Dysmorphia and developmental anomalies in the inborn errors of metabolism

Dismorfologija je dio kliničke genetike koji proučava odstupanje od uobičajene morfologije u populaciji koristeći specifična obilježja u dijagnostici i otkrivanju sindromskih poremećaja. Dismorfične crte lica i prirođene razvojne anomalije drugih organa mogu biti vidljive pri rođenju ili se uočavaju u kasnijem životnom periodu. Iako pri razmatranju dismorfije kod nekog bolesnika obično prvo ne razmišljamo o nasljednim metaboličkim bolestima, prepoznavanje specifičnog fenotipa vezanog uz ovu skupinu bolesti može biti važan dijagnostički trag, osobito kada su prisutni i drugi simptomi kao što su različita neurološka odstupanja, abnormalnosti skeleta, bolesti jetre, zastoj u razvoju, kardiomiopatije ili abnormalnosti oka. Spoznaja o prisutnosti fizičkih odstupanja kod nasljednih metaboličkih bolesti i primjeri bolesti prikazani u tekstu važni su jer premošćuju tradicionalne podjele te povezuju dismorfologiju i metabolizam.Dysmorphology is a part of genetics that studies the deviation from normal morphology in a population using dysmorphic features in the diagnostic workup and delineation of syndromic disorders. Dysmorphic features of the face and congenital anomalies of other organs can be recognized at birth or later in life. Although considering dysmorphia in a patient, we usually do not first think of inherited metabolic diseases, identification of specific phenotypic features can be an important diagnostic clue for many inherited metabolic diseases, especially when they are associated with other symptoms, including neurological problems, skeletal abnormalities, liver disease, developmental delay, cardiomyopathy, or ocular abnormalities. Knowledge about the physical deviations in inherited metabolic diseases and the examples presented in the text are important because they bridge traditional divisions and connect dysmorphology and metabolis

Cleft lip and cleft palate from the genetic aspect

Rascjepi usne i nepca pripadaju skupini najčešćih prirođenih anomalija. Mogu se javiti izolirano ili u sklopu sindroma. Novorođenče s rascjepom vjerojatno će imati poteškoće s hranjenjem, kasnije su moguće poteškoće sluha, razvoja govora i denticije, nerijetko se javljaju socijalne i psihološke teškoće. Stoga je problematika ovih bolesnika značajna s osobnog i društvenog stajališta, a najbolji uspjesi postižu se timskim pristupom. Bilo da se javljaju kao dio sindroma ili izolirano, identifi kacija brojnih gena i genskih lokusa u etiologiji rascjepa predmet je brojnih istraživanja koja se služe različitim genetičkim pristupima. Zahvaljujući razvoju metoda sekvenciranja svih egzona i asocijacijskih studija s obuhvaćenjem cijelog genoma, posljednjih godina postignut je značajan napredak u razjašnjavanju etiologije rascjepa.Orofacial clefts are one of the most common craniofacial malformations in newborns. They can occur as part of a distinct genetic syndrome, multiple congenital anomaly syndrome or as an isolated malformation. Aff ected individuals initially face feeding diffi culties, and speech, hearing and dental problems later in life. Patients can experience lifelong psychosocial eff ects from these malformations. The best treatment success is achieved by multidisciplinary team approach. Identifi cation of many genes and loci that contribute to the etiology of these disorders has been the subject of numerous studies using multiple genetic approaches. Signifi cant progress has been made recently due to advances in the sequencing and genotyping technologies, primarily through the use of whole exome sequencing and genome-wide association studies

Palijativno kardiokirurško liječenje u djeteta s Edwardsovim sindromom

Trisomy of the 18th chromosome, also known as Edwards syndrome, occurs in 1:5000 live births. It is accompanied by low birth weight, low-lying ears, micrognathia, flexion contractures of the fingers, hypotonia, structural heart diseases as well as anomalies of other organs, and severe psychomotor retardation. Unfortunately, only 5 to 10% of children live to the first year.Trisomija kromosoma 18 ili Edwardsov sindrom javlja se u 1:5000 živorođene djece. Karakterizira ju niska rodna masa, tipične anomalije poput nisko položenih uški, mikrognatije, fleksijskih kontraktura prstiju šaka, hipotonije, strukturnih bolesti srca i drugih organa uz teško psihomotorno zaostajanje. Očekivani životni vijek je zbog spomenutih anomalija iznimno skraćen, samo 5 do 10% djece doživi prvu godinu. Stoga se ovaj sindrom smatra teško spojivim sa životom, a medicinske intervencije kod živorođenih su uglavnom u domeni palijativne skrbi

Use of microsatellite loci in prenatal and postnatal diagnosis of aneuploidy and uniparental disomy

