Rare Pediatric Disorder Research Articles

Proteomic Analysis of Marinesco-Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss.

Marinesco–Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1.

Short anagen syndrome: A case series and algorithm for diagnosis

The short anagen syndrome (SAS) is a rare idiopathic pediatric disorder characterized by the short duration of the anagen phase. SAS mainly affects Caucasian children. Parents complain of their child's inability to grow long hair. Topical minoxidil may be an effective treatment for SAS; however, a slow spontaneous improvement is typical. Our aim was to collect data on out cases of SAS and create an algorithm to facilitate diagnosis of SAS. A retrospective review of 25 patients with SAS was performed within the Dermatology Department of the University of Bologna. We collected data regarding symptoms, pull test, hair card test, trichoscopy, trichogram, treatments, including biotin and minoxidil, and clinical outcome. Characteristic findings included parental reporting that the hair had not required a haircut, hair card test showing hairs with conical-shaped tips, and hair shafts of different diameters, with more 10%-20% of hair shafts less than 60μm thick on trichoscopy. Trichogram revealed an increased percentage of telogen hair with normal hair shafts and tapering ends. The mean anagen-to-telogen ratio was 66:34 (normal ratio 90:10). We developed an algorithm to facilitate the diagnosis of this rare hair disease using clinical examination and invasive and non-invasive testing to differentiate SAS from other forms of pediatric alopecia. In conclusion, the collected data of the therapy showed that biotin alone or in combination with topical minoxidil is an effective treatment for SAS.

Precision genetic cellular models identify therapies protective against ER stress

Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Pediatric Voice Disorders from the Perspective of Rare Diseases

This study aims to present rare pediatric voice disorders, which are usually reported as case reports in the literature, with their clinical features, treatment options, and prognosis, and to emphasize clinical findings that may be associated with rare diseases. The clinical records of the pediatric patients presented with dysphonia were reviewed between 2014 and 2019. The terminology "rare disease" is used to describe diseases where the average prevalence thresholds are between 40 to 50 cases/100,000 people. Age, gender, symptoms, laryngeal examination findings, histopathological results, treatment modalities and follow-up results of rare laryngeal pathologies were reviewed. 274 children were diagnosed with and treated for voice disorders at our institution. Seven patients were identified with rare laryngeal pathologies. Four patients diagnosed with lipoid proteinosis, two patients with neurofibroma and one patient with amyloidosis. One patient was known to have neurofibromatosis type-1, while the others did not have any previously diagnosed diseases, dysphonia was the initial clinical presentation. There are some clues that bring to mind rare entities. Firstly, these patients generally present with various systemic manifestations. Secondly, if there is any discrepancy between voice quality and endoscopic laryngeal examination, the diagnosis should be reconsidered. Thirdly, in the case of the prolonged dysphonia recalcitrant to treatment, the clinician should reassess the treatment or the diagnosis.

The “Eyes” Have It. Ophthalmological Findings of Bilateral Cataract in a Boy with Hypoparathyroidism

Background: Hypoparathyroidism is a relatively rare pediatric endocrine disorder in which parathyroid hormone (PTH) production is low or absent, resulting in low serum calcium and high phosphorus. In children, hypoparathyroidism is either congenital or acquired and is often associated with a genetic syndrome. Clinical manifestations include neuromuscular hyperexcitability, tetany, cardiac arrhythmias, and seizure. Radiographic findings include basal ganglia calcifications. In adult literature, ophthalmological findings of lenticular opacities and cataract have also been reported in hypoparathyroidism. Due to the rarity of this condition, there is a paucity of ophthalmological findings in children. We report a pediatric case with severe hypocalcemia, recurrent generalize seizures, intracranial calcifications and bilaterally cataracts secondary to hypoparathyroidism. Case: A 7-year-old boy, from a remote area in China, presented to a local hospital with one-year history of paresthesia in hands and feet. Initial lab evaluation revealed hypocalcemia with serum calcium of 1.76 mmol/L (2.03-2.68). Oral calcium supplement was started but symptoms progressively worsened. He was transferred to a tertiary hospital for further evaluation. On admission, physical exam was significant for positive Chvostek and Trousseau signs and lab evaluation showed serum calcium: 1.28 mmol/L (2.15-2.57), phosphorus: 4.2 mmol/L (0.95-1.75), magnesium: 0.97 mmol/L (0.73-1.06), PTH: 2.2 pg/mL (8.7-79), and 25(OH)Vit D: 97.1 mmol/L (36-126). Multiple symmetrical calcifications were found in the frontal lobe and basal ganglia. Ophthalmology consultation revealed bilateral cataracts with impaired vision. Trio whole exome sequencing with copy number variation testing reveled no pathogenic or likely pathogenic copy number and sequence level variants. He was diagnosed with idiopathic acquired hypoparathyroidism. The seizure disorder, intracranial calcification, and bilateral cataracts were attributed to severe and prolonged hypocalcemia secondary to hypoparathyroidism. He had a second episode of seizure after he was admitted, and seizure resolved after treated with midazolam and IV calcium gluconate. He was started on 1,25 (OH)2 vitamin D. Clinical symptoms resolved and he became biochemically eucalcemic with titrated therapy. Summary: Although lenticular changes have been observed in adults with hypoparathyroidism since the 1950’s, hypoparathyroidism and resulting cataract formations are relatively rare. Proposed mechanism of cataract formation in hypoparathyroidism is prolonged hypocalcemia resulting in membrane damage in the aqueous humor and subsequent sodium content increase in the lens. To our knowledge there are no prior pediatric reports of cataracts associated with hypoparathyroidism and signifies the importance of ophthalmologic referral and evaluation.

