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Pathophysiology of Sleep-Disordered Breathing in Children and Neonates
Published in Susmita Chowdhuri, M Safwan Badr, James A Rowley, Control of Breathing during Sleep, 2022
Sofia Konstantinopoulou, Ignacio E Tapia
This is a rare disorder of respiratory and autonomic regulation, usually presenting in newborns and occasionally in older children and adults due to PHOX2B gene mutation (67). The neonatal presentation is typically associated with larger polyalanine repeat mutation of the PHOX2B gene. Patients with CCHS have intact voluntary control of ventilation but lack automatic control; and hypoventilation occurs either only during sleep or while awake and asleep. Patients usually have a decreased tidal volume and respiratory rate during sleep, thus requiring ventilatory support (68, 69). Although most patients breathe adequately during wakefulness, a subset requires ventilatory support 24 hr/day. However, even those who breathe adequately awake have been shown to have mild hypoventilation in association with increased metabolic demands such as exercise (70). CCHS may be associated with Hirschsprung's disease, autonomic dysfunction (decreased heart rate, hypotension) (71), neural tumors (ganglioneuromas, ganglioneuroblastomas), swallowing dysfunction when young (72), and minor ocular abnormalities (73).
Familial Neuroblastoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The PHOX2B gene located on chromosome 4p13 encodes a master regulator of autonomic nervous system development. Germline, loss-of-function mutations in the PHOX2B gene are responsible for a smaller subset (∼10%) of familial neuroblastoma cases. Interestingly, polyalanine repeat expansion mutations (PARM, typically duplication mutations) in the second polyalanine stretch of PHOX2B exon 3 are associated with CCHS, in which neuroblastoma is occasionally present (with 1%–2% neuroblastoma risk); whereas nonpolyalanine repeat expansion mutations (NPARM, typically missense, frameshift, or truncating mutations) in PHOX2B exons 1, 2 or 3 are found in patients with both CCHS and HSCR, in which neuroblastoma occurs at increased frequency (with 45% neuroblastoma risk) (see Chapter 4 for details).
Classification of sleep disorders
Published in S.R. Pandi-Perumal, Meera Narasimhan, Milton Kramer, Sleep and Psychosomatic Medicine, 2017
Sleep-related hypoventilation disorders consist of seven disorders that meet diagnostic criteria for sleep-related hypoventilation with or without oxygen desaturation. Obesity hypoventilation is hypoventilation during wakefulness (PaCO2 >45 mmHg) in the presence of obesity (BMI >30 kg/m2). Congenital central alveolar hypoventilation syndrome is diagnosed when the sleeprelated hypoventilation is associated with the PHOX2B gene. Late-onset central hypoventilation with hypothalamic dysfunction consists of sleeprelated hypoventilation without symptoms in the first few years of life and the PHOX2B gene is not present. Idiopathic central alveolar hypoventilation consists of sleep-related hypoventilation with the presence of lung or airway disease or any other known cause. Sleep-related hypoventilation due to a medication or substance consist of sleep-related hypoventilation when a medication or substance is known to be the primary cause. Sleep-related hypoventilation due to a medical disorder consists of sleep-related hypoventilation due to a lung or airway disease, or other medical cause. Sleeprelated hypoxemia disorder is arterial oxygen saturation of ≤88% in adults or ≤90% in children for ≥5 minutes. Polysomnography is not required. Snoring and catathrenia (prolonged expiratory expiration in REM sleep) are regarded as isolated symptoms or normal variants.
