National Pediatric Center Research Articles

Clinical features of pediatric Danon disease and the importance of early diagnosis

Successful therapy in a cohort with early onset Danon disease (DD) highlights the potential importance of earlier disease recognition. We present experience from the largest National Pediatric Center in Russia for cardiomyopathy patients. This report focuses on identification of early clinical features of DD in the pediatric population by detailed pedigree analysis and review of medical records. ResultsNine patients (3 females) were identified with DD at the Russian National Medical Research Center of Children's Health (“National Pediatric Center”) aged birth to 16 years. At presentation/evaluation: all patients had left ventricular hypertrophy (LVH), ECG features of Wolff-Parkinson-White (WPW), and an increase in hepatic enzymes (particularly lactate dehydrogenase (LDH)); three had marked increase in NT-proBNP; two had HCM with impaired LV function; one had LVH with LV noncompaction; five had arrhythmia with paroxysmal supraventricular and/or ventricular tachycardia. Two teenagers died at ages 16–17 from refractory heart failure and two underwent heart transplantation. All patients were found to have a pathogenic/likely pathogenic variant in the LAMP2 gene, six patients had no family history and a de novo evolvement was documented in 4/6 of those available for genetic tested. Retrospective review related to family background and earlier clinical evaluations revealed a definitive or highly suspicious family history of DD in 3, early clinical presentation with cardiac abnormalities (ECG, echo) in 3, and cerebral, hepatic and/or neuromuscular symptoms in 5. Abnormalities were detected 9,5 months to 5,8 years, median 3,5 years prior to referral to the National Pediatric Center. ConclusionThe earliest clinical manifestations of Danon disease occur in the first 12 years of life with symptoms of skeletal muscle and cerebral disease, raised hepatic enzymes, and evidence of cardiac disease on ECG/echo.

Quality care close to home: Objectives and early outcomes of a second paediatric heart transplant service in Australia.

We describe the experience of a new paediatric heart transplant (HT) centre in Australia. New South Wales offers quaternary paediatric cardiac services including comprehensive care pre- and post-HT; however, perioperative HT care has previously occurred at the national paediatric centre or in adult centres. Internationally, perioperative HT care is highly protocol-driven and a majority of HT occurs in low volume centres. Establishing a low volume paediatric HT centre in New South Wales offers potential for quality HT care close to home. Retrospective review of programme data for the first 12 months was undertaken. Patient selection was audited against the programme's intended initiation criteria. Longitudinal patient data on outcomes and complications were obtained from patient medical records. The programme's initial phase offered HT to children with non-congenital heart disease and no requirement for durable mechanical circulatory support. Eight patients met criteria for HT referral. Three underwent interstate transfer to the national paediatric centre. Five children (13-15 years, weight 36-85 kg) underwent HT in the new programme. Individual predicted 90-day mortality was 1.3-11.6%, with increased risk for recipients transplanted from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and with restrictive/hypertrophic cardiomyopathies. Survival at 90 days and for duration of follow-up is 100%. Observed programme benefits include mitigation of family dislocation and improved continuity of care within a family-centred programme. Audit of the first 12 months' activity of a second paediatric HT centre in Australia demonstrates adherence to proposed patient selection criteria and excellent 90-day patient outcomes. The programme demonstrates feasibility of care close to home, providing continuity for all patients including those requiring increased rehabilitation and psychosocial support post-transplantation.

