Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine

@article{WeeseMayer2009CongenitalCH,
  title={Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine},
  author={Debra E. Weese-Mayer and Casey M. Rand and Elizabeth M Berry-Kravis and Larry Jennings and Darius A. Loghmanee and Pallavi P. Patwari and Isabella Ceccherini},
  journal={Pediatric Pulmonology},
  year={2009},
  volume={44}
}
The modern story of CCHS began in 1970 with the first description by Mellins et al., came most visibly to the public eye with the ATS Statement in 1999, and continues with increasingly fast paced advances in genetics. Affected individuals have diffuse autonomic nervous system dysregulation (ANSD). The paired‐like homeobox gene PHOX2B is the disease‐defining gene for CCHS; a mutation in the PHOX2B gene is requisite to the diagnosis of CCHS. Approximately 90% of individuals with the CCHS… 
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Congenital Central Hypoventilation Syndrome (CCHS) and PHOX2B Mutations
PHOX2B mutations in patients with Ondine–Hirschsprung disease and a review of the literature
TLDR
Two unrelated Korean patients with Ondine–Hirschsprung disease were diagnosed and the patient's clinical manifestations were apnea and cyanosis requiring immediate endotracheal intubation, recurrent hypoventilation with hypercapnia, hypoxia after ventilator removal, and abdominal distension since birth.
Two novel mutations in exon 3 of PHOX2B gene: think about congenital central hypoventilation syndrome in patients with Hirschsprung disease
TLDR
Three patients affected by CCHS for which two novel mutations on exon 3 of PHOX2B gene were detected are described and the description of these novel mutations and related clinical phenotypes allows to expand the knowledge into NPARM spectrum.
Genetic diseases: congenital central hypoventilation, Rett, and Prader-Willi syndromes.
  • J. Gallego
  • Medicine, Biology
    Comprehensive Physiology
  • 2012
TLDR
Current knowledge on three rare genetic disorders of respiratory control, congenital central hypoventilation syndrome (CCHS), Rett syndrome (RTT), and Prader-Willi syndrome is summarized, with special emphasis on the associated brain abnormalities.
An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management.
TLDR
The importance of PHOX2B testing in diagnosing and treating patients with CCHS is demonstrated and a review of pertinent literature allowed for the development of a document that summarizes recent advances in understanding CCHs and expert interpretation of the evidence for management of affected patients.
Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation
TLDR
A greater awareness is required to diagnose late-onset CCHS and follow-up and ventilator support adjustment prevent serious hypoxia and hypercapnia, which impair cardiovascular and neurocognitive functions.
Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series
TLDR
The case of a family with nonpolyalanine repeat mutations that uncharacteristically has many individuals who were mildly symptomatic and only diagnosed after genetic testing is reported, highlighting the highly variable clinical presentation of this condition and the need for clinicians to remain vigilant.
How the Management of Children With Congenital Central Hypoventilation Syndrome Has Changed Over Time: Two Decades of Experience From an Italian Center
TLDR
Although invasive ventilation is often required by patients with severe genotype/phenotype, gradual acquisition of specific skills in the management of patients with CCHS and technological improvements in mechanical ventilation allowed us to improve the therapeutic approach in this population.
Heterozygous 24‐polyalanine repeats in the PHOX2B gene with different manifestations across three generations
TLDR
These findings add to the accumulating evidence that the 24‐polyalanine repeat in the PHOX2B is a disease‐causing mutation and careful monitoring after anesthesia, sedation, or respiratory illnesses should be exercised when evaluating asymptomatic family members with this genotype.
American Thoracic Society Documents An Official ATS Clinical Policy Statement : Congenital Central Hypoventilation Syndrome Genetic Basis , Diagnosis , and Management
TLDR
The importance of PHOX2B testing in diagnosing and treating patients with CCHS is demonstrated and the expert interpretation of the evidence for management of affected patients is provided to provide an update on recommendations for diagnosis and treatment.
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References

SHOWING 1-10 OF 118 REFERENCES
Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b
Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970. A genetic basis…
Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype.
TLDR
These data suggest that nonpolyalanine repeat mutations produce more severe disruption of PHOX2B function and patients carrying these mutations should be evaluated for HSCR and neural crest tumors.
Molecular analysis of congenital central hypoventilation syndrome
TLDR
The prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS is confirmed and the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.
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
TLDR
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.
PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome.
TLDR
Analysis of genotype-phenotype interactions strongly supports the contention that patients with CCHS who develop malignant TSNS will harbor either a missense or a frameshift heterozygous mutation of the PHOX2B gene, highlighting the link between congenital malformations and tumor predisposition when a master gene in development is mutated.
Mutational analysis of the RNX gene in congenital central hypoventilation syndrome.
TLDR
Mutation screening of the RNX gene in a set of 13 patients affected with CCHS concluded that RNX, and presumably its expression, are not altered in the authors' index cases of CCHs.
Idiopathic congenital central hypoventilation syndrome: evaluation of brain-derived neurotrophic factor genomic DNA sequence variation.
TLDR
A genetic basis for CCHS is supported, though mutations of BDNF are not consistent in this disorder, because of altered respiratory control in the BDNF knock-out mouse model and localization to the enteric nervous system in human tissue.
Congenital central hypoventilation syndrome associated with Hirschsprung's disease: mutation analysis of the RET and endothelin-signaling pathways.
  • T. Sakai, A. Wakizaka, Y. Nirasawa
  • Medicine
    European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery ... [et al] = Zeitschrift fur Kinderchirurgie
  • 2001
TLDR
Both the RET and EDNRB may play important roles in the modulation of neurocristopathies; however, further systemic studies in a large population of patients and control subjects are necessary for elucidating the pathogenesis of this disorder.
PHOX2B germline and somatic mutations in late-onset central hypoventilation syndrome.
TLDR
Data indicate that PHOX2B gene mutations should be systematically examined in any adult with unexplained central hypoventilation and raise the question of follow-up for apparently healthy parents found to harbor a somatic mosaic for the PHOx2B mutation identified in their child.
Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients
TLDR
The apparent functional defect possibly stems from an abnormal migration or differentiation of neural crest derived cells into the autonomic ventilatory control system and may be regarded as a feature of complex neurocristopathies, as confirmed by the observation of a combination of CCHS and other neuroc Cristopathies.
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