Advances in the molecular biology and pathogenesis of congenital central hypoventilation syndrome—implications for new therapeutic targets
Published in Expert Opinion on Orphan Drugs, 2018
Simona Di Lascio, Roberta Benfante, Silvia Cardani, Diego Fornasari
However, our knowledge of the identity of PHOX2B targets is limited to only a handful of genes, and it is urgent to develop experimental approaches to fill this gap. In principle, two different genome-wide approaches could be used to obtain overlapping information: chromatin immunoprecipitation (ChIP) and RNA sequencing (RNA-seq). The first provides information about genes that are directly regulated by PHOX2B, whereas RNA-seq identifies the genes that are directly or indirectly regulated, including genes regulated by a transcription factor such as TLX2, whose expression is under the control of PHOX2B. A third approach (two-hybrid screening) would provide complementary information by allowing the identification of PHOX2B interactors such as co-repressors, co-activators, and chromatin modifiers, whose interactions with the mutated variants of PHOX2B are altered. The identification of PHOX2B target genes would make it possible to test commercially available or new molecules in cellular and animal models to evaluate their usefulness in CCHS.
Congenital central hypoventilation syndrome: diagnosis and management
Published in Expert Review of Respiratory Medicine, 2018
Melissa A. Maloney, Sheila S. Kun, Thomas G. Keens, Iris A. Perez
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder defined by a failure in autonomic control of breathing secondary to mutations in the paired-like homeobox (PHOX2B) gene [1–3]. Patients with CCHS demonstrate dysregulation of breathing that is most severe during sleep and do not exhibit normal physiologic responses to hypercapnia or hypoxia [1,4–7]. As of 2010, over 1000 genetically confirmed cases of CCHS have been documented worldwide with an estimated prevalence of 1 in 200,000 live births in France and 1 in 148,000 live births in Japan [1,8,9]. While the hallmark of CCHS is alveolar hypoventilation, autonomic dysfunction is manifested in numerous organ systems. Increased disease awareness and identification of the disease-defining PHOX2B gene has allowed for earlier diagnosis and intervention, allowing these patients to live into adulthood. In this review, we will discuss clinical presentation, diagnostic approach, management strategies, and current challenges in the care of CCHS patients.
The expression of PHOX2B in bone marrow and peripheral blood predicts adverse clinical outcome in non-high-risk neuroblastoma
Published in Pediatric Hematology and Oncology, 2022
Hongjun Fan, Tianyu Xing, Huimin Hong, Chao Duan, Wen Zhao, Qian Zhao, Xisi Wang, Cheng Huang, Shuai Zhu, Mei Jin, Yan Su, Chao Gao, Xiaoli Ma
The 2-year EFS and OS rates of the 132 patients were 94.7 ± 2.0%, and 97.7 ± 1.3%, respectively, with a median follow-up time of 28.5 months (range, 3–44 months). As shown in Figure 2 and 3, patients with a positive PHOX2B expression in BM and PB samples at diagnosis had lower EFS and OS rates than those with no PHOX2B expression (p < 0.001). The 2-year EFS rates were 76.9 ± 8.3% and 63.6 ± 14.5% in patients with a positive PHOX2B expression in BM and PB samples, respectively, at diagnosis. The patients with INRGSS stages M and MS, 1p LOH, and high levels of LDH, SF and NSE had significantly decreased 2-year EFS rates (p < 0.05). The expression of PHOX2B in BM and PB samples at diagnosis also affected the 2-year OS (88.5 ± 6.3% and 81.8 ± 11.6%). The 2-year OS rates were poorer in patients with high levels of LDH and SF, and 11q LOH (p < 0.05) (Table 3). Multivariate analysis showed that the positive PHOX2B expression in BM [hazard ratio (HR): 22.28, 95% confidence interval: 2.45–202.49, P = 0.006], and PB (HR: 4.41, 95% confidence interval: 1.08–18.02, P = 0.039) samples at diagnosis were both significant predictors of a low EFS. The number of event occurrences in patients with different clinical characteristics is also shown in Table 3. The details of all the 9 patients experiencing relapse or progression during the follow-up are shown in Table 4. There were 18 patients for whom the expression of PHOX2B was detected in the BM while demonstrating no evidence of involvement with neuroblastoma by BM cytology/immunocytology. The clinical characteristics of these patients are shown in Table 5. The 2-year EFS and OS of the 18 patients were both 94.4 ± 5.4%.