Common Acute Lymphoblastic Leukemia Ph＋ Following Langerhans Cell Histiocytosis in a Multi-Malformed Child with INV (9) (p12;q13) (mat):Case Report

The occurrence of Langerhans cell histiocytosis (LCH) and another malignancy in the same patient is infrequent but has been recognized. The genetic changes that could be responsible for LCH and/or concomitant leukemia development are obscure. To the best of our knowledge, this is the first description of constitutional maternally derived inv (9) (p12;q13) in an LCH patient, and also of the development of common ALL Ph after LCH diagnosis and therapy. The potential significance of these findings [inv (9)LCHALL Ph] and their mutual relationship are unknown. Therefore, cooperative studies of large numbers of patients are needed to identify the common risk factors, if any

Pneumokokno povezani hemolitsko-uremički sindrom nakon invazivne pneumokokne bolesti kod dvogodišnje djevojčice

The haemolytic uremic syndrome is characterized by microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure and is the most common in children under the age of 4. The etiology can be associated with some infectious agents like Streptococcus pneumoniae. We review the case of a 2-year-old girl presenting with invasive pneumococcal disease followed by the haemolytic uremic syndrome. The onset of the haemolytic uremic syndrome clinical manifestation was preceded by un upper respiratory tract infection. The physical finding was in extremely bad condition with pallor. She was adinamic, confused, dispnoic, dehydrated with peripheral circulatory failure. Tubular breath sounds with moist rales on both sides of the lung were registered as well as liver and spleen enlargement. Presenting clinical and laboratory data we confirmed that, in our case, following the invasive pneumococcal disease (pleuropneumonia, sepsis and septic shock), Streptococcus pneumoniae was the trigger of HUS. High doses of corticosteroids, fresh frozen plasma, antibiotics, and intravenous immunoglobulins were a successful treatment.Hemoliticko-uremicki sindrom karakterizira mikroangiopatska hemoliticka anemija, trombocitopenija i akutno zatajenje bubrega. Najcešce se javlja u djece u dobi mladoj od 4 godine. Etiologija je povezana s nekim infektološkim agensima kao što je Streptococcus pneumoniae. Prikazali smo slucaj dvogodišnje djevojcice s invazivnom pneumokoknom bolesti s hemoliticko-uremickim sindromom. Bolest je pocela infekcijom gornjeg respiratornog trakta. Djevojcica je primljena u vrlo teškom stanju, ekstremno blijeda, adinamicna, konfuzna, dispnoicna, dehidrirana u kolapsu periferne cirkulacije. Obostrano nad plucima culi su se brojni bronhiticki hropci, a jetra i slezena su bile uvecane. Klinicki i laboratorijski potvrdili smo da je u djevojcice pneumokokna invazivna bolest (pleuropneumonija, sepsa i septicki šok) uzrokovana Streptokokom pneumonije potaknula nastanak hemoliticko-uremickog sindroma. Uspješno izljecenje postignuto je primjenom visokih doza kortikosteroida, svježe smrznute plazme, antibiotika i intravenoznih imunoglobulina

De Novo NEMO Gene Deletion (D4–10) – A Cause of Incontinentia Pigmenti in a Female Infant: A Case Report

Incontinentia pigmenti (IP) is a rare, inherited, multisystem genodermatosis. It is transmitted as an X-linked dominant trait. The disorder is a consequence of mutations in the NEMO gene (Xq28) that completely abolish expression of the NF-kappaB essential modulator. Here we present a female infant of healthy nonconsanguinous, young parents with a clinically evident first phase of IP. PCR analysis of patient’s peripheral blood lymphocytes DNA was done for detection of NEMO D4–10 deletion. Skin changes present at birth appertain to first inflammatory stage. However, a pathohistological feature of the skin biopsy showed second phase of disease. Genetic testing of diseased child revealed D4–10 in NEMO gene. However, the assumption that the female child has familial IP was rejected as PCR performed on the mother’s leukocytes did not record the presence of the same mutation. Moreover, the existence of a healthy male infant of the same mother as well as the lack of any phenotypic signs of the disease in other family members additionally support that IP was not inherited, but it was a consequence of de novo NEMO gene mutation. In conclusion, here we describe a Croatian female with clinical IP phenotype having de novo genomic rearrangements in the NEMO gene