Subglottic hemangioma—prevalence, clinical presentation and treatment

This retrospective study aimed to investigate the clinical features and treatment of pediatric subglottic hemangioma (SH), identify risk factors for treatment-induced adverse effects, and identify a strategy for timely therapy discontinuation in children diagnosed with SH at the national pediatric center. Medical records of patients presented with stridor from 2010 to 2020 were retrieved and assessed, the diagnosis of SH was established via flexible bronchoscopy, and the patients were treated using propranolol with a subsequent gradual dose increase to 3 mg/kg body weight daily. A two-week oral steroids trial was added for those with circumferential lesions. Early indicators of a good therapeutic response included decreased stridor and primary lesion size on follow-up bronchoscopy performed one week after propranolol commencement. Duration of therapy, tailored individually based on bronchoscopy findings, and at least twelve months of treatment were the two main criteria for deciding therapy termination. Outpatient visits were arranged at least every three months. Our results showed that SH was the third most frequent cause of stridor (15/137 patients), and biphasic stridor was uniformly present as a typical symptom. Both clinical improvement and bronchoscopy findings confirmed the efficacy of the treatment. The mean therapy duration was 17 months. The only significant adverse event observed was hypoglycemic seizures in one infant. Contributory factors were all prematurity, high propranolol dose (3 mg/kg) and poor oral intake. Collectively, defining a safe and timely protocol for therapy cessation and avoidance of risk factors for adverse effects is the mainstay of SH treatment.

Sindrom kongenitalne centralne hipoventilacije - heterogenost kliničke prezentacije, modaliteti ventilatorne potpore i ishodi

Introduction/aim: Central congenital hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by autonomic dysregulation and alveolar hypoventilation with ventilatory support being the cornerstone of long-term survival. The aim was to present different ventilatory strategies in CCHS. Material and methods: The study included retrospectively analyzed medical records of five patients diagnosed with CCHS in a national pediatric center. Alveolar hypoventilation was evidenced by noninvasive continuous transcutaneous capnometry and central sleep-disordered breathing documented by polygraphy. Clinical evaluation included cardiac evaluation, rectal biopsies, and urinalysis of catecholamine levels. Life-threatening cardiac arrhythmias were indications for pacemaker implantation. Genetic analyses of alanine residues in paired-like homeobox 2B gene (PHOX2B) confirmed the diagnosis. Results: A range of pathogenic changes in the PHOX2B gene resulted in varying clinical outcomes. 3/4 (75%) of patients with an early onset were ventilated continuously through a tracheostomy tube, while one patient was successfully treated with noninvasive ventilation (NIV) as the preferred option. Additionally, NIV was applied in one child with early-onset disease after decannulation. Finally, NIV was also feasible in a case with late-onset disease presented by the time of four years with symptoms of pulmonary hypertension. There were no serious side effects of ventilation, and one patient died due to cardiac arrhythmias. Conclusion: Invasive mechanical ventilation remains the treatment of choice in most children with early-onset disease. However, the indications for NIV have been widened from overnight ventilation in the late-onset course to selected cases with early-onset disease. The timely switch from IMV to NIV has been popularized in recent years worldwide.

Joint Manifestations in Children with Familial Mediterranean Fever in Armenia: Clinical and Genetic Characteristics

Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease in the group of Hereditary periodic fever syndromes (HPFS), characterized by recurrent, self-limited attacks of fever and polyserositis, which last 2-4 days. It manifests mainly in childhood and often has early onset, resolve without sequels. Genetic testing of FMF is efficient and allows diagnosing of atypical cases. FMF is a significant health care problem in Armenia because of high frequency of carriers of MEFV mutations 1:3 - 4 (0.21) and marked FMF prevalence 54.7 per 10`000 of the total population. Articular symptoms are found in about 45% of cases. They usually manifest as acute recurrent arthritis (ARA) or arthralgia, but more rarely also chronic arthritis can be found. We aimed to investigate clinical and genetic characteristics of the joint manifestations in Armenian children with FMF. The charts of all 715 patients with proven diagnosis of FMF at the National Pediatric Center (NPC) for FMF were reviewed for joint manifestations. The diagnosis of FMF and disease severity were determined according to the Tel-Hashomer criteria and molecular-genetic detection of 12 MEFV mutations common for Armenians. The characteristics of joint manifestations and overall FMF disease were then compared to MEFV mutation analysis. There were 438 boys and 277 girls with an age at diagnosis between 3 months and 17 years (mean age: 8.64±0.17). Joint involvement was observed in 56.4% of all 715 cases. The manifestation was ARA in 30.5%, arthralgia in 21.2% and chronic arthritis (CA) in 4.7%, which would also qualify for a diagnosis of JIA. The frequency of ARA was associated with M694V mutation, mainly M694V homozygous and M694V heterozygous genotypes. The risk of CA depended on MEFV genotype of the FMF patients and was the highest in M694Vheterozygotes and M694Vhomozygotes. M694V heterozygous genotype was noticed significantly more frequently among FMF patients with spondyloarthritis in comparison to those without it. The probability of the development of CA among FMF patients without M694V mutation was significantly higher also in heterozygotes in comparison to compound-heterozygotes. We concluded, that the frequency of joint involvement among Armenian pediatric FMF patients was high - 56.4%, especially for CA. Chronic arthritis may be the first manifestation of FMF and occurred usually in patients with severe M694V mutations. Patients of Armenian origin with refractory arthritis should be asked for isolated febrile attacks, hemorrhagic vasculitis, episodes of pleuritis and family history to rule out FMF.

