[Kids Lung Registry and Child-EU Project - Progress in Rare and Interstitial Lung Diseases in Childhood Through Collaboration]. / Kinderlungenregister (chILD-EU) ­ Zusammenarbeit führt zu Fortschritten bei den seltenen und interstitiellen Lungenerkrankungen.

BACKGROUND: Progress in rare and interstitial lung disease in childhood can most usefully be achieved through systematic, registry-based collection. QUESTION AND METHODS: What are the practicalities and benefits of participating in the pediatric lung registry/chILD-EU project? We report our clinical experiences. RESULTS: Pediatricians and pediatric pulmonologists identify children with rare lung diseases. These are reported to the Kid's Lung Register after parental consent. Clinical data, imaging, and blood are sent to the registry. Genetic analysis can be arranged if desired. With completeness of the data, a peer-review process by pediatric radiology, possibly lung pathology, clinical and possibly genetic experts takes place in an interdisciplinary conference. A working diagnosis is established and communicated to the responsible physician via the registry and, if necessary, further discussed in case-related discussions. Assistance in entering the data is provided by the registry. Follow-ups are performed annually, and all registered physicians are invited to regular, web-based case discussions. Significant questions are answered in scientific projects and jointly published (>110 publications to date). CONCLUSIONS: Due to voluntary additional work of all participants beyond clinical routine, more than 1000 children with rare lung diseases have been included in the registry with biobank to date. A deeper understanding of the clinical courses of large cohorts of rare diseases and the initial description of new entities contributes to better care for these children.

ABCA3-related interstitial lung disease beyond infancy.

BACKGROUND: The majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year. METHOD: Over a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly. RESULTS: At the end of the observation period, median age was 6.3 years (IQR: 2.8-11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss -1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, the ABCA3 sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function. CONCLUSION: The natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

Case Report: Stüve-Wiedemann syndrome-a rare cause of persistent pulmonary hypertension of the newborn.

Introduction: Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition characterized by hypoxemia due to elevated pulmonary vascular resistance. PPHN commonly arises secondary to various underlying conditions, including infection, meconium aspiration, and respiratory distress syndrome. Management includes pulmonary vasodilators, mechanical ventilation, oxygen supplementation, vasopressors, and volume replacement. Stüve-Wiedemann syndrome (SWS), a rare genetic disorder characterized by bone dysplasia, respiratory distress, hyperthermia, and swallowing difficulties, may present with pulmonary hypertension, indicating a poor prognosis. Case description: A term female neonate presented with secondary respiratory failure and severe PPHN of unknown etiology on the second day of life, necessitating intubation. Clinical findings included facial dysmorphia, camptodactyly, skeletal anomalies, and generalized muscular hypotonia. High-frequency oscillation ventilation and surfactant administration yielded marginal improvement. On the third day of life, a severe pulmonary hypertensive crisis necessitated inhaled and systemic pulmonary vasodilators along with volume and catecholamine therapy. Whole exome sequencing revealed a homozygous mutation in the leukemia inhibitory factor receptor (LIFR) gene, consistent with Stüve-Wiedemann syndrome. Discussion/conclusion: The case underscores the importance of considering and prompting evaluation of rare genetic causes in the differential diagnosis of PPHN, especially when other abnormalities are present and conventional therapies prove inadequate. Therapeutic strategies must account for the different pathophysiology of primary PPHN including vascular remodeling, as seen in SWS, which may not respond to pulmonary vasodilators typically employed in secondary PPHN due to vasoconstriction. In this case, the patient responded well to treatment for primary PPHN, but the use of high-frequency oscillation ventilation and surfactant was not helpful.

[Special diagnostics in pediatric urology-Ultrasound, VCUG, CT and MRI : Part 1: tips for the practice]. / Spezielle Diagnostik in der Kinderurologie ­ konventionelle und spezielle Sonographie, MCU, CT und MRT : Teil 1: Tipps für die Praxis.

The diagnostics and treatment of pediatric urology patients in the clinical routine can be extremely challenging. In comparison to adult patients, congenital diseases, more time consuming examinations and limited options in addition to the parents' expectations must be taken into account in the diagnostic work up. In this first of two parts we will delve into ultrasound diagnostics as the cornerstone in the diagnostic pathway of children with hydronephrosis ans take a closer look on contrast enhanced ultrasound (CEUS). Conventional voiding cystourethrography still plays a major role in the diagnostic pathway of vesicoureteric reflux and will be treated in this article. Computed tomography should only be considered in pediatric patients in rare cases, always taking radiation into critical account. Magnetic resonance imaging provides an excellent anatomical overview without exposing the child to unnecessary radiation. This article provides an overview on the diagnostic imaging studies in pediatric urology and brings tips for the diagnostic evaluation.