Patau sindrom

Genetic syndromes caused by chromosomal aberrations involve a recognizable pattern of multiple congenital anomalies with increased neonatal and infant mortality, making care challenging for the family, primary care practitioners, and specialists. About 28% of children born with trisomy 13 die during the fi rst week of life. The median life expectancy is about 2.5 days. We present a 12-year-old girl, the longest living patient with Patau syndrome in Croatia, followed-up from the birth until the age of 12 years. The conventional nonintervention approach has been revised and we suggest changing the traditional view of the condition.Genetski sindromi uzrokovani kromosomnim aberacijama uključuju prepoznatljivi obrazac višestrukih prirođenih anomalija s povećanom smrtnošću novorođenčadi i dojenčadi, što skrb za njih čini teškom za obitelj, liječnike primarne zdravstvene skrbi i specijaliste. Oko 28% djece rođene s trisomijom 13 umire tijekom prvog tjedna života. Srednje očekivano trajanje života je oko 2,5 dana. Prikazujemo 12-godišnju djevojčicu, najduže živuću bolesnicu s Patauovim sindromom u Hrvatskoj, koju pratimo od rođenja do njezine sadašnje dobi od 12 godina. Konvencionalni pristup zasnovan na izostanku intervencije doživio je reviziju, a mi predlažemo promjenu tradicionalnog pogleda na ovo stanje

Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation

Distal arthrogryposis (DA) is a clinically and genetically heterogeneous disorder with multiple joint contractures. We describe a female DA patient with hand and foot deformities, and right-sided torticollis. Using exome sequencing, we identified a novel TNNI2 mutation (c.485>A, p.Arg162Lys) in the patient and her father. The father has no typical DA but hip dysplasia. This may explain the clinical features of DA2B in this family, but with variable clinical expression

Osteogenesis imperfecta - pamidronate treatment in Split Clinical Hospital Centre

Osteogenesis imperfecta (OI) ili bolest krhkih kostiju je klinički, biokemijski i genski heterogena bolest veziva. Glavna osobina bolesti su lomljive i osteoporotične kosti. Indikacija za početak liječenja postavlja se u djece nakon dva koštana loma. Od 2002.-2010. godine u KBC Split praćeno je i liječeno 7 djevojčica i 6 dječaka u kojih je temeljem kliničke slike postavljena dijagnoza OI. U osmero djece OI tip I, u dvoje tip III, i u po jednomu djetetu tip V, VI i VII. U svrhu dijagnosticiranja bolesti, te tijekom i nakon provedenoga liječenja praćene su vrijednosti mineralne gustoće kostiju. Osmero je djece liječeno intravenskom primjenom pamidronata. Liječenje je poboljšalo mineralnu gustoću kostiju, što je doprinijelo prestanku lomova kostiju u šestero liječene djece. Svim oboljelim osobama preporučeno je i uzimanje hrane bogate kalcijem i vitaminima. Fizikalnu terapiju koristilo je 10-ero djece. Kirurški zahvati zbog ispravljanja deformiteta provedeni su u troje djece. Zaključno, liječenje pamidronatom dokinulo je pojavu prijeloma kostiju i smanjenje bolova u kostima u sve liječene djece, uz istovremeno povećanje vrijednosti mineralne gustoće kostiju, a bez nuspojava uzrokovanih uzimanjem lijeka. U liječenju OI od iznimne je važnosti multidisciplinarni pristup oboljelom djetetu, uz suradnju pedijatra – genetičara s dječjim kirurgom, specijalistom fizikalne medicine i rehabilitacije, i ostalim specijalistima. U KBC-u Split se osobita pozornost poklanja praćenju djece, edukaciji djeteta i roditelja o naravi bolesti, te adekvatnoj rehabilitaciji nakon prijeloma.Osteogenesis imperfecta or brittle bone disease is a clinical, biochemical and genetical heterogeneous disorder of the connective tissue. Fragile and osteoporotic bones are its main feature. From 2002-2010 seven girls and six boys were treated at CHC Split. Based on clinical symptoms, they all had OI, eight of them had type I, two type III and the rest type V, VI and VII respectively. Eight of them were treated with intravenous application of pamidronate. This treatment increased bone density and reduced the incidence of fractures. To all of them we strongly recommended food rich in calcium and vitamins. Ten children undertook physical therapy and three had surgical procedures to correct their deformities. Pamidronate treatment abolished the occurrence of bone fractures and reduced pain in all treated children, along with the increase of bone mineral density, but without side effects caused by the drugs. In this treatment of OI, a multidisciplinary approach is crucial. The cooperation of pediatricians – geneticists with children\u27s surgeons, specialists in physical medicine and rehabilitation, and other specialists is very important. At CHC Split, special attention is needed for monitoring and educating children and parents on the nature of the disease and adequate rehabilitation after fracture

