Urinary Biomarkers as a Proxy for Congenital Central Hypoventilation Syndrome Patient Follow-Up
Marta PeruzziMatteo RamazzottiRoberta DamianoMarzia VasarriGiancarlo la MarcaCinzia ArzilliRaffaele PiumelliNiccolò NassiDonatella Degl’Innocenti
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Abstract:
Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system and in particular of the respiratory control during sleep. No drug therapy is, to date, available; therefore, the survival of these patients depends on lifelong ventilatory support during sleep. Reactive oxygen species (ROS)-induced oxidative stress is a recognized risk factor involved in the pathogenesis of several chronic diseases. Therefore, monitoring systemic oxidative stress could provide important insights into CCHS outcomes. Because ROS-induced oxidative products are excreted as stable metabolites in urine, we performed an HPLC-MS/MS analysis for the quantitative determination of the three main representative oxidative biomarkers (i.e., diY, MDA, and 8-OHdG) in the urine of CCHS patients. Higher levels of urinary MDA were found in CCHS patients compared with age-matched control subjects. The noteworthy finding is the identification of urinary MDA as relevant biomarker of systemic oxidative status in CCHS patients. This study is a concise and smart communication about the impact that oxidative stress has in CCHS, and suggests the monitoring of urinary MDA levels as a useful tool for the management of these patients.Keywords:
Pathogenesis
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by ventilatory insensitivity to hypercapnia and hypoxemia during sleep and/or wakefulness presenting in infancy, childhood or adulthood.Paired-like homeobox 2B (PHOX2B) is the disease-defining gene for CCHS, which includes 2 mutation types, polyalanine repeat expansion mutation(PARM) and non- PARM.The CCHS-phenotype is associated with PHOX2B genotype.Children with CCHS typically have normal breathing when awake, while have progressive shallow breathing, cyanosis, hypercapnia and hypoxemia when asleep, but they don′t response with respiratory effort.CCHS patients mainly present at birth, some may present in adult years.CCHS is also associated with generalized dysfunction of the autonomic nervous system, and Hirschsprung disease and tumors of neural crest origin are associated with the disease.Non-invasive ventilation is an effective treatment and it can increase the quality of life for CCHS patient.
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Congenital central hypoventilation syndrome; Infant; Paired-like homeobox 2B
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Congenital central hypoventilation syndrome (CCHS) is a rare condition caused by pathogenic variants of the
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Congenital central hypoventilation syndrome (CCHS) is a disorder of the autonomic nervous system characterized by a decreased response to hypercarbia. CCHS is frequently associated with congenital megacolon; the combination is called Haddad syndrome. CCHS is associated with dysfunction in respiratory features of the autonomic nervous system and with other disorders, including facial deformities, cardiovascular symptoms, and tumors. Patients with CCHS frequently have a mutation in the homeobox protein 2b (PHOX2B) gene. Most mutations involve heterozygous expansion of alanine repeats (GCN). Interestingly, a higher polyalanine repeat number is associated with a more severe clinical phenotype. To clarify the role of PHOX2B in disease pathogenesis, we introduce and review the clinical and molecular features of CCHS and Haddad syndrome.
Megacolon
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Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease characterized by autonomic nervous system dysregulation. Central hypoventilation is the most prominent and clinically important presentation. CCHS is caused by mutations in paired‐like homeobox 2b ( PHOX2B ) and is inherited in an autosomal dominant pattern. A co‐occurrence of two asymptomatic PHOX2B variants with a classical CCHS presentation highlights the importance of clinical PHOX2B testing in parents and family members of all CCHS probands. Despite being an autosomal dominant disease, once a polyalanine repeat expansion mutation has been identified, sequencing of the other allele should also be considered.
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Congenital central hypoventilation syndrome (CCHS), a rare disorder typically presenting in the newborn period, results from PHOX2B polyalanine repeat mutations in over 90% of cases. It is characterized by alveolar hypoventilation, symptoms of autonomic nervous system dysregulation, and in a subset of cases Hirschsprung’s disease and later tumors of neural crest origin. We describe a preterm infant with severe phenotype of CCHS and hyperinsulinism. A novel de novo heterozygote missence mutation (Gly68Cys) in the PHOX2B gene could be identified. Based on the observation of three patients presenting with the combination of congenital hyperinsulinism and CCHS, hyperinsulinism might represent an additional clinical feature of CCHS.
Congenital hyperinsulinism
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Abstract: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system (ANS) and respiratory control. This disorder, formerly referred to as Ondine's curse, is due to a mutation in the PHOX2B gene that affects the development of the neural crest cells. CCHS has an autosomal dominant pattern of inheritance. Majority of the patients have a polyalanine repeat mutation (PARM) of the PHOX2B , while a small group has non-PARM (NPARM). Knowledge of the patient's PHOX2B gene mutation helps predict a patient's clinical presentation and outcome and aids in anticipatory management of the respiratory and ANS dysfunction. Keywords: diaphragm pacing, noninvasive positive pressure ventilation, genetic counseling, genetic testing, CCHS, PHOX2B, congenital central hypoventilation syndrome
Genetic disorder
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Congenital hyperinsulinism
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