[Special diagnostics in pediatric urology-Nuclear medicine diagnostics, advanced diagnostics for bladder voiding disorders and imaging diagnostics in the operating room : Tips for the practice part 2]. / Spezielle Diagnostik in der Kinderurologie ­ Nuklearmedizinische Diagnostik, weiterführende Diagnostik bei Blasenentleerungsstörungen und bildgebende Diagnostik im OP : Teil 2: Tipps für die Praxis.

The diagnostics and treatment of pediatric urology patients in the clinical routine can be extremely challenging. In contrast to adult patients, the main concerns in the diagnostics of congenital diseases are time consuming examinations and limited options in addition to the expectations of the parents. The exact knowledge of the diagnostic possibilities in association with the correct interpretation of the indications is essential. Simple processes can be much more time consuming because of a lack of compliance, especially in very young children. Sonography is considered the standard for imaging in pediatric urology. Profound knowledge of the embryonal development and also physiological processes throughout childhood contribute to making the correct diagnosis. This article deals with the possibilities of nuclear medicine diagnostics, advanced diagnostics in bladder voiding disorders and finally imaging diagnostics in the pediatric urological operating room.

Organ doses in preterm and full-term neonates and infants - a retrospective study on 1,064 chest radiographs.

BACKGROUND: Chest radiography is the most frequent X-ray examination performed in the neonatal period. However, commonly used dosimetric entities do not describe the radiation risk sufficiently. OBJECTIVE: The aim of this study was to investigate selected organ doses and total body dose of chest radiographs in preterm and full-term neonates and infants. MATERIALS AND METHODS: In this retrospective study, we evaluated 1,064 chest radiographs of 136 preterm and 305 full-term babies with respect to field size and centering. We calculated the entrance dose from the dose-area product. Upper and lower field borders referred to the corresponding vertebrae. We calculated individual organ doses of the thyroid, the breast, the liver and active bone marrow for each chest radiograph using the neonatal PCXMC program, a Monte Carlo program for calculating patient doses in medical X-ray examinations. RESULTS: The median field size of chest radiographs ranged from 90 cm2 in preterm neonates at birth to 290 cm2 in full-term infants at the age of 6 months. Median values of entrance dose varied, depending on age, from 15 µGy to 25 µGy. The median organ doses ranged 1-20 µSv for the thyroid, 3-30 µSv for the breast, 2-20 µSv for the liver and 0.5-3.5 µSv for the bone marrow in preterm and full-term neonates and infants, respectively. CONCLUSION: The analysis of chest radiographs in preterm and full-term neonates and infants revealed high variability in field size. By contrast, the entrance dose varied to a minor extent. Organ dose calculations using the PCXMC program might be a valuable tool to calculate the individual radiation risk in neonates and infants.

Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy.

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi-allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD-EU register database and an in-house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi-allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.

Successful percutaneous treatment with the Konar MF™-VSD Occluder in an infant with Abernethy syndrome-case report.

Cyanosis persisting after surgical repair of complex congenital heart disease (CHD) may be related to the underlying disease. However, extracardiac causes should be also considered. We report on a patient with heterotaxy syndrome and double outlet right ventricle, in whom postoperative cyanosis was associated with an Abernethy malformation type II causing a hepatopulmonary syndrome. Despite this complex anatomy, interventional closure of the portosystemic shunt was done with a Konar MF™-VSD Occluder. The patient recovered rapidly with relief of cyanosis within one month. This case highlights the importance of a careful diagnostic assessment in patients with complex CHD, who presents cyanoses after surgical repair. In addition, it shows the feasibility and safety of a percutaneous approach with complete closure of the vascular malformation in a patient with a complex anatomy.

FARS1-related disorders caused by bi-allelic mutations in cytosolic phenylalanyl-tRNA synthetase genes: Look beyond the lungs!

Aminoacyl-tRNA synthetases (ARSs) catalyze the first step of protein biosynthesis (canonical function) and have additional (non-canonical) functions outside of translation. Bi-allelic pathogenic variants in genes encoding ARSs are associated with various recessive mitochondrial and multisystem disorders. We describe here a multisystem clinical phenotype based on bi-allelic mutations in the two genes (FARSA, FARSB) encoding distinct subunits for tetrameric cytosolic phenylalanyl-tRNA synthetase (FARS1). Interstitial lung disease with cholesterol pneumonitis on histology emerged as an early characteristic feature and significantly determined disease burden. Additional clinical characteristics of the patients included neurological findings, liver dysfunction, and connective tissue, muscular and vascular abnormalities. Structural modeling of newly identified missense mutations in the alpha subunit of FARS1, FARSA, showed exclusive mapping to the enzyme's conserved catalytic domain. Patient-derived mutant cells displayed compromised aminoacylation activity in two cases, while remaining unaffected in another. Collectively, these findings expand current knowledge about the human ARS disease spectrum and support a loss of canonical and non-canonical function in FARS1-associated recessive disease.

