ZSCAN1 Autoantibodies Are Associated with Pediatric Paraneoplastic ROHHAD.

OBJECTIVE: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), is a severe pediatric disorder of uncertain etiology resulting in hypothalamic dysfunction and frequent sudden death. Frequent co-occurrence of neuroblastic tumors have fueled suspicion of an autoimmune paraneoplastic neurological syndrome (PNS); however, specific anti-neural autoantibodies, a hallmark of PNS, have not been identified. Our objective is to determine if an autoimmune paraneoplastic etiology underlies ROHHAD. METHODS: Immunoglobulin G (IgG) from pediatric ROHHAD patients (n = 9), non-inflammatory individuals (n = 100) and relevant pediatric controls (n = 25) was screened using a programmable phage display of the human peptidome (PhIP-Seq). Putative ROHHAD-specific autoantibodies were orthogonally validated using radioactive ligand binding and cell-based assays. Expression of autoantibody targets in ROHHAD tumor and healthy brain tissue was assessed with immunohistochemistry and mass spectrometry, respectively. RESULTS: Autoantibodies to ZSCAN1 were detected in ROHHAD patients by PhIP-Seq and orthogonally validated in 7/9 ROHHAD patients and 0/125 controls using radioactive ligand binding and cell-based assays. Expression of ZSCAN1 in ROHHAD tumor and healthy human brain tissue was confirmed. INTERPRETATION: Our results support the notion that tumor-associated ROHHAD syndrome is a pediatric PNS, potentially initiated by an immune response to peripheral neuroblastic tumor. ZSCAN1 autoantibodies may aid in earlier, accurate diagnosis of ROHHAD syndrome, thus providing a means toward early detection and treatment. This work warrants follow-up studies to test sensitivity and specificity of a novel diagnostic test. Last, given the absence of the ZSCAN1 gene in rodents, our study highlights the value of human-based approaches for detecting novel PNS subtypes. ANN NEUROL 2022;92:279-291.

Sex differences in the relationship of sleep-disordered breathing and asthma control among children with severe asthma.

OBJECTIVE: Children with severe asthma are underrepresented in studies of the relationship of sleep-disordered breathing (SDB) and asthma and little is known about sex differences of these relationships. We sought to determine the relationship of SDB with asthma control and lung function among boys and girls within a pediatric severe asthma cohort. METHODS: Patients attending clinic visits at the Boston Children's Hospital Pediatric Severe Asthma Program completed the Pediatric Sleep Questionnaire (PSQ), Asthma Control Test (ACT) and Spirometry. The prevalence of SDB was defined as a PSQ score >0.33. We analyzed the association between PSQ score and both ACT score and spirometry values in mixed effect models, testing interactions for age and sex. RESULTS: Among 37 subjects, mean age was 11.8 years (4.4) and 23 (62.2%) were male, the prevalence of SDB was 43.2% (16/37). Including all 80 observations, there was a moderate negative correlation between PSQ and ACT scores (r=-0.46, p < 0.001). Multivariable linear regression models revealed a significant sex interaction with PSQ on asthma control (p = 0.003), such that for each 0.10 point increase in PSQ there was a 1.88 point decrease in ACT score for females but only 0.21 point decrease in ACT score for males. A positive PSQ screen was associated with a 9.44 point (CI 5.54, 13.34, p < 0.001) lower ACT score for females and a 3.22 point (CI 0.56, 5.88, p = 0.02) lower score for males. CONCLUSIONS: SDB is common among children with severe asthma. Among children with severe asthma, SDB in girls portends to significantly worse asthma control than boys.Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.1897838.

Early Management of Infants With Robin Sequence: An International Survey and Algorithm.