Najveći udio svih kromosomopatija u čovjeka čine Downov (trisomija kromosoma 21), Edwardsov (trisomija kromosoma 18) i Patauov (trisomija kromosoma 13) sindrom. Navedena činjenica uputila je na potrebu uvođenja metoda koje bi omogućile brzu dijagnostiku najčešćih numeričkih kromosomskih poremećaja, što je od osobite važnosti u prenatalnoj dijagnostici. Analiza mikrosatelitskih lokusa ili lokusa STR primjenom metode PCR-STR omogućila je brzu dijagnostiku najčešćih aneuploidija u vremenskom razdoblju od jednog do tri dana. Prednost analize lokusa STR u prenatalnoj i postnatalnoj dijagnostici očituje se i u mogućnosti utvrđivanja podrijetla kromosoma u dijagnostici uniparentne disomije. U KBC-u Zagreb brza prenatalna i postnatalna dijagnostika aneuploidija i uniparentne disomije provedena je primjenom analize mikrosatelitskih lokusa kromosoma 7, 11, 13, 14, 15, 18, 21, X i Y. Cilj rada je prikazati dijagnostičku vrijednost primijenjenih mikrosatelitskih lokusa na navedenim kromosomima. Prenatalnim pretraživanjem 2072 uzorka plodovih voda kod njih 55 (2,65%) otkrivena je promjena u broju kromosoma. Očekivano, u najvećem broju uzoraka (n=35) otkrivena je trisomija kromosoma 21. U uzorku od 54-ero ispitanika sa sumnjom na uniparentnu disomiju kod njih 13-ero nađena je uniparentna disomija kromosoma 15 (UPD15). Rezultati metode PCR-STR bili su u skladu s rezultatima metode klasične citogenetike. Zaključno možemo reći da je kombinacija mikrosatelitskih lokusa koju primjenjujemo dostatno informativna za uspješno određivanje aneuploidije kromosoma 13, 18, 21, X i Y i uniparentne disomije kromosoma 7,11,14 i 15.The largest proportion of all chromosomal anomalies in humans are syndromes Down (trisomy of chromosome 21), Edwards (trisomy of chromosome 18) and Patau (trisomy of chromosome 13). This fact has revealed the need to introduce methods that would allow rapid diagnosis of the most common numerical chromosomal abnormalities, which is of special importance in prenatal diagnosis. Analysis of the microsatellite or STR locus with the PCR-STR method has given us the possibility of fast diagnosis of the most frequent aneuploidies within one to three days. The advantage of the analysis of STR loci in prenatal and postnatal diagnosis lies in the ability to determine the origin of chromosomes in the diagnosis of uniparental disomy. At the Zagreb University Hospital Centre, rapid prenatal and postnatal diagnosis of aneuploidy and uniparental disomy was performed using analysis of the microsatellite loci of chromosomes 7, 11, 13, 14, 15, 18, 21, X and Y. The purpose of the work was to show diagnostic value of the microsatellite loci on the above listed chromosomes. On prenatal screening of 2072 amniotic fl uid samples, 55 (2.65%) showed change in the number of chromosomes. As expected, the largest number of samples (n=35) showed trisomy of chromosome 21. Uniparental disomy of chromosome 15 (UPD15) was demonstrated in 13 of 54 subjects with suspicion of uniparental disomy. The results of the PCR-STR method were in accordance with the results of conventional cytogenetics. In conclusion, the combination of STR loci that we use is considered good enough to determine aneuploidy of chromosomes 13, 18, 21, X and Y, and uniparental disomy of chromosomes 7, 11, 14 and 15

Usporedba različitih dijagnostičkih smjernica za dijagnozu sindroma aktivacije makrofaga koji komplicira sistemski tip juvenilnog idiopatskog artritisa: iskustvo jednog centra

