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To present patients with Crigler-Najjar syndrome type 1 (CN1). It is a rare autosomal recessive disorder with an incidence of 1: 1 000 000 live births, characterised by severe unconjugated hyperbilirubinemia which arises as a consequence of the absence of hepatic bilirubin uridine diphosphate glucuronosyl transferase(UGT1A1) activity. In the last 30 years we treated seven children with this syndrome at the Department of Pediatrics, University Hospital Center Zagreb. They were from five families- two pairs of siblings (brother and sister) and three unrelated patients (two boys and a girl). Genetic testing of UGT1A1 gene was performed in six patients (two pairs of siblings and two unrelated boys). Unfortunately, one patient’s result was lost. Three patients had frameshift mutations in exon 1: Patient 1 (c.722_723delAG p.Glu241Glyfs*16), Patients 2 and 3 were siblings and had identical mutation (c.717_718delAG p.Q239fsX256). Two patients (4 and 5, also siblings) had identical nonsense mutation in exon 3 (c.1021C>T p.Arg341*). Genetic testing, as it was not widely available at the time, was not performed in one girl whose diagnosis was made by the chromatographic analysis of bilirubin glucuronides in the bile. Four patients underwent a liver transplant from living related donors. In two auxillary procedure was performed (siblings at the age of 7 and 9 years) and in two segmental liver transplant (at the age of 6 and 10 years). Prior to surgery, there was also an unsuccessful attempt of hepatocyte transplantation in one patient. Three liver transplant procedures were successful, and one patient died in the early post-operative course due to primary graft dysfunction. Three patients who have not yet undergone liver transplant (a 3-year-old boy and two siblings 1.5-year-old girl and her 6-month-old brother) are currently treated with phototherapy. At least 10-14 hours long treatment is necessary to keep their bilirubin at an acceptable level (around 250 umol/L). Their psychomotor development is appropriate and they have no neurologic impairment. Considering the number of births per year in Croatia we noticed a remarkably high incidence of CN1, more than five times as expected (5,4: 1 000 000). We don’t have explanation for this finding, at least not by mutations observed. Nevertheless, three of our patients are offspring of two families originating in small Croatian enclave in Kosovo where they were isolated for several centuries. Perhaps there are epigenetic factors we are unaware of that may play a role and contribute to this unexpectedly high incidence.