P0237 / #1004: PHYSICAL REHABILITATION DURING VA ECMO WITH CENTRAL CANNULATION AS A BRIDGE TO LUNG TRANSPLANT IN AN INFANT

Aims & Objectives: Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare pediatric disorder with a grim prognosis requiring lung transplantation for survival. Veno-Arterial Extracorporeal membrane oxygenation (VA-ECMO) support can be utilized as a bridge to transplantation, but with prolonged use of this strategy can be associated with severe deconditioning due to the need for neuromuscular blockade and long-term sedation for circuit integrity in infants. Methods: Case Report Results: We report a case of an 8-month-old male transferred to our pediatric critical care unit for pulmonary hypertension management in the setting of right ventricular dysfunction. He was found to have severe PVOD requiring extracorporeal life support as a bridge to lung transplantation. He was cannulated onto peripheral VA ECMO. Due to prolonged peripheral VA ECMO and difficulties with rehabilitation, the patient was transitioned to central cannulation with placement of Berlin cannulas in the pulmonary artery and ascending aorta. After this, his sedation was weaned and he was able to participate in physical therapy. Post-transplant, he had musculoskeletal weakness impacting his gross motor skills and functional mobility. He has received intensive physical and occupational outpatient therapy and continues to demonstrate progression. At 14-months-old, he is able to walk a few steps, grasp objects, and his truncal tone continues to improve. Conclusions: Conclusion: Central cannulation with Berlin cannulas is a novel approach that has not been described in the literature as a bridge to transplant in pediatrics. This modality allows patients to receive physical therapy while on VA ECMO with minimal risk of cannula displacement.

GRIN database: A unified and manually curated repertoire of GRIN variants.

Glutamatergic neurotransmission is crucial for brain development, wiring neuronal function, and synaptic plasticity mechanisms. Recent genetic studies showed the existence of autosomal dominant de novo GRIN gene variants associated with GRIN-related disorders (GRDs), a rare pediatric neurological disorder caused by N-methyl- d-aspartate receptor (NMDAR) dysfunction. Notwithstanding, GRIN variants identification is exponentially growing and their clinical, genetic, and functional annotations remain highly fragmented, representing a bottleneck in GRD patient's stratification. To shorten the gap between GRIN variant identification and patient stratification, we present theGRIN database (GRINdb), a publicly available, nonredundant, updated, and curated database gathering all available genetic, functional, and clinical data from more than 4000 GRIN variants. The manually curated GRINdb outputs on a web server, allowing query and retrieval of reported GRIN variants, and thus representing a fast and reliable bioinformatics resource for molecular clinical advice. Furthermore, the comprehensive mapping of GRIN variants' genetic and clinical information along NMDAR structure revealed important differences in GRIN variants' pathogenicity and clinical phenotypes, shedding light onGRIN-specific fingerprints. Overall, the GRINdb and web server is a resource for molecular stratification of GRIN variants, delivering clinical and investigational insights into GRDs. GRINdb is accessible at http://lmc.uab.es/grindb.

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Novel deletion and 2397 G>T mutations of the EXT1 gene identified in two Chinese pedigrees with hereditary multiple exostoses using exon sequencing.

