Giancarlo Ottonello

PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome

Congenital Central Hypoventilation syndrome (CCHS (MIM 209880)) is a rare disorder, with fewer than 200 patients currently reported worldwide, characterised by absence of adequate autonomic control of respiration with decreased sensitivity to hypercapnia and hypoxia, in the absence of neuromuscular or lung disease, or an identifiable brain stem lesion.1 Children with CCHS show an adequate ventilation while awake but hypoventilate during sleep. More severely affected children hypoventilate both when awake and during sleep.1 CCHS has been reported in association with several disorders, among which aganglionic megacolon (Hirschsprung disease, HSCR) and tumours of neural crest origin, reflecting a common molecular pathogenesis sustained by defects of one or more genes that control the correct development of neural crest derived cell lineages.1–3 A genetic aetiology has long been hypothesised for CCHS based on recurrence reported in siblings, in half siblings and in affected children born to women with CCHS.2–6 More recently, a generalised autonomic nervous system (ANS) imbalance has been observed among children with CCHS and an increased incidence of ANS dysfunctions (ANSD) reported among relatives of 56 patients with CCHS, as against relatives of 56 matched controls.7 A family transmission study has shown that the risk of developing an ANSD symptom including CCHS, regarded as the most severe expression of ANS imbalance, mainly depends on the genotype at a major locus, while significant residual variants could be due to additional minor genes, modifying loci effects or environmental factors.8 Genes involved in the ANS development, like the RET proto-oncogene, its ligand GDNF , the Endothelin 3 gene, the Brain Derived Neurotrophic Factor ( BDNF ) and the RNX genes, have been tested and a few mutations found, showing no cosegregation with the disease phenotype in CCHS families.9–13 The PHOX2B gene encodes a 314 amino acids …

Home mechanical ventilation in children: retrospective survey of a pediatric population.

Background: Home care support is beneficial for children needing mechanical ventilation, when clinically stable.

Survival of Patients With Spinal Muscular Atrophy Type 1

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive disease and is usually fatal in the first year of life. METHODS: A retrospective chart review was performed of SMA1 patients and their outcomes according to the following choices: letting nature take its course (NT); tracheostomy and invasive mechanical ventilation (TV); continuous noninvasive respiratory muscle aid (NRA), including noninvasive ventilation; and mechanically assisted cough. RESULTS: Of 194 consecutively referred patients enrolled in this study (103 males, 91 females), NT, TV, and NRA were chosen for 121 (62.3%), 42 (21.7%), and 31 (16%) patients, respectively. Survival at ages 24 and 48 months was higher in TV than NRA users: 95% (95% confidence interval: 81.8%–98.8%) and 67.7% (95% confidence interval: 46.7%–82%) at age 24 months (P < .001) and 89.43% and 45% at age 48 months in the TV and NRA groups, respectively (P < .001). The choice of TV decreased from 50% (1992–1998) to 12.7% (2005–2010) (P < .005) with a nonstatistically significant increase for NT from 50% to 65%. The choice of NRA increased from 8.1% (1999–2004) to 22.7% (2005–2010) (P < .001). CONCLUSIONS: Long-term survival outcome is determined by the choice of the treatment. NRA and TV can prolong survival, with NRA showing a lower survival probability at ages 24 and 48 months.

Noninvasive ventilation and low-flow veno-venous extracorporeal carbon dioxide removal as a bridge to lung transplantation in a child with refractory hypercapnic respiratory failure due to bronchiolitis obliterans.

Objective: To report the successful management of end-stage hypercapnic respiratory failure through the association of noninvasive mechanical ventilation and a novel automated device (Decapsmart) of low-flow veno-venous extracorporeal CO2 removal. Design: Case report. Settings: Pediatric intensive care unit at a tertiary care childrens hospital. Patient: A pediatric patient affected by bronchiolitis obliterans with refractory hypercapnic respiratory failure. The patient received successful lung transplantation after respiratory support with noninvasive mechanical ventilation and a novel automated device of low-flow veno-venous extracorporeal CO2 removal. Interventions: Treatment of end-stage hypercapnic respiratory failure with the association of noninvasive ventilation and low-flow veno-venous extracorporeal CO2 removal as a bridge to lung transplantation. Measurements and Main Results: Respiratory support controlling hypercapnia, limiting volutrauma, barotraumas, and preventing the incidence of ventilator-associated pneumonia/lung colonization. Conclusion: Noninvasive mechanical ventilation and Decapsmart have proven efficacious in managing refractory hypercapnic respiratory failure in a pediatric patient awaiting lung transplantation.

Congenital central hypoventilation syndrome: genotype–phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation

Parodi S, Vollono C, Baglietto MP, Balestri M, Di Duca M, Landri PA, Ceccherini I, Ottonello G, Cilio MR. Congenital central hypoventilation syndrome: genotype–phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation.

