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According to the U.S. Food & Drug Administration, less than 10% of these rare diseases currently have an approved treatment or therapy [2]. [...]recent development of new genetic technologies appears primed to aid in both diagnosis and treatment of rare diseases. Once the genetic underpinning of a rare disease is understood, new techniques such as gene therapy or gene editing have demonstrated success in treating or even curing certain rare disorders [7, 8–9]. [...]advances in data availability and consistent terminology will be critical to further advancing rare disease research.

Background Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands. Results Detailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands. Conclusions ROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.

Neonatal care, particularly for premature babies, is complicated by the infants' fragility and by the need for a large number of tethered sensors to be attached to their tiny bodies. Chung et al. developed a pair of sensors that only require water to adhere to the skin and allow for untethered monitoring of key vital signs (see the Perspective by Guinsburg). On-board data processing allowed for efficient wireless near-field communication using standard protocols. The absence of cables makes it easier to handle the infants and allows for skin-to-skin contact between the babies and their parents or caregivers. Science , this issue p. eaau0780 ; see also p. 924 Battery-free, skin-like sensors enable wireless, high-fidelity measurement of vital signs in fragile infants. Existing vital sign monitoring systems in the neonatal intensive care unit (NICU) require multiple wires connected to rigid sensors with strongly adherent interfaces to the skin. We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations. The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems.

The standard of clinical care in many pediatric and neonatal neurocritical care units involves continuous monitoring of cerebral hemodynamics using hard-wired devices that physically adhere to the skin and connect to base stations that commonly mount on an adjacent wall or stand. Risks of iatrogenic skin injuries associated with adhesives that bond such systems to the skin and entanglements of the patients and/or the healthcare professionals with the wires can impede clinical procedures and natural movements that are critical to the care, development, and recovery of pediatric patients. This paper presents a wireless, miniaturized, and mechanically soft, flexible device that supports measurements quantitatively comparable to existing clinical standards. The system features a multiphotodiode array and pair of light-emitting diodes for simultaneous monitoring of systemic and cerebral hemodynamics, with ability to measure cerebral oxygenation, heart rate, peripheral oxygenation, and potentially cerebral pulse pressure and vascular tone, through the utilization of multiwavelength reflectance-mode photoplethysmography and functional near-infrared spectroscopy. Monte Carlo optical simulations define the tissue-probing depths for source–detector distances and operating wavelengths of these systems using magnetic resonance images of the head of a representative pediatric patient to define the relevant geometries. Clinical studies on pediatric subjects with and without congenital central hypoventilation syndrome validate the feasibility for using this system in operating hospitals and define its advantages relative to established technologies. This platformhas the potential to substantially enhance the quality of pediatric care across a wide range of conditions and use scenarios, not only in advanced hospital settings but also in clinics of lower- and middle-income countries.

There is discussion of a neurocristopathy basis (CCHS and ROHHAD), obesity-related conditions (PWS and ROHHAD), DNA methylation and parental expression of critically imprinted genes (RS and PWS), highly conserved genes that are transcription factors or have a key role in transcription (CCHS and RS), evolving phenotype with advancing age (ROHHAD) vs. fairly stable phenotypes, and more. [...]after decades of research, two of these rare conditions have recently gained approval for medications that effectively modify the clinical phenotype to decrease disease burden (FD and RS). Taken together, this special edition of Clinical Autonomic Research should inspire deep thoughts into the autonomic nervous system in health and disease, and how each of us might recognize how dysfunction of this system that functions automatically and impacts virtually all organ systems to sustain life and optimize health is itself a biomarker that requires recognition as an integral consideration in the care of all pediatric patients.

The “bedside-to-bench” Congenital Central Hypoventilation Syndrome (CCHS) research journey has led to increased phenotypic-genotypic knowledge regarding autonomic nervous system (ANS) regulation, and improved clinical outcomes. CCHS is a neurocristopathy characterized by hypoventilation and ANS dysregulation. Initially described in 1970, timely diagnosis and treatment remained problematic until the first large cohort report (1992), delineating clinical presentation and treatment options. A central role of ANS dysregulation (2001) emerged, precipitating evaluation of genes critical to ANS development, and subsequent 2003 identification of Paired-Like Homeobox 2B ( PHOX2B ) as the disease-defining gene for CCHS. This breakthrough engendered clinical genetic testing, making diagnosis exact and early tracheostomy/artificial ventilation feasible. PHOX2B genotype-CCHS phenotype relationships were elucidated, informing early recognition and timely treatment for phenotypic manifestations including Hirschsprung disease, prolonged sinus pauses, and neural crest tumors. Simultaneously, cellular models of CCHS-causing PHOX2B mutations were developed to delineate molecular mechanisms. In addition to new insights regarding genetics and neurobiology of autonomic control overall, new knowledge gained has enabled physicians to anticipate and delineate the full clinical CCHS phenotype and initiate timely effective management. In summary, from an initial guarantee of early mortality or severe neurologic morbidity in survivors, CCHS children can now be diagnosed early and managed effectively, achieving dramatically improved quality of life as adults.