BackgroundHereditary multiple exostoses (HME), a rare genetic pediatric disorder, has a peculiar pathogenic mechanism. The results of previous studies have shown that HME is associated with mutations of the EXT1 and EXT2 genes at a molecular genetics level. In our study, two families who received therapy in the Department of Orthopedics of Shanghai Children’s Hospital between June, 2017 and November, 2018 were recruited, and a mutational analysis of the EXT1 genes was conducted to further elucidating the relationship between HME and EXT1.MethodsVenous blood samples were collected from individuals with HME and their families. Exon sequencing and RT-PCR were performed to comprehensively analyze 11 exons of the EXT1 gene.ResultsThe deletion of exon 7 and the 2397 G>T mutation in exon 7 caused deletion mutation and nonsense mutation only in the HME patients. The mutations in exon 7 were tested and verified by Sanger sequencing. RT-PCR showed that the mRNA expression of EXT1 was significantly decreased in the mutation samples compared with the normal samples, which exerted a great influence on the function of EXT1.ConclusionsThis study identified new mutation sites for the pathogenesis of HME and further clarified the relationship between HME and EXT1.

DMD & BMD – CLINICAL: P.56 Disease attributes most important from a societal perspective: A case study involving Duchenne muscular dystrophy

Within value frameworks evaluating costs and benefits of new therapies, all disease and treatment attributes that society deems important should be considered. Therefore, societal views on these attributes should guide health research priorities. However, little data exist on how the general public values these different attributes. The objective was to identify the importance of attributes characterizing rare pediatric disorders from a societal perspective. Attributes were identified based on an ISPOR Task Force on US Value Assessment Frameworks and literature review.

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.

Background: Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility.Methods: After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants sequencing, which used shared initial libraries.Results: 26 pathogenic or likely pathogenic single nucleotide variants and 11 copy number variants were identified in 32 patients. 65.4% (17/26) of the SNVs were novel. The overall diagnosis rate was 53.3%. For the patients with positive results, 22 (36.7%) patients were diagnosed by whole exome sequencing and 10 (16.7%) patients were diagnosed by copy number variants sequencing. We also reviewed clinical impact on selected cases.Conclusion: We adopted an approach by performing parallel tests of trio whole exome sequencing and copy number variants sequencing with shared initial libraries. This strategy is relatively efficient and cost-effective for the diagnosis of rare pediatric disorders with high heterogeneity.

1252 Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Syndrome in a Patient on Stimulants and Normal BMI at the Time of Diagnosis: A Case Report and Literature Review

Abstract Introduction ROHHAD is a rare and complex pediatric disorder presenting in early childhood with rapid onset obesity, followed by central hypoventilation, hypothalamic dysfunction, endocrine disorders, and neurobehavioral disorders. Report of Case We present a unique case of a 6-year-old girl diagnosed with ROHHAD in the setting of normal Body Mass Index (BMI). Patient had a history of food-seeking behavior, hyperphagia, and rapid onset obesity at the age of 4 years old with subsequent development of autonomic dysregulation, hypoventilation, and neurobehavioral disorders. At the time of evaluation in Sleep Medicine Clinic for snoring and disrupted sleep the patient had been treated for hyperactivity with several appetite-suppressing stimulant medications leading to weight loss and causing her to have a normal BMI. The original polysomnogram demonstrated severe Obstructive Sleep Apnea (OSA) with obstructive Apnea-Hypopnea Index (AHI) of 11.2/hour and was concerning for hypoventilation based on the end-tidal CO2 values and morning blood gas. Despite improvement in OSA with CPAP therapy, the patient’s hypercapnia persisted. The overall clinical presentation resulted in extensive multispecialty workup, which ultimately led to the diagnosis of ROHHAD syndrome despite the patient’s normal BMI. Conclusion ROHHAD syndrome is a rare and complex pediatric disorder requiring multi-disciplinary approach, with early diagnosis and intervention being essential for management of the condition. Hypothalamic obesity is one of the diagnostic hallmarks of ROHHAD. However, about half of patients with ROHHAD develop neurobehavioral disorders, which might require treatment with stimulant medications. Literature review revealed several case reports addressing the effect of stimulant medications on hypothalamic obesity, however none focusing on patients with ROHHAD syndrome. This case raises questions about the role of appetite-suppressing medications in the management of obesity in patients with ROHHAD. It also suggests possible need for further specific workup in patients on stimulants with hypoventilation in the absence of obesity.

Epidemiology of Pediatric NMOSD in Germany and Austria.

