije kliničkih znakova, simptoma ili obrazaca ponašanja, koji bi upućivali na dijagnozu genetičkog poremećaja. Sve veći broj genetičkih poremećaja (više od 6.000 opisanih) s još većim brojem opisanih specifičnih kombinacija kliničkih obilježja doveo je do pokušaja njihovog sistematiziranja u baze podataka koje na jednom mjestu okupljaju relevantne informacije o svim poznatim genetičkim poremećajima. Elektroničke genetičke baze podataka zbog svoje su sveobuhvatnosti i jednostavnosti korištenja izvrstan medij za edukaciju iz kliničke genetike, ali i neizostavan dio svakodnevnog rada u kojem služe kao pomoć pri evaluaciji bolesnika i postavljanju ispravne diferencijalne dijagnoze malformacijskih sindroma i genetičkih poremećaja općenito. Klinička genetika je umjetnost i vještina vizualnog prepoznavanja i uspoređivanja obilježja; dijagnoza genetičkog poremećaja uvijek je zahtjevan, a ponekad i dugotrajan proces u kojem genetičke baze podataka mogu znatno pomoći. Iako sve baze podataka omogućuju pretraživanje po kliničkim obilježjima (simptomima i znakovima), odnosno njihovim kombinacijama, čime se dobiva ispis najizglednijih genetičkih poremećaja, dobiveni popis samo je prvi korak u dijagnostičkom procesu, te zahtijeva daljnje proučavanje medicinski relevantne literature, kao i ponovne preglede djeteta kada se ciljano traže specifična obilježja i dodatna klinička obrada.Congenital anomalies occur in 3-5 % of all newborn children and represent a significant part of prenatal and infant mortality and morbidity. Although patients with multiple congenital anomalies represent a diagnostic challenge for pediatricians and clinical geneticists, it is necessary to recognize specific combinations of clinical signs, simptoms and behaviour patterns which leads to the diagnosis of a genetic disorder. The constantly increasing number of genetic disorders (over 6.000 described) with an even larger number of specific combinations of clinical features has led to an attempt of systematization of all known genetic disorders into several genetic databases. The comprehensiveness and simple organization of electronic genetic databases makes them an exceptional educational media for the training of clinical genetics and an inevitable part of everyday work in clinical genetics where they are used in the evaluation of patients and establishment of proper differential diagnosis of malformation syndromes and genetic diseases in general. Clinical genetics is a combination of art and skills in visual recognition and comparison of features, and the diagnosis of a genetic disorder is always a demanding and sometimes a time-consuming process where genetic databases can be of significant help. However, although all genetic databases can be searched according to clinical features and their specific combinations which will provide a list of the most likely syndromes, the obtained list of disorders is only a first step in the diagnostic process and demands further investigation of medically relevant literature, as well as repeated examinations of the patient when specific features and additional analyses are sought

Electronic databases of human genetic disorders: the fundamentals of differential diagnosis in clinical genetics

Kongenitalne anomalije zahvaćaju 3 – 5 % sve novorođene djece, te čine značajan postotak morbiditeta i mortaliteta u prenatalnom razdoblju i dojenačkoj dobi. Iako bolesnik s multiplim kongenitalnim anomalijama predstavlja dijagnostički izazov za pedijatre i kliničke genetičare, nužno je prepoznati specifične kombinacije kliničkih znakova, simptoma ili obrazaca ponašanja, koji bi upućivali na dijagnozu genetičkog poremećaja. Sve veći broj genetičkih poremećaja (više od 6.000 opisanih) s još većim brojem opisanih specifičnih kombinacija kliničkih obilježja doveo je do pokušaja njihovog sistematiziranja u baze podataka koje na jednom mjestu okupljaju relevantne informacije o svim poznatim genetičkim poremećajima. Elektroničke genetičke baze podataka zbog svoje su sveobuhvatnosti i jednostavnosti korištenja izvrstan medij za edukaciju iz kliničke genetike, ali i neizostavan dio svakodnevnog rada u kojem služe kao pomoć pri evaluaciji bolesnika i postavljanju ispravne diferencijalne dijagnoze malformacijskih sindroma i genetičkih poremećaja općenito. Klinička genetika je umjetnost i vještina vizualnog prepoznavanja i uspoređivanja obilježja; dijagnoza genetičkog poremećaja uvijek je zahtjevan, a ponekad i dugotrajan proces u kojem genetičke baze podataka mogu znatno pomoći. Iako sve baze podataka omogućuju pretraživanje po kliničkim obilježjima (simptomima i znakovima), odnosno njihovim kombinacijama, čime se dobiva ispis najizglednijih genetičkih poremećaja, dobiveni popis samo je prvi korak u dijagnostičkom procesu, te zahtijeva daljnje proučavanje medicinski relevantne literature, kao i ponovne preglede djeteta kada se ciljano traže specifična obilježja i dodatna klinička obrada.Congenital anomalies occur in 3-5 % of all newborn children and represent a significant part of prenatal and infant mortality and morbidity. Although patients with multiple congenital anomalies represent a diagnostic challenge for pediatricians and clinical geneticists, it is necessary to recognize specific combinations of clinical signs, simptoms and behaviour patterns which leads to the diagnosis of a genetic disorder. The constantly increasing number of genetic disorders (over 6.000 described) with an even larger number of specific combinations of clinical features has led to an attempt of systematization of all known genetic disorders into several genetic databases. The comprehensiveness and simple organization of electronic genetic databases makes them an exceptional educational media for the training of clinical genetics and an inevitable part of everyday work in clinical genetics where they are used in the evaluation of patients and establishment of proper differential diagnosis of malformation syndromes and genetic diseases in general. Clinical genetics is a combination of art and skills in visual recognition and comparison of features, and the diagnosis of a genetic disorder is always a demanding and sometimes a time-consuming process where genetic databases can be of significant help. However, although all genetic databases can be searched according to clinical features and their specific combinations which will provide a list of the most likely syndromes, the obtained list of disorders is only a first step in the diagnostic process and demands further investigation of medically relevant literature, as well as repeated examinations of the patient when specific features and additional analyses are sought