PURPOSE: There is no widely accepted protocol for management of infants with Robin sequence (RS) who present with airway obstruction and feeding impairment. The purposes of this study were to evaluate diagnostic and treatment preferences of clinicians from the United States and non-US countries and to use these data to propose an algorithm for early management of infants with RS. MATERIALS AND METHODS: A cross-sectional study was implemented using a survey, which was distributed to craniofacial surgeons and non-surgeon physicians involved in management of infants with RS. Predictor variables were nationality, specialty, and surgical volume. Outcome variables included survey responses regarding preferences for evaluation and early treatment of patients with RS. A diagnostic and early treatment algorithm was proposed based on the most common survey responses. Descriptive and analytic statistics were calculated and a P less than .05 was considered significant. RESULTS: A total of 275 responses were received and 82 were excluded, leaving a final sample of 193 participants: 155 (80%) surgeons and 38 (20%) non-surgeon physicians. Thirty-seven US states were represented by 143 (74%) respondents and 50 (26%) participants were from 19 non-US countries. There were 96 (50%) low-volume and 97 (50%) high-volume respondents. There was general agreement in methods for evaluation and early treatment among respondents; the only significant differences were 1) US surgeons operate earlier to address airway obstruction than those from other countries (P = .001), 2) high-volume providers tend to operate earlier (P = .017) and to choose mandibular distraction more frequently (P = .003) than low-volume respondents, and 3) mandibular distraction is the preferred operation in the United States, but several operations for airway improvement are used equally in non-US countries (P < .001). CONCLUSION: Despite variation in the evaluation and treatment of infants with RS, this international and multispecialty survey showed trends that could represent best practices. An algorithm based on these findings is proposed.

Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.

Asthma Management in the Era of the COVID-19 Pandemic.

Asthma is common in children and exacerbations are usually triggered by respiratory viruses. There was considerable concern about the impact of COVID-19 on children with asthma. It was expected that children with asthma would fare poorly during the pandemic. However, the reported effect of the COVID-19 pandemic on pediatric asthma including acute asthma admissions, does not appear to be significant, but this needs careful follow-up. The socioeconomic effects of the pandemic and reduced healthcare access could potentially impact on ongoing delivery of health care in chronic respiratory conditions including asthma, especially in resource-poor settings. Children with chronic asthma need to be treated as per internationally published guidelines with innovative models of disease monitoring and ongoing care during the pandemic. During the pandemic, children with acute asthma need to be managed carefully based on local guidelines and using strict infection control policies. The use of technology such as telehealth and various tools of asthma management including questionnaires and digital monitoring will play an important role in asthma management during the pandemic. Medical professionals, healthcare administrators, and governments should be sensitive to the evolving needs of the community and work closely to continue to provide services in a challenging yet unresolved pandemic.

Sleep endoscopy-directed management of Arnold-Chiari malformation: a child with persistent obstructive sleep apnea.

None: Arnold-Chiari malformations are structural defects in the base of the skull and cerebellum, when part of the cerebellar tonsils herniates through the foramen magnum into the upper spinal canal, compressing against the brainstem. This anatomical defect can be asymptomatic but often presents with symptoms such as headaches, stridor, dysphagia, and nystagmus. It also presents with a variety of sleep-related breathing disorders such as snoring, obstructive sleep apnea, central sleep apnea, bradypnea, and sleep hypoventilation. Sometimes these conditions can coexist in one patient. Although obstructive sleep apnea can be a manifestation of Arnold-Chiari malformation, identifying causality and the site of obstruction in these children can be a diagnostic challenge. We review the case of a 14-month-old male who presented with noisy breathing and obstructive sleep apnea diagnosed on sleep study that was refractory to initial upper airway surgery. Although a brain computed tomography scan done in the emergency room for altered mental status revealed a type 1 Arnold-Chiari malformation, and a flexible awake laryngoscopy was normal, subsequent drug-induced sleep endoscopy was helpful in justifying surgical decompression of the Arnold-Chiari malformation that resulted in complete resolution of the obstructive sleep apnea.

Persistent Central Apnea and Long-Term Outcome After Posterior Fossa Decompressive Surgery for Arnold Chiari Type 1 Malformation in a Pediatric Patient.