Background: Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory demyelinating disorders of the central nervous system mainly characterized by recurrent episodes of uni- or bilateral optic neuritis (ON), transverse myelitis (TM) and brainstem syndromes (BS). The majority of adult patients has serum antibodies directed against the water channel protein aquaporin 4 (AQP4-abs). In pediatric patients, AQP4-abs are less, while antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) are more frequently detectable than in adults. Some children with NMOSD have neither AQP4- nor MOG-ab (double-seronegative).Objective: Evaluation of epidemiological data regarding incidence and prevalence of pediatric NMOSD in Germany and Austria.Methods: We recruited pediatric NMOSD patients between 1 March 2017 and 28 February 2019 with five different tools: (1) ESPED (Surveillance Unit for Rare Pediatric Disorders in Germany), (2) ESNEK (Surveillance for Rare Neurological Disorders during Childhood), (3) pediatric neurology working group within the Austrian Society of Pediatrics and Adolescent Medicine, (4) BIOMARKER Study and (5) NEMOS (Neuromyelitis optica Study Group). We requested data regarding clinical symptoms, antibody status, therapy regimen and response via a standardized questionnaire.Results: During the 2-year recruitment period, 46 (both incidental and prevalent) patients with a suspected diagnosis of NMOSD were brought to our attention. Twenty-two of these patients did not fulfill the inclusion criteria. Of the remaining 24 children, 22 had a median age at onset of 11 (range 3–17) years and 16/22 were female (72.7%) (no data in two patients). Sixteen of 24 patients were AQP4-ab positive (67%), 4/24 MOG-ab positive (16.7%), three children were double-seronegative and in one patient no antibody testing was done. We calculated an incidence rate of 0.022 per 100,000 person-years for Germany, while there was no incidental case in Austria during the recruitment period. The prevalence rate was 0.147 and 0.267 per 100,000 persons in Germany and Austria, respectively.Conclusion: Pediatric NMOSD, with and without associated antibodies, are very rare even considering the different limitations of our study. An unexpected finding was that a considerable proportion of patients was tested neither for AQP4- nor MOG-abs during diagnostic work-up, which should prompt to establish and disseminate appropriate guidelines.

Advanced therapy clinical trials for rare pediatric disorders: key challenges and lessons learned

Advanced therapy clinical trials for rare pediatric disorders: key challenges and lessons learned

Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase

WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.

A novel, hybrid, single- and multi-site clinical trial design for CLN3 disease, an ultra-rare lysosomal storage disorder.

Travel burden often substantially limits the ability of individuals to participate in clinical trials. Wide geographic dispersion of individuals with rare diseases poses an additional key challenge in the conduct of clinical trials for rare diseases. Novel technologies and methods can improve access to research by connecting participants in their homes and local communities to a distant research site. For clinical trials, however, understanding of factors important for transition from traditional multi-center trial models to local participation models is limited. We sought to test a novel, hybrid, single- and multi-site clinical trial design in the context of a trial for Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 disease), a very rare pediatric neurodegenerative disorder. We created a "hub and spoke" model for implementing a 22-week crossover clinical trial of mycophenolate compared with placebo, with two 8-week study arms. A single central site, the "hub," conducted screening, consent, drug dispensing, and tolerability and efficacy assessments. Each participant identified a clinician to serve as a collaborating "spoke" site to perform local safety monitoring. Study participants traveled to the hub at the beginning and end of each study arm, and to their individual spoke site in the intervening weeks. A total of 18 spoke sites were established for 19 enrolled study participants. One potential participant was unable to identify a collaborating local site and was thus unable to participate. Study start-up required a median 6.7 months (interquartile range = 4.6-9.2 months). Only 33.3% (n = 6 of 18) of spoke site investigators had prior clinical trial experience, thus close collaboration with respect to study startup, training, and oversight was an important requirement. All but one participant completed all study visits; no study visits were missed due to travel requirements. This study represents a step toward local trial participation for patients with rare diseases. Even in the context of close oversight, local participation models may be best suited for studies of compounds with well-understood side-effect profiles, for those with straightforward modes of administration, or for studies requiring extended follow-up periods.

Obstructive Sleep Apnea in Children With Beckwith-Wiedemann Syndrome.

Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder that includes a spectrum of clinical findings including macroglossia, especially in those with loss of methylation at the imprinting control region (IC2 LOM) on chromosome 11. Children with BWS can have very severe obstructive sleep apnea (OSA), but the prevalence of OSA in this population is poorly understood, as is the relationship between OSA and the BWS genotype/phenotype. We hypothesized that there would be a high prevalence of OSA in children with BWS, and that OSA would be more severe in children with IC2 LOM. Medical records from children evaluated from March 2015 through January 2018 were reviewed for results from polysomnography, genetic testing, and clinical assessment. A total of 26 children with BWS not previously treated for OSA underwent polysomnography, genetic testing, and clinical assessment. Median (range) age was 5 months (3 days to 33 months). Most children, 20 (76.9%), had an obstructive apnea-hypopnea index (OAHI) > 2 events/h. Median (range) OAHI was 4.4 events/h (0 to 56.1 events/h). OAHI was significantly greater in participants younger than 6 months compared with those older than 6 months (P = .008). Those with IC2 LOM did not have a greater OAHI (P = .61) than those with other genetic causes of BWS, but OAHI had a strong positive correlation with BWS clinical score (Spearman rho = .54, P = .004). There is a high prevalence of OSA in children with BWS with macroglossia. Younger children with BWS and those with more phenotypic features may be at greatest risk of OSA.

