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

Abstract

Summary. 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 phenotype will be heterozygous for a polyalanine repeat expansion mutation (PARM); the normal allele will have 20 alanines and the affected allele will have 24-33 alanines (genotypes 20/24-20/33). The remaining $10% of individuals with CCHS will have a non-PARM (NPARM), in the PHOX2B gene; these will be missense, nonsense, or frameshift. CCHS and PHOX2B are inherited in an autosomal dominant manner with a stable mutation. Approximately 8% of parents of a CCHS proband will be mosaic for the PHOX2B mutation. A growing number of cases of CCHS are identified after the newborn period, with presentation from infancy into adulthood. An improved understanding of the molecular basis of the PHOX2B mutations and of the PHOX2B genotype/CCHS phenotype relationship will allow physicians to anticipate the clinical phenotype for each affected individual. To best convey the remarkable history of CCHS, and to describe the value of recognizing CCHS as a model for translational and transitional autonomic medicine, we present this review article in the format of a chronological story, from 1970 to the present day.

Genotype–phenotype relationship in Japanese patients with congenital central hypoventilation syndrome

“…[21][22][23] Disease severity in the patients carrying PARMs increases with increasing expansion of the alanine repeats. 20,24,25 The patients carrying long PARMs or most NPARMs present with severe phenotype in neonatal period. 26 In contrast, the individuals carrying 25 PARM or 24 PARM exhibit hypoventilation during the neonatal period or after the neonatal period and occasionally have no symptoms.…”

“…19 Over 90% of patients with CCHS are heterozygous for polyalanine repeat expansion mutations (PARMs) in PHOX2B that can range from 24 to 33 alanines, and remaining 10% of patients have heterozygous non-PARMs (NPARMs) that include missense, nonsense and frameshift mutations in PHOX2B. 20 Approximately 25% of the PARMs is inherited from the parents with somatic mosaicism or constitutive mutation, and the rest of~75% is de novo during spermatogenesis. [21][22][23] Disease severity in the patients carrying PARMs increases with increasing expansion of the alanine repeats.…”

“…26 In contrast, the individuals carrying 25 PARM or 24 PARM exhibit hypoventilation during the neonatal period or after the neonatal period and occasionally have no symptoms. 2,20 Our facilities have provided a molecular diagnostic service for the majority of CCHS patients in Japan. Herein, we report an estimate of the incidence of CCHS in Japan and an analysis of the genotypephenotype relationship.…”

Presentation and Treatment of Monozygotic Twins with Congenital Central Hypoventilation Syndrome

“…More than 90% of CCHS patients have polyalanine repeat mutations (24 to 33 repeats) in the PHOX2B gene; a genotypephenotype correlation exists between the size of the PHOX2B expanded allele and the severity of symptoms (17)(18)(19). The remaining 10% of patients with CCHS are heterozygous for a nonpolyalanine repeat mutation and are at greater risk for neurocristopathies and Hirschsprung's disease (19,20).…”

Congenital Central Hypoventilation Syndrome: A Comprehensive Review and Future Challenges

“…The more prevalent polyalanine expansion is a 7-alanine expansion [22,23]. Expansions range from 15 to 39 nucleotide insertions and, as already mentioned, a genotype-phenotype correlation exists between the size of the expanded allele and the severities of the symptoms [24][25][26]. Unequal crossover has been speculated as the expanding mechanism [27].…”