Down Syndrome: Parental Origin, Recombination, and Maternal Age

The aims of the present study were to assess (1) the parental origin of trisomy 21 and the stage in which nondisjunction occurs and (2) the relationship between altered genetic recombination and maternal age as risk factors for trisomy 21. The study included 102 cases with Down syndrome from the Croatian population. Genotyping analyses were performed by polymerase chain reaction using 11 short tandem repeat markers along chromosome 21q. The vast majority of trisomy 21 was of maternal origin (93%), followed by paternal (5%) and mitotic origin (2%). The frequencies of maternal meiotic I (MI) and meiotic II errors were 86% and 14%, respectively. The highest proportion of cases with zero recombination was observed among those with maternal MI derived trisomy 21. A higher proportion of telomeric exchanges were presented in cases with maternal MI errors and cases with young mothers, although these findings were not statistically significant. The present study is the first report examining parental origin and altered genetic recombination as a risk factor for trisomy 21 in a Croatian population. The results support that trisomy 21 has a universal genetic etiology across different human populations

The importance of DNA analysis of the human papilloma virus in patohystological material of spontaneous abortions with aneuploidy in parents with normal constitutional karyotypes

Pobačaj je najčešća komplikacija trudnoće. Rizik za svaki sljedeći povećava se s brojem prijašnjih pobačaja. Izgleda da su aberacije kromosoma i virusne infekcije, posebice one nastale neposredno ili tijekom ranog perioda trudnoće na prvom mjestu, od brojnih mogućih uzroka. Preranom prekidu trudnoće doprinose i različiti vanjski čimbenici, posebice neprimjereni radni uvjeti. Cilj istraživanja bio je ispitati hipotezu da su dvije promjene odgovorne za nastanak aneuploidija koje rezultiraju spontanim pobačajem. Prvi događaj bi bile ranije bolesti mokraćno-spolnog sustava ispitanika kao i spontani pobačaji u II generaciji srodnika što stvara predispoziciju prema spontanim pobačajima. Drugi bi događaj bio kronično prisustvo virusa EBV u žena i muškarca. Nađeno je da nema značajne razlike između prosječnih godina žena i muškaraca za bilo koji broj spontanih pobačaja te da starost žena ne utječe na učestalost pobačaja. I muškarci i žene imali su ranije infekcije mokraćnog i/ili spolnog sustava. Srodnici u II generaciji i žena i muškaraca imali su dvostruko veći broj spontanih pobačaja nego opća populacija (prvi udarac). Nađene su varijacije u populaciji (per inv 9 i 9qh+) u konstitucijskim kariotipovima ispitanika. Pronađeno je, u ispitanika, prisustvo protutijela za neke viruse (EBV, CMV i HSV-2). Reaktivacija latentne infekcije s EBV-om predstavlja drugi udarac. Aneuploidija ili tetraploidija nađena je u 23% uzoraka. Nije dokazana prisutnost HPV-a u tkivu posteljice. Potvrđena je postavljena hipoteza o dvostrukom udarcu. Nije potvrđena hipoteza o ulozi HPV-a kao prvog udarca u nastanku aneuploidije. Dokazano je da EBV i drugi mikroorganizmi mogu djelovati kao “drugi udarac”, koji će započeti niz molekulskih i imunoloških događanja i uzrokovati promjene na diobenom vretenu za vrijeme mejoze ili u kasnijim mitotičkim diobama.An abortion is the most frequent complication of pregnancy. Among other various causes, it seems that chromosome aberrations and viral infections come first. The purpose of this research is to establish the hypothesis that two hits are responsible for aneuploidy which results in spontaneous abortion. The first hit could have been triggered by patient's former diseases of urinary and/or genital system. The number of spontaneous abortions recorded in their siblings of second generations creates predisposition that may end with termination of pregnancy. The second hit is usually triggered by chronic presence of EBV virus in male or/and female partner. It has been demonstrated that there is no significant relation between the age of male or female partners and the number of spontaneous abortions. Both males and females had former urinary or/and genital infections and the number of spontaneous abortions among the siblings of second generation is twice as high in relation to average population. Variations in constitutional karyotypes (per inv 9, 9qh+) are also evident as well as presence of antibodies for EBV, CMV, or HSV2 viruses. Reactivation of latent EBV infection provides possibility for second hit. Aneuploidy or tetraploidy is found at 23% of samples. The presence of HPV genome in placenta tissue is not verified. Although we could not verify the presence of HPV virus in analysed tissue, it is clearly evident from statistical data that EBV and other viruses triggered the second hit, so it is possible that HPV could be one of triggers in the theory of two hits. Therefore we think that the presumed hypothesis of two hits is clearly established. The second hit causes a series of molecular and immunological changes, including changes in spindle apparatus during meiosis or in later mitotic divisions