Osteogenesis imperfecta: pregled suvremenih spoznaja o radiologiji koštanoga sustava i nove genetske spoznaje

Osteogenesis imperfecta is a genetically and clinically heterogeneous disorder of bone and connective tissue characterized by osteoporosis, fragile bones, hyperextensible joints, dentinogenesis imperfecta, bluish coloration of the sclerae, and adult-onset hearing loss. Medical history, careful physical examination, radiographic features of fractures, and biochemical analysis of skin collagen are the four cornerstones of accurate diagnosis. As osteogenesis imperfecta affects the whole skeleton, radiologic diagnostic features could be seen on any bone at any age of the patient. A radiology specialist should be aware of subtle changes seen on radiographs of axial skeleton (i.e. skull, spine and pelvic bones) and appendicular skeleton (i.e. long and short bones of extremities) as well as of specific osteogenesis features (i.e. “popcorn” calcifications) and difficult differential diagnosis (i.e. hypertrophic callus formation versus osteosarcoma; child abuse fractures versus true osteogenesis imperfecta). About 300 different mutations have been identified within COL1A1 and COL1A2 genes that encode the chains of type I collagen. More than 90% of these are heterozygous single base pair mutations unique to the affected individuals within families. Depending on the location of the mutation within the collagen gene, these produce a variety of clinical pictures which range from mild (OI type 1), lethal (OI type 2) to severely deforming (OI type 3) and mildly deforming (OI type 4). Each of the four types has a common radiologic appearance that helps in establishing the diagnosis. However, recent findings have confirmed that new genes other than type I collagen could be responsible for three new types of OI (OI type 5; OI type 6 and rhizomelic OI). Here we describe the complexity of the phenotype-genotype correlation in OI, and the recently proposed new classification.Osteogenesis imperfecta (OI) je genetski i klinički heterogena bolest kosti i vezivnoga tkiva s odrednicama: osteoporoza; lomljivost kostiju; labavost zglobova, dentinogenesis imperfecta; plavičaste bjeloočnice i nagluhost u odrasloj dobi. Ključ točne dijagnoze su četiri bitna postupka: precizna anamneza; pažljiv fizikalni pregled; uočavanje radioloških značajka prijeloma i promjena kostiju i biokemijska analiza kolagena kože. Uobičajena je podjela na četiri tipa OI: od blagog (tip 1), letalnog (tip 2) do teško deformirajućeg (tip 3) i umjereno deformirajućeg oblika (tip 4). Svaki od četiri tipa ima zasebne radiološke značajke koje pomažu kod postavljanja točne dijagnoze i klasificiranja. Dijagnostičko-radiološki znaci postoje na cijelom mišićno koštanom sustavu od novorođenačke do kasne životne dobi. Za radiologa je važno prepoznati brojne sićušne i specifične promjene na rendgenogramima aksijalnog (lubanja, kralješnica, zdjelica) i apendikularnog (kosti udova) skeleta. Znaci korisni u diferenciranju osteosarkoma prema stvaranju hipertrofičnog koštanog kalusa kod OI i drugi posebni znaci bolesti, primjerice metafizne “popcorn” kalcifikacije, prepoznaju se dobrom radiološkom obradom. Dosad je otkriveno oko 300 različitih mutacija na COL1A1 i COL1A2 genima odgovornima za oblikovanje lanaca kolagena tip I. Klinička slika OI razlikuje se prema mjestu mutacije na genu za kolagen. Nedavni nalazi su potvrdili da i drugi geni, uz kolagen tip 1, mogu biti odgovorni za nastanak tri nova tipa OI: tip 5; tip 6 i rizomelični tip OI. Nadalje, u tekstu je opisana složenost fenotipske i genotipske korelacije, kao i nedavno predložena nova klasifikacija OI