Spinalna mišićna atrofi ja je autosomno recesivna, progresivna degenerativna bolest uzrokovana mutacijom gena SMN1 (survival of motor neuron 1) na kromosomu 5q. Djelotvorno zbrinjavanje bolesnika i utjecaj standardiziranog terapijskog pristupa radi postizanja kakvoće života zahtijeva multidisciplinski terapijski pristup i koordinaciju velikog broja stručnjaka - užih specijalista. Rana primjena neinvazivne ventilacije i aparata za potpomognuto iskašljavanje te ortopedski pristup rješavanju skolioze značajno povoljno utječu na prirodni tijek bolesti. Uspješan ishod terapijskih postupaka započinje ranom primjenom modifi cirajuće genetičke i genske terapije. Protusmjerni oligonukleotid nusinersen i mala molekula (risdiplam) usmjereni su na uključivanje egzona 7 u SMN2 mRNK te stvaranja stabilnog i funkcionalnog proteina, a genska terapija (onasemnogen abeparvovec) nadomjesna je terapija mutiranog gena SMN1. Rezultati primjene nusinersena upućuju na to da je napredak na testovima motoričkih funkcija najznačajniji u prvih 6 - 12 mjeseci primjene, osobito za spinalnu mišićnu atrofi ju tip 1, uz dobru podnošljivost s malim brojem nuspojava. Rana primjena modifi cirajuće terapije spinalne mišićne atrofi je, ponajprije u tipu 1, povezana je s promjenom prirodnog tijeka i ishoda bolesti u smislu zaustavljanja njene progresije i napretka u razvoju. Zasad nema međunarodno prihvaćenih kriterija za uključivanje bolesnika u gensku i genetičku terapiju prema tipovima, dobi, trajanju bolesti i ovisnosti o trajnoj mehaničkoj ventilaciji. Potrebna su dodatna ispitivanja radi procjene učinkovitosti terapije temeljem procjene motoričkih funkcija i stupnjeva motoričkog razvoja, terapijskog „prozora“, procjene ishoda pomoću biomarkera bolesti, trajanja liječenja, doze lijeka, nuspojava vezanih za dugotrajnu primjenu i ishoda terapije, ponajprije učinka na poremećaje ventilacije i gutanja, učinka na razvoj skolioze, kognitivnog razvoja te rasta i autonomnih funkcija te procjene objektivnosti ljestvica za procjenu motoričkih funkcija. Zaključak. Rano prepoznavanje kliničkih znakova, novorođenački probir i rana genetička dijagnoza, primjena ciljane terapije koja modifi cira tijek bolesti, redovito multidisciplinsko timsko praćenje i liječenje poremećaja disanja, ortopedskih i gastroenteroloških komplikacija bolesti, kao i rani početak tranzicijskog razdoblja neizostavan su dio skrbi o bolesnicima sa spinalnom mišićnom atrofi jom. Radi unapređenja zbrinjavanja i njege bolesnika, kao i standardizacije skrbi o njima značajna je kontinuirana evaluacija kriterija za uključivanje i prekid modifi cirajuće terapije te individualni pristup svakom bolesniku i poticanje osnivanja i redovitog obnavljanja registra bolesnika s neuromuskularnim bolestima s podatcima vezanim za ishod liječenja na nacionalnoj razini i u različitim zemljama širom svijeta, te njihovo međusobno povezivanje i suradnja., Spinal muscular atrophy is an autosomal recessive, progressive degenerative disease caused by mutation of the SMN1 (survival of motor neuron 1) gene on chromosome 5q. Eff ective patient care and success of standardized therapeutic approaches taken to achieve better quality of life require multidisciplinary therapeutic approach and coordination of a large number of specialists. Successful outcome of diagnostic and therapeutic procedures is based on the application of the standardized procedure. It begins with early recognition of clinical signs and symptoms, as well as the risk of complications. Early application of non-invasive ventilation and cough assist device together with orthopaedic approach to scoliosis signifi cantly alter the natural course of the disease. Antisense oligonucleotide (AON) nusinersen and small molecules are directed to enhancing inclusion of exon 7 in SMN2 mRNK and formation of a stable and functional protein, and gene therapy (onasemnogene abeparvovec) is an example of SMN1 gene replacement therapy. Results of treatment with nusinersen show improvement on motor function scales, which is most pronounced in the fi rst 6 to 12 months of therapy in spinal muscular atrophy type I, with good tolerability and safety. Earlier application of modifying therapy for spinal muscular atrophy, primarily for type I, may signifi cantly change of the natural course and outcomes of the disease in terms of halting disease progression, as well as establishing progress in motor development. There are currently no strict internationally accepted criteria for inclusion of diff erent genetic or gene therapies in patients according to disease type or duration, patient age and dependence on permanent mechanical invasive ventilation. Additional studies are required to evaluate therapeutic effi cacy, therapeutic window, duration of treatment, drug dose, side eff ects related to long-term use and treatment outcome, preferably eff ects on ventilation and swallowing, eff ect on cognitive development, scoliosis, growth and autonomic function, and objectivity of the rating scale for motor functions. In conclusion, early genetic diagnosis, neonatal screening and application of target therapy that modifi es the course of the disease, timely monitoring and treatment of respiratory, cardiologic and gastroenterological complications, as well as early onset of the transition period are crucial parts of the care for spinal muscular atrophy patients. In order to improve patient care, it is important to enable treatment possibilities according to standards of care, ongoing evaluation of the criteria for inclusion and termination of modifying therapy, relieving centres for tertiary level of care, reducing the number of disease related hospitalizations and individual access to each patient, along with encouraging the establishment of patient registries for neuromuscular disorders at the national level, as well as in diff erent countries around the world, and their interconnection and cooperation.