ABSTRACT: Arnold Chiari malformation (ACM) is the most common cause of central sleep apnea (CSA) in otherwise healthy children. Although there are several case reports and series reported on this topic, there are limited descriptions of the long-term course of these children after the surgical interventions. Posterior fossa decompression surgery to relieve pressure of the herniating cerebellum on the brainstem is generally thought to significantly improve CSA in most cases, however, there are very limited data on the natural course of CSA in children following decompression surgery. There may be a subset of children in whom it may take much longer for CSA to resolve, and in some it may not resolve completely. Hence, these children need to be followed closely with sleep studies to document resolution of CSA. In this case report, we describe a 10-year-old male with severe CSA who was subsequently diagnosed with type 1 ACM and underwent posterior fossa decompressive surgery. However after surgery, although there was improvement in his CSA, he still had a significant degree of residual CSA which required bilevel positive pressure therapy and took more than 7.5 years to resolve. This case report illustrates the need for close follow-up in these children and for providers to understand the natural course so they can accurately counsel families about expectations after surgical treatments.

An Unusual Case of Noisy Breathing in an Infant.

ABSTRACT: Laryngomalacia is a common cause of chronic noisy breathing that can present as stridor in infants and neonates. Mild cases of laryngomalacia are usually followed clinically and managed conservatively. However, the evaluation and diagnosis could be challenging in some patients. We present a case of a 3-week-old male infant with persistent and worsening noisy breathing, snoring, and poor weight gain, prompting further evaluation. The patient had an initial diagnosis of laryngomalacia and obstructive sleep apnea with complete resolution of loud breathing with continuous positive airway pressure. A repeated evaluation of the upper airway for further investigation led to the diagnosis of a neck mass compressing the airway. We review the clinical presentation, management, and follow-up of this patient, as well as the literature of possible etiologies. In the case of our patient, timely diagnosis and treatment had significant prognostic implications.

Asthma Management in the Era of Smart-Medicine: Devices, Gadgets, Apps and Telemedicine.

Asthma is the most common chronic pediatric condition. Effective asthma management requires a proactive and inclusive approach that controls the patient's symptoms and prevents recurrence of exacerbations. Clinicians should encourage patients to become involved in their management since self-management approaches have proven to be an effective means for chronic illness treatment. Novel forms of self-monitoring and management are technological interventions. In the last decade, novel technology has been developed and used to improve asthma control since it is a powerful agent that addresses a variety of challenges in chronic disease management such as education, communication and adherence. A myriad of technology-based strategies are available although many of these are not evidence based and further studies are needed to evaluate their efficacy in specific asthma-control endpoints. Herein, authors present a review of current and future technology-based options for asthma management and a comparison between them.

Sleep disordered breathing in Bardet-Biedl Syndrome.

INTRODUCTION: Bardet-Biedl Syndrome (BBS) is an autosomal recessive ciliopathy, and obesity is among its defining characteristics. Consequently, the incidence of sleep disordered breathing (SDB) in this population is expected to be high. Due to its relative rarity, the nature of SDB in this population is poorly described. The objective of this study was to review a single institutional experience in the assessment and management of SDB in patients with BBS. METHODS: Retrospective chart review of tertiary care, academic pediatric hospital. RESULTS: 20 patients with BBS were evaluated over a 25-year period. Median age at initial consultation was 69 months; half of these patients were referred before the diagnosis of BBS was made. Eighteen of twenty patients had symptoms of sleep-disordered breathing. Median follow-up duration was 17.5 months. A wide range of polysomnographic outcomes was observed, including obstructive apnea-hypopnea indexes of 0-195 events/hour. Patients were managed with adenotonsillectomy and/or non-invasive positive pressure ventilation. CONCLUSIONS: SDB is commonly seen in BBS. These patients should be routinely screened for OSA and if present, a polysomnogram should be obtained. Based on patient characteristics, the failure rate of primary surgical intervention, namely adenotonsillectomy, is expected to be high. Further investigation into the role of ancillary diagnostic testing is still needed.