Flexible Bronchoscopy in Evaluation of Persistent Wheezing in Children-Experiences from National Pediatric Center.

Background and objectives: Persistent wheezing (PW) is defined as prolonged or recurrent episodes of wheezing despite regular treatment. Flexible bronchoscopy (FB) is recommended to determine the etiology of PW in children. This study aimed to determine the etiology of PW based on FB findings in a national pediatric center. Materials and Methods: Children presenting with PW that underwent flexible bronchoscopy from April 2016 to August 2019 at the Mother and Child Health Institute of Serbia were included in this observational study. After endoscopic evaluation, bronchoalveolar lavage fluid (BALF) samples were taken and further analyzed. Quantitative microbiology, cytological analysis and oil-red staining of specimens were performed to determine cellular constituents and presence of lipid laden macrophages (LLM). Upper gastrointestinal series were performed to exclude gastroesophageal reflux disease, swallowing dysfunction and vascular ring. Results: Pathological findings were revealed in 151 of 172 study participants, with bacterial lower airway infection (BLAI) (48.3%) and primary bronchomalacia (20.4%) as the most common. Younger participants were hospitalized for significantly longer periods (ρ = −0.366, p < 0.001). Study participants with BLAI and associated mucus plugging were notably younger (p < 0.001). Presence of LLM in BALF was not associated with findings of upper gastrointestinal series. All patients with confirmed BLAI were treated with oral antibiotics. Although FB is considered to be invasive, there were no complications associated with the procedure. Conclusions: Flexible bronchoscopy has an exceptional diagnostic value in evaluation of PW. In younger patients with BLAI, presence of mucus plugs may complicate the clinical course, so significant benefits can be achieved with therapeutic lavage during bronchoscopy.

Non-vascularised Fibular Autograft for Reconstruction of Paediatric Bone Defects: An Analysis of 10 Cases.

Aim and objectiveFibular autograft is a known technique for the reconstruction of traumatic and non-traumatic bone defects in both adult and paediatric populations. We aim to describe our outcomes using various stabilisation methods for non-vascularised fibular autograft to reconstruct both benign and malignant tumours in a paediatric population in a National Paediatric Centre over the past 14 years.Materials and methodsThis was a retrospective review of 10 paediatric cases with non-traumatic primary bone defects in a National Paediatric Centre. Criteria for inclusion were all non-traumatic primary bone defects requiring reconstruction with a non-vascularised fibular autograft in the diaphyseal or metaphyseal regions of the bone. The primary outcome measures were union and time to union (weeks). Time to union was illustrated using Kaplan–Meier curves. Secondary outcome measures included postoperative fracture, infection (deep and superficial), time to full weight-bearing and all-cause revision surgery.ResultsThe mean length of follow-up was 63 months for the entire cohort (9–168, SD = 48.6). There was no loss to follow-up. Six lesions were located in the tibia, two in the femur and the remaining two were located in the ulna and third metacarpal. Union was ultimately achieved in 8 of the 10 patients using this donor autograft. The mean time to union was 28 weeks (10–99, SD = 29.8). There were four complications of autograft fracture. The mean time to fracture was 17 weeks (9–32, SD = 10.71). In all four of these cases, the patient achieved union at final follow-up. There were two superficial and two deep infections recorded. Three resolved with the use of antimicrobial therapy and one deep infection ultimately required insertion of an intercalary prosthesis to treat the infected non-union of the fibular graft site.ConclusionThe use of non-vascularised fibular autograft for the reconstruction of tumours is an effective surgical technique in a paediatric cohort. We report the largest known series of malignant paediatric tumours treated with this technique to date.Clinical significanceNon-vascularised fibular autograft is successful in the reconstruction of large bone defects secondary to malignant paediatric bone tumours.How to cite this articleSheridan GA, Cassidy JT, Donnelly A, et al. Non-vascularised Fibular Autograft for Reconstruction of Paediatric Bone Defects: An Analysis of 10 Cases. Strategies Trauma Limb Reconstr 2020;15(2):84–90.