We describe a unique case of an 8‐month‐old male child with two different and genetically unrelated entities. Haemophilia A (HA) is caused by a deficiency of functional plasma clotting fac‐tor VIII (FVIII) with X‐linked recessive traits, while inheritance of Shwachman‐Diamond syndrome (SDS) follows autosomal recessive biallelic mutations in DNA JC21 (c.183_184delTAinsCT) with exo‐crine pancreatic insufficiency, impaired hematopoiesis and leukae‐ mia predisposition. These two separate diseases combined together present a challenge to a physician regarding their combined clinical presentation and ambiguous prognosis. Hence, in this Letter we present an example of complex clarification of genetically combined haematologic cases.

Objectives Functional constipation in children should be diagnosed in primary care, based on Rome criteria. Management in tertiary care is rarely needed. The aim of this study was to assess the frequency and structure of paediatric patients diagnosed with functional constipation in a tertiary hospital setting. Methods This study enrolled children referred to the paediatric gastroenterologist (PG) at the UHC Zagreb from January 1st 2017 to December 31st 2017 (N=1729). Data on patients was extracted retrospectively from clinical records. The subjects were classified in three age groups: infants and toddlers (0–3 years), children (4–10 years) and adolescents (11–18 years). Descriptive statistics and chi-square test were used, statistical significance was determined as p Results After appropriate evaluation, about 8% of all outpatients seen by the PG at the UHC Zagreb during year 2017 had functional constipation with or without encopresis (7.63% or 132 patients, boys: 56,1% vs girls: 43,9%). Half of the patients were in the age group of 4 to 10 years (66/132 or 50%), about 1/3 was 0 to 3 years old (41/132), and about 1/5 were adolescents (25/132). It was the most common functional gastrointestinal disorder (FGID) (132/328 or 40.24%), both in girls and boys. Also, it was the leading FGID in the infant/toddler (41/57) and the children group (66/124). Retentive encopresis was present in about 1/5 of children (29/132 or 21.9%) Accompanied encopresis was mainly observed in the age group of 4–10 years (22/66 or 33.3%, χ²=9.9431, p Discussion Frequency of functional constipation in paediatric patients in tertiary hospital setting, as well as sex and age distribution, is comparable to reported incidences in the population. The discordance of referral and final diagnosis shows that constipation is not adequately recognized in primary care, but when recognized, it is mostly diagnosed correctly. Conclusion Functional constipation is not recognized enough in primary care and more efforts are needed to assure a positive diagnosis of this disorder prior to the referral to tertiary care.

Esophageal stricture is one of the most common gastrointestinal complication in epidermolysis bullosa patients. We describe the technique of esophageal stricture dilatation, with a focus on safety and procedural modifications. Case series of 6 patients diagnosed with epidermolysis bullosa who underwent esophageal dilatation in our unit. Type of epidermolysis bullosa, patient’s age, dilatation technique, dysphagia free interval and complications were recorded. Four females and two males underwent a total of 31 dilatations during a 4-year follow-up. Most common dilatation technique was “through-the-scope” with three-stage baloons without radiology control, and in one case Savary bougi. Dilatation is usually done as an outpatient procedure with patients being discharged 3–4 h after the procedure. Mean dysphagia free interval is 7 months, longer is older patients. “Through-the-scope” baloons could be the best way to perform esophageal dilatation in epidermolysis bullosa patients. The procedure is short, safe with high success rate and dysphagia free interval and minimal complications.