A novel missense mutation in the PHOX2B gene is associated with late onset central hypoventilation syndrome.

We report the case of a 15‐month‐old male suffering from Late Onset Congenital Central Hypoventilation Syndrome and recto‐sigmoid Hirschsprungs disease, an association that has not been reported thus far. Nevertheless, our patient showed a missense mutation of the PHOX2B gene already known in isolated late onset central hypoventilation, resulting in a substitution of the Ala140 residue with a Glu residue (p.A140E). The present association of LO‐CHS and HSCR in a patient harboring a rare and atypical PHOX2B mutation allows to refine the mutational spectrum of this disease and suggests individualized ventilatory care along with specific surgical and oncological approaches. Pediatr Pulmonol. 2008; 43:1036–1039.

Spinal muscular atrophy type 1: Avoidance of hospitalization by respiratory muscle support

Objective: The aim of this study was to report the outcomes of an oximetry protocol using up to continuous full ventilator-setting noninvasive ventilation (NIV) and mechanically assisted coughing (MAC) to avoid episodes of acute respiratory failure and hospitalizations for children with spinal muscular atrophy type 1 under 3 yrs of age. Design: This study was a retrospective chart review of 16 patients with spinal muscular atrophy type 1 under 3 yrs of age consecutively referred for respiratory decompensations resulting in continuous NIV dependence and oxyhemoglobin desaturation. An avoided hospitalization was defined by the need for continuous NIV using high span bilevel positive airway pressure and reversal of desaturations by MAC in the home setting. The protocol included training and equipping parents to use NIV, MAC, and basic life support. Results: There were 49 acute episodes (1.20/patient per year), of which 43 met the criteria for an avoided hospitalization. Therefore, only six episodes (0.15/patient per year) required hospitalization, and four required endotracheal intubation (0.1/patient per year). Three of the four were extubated after 4, 9, and 15 days, respectively, to full NIV support and aggressive MAC. The fourth patient, for whom NIV could not be provided, underwent an emergency intubation at home and died at the age of 40 mos. Conclusions: A protocol including high span bilevel positive airway pressure along with MAC to expel airway secretions and normalize oxyhemoglobin saturation can be used by trained caregivers to avoid episodes of acute respiratory failure and hospitalization for children with spinal muscular atrophy type 1 under 3 yrs of age.

Noninvasive ventilation in a child affected by achondroplasia respiratory difficulty syndrome

Achondroplasia can result in respiratory difficulty in early infancy, from anatomical abnormalities such as mid‐facial hypoplasia and/or adenotonsillar hypertrophy, leading to obstructive apnea, or to pathophysiological changes occurring in nasopharyngeal or glossal muscle tone, related to neurological abnormalities (foramen magnum and/or hypoglossal canal problems, hydrocephalus), leading to central apnea. More often, the two respiratory components (central and obstructive) are both evident in mixed apnea. Polysomnographic recording should be used during preoperative and postoperative assessment of achondroplastic children and in the subsequent follow‐up to assess the adequacy of continuing home respiratory support, including supplemental oxygen, bilevel positive airway pressure, or assisted ventilation.

Proceedings of the fourth international conference on central hypoventilation

Central hypoventilation syndromes (CHS) are rare diseases of central autonomic respiratory control associated with autonomous nervous dysfunction. Severe central hypoventilation is the hallmark and the most life-threatening feature. CHS is a group of not-fully defined disorders. Congenital CHS (CCHS) (ORPHA661) is clinically and genetically well-characterized, with the disease-causing gene identified in 2003. CCHS presents at birth in most cases, and associated with Hirschsprung’s disease (ORPHA99803) and neural crest tumours in 20% and 5% of cases, respectively. The incidence of CCHS is estimated to be 1 of 200,000 live births in France, yet remains unknown for the rest of the world. In contrast, late-onset CHS includes a group of not yet fully delineated diseases. Overlap with CCHS is likely, as a subset of patients harbours PHOX2B mutations. Another subset of patients present with associated hypothalamic dysfunction. The number of these patients is unknown (less than 60 cases reported worldwide). Treatment of CHS is palliative using advanced techniques of ventilation support during lifetime. Research is ongoing to better understand physiopathological mechanisms and identify potential treatment pathways.The Fourth International Conference on Central Hypoventilation was organised in Warsaw, Poland, April 13–15, 2012, under the patronage of the European Agency for Health and Consumers and Public Health European Agency of European Community. The conference provided a state-of-the-art update of knowledge on all the genetic, molecular, cellular, and clinical aspects of these rare diseases.

How wide is the ocular spectrum of Delleman syndrome

We describe a patient with cerebral and cutaneous features typical of oculocerebrocutaneous syndrome. The ocular anomalies observed have not been previously reported in patients affected with this syndrome.