The importance of DNA analysis of the human papilloma virus in patohystological material of spontaneous abortions with aneuploidy in parents with normal constitutional karyotypes

Pobačaj je najčešća komplikacija trudnoće. Rizik za svaki sljedeći povećava se s brojem prijašnjih pobačaja. Izgleda da su aberacije kromosoma i virusne infekcije, posebice one nastale neposredno ili tijekom ranog perioda trudnoće na prvom mjestu, od brojnih mogućih uzroka. Preranom prekidu trudnoće doprinose i različiti vanjski čimbenici, posebice neprimjereni radni uvjeti. Cilj istraživanja bio je ispitati hipotezu da su dvije promjene odgovorne za nastanak aneuploidija koje rezultiraju spontanim pobačajem. Prvi događaj bi bile ranije bolesti mokraćno-spolnog sustava ispitanika kao i spontani pobačaji u II generaciji srodnika što stvara predispoziciju prema spontanim pobačajima. Drugi bi događaj bio kronično prisustvo virusa EBV u žena i muškarca. Nađeno je da nema značajne razlike između prosječnih godina žena i muškaraca za bilo koji broj spontanih pobačaja te da starost žena ne utječe na učestalost pobačaja. I muškarci i žene imali su ranije infekcije mokraćnog i/ili spolnog sustava. Srodnici u II generaciji i žena i muškaraca imali su dvostruko veći broj spontanih pobačaja nego opća populacija (prvi udarac). Nađene su varijacije u populaciji (per inv 9 i 9qh+) u konstitucijskim kariotipovima ispitanika. Pronađeno je, u ispitanika, prisustvo protutijela za neke viruse (EBV, CMV i HSV-2). Reaktivacija latentne infekcije s EBV-om predstavlja drugi udarac. Aneuploidija ili tetraploidija nađena je u 23% uzoraka. Nije dokazana prisutnost HPV-a u tkivu posteljice. Potvrđena je postavljena hipoteza o dvostrukom udarcu. Nije potvrđena hipoteza o ulozi HPV-a kao prvog udarca u nastanku aneuploidije. Dokazano je da EBV i drugi mikroorganizmi mogu djelovati kao “drugi udarac”, koji će započeti niz molekulskih i imunoloških događanja i uzrokovati promjene na diobenom vretenu za vrijeme mejoze ili u kasnijim mitotičkim diobama.An abortion is the most frequent complication of pregnancy. Among other various causes, it seems that chromosome aberrations and viral infections come first. The purpose of this research is to establish the hypothesis that two hits are responsible for aneuploidy which results in spontaneous abortion. The first hit could have been triggered by patient's former diseases of urinary and/or genital system. The number of spontaneous abortions recorded in their siblings of second generations creates predisposition that may end with termination of pregnancy. The second hit is usually triggered by chronic presence of EBV virus in male or/and female partner. It has been demonstrated that there is no significant relation between the age of male or female partners and the number of spontaneous abortions. Both males and females had former urinary or/and genital infections and the number of spontaneous abortions among the siblings of second generation is twice as high in relation to average population. Variations in constitutional karyotypes (per inv 9, 9qh+) are also evident as well as presence of antibodies for EBV, CMV, or HSV2 viruses. Reactivation of latent EBV infection provides possibility for second hit. Aneuploidy or tetraploidy is found at 23% of samples. The presence of HPV genome in placenta tissue is not verified. Although we could not verify the presence of HPV virus in analysed tissue, it is clearly evident from statistical data that EBV and other viruses triggered the second hit, so it is possible that HPV could be one of triggers in the theory of two hits. Therefore we think that the presumed hypothesis of two hits is clearly established. The second hit causes a series of molecular and immunological changes, including changes in spindle apparatus during meiosis or in later mitotic divisions