Osteogenesis imperfecta: pregled suvremenih spoznaja o radiologiji koštanoga sustava i nove genetske spoznaje

Osteogenesis imperfecta is a genetically and clinically heterogeneous disorder of bone and connective tissue characterized by osteoporosis, fragile bones, hyperextensible joints, dentinogenesis imperfecta, bluish coloration of the sclerae, and adult-onset hearing loss. Medical history, careful physical examination, radiographic features of fractures, and biochemical analysis of skin collagen are the four cornerstones of accurate diagnosis. As osteogenesis imperfecta affects the whole skeleton, radiologic diagnostic features could be seen on any bone at any age of the patient. A radiology specialist should be aware of subtle changes seen on radiographs of axial skeleton (i.e. skull, spine and pelvic bones) and appendicular skeleton (i.e. long and short bones of extremities) as well as of specific osteogenesis features (i.e. “popcorn” calcifications) and difficult differential diagnosis (i.e. hypertrophic callus formation versus osteosarcoma; child abuse fractures versus true osteogenesis imperfecta). About 300 different mutations have been identified within COL1A1 and COL1A2 genes that encode the chains of type I collagen. More than 90% of these are heterozygous single base pair mutations unique to the affected individuals within families. Depending on the location of the mutation within the collagen gene, these produce a variety of clinical pictures which range from mild (OI type 1), lethal (OI type 2) to severely deforming (OI type 3) and mildly deforming (OI type 4). Each of the four types has a common radiologic appearance that helps in establishing the diagnosis. However, recent findings have confirmed that new genes other than type I collagen could be responsible for three new types of OI (OI type 5; OI type 6 and rhizomelic OI). Here we describe the complexity of the phenotype-genotype correlation in OI, and the recently proposed new classification.Osteogenesis imperfecta (OI) je genetski i klinički heterogena bolest kosti i vezivnoga tkiva s odrednicama: osteoporoza; lomljivost kostiju; labavost zglobova, dentinogenesis imperfecta; plavičaste bjeloočnice i nagluhost u odrasloj dobi. Ključ točne dijagnoze su četiri bitna postupka: precizna anamneza; pažljiv fizikalni pregled; uočavanje radioloških značajka prijeloma i promjena kostiju i biokemijska analiza kolagena kože. Uobičajena je podjela na četiri tipa OI: od blagog (tip 1), letalnog (tip 2) do teško deformirajućeg (tip 3) i umjereno deformirajućeg oblika (tip 4). Svaki od četiri tipa ima zasebne radiološke značajke koje pomažu kod postavljanja točne dijagnoze i klasificiranja. Dijagnostičko-radiološki znaci postoje na cijelom mišićno koštanom sustavu od novorođenačke do kasne životne dobi. Za radiologa je važno prepoznati brojne sićušne i specifične promjene na rendgenogramima aksijalnog (lubanja, kralješnica, zdjelica) i apendikularnog (kosti udova) skeleta. Znaci korisni u diferenciranju osteosarkoma prema stvaranju hipertrofičnog koštanog kalusa kod OI i drugi posebni znaci bolesti, primjerice metafizne “popcorn” kalcifikacije, prepoznaju se dobrom radiološkom obradom. Dosad je otkriveno oko 300 različitih mutacija na COL1A1 i COL1A2 genima odgovornima za oblikovanje lanaca kolagena tip I. Klinička slika OI razlikuje se prema mjestu mutacije na genu za kolagen. Nedavni nalazi su potvrdili da i drugi geni, uz kolagen tip 1, mogu biti odgovorni za nastanak tri nova tipa OI: tip 5; tip 6 i rizomelični tip OI. Nadalje, u tekstu je opisana složenost fenotipske i genotipske korelacije, kao i nedavno predložena nova klasifikacija OI