Clival fractures in children: a challenge in the trauma room setting!

OBJECTIVE: A clival fracture is a rare but life-threatening traumatic brain injury in the adult and pediatric populations. To date, there are very few conclusive recommendations in the literature concerning the diagnosis and treatment of pediatric clival fractures. METHODS: In 2014 and 2015, two pediatric patients with severe blunt head trauma and clival fractures were evaluated and treated at a level I trauma center. Both cases are documented and supplemented by an extensive review of the literature focusing on the diagnostic workup, classification, and clinical course of clival fractures in children. RESULTS: The clinical course of two children (8 and 9 years old) with clival fractures in concert with other intra- and extracranial injuries was analyzed. A total of 17 papers encompassing 37 patients (age range, 1-18 years) were included for a systematic review. The literature review revealed a mortality rate of 23% in pediatric patients with a clival fracture. Over 50% of the patients presented with cranial nerve damage, and two-thirds suffered from intracranial vascular damage or intracerebral bleeding. CONCLUSIONS: Clival fractures are a very rare but severe consequence of blunt head trauma in the pediatric population and may be challenging to diagnose, especially in cases with an unfused sphenooccipital synchondrosis. Vascular damage following clival fractures appears to be as common in pediatric patients as in adults. Therefore, contrast-enhanced CT of the cervical spine and head and/or magnetic resonance angiography is strongly recommended to rule out vascular injury of the extra- and intracranial brain-supplying vessels within the trauma room setting.

One-year outcomes in a multicentre cohort study of incident rare diffuse parenchymal lung disease in children (ChILD).

We performed a prospective, observational, cohort study of children newly diagnosed with children's interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3-7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88-96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8-12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.

A Knee Size-Independent Parameter for Malalignment of the Distal Patellofemoral Joint in Children.

INTRODUCTION: Patellar instability (PI) is a common finding in children. Current parameters describing patellofemoral joint alignment do not account for knee size. Additionally, most parameters utilize joint-crossing tibiofemoral landmarks and are prone to errors. The aim of the present study was to develop a knee size-independent parameter that is suitable for pediatric or small knees and determines the malpositioning of the distal patellar tendon insertion solely utilizing tibial landmarks. METHODS: Sixty-one pediatric knees were included in the study. The tibial tubercle posterior cruciate ligament distance (TTPCL) was measured via magnetic resonance imaging (MRI). The tibial head diameter (THD) was utilized as a parameter for knee size. An index was calculated for the TTPCL and THD (TTPCL/THD). One-hundred adult knees were analyzed to correlate the data with a normalized cohort. RESULTS: The THD was significantly lower in healthy females than in males (69.3 mm ± 0.8 mm vs. 79.1 mm ± 0.7 mm; p < 0.001) and therefore was chosen to serve as a knee size parameter. However, no gender differences were found for the TTPCL/THD index in the healthy adult study cohort. The TTPCL/THD was significantly higher in adult PI patients than in the control group (0.301 ± 0.007 vs. 0.270 ± 0.007; p=0.005). This finding was repeated in the PI group when the pediatric cohort was analyzed (0.316 ± 0.008 vs. 0.288 ± 0.010; p=0.033). CONCLUSION: The TTPCL/THD index represents a novel knee size-independent measure describing malpositioning of the distal patellar tendon insertion determined solely by tibial landmarks.

Intrarenal reflux, an overlooked entity - retrospective analysis of 1,166 voiding cysturethrographies in children.

BACKGROUND: The significance of intrarenal reflux as a risk factor for renal scarring and hypertension has been discussed. Fluoroscopic detection of intrarenal reflux depends on the equipment, the training of the radiologists and the timing of spot film acquisition. OBJECTIVE: To evaluate the prevalence of intrarenal reflux and its association with age, gender, grade of vesico-uretero-renal reflux and the renal segments affected. MATERIALS AND METHODS: We retrospectively analysed 1,166 voiding cysturethrographies. Patients' ages ranged from 1 day old to 19 years old. Vesico-uretero-renal reflux was detected in 209 female and 164 male patients using a standardised technique with digital pulsed fluoroscopy. The point in time and grade of reflux were documented with spot films. All radiographs showing reflux were assessed for the occurrence of intrarenal reflux. RESULTS: Intrarenal reflux was detected in 41 of 373 (11%) patients with vesico-uretero-renal reflux. Unilateral intrarenal reflux was found in 30 patients and bilateral in 11. The left kidney was more frequently affected than the right (31 versus 21). Only patients younger than 9 years of age were affected (mean age: 1.6 years, median: 0.8 years). Intrarenal reflux was independent of gender and was most frequently observed in grade IV reflux (59.6%) and less often in grade V (23.1%) and grade III (17.3%). CONCLUSION: Intrarenal reflux in this study was detected in 11% of patients with vesico-uretero-renal reflux, predominantly with reflux grade IV and in patients younger than 4 years old.