Background Infantile free sialic acid storage disease (ISSD) is a severe multisystemic disorder characterized by the accumulation of free sialic acid in lysosomes. Case presentation The patient presented prenatally with fetal ascites and large scrotal hernias, without pleural or pericardial effusion. During the infantile period, he was diagnosed with permanent isolated immunoglobulin G (IgG) hypogammaglobulinemia, which thus far has rarely been associated with ISSD. The analysis of the SLC17A5 gene revealed a novel homozygous 94 bp gene deletion. We further provide a detailed description of pre- and postnatal clinical and radiographic findings. Conclusions Fetal ascites could be the first sign of several lysosomal storage diseases (LSDs), including ISSD. The analysis of LSD gene panels is an effective approach to diagnosis in the case of non-specific symptoms and when specific biochemical tests are not easily available.

BACKGROUND: Patients with congenital diaphragmatic hernia (CDH) have a high residual morbidity rate. We compared self-reported health-related quality of life (HRQoL) between patients with CDH and healthy children. ----- METHODS: Forty-five patients with CDH who were born from January 1, 1990, through February 15, 2015, were matched to healthy, age-matched control participants at a 1:2 ratio. The health records of the study participants were reviewed to determine comorbid conditions, and HRQoL was assessed by both the participants and their parents with the Pediatric Quality of Life Inventory (PedsQL). The HRQoL scores of the patients with CDH and the control participants were compared by using analysis of variance to adjust for age group and sex. Among patients with CDH, analysis of variance was used to compare HRQoL scores across groups defined according to their characteristics at initial hospitalization, postdischarge events, and comorbid conditions. ----- RESULTS: Compared with control participants, patients with CDH had lower mean PedsQL scores, as reported by the parent and child, for the physical and psychosocial domains (P

Biallelic mutations in the post-GPI attachment to proteins 3 (PGAP3) gene cause hyperphosphatasia with mental retardation syndrome 4 (HPMRS4), which is characterized by elevated serum alkaline phosphatase, severe psychomotor developmental delay, seizures, and facial dysmorphism. To date, 15 PGAP3 mutations have been reported in humans. Here we report a novel homozygous PGAP3 mutation (c.314C>A, p.Pro105Gln) in a Croatian patient and fully describe the clinical features.

To prevent the development of malnutrition in hospitalized children, it is important to develope an early identification of nutritional depletion, ideally at the time of admission to the hospital. In 2009 Hulst et al. proposed new guidelines for assessing the nutritional status of hospitalized children called STRONGkids questionnaire (Screening Tool Risk on Nutritional Status and Growth). This study was designed to describe the current prevalence of malnutrition on admission to a pediatric gastroenterology hospital unit and to compare the value and feasibility of STRONGkids scoring system versus anthropometric World Health Organization (WHO) criteria in identifying children at risk of developing malnutrition during hospital stay. The prospective observational study involved 124 children hospitalized at the Department of Pediatrics, University Hospital Center Zagreb. Nutritional status and risk for malnutrition were estimated by STRONGkids questionnaire and anthropometric measurements of subjects. Statistical analysis was performed using the computer program STATISTICS 10, StatSoft. Inc. 1984-2011 ; using descriptive statistics, Fisher's exact (FE) test and non- parametric Kruskal-Wallis (KW) test. Total malnutrition was observed in 18.5% of patients. Larger number of children at risk for malnutrition were identified by STRONGkids questionnaire than by anthropometric measurements (STRONGkids questionnaire: 75.8% ; anthropometric measures: 40.3%). Patients that lost weight during hospitalization (33.1%) were further analyzed: 8/41 were not detected to be at risk by either method, 11/41 were identified by STRONGkids and anthropometry, and 22/41 were detected only by STRONGkids (Fisher's exact test p=0, 08). This study justifies the inclusion of the STRONGkids questionnaire in the initial evaluation of children on admission to the hospital, in order to recognize those who need special nutritional support and thus prevent the development of malnutrition during hospitalization.

IBD may compromise skeletal integrity in children and is a recognised risk of osteoporosis in adulthood. The aim was to assess bone metabolism in children with IBD at diagnosis and one year after the onset. There were 58 children (36 female, 22 male), 41 with Crohn's 17 with UC. Our results indicate that IBD in children did not considerably impair the skeleton, but 69% of our patients had hypovitaminosis D. It should be treated.