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

Abstract

Examine the genotype-phenotype relationship in Japanese congenital central hypoventilation syndrome (CCHS) patients and estimate the incidence of CCHS in Japan. Subjects were 92 Japanese patients with PHOX2B mutations; 19 cases carried 25 polyalanine repeat expansion mutations (PARMs); 67 cases carried 26 or more PARMs; and 6 had non-PARMs (NPARMs). We collected clinical data in all patients and estimated the development or intelligent quotients only in the patients carrying 25 PARM. The estimated incidence of CCHS was greater than one case per 148 000 births. Polyhydramnios was observed in three cases. Twelve infants exhibited depressed respiration at birth. In 19 cases carrying 25 PARM, the male-to-female ratio was ~3, no cases had Hirschsprung disease; 7 cases (37%) developed hypoventilation after the neonatal period, and 8 cases (42%) had mental retardation. In other 73 cases carrying 26 or more PARMs or NPARMs, male-to-female ratio was equal; patients frequently complicated with Hirschsprung disease and constipation, and all patients presented with hypoventilation in the neonatal period. Clinical symptoms were severe in most patients carrying long PARMs and NPARMs. In 25 PARM, additional genetic and/or epigenetic factors were required for CCHS development and male sex is likely a predisposing factor. The patients carrying 25 PARM frequently had mental retardation likely because they were not able to receive appropriate ventilation support following a definitive diagnosis owing to subtle and or irregular hypoventilation. Molecular diagnosis provides a definitive diagnosis and enables to receive appropriate ventilator support.

Congenital central hypoventilation syndrome: Broader cognitive deficits revealed by parent controls

“…Neuroimaging studies of adolescents with CCHS have provided clear evidence of structural and functional abnormalities of brain systems involved in autonomic regulation that might result in altered neurological outcomes . A report of Japanese infants with CCHS who had delayed diagnosis and management with supplemental oxygen rather than tracheostomy/artificial ventilation in the newborn period indicates the impact of postnatal physiologic compromise on neurocognitive outcome especially when compared with our report in preschool children with CCHS…”

“…It could also be that the quality of overall clinical management provided to patients in our sample was sufficiently high to prevent these factors from causing adverse cognitive effects. Indeed, a recent report of adverse neurocognitive outcomes in a CCHS cohort lacking both early patient identification and conservative management as recommended by the ATS Statement on CCHS suggests the pivotal role of early childhood management of CCHS in optimizing cognitive outcomes …”

Congenital central hypoventilation syndrome mimicking mitochondrial disease

“…The phenotype of our patient was similar to other patients with LO‐CCHS, which was previously reported in heterozygous 24 PAR 10, 11 and some of 25 PAR 2, 18, 19, 20, 21. Her ascites, pleural effusion, hepatomegaly, as well as pulmonary hypertension, right ventricular hypertrophy, and right atrium enlargement could be explained from pulmonary and cardiac failure.…”

“…Neurocognitive impairment has been reported in patients with CCHS; however, in the patients with 20 of 25 genotypes; most are not be affected 2, 17, 22 if they received proper management and adequate brain oxygen. Most of the later‐onset patients presented after sedation or general anesthesia, or after severe respiratory infection/illness with inadequate respiratory effort as a clinical phenotype 11, 18.…”

Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene

“…1,2 ). CCHS typically presents in the newborn period as hypoventilation due to missing responses both to hypercapnia (central chemoreceptors) and hypoxia (peripheral chemoreceptors) most pronounced during sleep (ref.…”