Reducing the need for general anesthesia in the repair of choanal atresia with steroid-eluting stents: A case series

IntroductionChoanal atresia (CA) is a rare pediatric congenital disorder resulting in upper airway obstruction and respiratory distress in the setting of obligate nasal breathing in infants. In 2016, a novel technique was reported in the literature utilizing drug-eluting stents to correct CA. However, 2 out of 3 patients in the study required a second operation under general anesthesia. The repeated visits to the operating room for evaluations and debridement under general anesthesia continues to be a concern for increased morbidity and mortality in infants undergoing repair of CA. MethodsA case series of three (3) patients who underwent repair of CA. Outcomes were measured by post-operative, in-office flexible nasoendoscopy. ResultsEach patient was implanted with mometasone furoate drug-eluting stents at the conclusion of the operation. Post-operatively, patients were instructed to perform nasal saline rinses 3–4 times daily. Outpatient follow-up between 6 and 17 months showed patent nasal passages on nasal endoscopy. There were no post-operative complications. Moreover, patients only underwent a single episode of general anesthesia at time of initial repair. ConclusionsIn our study, we report successful outcomes using drugeluting stents for one-stage surgical correction of CA, therefore negating the need for children to undergo multiple subjections to general anesthetics.

Modeling rare pediatric neurogenetic disorders with IPSCs

Intensive research has been performed to identify the pathological mechanisms of many pediatric neurogenetic disorders and to identify potential therapeutic targets. Although research into many pediatric neurological disorders has provided tremendous insight into the mechanisms of disease, effective treatments remain elusive. A significant impediment to progress has been a lack of thorough disease models. Transgenic/knockout animal models have been very valuable in determining the mechanisms of many neurogenetic disorders; however, these models cannot always mimic human-specific pathology and can be inadequate in representing human pathogenesis. This can be especially true for diseases of the nervous system. Alternatively, human patient-derived nervous tissue can be dangerous to acquire and difficult to propagate. The development of patient-derived induced pluripotent stem cells (IPSCs) has given researchers a fresh means of modeling these disorders with renewable human cells that can be used to generate neurons and glia. IPSCs are somatic cells that are reprogrammed back to a pluripotent stage, which can provide an unlimited source of human cells possessing patient-specific genetic mutations. Their potential to be differentiated into any cell type enables them to be a flexible platform to investigate neurogenetic disease. Of course, efficient methods for differentiating IPSCs into homogeneous populations of somatic cells must be established to provide the “disease-in-a-dish” systems. We will discuss the current methods for generating IPSC-derived neural cells to model pediatric neurogenetic disorders, as well as provide examples of the disorders that have been studied that include several neurodevelopmental and neurodegenerative disorders (Rett syndrome, spinal muscular atrophy, hereditary spastic paraplegias, and leukodystrophies). In addition, we provide examples on how patient-specific neural cells can be used in therapeutic development with high-throughput drug screening platforms or with correction via genome editing.

Sialidosis: A Review of Morphology and Molecular Biology of a Rare Pediatric Disorder.

Sialidosis (MIM 256550) is a rare, autosomal recessive inherited disorder, caused by α-N-acetyl neuraminidase deficiency resulting from a mutation in the neuraminidase gene (NEU1), located on 6p21.33. This genetic alteration leads to abnormal intracellular accumulation as well as urinary excretion of sialyloligosaccharides. A definitive diagnosis is made after the identification of a mutation in the NEU1 gene. So far, 40 mutations of NEU1 have been reported. An association exists between the impact of the individual mutations and the severity of clinical presentation of sialidosis. According to the clinical symptoms, sialidosis has been divided into two subtypes with different ages of onset and severity, including sialidosis type I (normomorphic or mild form) and sialidosis type II (dysmorphic or severe form). Sialidosis II is further subdivided into (i) congenital; (ii) infantile; and (iii) juvenile. Despite being uncommon, sialidosis has enormous clinical relevance due to its debilitating character. A complete understanding of the underlying pathology remains a challenge, which in turn limits the development of effective therapeutic strategies. Furthermore, in the last few years, some atypical cases of sialidosis have been reported as well. We herein attempt to combine and discuss the underlying molecular biology, the clinical features, and the morphological patterns of sialidosis type I and II.