Disorders of autonomic functions are typically characterized by disturbances in multiple organ systems. These disturbances are often comorbidities of common and rare diseases, such as epilepsy, sleep apnea, Rett syndrome, congenital heart disease or mitochondrial diseases. Characteristic of many autonomic disorders is the association with intermittent hypoxia and oxidative stress, which can cause or exaggerate a variety of other autonomic dysfunctions, making the treatment and management of these syndromes very complex. In this review we discuss the cellular mechanisms by which intermittent hypoxia can trigger a cascade of molecular, cellular and network events that result in the dysregulation of multiple organ systems. We also describe the importance of computational approaches, artificial intelligence and the analysis of big data to better characterize and recognize the interconnectedness of the various autonomic and non-autonomic symptoms. These techniques can lead to a better understanding of the progression of autonomic disorders, ultimately resulting in better care and management.

Background In extremely preterm infants, persistence of cardioventilatory events is associated with long-term morbidity. Therefore, the objective was to characterize physiologic growth curves of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants during the first few months of life. Methods The Prematurity-Related Ventilatory Control study included 717 preterm infants <29 weeks gestation. Waveforms were downloaded from bedside monitors with a novel sharing analytics strategy utilized to run software locally, with summary data sent to the Data Coordinating Center for compilation. Results Apnea, periodic breathing, and intermittent hypoxemia events rose from day 3 of life then fell to near-resolution by 8–12 weeks of age. Apnea/intermittent hypoxemia were inversely correlated with gestational age, peaking at 3–4 weeks of age. Periodic breathing was positively correlated with gestational age peaking at 31–33 weeks postmenstrual age. Females had more periodic breathing but less intermittent hypoxemia/bradycardia. White infants had more apnea/periodic breathing/intermittent hypoxemia. Infants never receiving mechanical ventilation followed similar postnatal trajectories but with less apnea and intermittent hypoxemia, and more periodic breathing. Conclusions Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Impact Physiologic curves of cardiorespiratory events in extremely preterm-born infants offer (1) objective measures to assess individual patient courses and (2) guides for research into control of ventilation, biomarkers and outcomes. Presented are updated maturational trajectories of apnea, periodic breathing, intermittent hypoxemia, and bradycardia in 717 infants born <29 weeks gestation from the multi-site NHLBI-funded Pre-Vent study. Cardioventilatory events peak during the first month of life but the actual postnatal trajectory is dependent on the type of event, race, sex and use of mechanical ventilation. Different time courses for apnea and periodic breathing suggest different maturational mechanisms.

Purpose CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype–phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype–phenotype correlations that will guide anticipatory management. Methods An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher’s exact test; further pairwise comparisons were made on significant results. Results Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function. Conclusion This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype–phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.

Background Congenital Central Hypoventilation Syndrome (CCHS) has devastating consequences if not diagnosed promptly. Despite identification of the disease-defining gene PHOX2B and a facial phenotype, CCHS remains underdiagnosed. This study aimed to incorporate automated techniques on facial photos to screen for CCHS in a diverse pediatric cohort to improve early case identification and assess a facial phenotype– PHOX2B genotype relationship. Methods Facial photos of children and young adults with CCHS were control-matched by age, sex, race/ethnicity. After validating landmarks, principal component analysis (PCA) was applied with logistic regression (LR) for feature attribution and machine learning models for subject classification and assessment by PHOX2B pathovariant. Results Gradient-based feature attribution confirmed a subtle facial phenotype and models were successful in classifying CCHS: neural network performed best (median sensitivity 90% (IQR 84%, 95%)) on 179 clinical photos (versus LR and XGBoost, both 85% (IQR 75–76%, 90%)). Outcomes were comparable stratified by PHOX2B genotype and with the addition of publicly available CCHS photos ( n  = 104) using PCA and LR (sensitivity 83–89% (IQR 67–76%, 92–100%). Conclusions Utilizing facial features, findings suggest an automated, accessible classifier may be used to screen for CCHS in children with the phenotype and support providers to seek PHOX2B testing to improve the diagnostics. Impact Facial landmarking and principal component analysis on a diverse pediatric and young adult cohort with PHOX2B pathovariants delineated a distinct, subtle CCHS facial phenotype. Automated, low-cost machine learning models can detect a CCHS facial phenotype with a high sensitivity in screening to ultimately refer for disease-defining PHOX2B testing, potentially addressing gaps in disease underdiagnosis and allow for critical, timely intervention.