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA), caused by exaggerated but ineff ective immune response. The aim of the study was to compare the capacity of the HLH-2004 guidelines with the capacity of the MAS guidelines from 2005, and with the new set of classifi cation criteria from 2016 in diagnosing MAS complicating sJIA. Th e study included 35 children aged 1-18 diagnosed with sJIA according to ILAR criteria and treated at the Department of Pediatrics, Division of Immunology and Rheumatology, Zagreb University Hospital Centre, in the period from 2009 to 2015. Out of 35 patients diagnosed with sJIA, there were 12 girls and 23 boys, with the mean age at disease onset (±SD) 5.51±3.65 years. Eight patients had fl are of disease. With the guidelines from 2005, MAS was diagnosed in six (17.1%) patients with sJIA. With the new set of classifi cation criteria from 2016, MAS was diagnosed in four (11.4%) patients with sJIA. MAS was not diagnosed with the HLH-2004 guidelines. In our study, four out of six patients had MAS at the onset of sJIA, and in the rest two it occurred during relapse. Two patients with MAS developed full-blown clinical picture while another four had incomplete clinical features with minor laboratory alteration. Due to the use of diff erent diagnostic guidelines, we found diff erence in the prevalence of MAS. It was slightly higher in comparison to available studies, while other researched features, such as clinical characteristics, were similar.Sindrom aktivacije makrofaga (MAS) potencijalno je smrtonosna komplikacija sistemskog tipa juvenilnog idiopatskog artritisa (sJIA) uzrokovana prekomjernim, ali neučinkovitim imunim odgovorom. Cilj ovoga istraživanja bio je usporediti dijagnostičku mogućnost smjernica HLH-2004 sa smjernicama za MAS iz 2005. godine, kao i s novim skupom klasifi kacijskih kriterija iz 2016. godine u dijagnostici MAS-a koji komplicira sJIA. U istraživanje je bilo uključeno 35 djece u dobi od 1 do 18 godina kojima je postavljena dijagnoza sJIA prema kriterijima ILAR-a i koja su liječena u Klinici za pedijatriju, Zavodu za imunologiju i reumatologiju Kliničkog bolničkog centra Zagreb u razdoblju od 2009. do 2015. godine. Od 35 bolesnika kojima je postavljena dijagnoza sJIA bilo je 12 djevojčica i 23 dječaka koji su u vrijeme početka bolesti bili prosječne dobi (±SD) 5,51±3,65 godina. Osmero bolesnika imalo je recidiv bolesti. Prema smjernicama iz 2005. godine dijagnoza MAS-a postavljena je u šestero (17,1%) bolesnika sa sJIA. Prema novom skupu klasifi kacijskih kriterija iz 2016. godine dijagnoza MAS-a postavljena je u četvero (11,4%) bolesnika sa sJIA. Dijagnoza MAS-a nije postavljena ni u jednog bolesnika prema smjernicama HLH-2004. U našem istraživanju četvero od šestero bolesnika imalo je MAS na početku sJIA, a u preostalih dvoje on se pojavio tijekom recidiva bolesti. Dvoje bolesnika s MAS-om razvilo je punu kliničku sliku bolesti, dok ih je preostalih četvoro imalo nepotpuna klinička obilježja s manjim odstupanjem u laboratorijskim nalazima. Primjenom različitih dijagnostičkih smjernica utvrdili smo razliku u učestalosti MAS-a. Učestalost je bila nešto viša u usporedbi s postojećim istraživanjima, dok su ostala istraživana obilježja poput kliničkih karakteristika bila slična

Diagnosis and surgical treatment of intestinal malrotation in a patient with Cornelia de Lange syndrome

Prikazujemo žensko dojenče s fenotipskim karakteristikama sindroma Cornelia de Lange kod kojeg je dokazana i uspješno kirurški liječena pridružena malrotacija crijeva. Svrha je rada upozoriti na činjenicu da malrotacija crijeva, iako ne pripada skupini učestalih simptoma sindroma Cornelia de Lange, ne smije biti izostavljena u diferencijalnoj dijagnostici gastrointestinalnih tegoba u navedenih bolesnika.We report on a female infant with phenotypic characteristics of Cornelia de Lange syndrome and associated, successfully surgically treated, intestinal malrotation. The purpose of this report is to point out that intestinal malrotation, as a rare element of Cornelia de Lange syndrome, should not be left out on the diff erential diagnosis of gastrointestinal symptoms in these patients

Pallister Killian Syndrome: Unusual Significant Postnatal Overgrowth in a Girl with otherwise Typical Presentation

Pallister Killian syndrome (PKS) is a rare genetic disorder caused by tetrasomy of the short arm of chromosome 12, revealed usually in mosaic distribution of an extra i(12)(p10) chromosome in fibroblasts. The syndrome presents with a recognizable pattern of findings including pigmentary skin changes, coarse face, high forehead, sparse anterior scalp hair, hypertelorism, seizures and progressive psychomotor developmental delay. It was first described independently by Pallister in 1977 and by Killian and Teschler-Nikola in 19811,2. We report a case of 21 month old girl with PKS and significant overgrowth. Cytogenetic analysis was performed using the GTG banding technique. The karyotype of cultured lymphocytes was normal. The karyotype from skin fibroblasts was established as mosaic tetrasomy of 12p 47,XX,+i(12) (p10)/46,XX. The origin of the extra marker chromosome was determinated by fluorescence in situ hybridization with chromosome 12 specific DNA probes confirming that supernumerary marker is chromosome i(12p) in 68% of cells. Despite the excessive postnatal growth we found low serum growth hormone levels and reduced response to pharmacological stimulation test. This is also the first report of a postnatal patient in our country