New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.

BackgroundWhole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD).MethodsWe performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family.ResultsLikely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification.ConclusionsWe suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0930-9) contains supplementary material, which is available to authorized users.

A Retrospective Series of 77 Pediatric Patients with Vertigo at a National Center for Child Health and Development

The evaluation and management of vertigo in children varies among institutional and medical specialties. The aim of this study was to describe the characteristics of vertigo in children presenting at a national pediatric center. Patients < 16 years old presenting with vertigo to the department of otolaryngology at a national center for child health and development from April 2004 to October 2009 were included (N = 77; 42 males and 35 females; average age, 8.7 ± 3.4 years) in this study. The most common diagnoses were vestibular migraine (VM; N = 21), benign paroxysmal vertigo (BPV; N =16), unilateral vestibulopathy (N = 12), and psychogenic vertigo (N = 8). Significant differences were observed in the frequency of the diagnoses between children aged older and younger than 7 years: BPV was most common in children < 7 years of age (p < 0.01) and VM was most common in ≥ 27 years of age (p < 0.05). Because obtaining adequate information from children for making a correct diagnosis is sometimes difficult, acquiring sufficient information from the parents is important. In addition, getting the parents to record the nystagmus during a vertigo attack with a digital camera or cellular phone can be useful because observing the nystagmus recorded on the video is helpful for making a diagnosis. Furthermore, the parents are participating in their child's care by attempting to record the attack, strengthening the relationship between the parents and the child. The incidence of psychogenic vertigo is low (less than 10%). Therefore, although physicians have recently tended to define the disorder as psychogenic when no objective abnormality is found in a patient, making a diagnosis of psychogenic vertigo is not recommended. Because vertigo can sometimes make a child anxious, delivering the correct diagnosis and treatment at the early stage is important for preventing anxiety in affected children.

Severe gastrointestinal haemorrhage, first manifestation of neonatal haemophilia A

HaemophiliaVolume 15, Issue 3 p. 817-819 Severe gastrointestinal haemorrhage, first manifestation of neonatal haemophilia A A. PICCIN, A. PICCIN National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's Hospital Irish Blood Transfusion Service Trinity College University, Dublin, IrelandSearch for more papers by this authorA. O’MARCAIGH, A. O’MARCAIGH National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorS. DEIRATANY, S. DEIRATANY National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorC. MC MAHON, C. MC MAHON National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorO. P. SMITH, O. P. SMITH National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's Hospital Trinity College University, Dublin, IrelandSearch for more papers by this author A. PICCIN, A. PICCIN National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's Hospital Irish Blood Transfusion Service Trinity College University, Dublin, IrelandSearch for more papers by this authorA. O’MARCAIGH, A. O’MARCAIGH National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorS. DEIRATANY, S. DEIRATANY National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorC. MC MAHON, C. MC MAHON National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's HospitalSearch for more papers by this authorO. P. SMITH, O. P. SMITH National Paediatric Centre for Coagulation and Haemostasis, Our Lady’s Children's Hospital Trinity College University, Dublin, IrelandSearch for more papers by this author First published: 21 April 2009 https://doi.org/10.1111/j.1365-2516.2009.01988.xCitations: 1 Dr Andrea Piccin, Irish Blood Transfusion Service, James’s Street, Dublin 8, Ireland.Tel: +353 (0) 1 432 2812; fax: +39 049 875 0693;e-mail: [email protected] Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume15, Issue3May 2009Pages 817-819 RelatedInformation