International management platform for children's interstitial lung disease (chILD-EU).

BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.

Pott's disease: a major issue for an unaccompanied refugee minor.

The incidence of TB in children in Germany has been on a rise since 2008, especially among foreign-born individuals. With rapidly increasing numbers of refugees from the numerous areas of conflict, this increase in incidence is not expected to halt, neither in Germany nor in Europe in general. We report a case of insufficient tracking in a 16-year-old unaccompanied refugee minor from Somalia who had a positive interferon γ release assay on arrival in Germany. No actions were undertaken, until 6 months later, an X-ray showed prominent hilar enlargement. Nine  months later, the patient presented to our hospital with abdominal pain, vomiting and B symptoms. Workup revealed a paravertebral abscess due to Pott's disease, a skeletal manifestation of Mycobacterium tuberculosis disease. The patient made a full recovery after a combination therapy for a total of 9 months.

Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study.

PURPOSE: The International Neuroblastoma Response Criteria (INRC) require serial measurements of primary tumors in three dimensions, whereas the Response Evaluation Criteria in Solid Tumors (RECIST) require measurement in one dimension. This study was conducted to identify the preferred method of primary tumor response assessment for use in revised INRC. PATIENTS AND METHODS: Patients younger than 20 years with high-risk neuroblastoma were eligible if they were diagnosed between 2000 and 2012 and if three primary tumor measurements (antero-posterior, width, cranio-caudal) were recorded at least twice before resection. Responses were defined as ≥ 30% reduction in longest dimension as per RECIST, ≥ 50% reduction in volume as per INRC, or ≥ 65% reduction in volume. RESULTS: Three-year event-free survival for all patients (N = 229) was 44% and overall survival was 58%. The sensitivity of both volume response measures (ability to detect responses in patients who survived) exceeded the sensitivity of the single dimension measure, but the specificity of all response measures (ability to identify lack of response in patients who later died) was low. In multivariable analyses, none of the response measures studied was predictive of outcome, and none was predictive of the extent of resection. CONCLUSION: None of the methods of primary tumor response assessment was predictive of outcome. Measurement of three dimensions followed by calculation of resultant volume is more complex than measurement of a single dimension. Primary tumor response in children with high-risk neuroblastoma should therefore be evaluated in accordance with RECIST criteria, using the single longest dimension.

Persistent Tachypnea of Infancy. Usual and Aberrant.

RATIONALE: Persistent tachypnea of infancy (PTI) is a specific clinical entity of undefined etiology comprising the two diseases neuroendocrine cell hyperplasia of infancy (NEHI) and pulmonary interstitial glycogenosis. The outcome of typical NEHI is favorable. The outcome may be different for patients without a typical NEHI presentation, and thus a lung biopsy to differentiate the diseases is indicated. OBJECTIVES: To determine whether infants with the characteristic clinical presentation and computed tomographic (CT) imaging of NEHI (referred to as "usual PTI") have long-term outcome and biopsy findings similar to those of infants with an aberrant presentation and/or with additional localized minor CT findings (referred to as "aberrant PTI"). METHODS: In a retrospective cohort study, 89 infants with PTI were diagnosed on the basis of clinical symptoms and, if available, CT scans and lung biopsies. Long-term outcome in childhood was measured on the basis of current status. MEASUREMENTS AND MAIN RESULTS: Infants with usual PTI had the same respiratory and overall outcomes during follow-up of up to 12 years (mean, 3.8 yr) as infants who had some additional localized minor findings (aberrant PTI) visualized on CT images. Both usual and aberrant PTI had a relatively favorable prognosis, with 50% of the subjects fully recovered by age 2.6 years. None of the infants died during the study period. This was independent of the presence or absence of histological examination. CONCLUSIONS: PTI can be diagnosed on the basis of typical history taking, clinical findings, and a high-quality CT scan. Further diagnostic measures, including lung biopsies, may be limited to rare, complicated cases, reducing the need for an invasive and potentially harmful procedure.

A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy.

PURPOSE: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. METHODS: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. RESULTS: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. CONCLUSION: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.