Ayako Sasaki1, Yumiko Kishikawa1, Reisuke Imaji2, Yu Fukushima3, Yukiko Nakamura4, Yutaka Nishimura5, Megumi Yamada6, Yoichi Mino7, Tetsuo Mitsui1, Kiyoshi Hayasaka1,8. 1. Department of Pediatrics, Yamagata University School of Medicine, Yamagata City, Japan. 2. Department of Pediatric Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan. 3. Division of Neonatology, Nagano Children's Hospital, Azumino, Nagano, Japan. 4. Department of Pediatrics, Kyorin University, Tokyo, Japan. 5. Division of Neonatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan. 6. Division of Neonatology, Saitama City Hospital, Saitama, Japan. 7. Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan. 8. Department of Pediatrics, Miyukikai Hospital, Kaminoyama, Yamagata, Japan.
Abstract
BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is caused by mutation of paird-like homeobox 2B (PHOX2B). Approximately 90% of patients were found to carry polyalanine repeat expansion mutation (PARM), and the remaining 10% had non-PARM (NPARM). In PARM, the length of the polyalanine expansion correlates with clinical disease severity. Most patients with NPARM have hypoventilation symptoms in the neonatal period and complications of Hirschsprung disease, dysregulation of autonomic nervous system, and tumors of neural crest origin. Data on the genotype-phenotype association may contribute to the clinical management of the disease. METHODS: We studied the genetic background of Japanese CCHS patients according to PHOX2B sequencing. RESULTS: Of 133 Japanese CCHS patients we identified 12 patients carrying 11 different NPARM (approx. 9% of the patients) and described the clinical manifestations in seven of them with the following novel mutations: c.941-945del5, c.678_693dup16, c.609_616del8, c.620_633del14, c.663_711del 49, c.448C>G and c.944G>C. All patients had hypoventilation in the neonatal period and also had Hirschsprung disease, with the exception of two patients carrying c.620_633del14 and c.663_711del49 mutations. The patient carrying the c.609_616del8 mutation also had a benign mediastinal tumor. CONCLUSION: Most patients carrying NPARM had severe symptoms with frequent complications, as in previous reports, and should be carefully monitored for various complications, including neural crest-derived tumor.
BACKGROUND:Congenital central hypoventilation syndrome (CCHS) is caused by mutation of paird-like homeobox 2B (PHOX2B). Approximately 90% of patients were found to carry polyalanine repeat expansion mutation (PARM), and the remaining 10% had non-PARM (NPARM). In PARM, the length of the polyalanine expansion correlates with clinical disease severity. Most patients with NPARM have hypoventilation symptoms in the neonatal period and complications of Hirschsprung disease, dysregulation of autonomic nervous system, and tumors of neural crest origin. Data on the genotype-phenotype association may contribute to the clinical management of the disease. METHODS: We studied the genetic background of Japanese CCHSpatients according to PHOX2B sequencing. RESULTS: Of 133 Japanese CCHSpatients we identified 12 patients carrying 11 different NPARM (approx. 9% of the patients) and described the clinical manifestations in seven of them with the following novel mutations: c.941-945del5, c.678_693dup16, c.609_616del8, c.620_633del14, c.663_711del 49, c.448C>G and c.944G>C. All patients had hypoventilation in the neonatal period and also had Hirschsprung disease, with the exception of two patients carrying c.620_633del14 and c.663_711del49 mutations. The patient carrying the c.609_616del8 mutation also had a benign mediastinal tumor. CONCLUSION: Most patients carrying NPARM had severe symptoms with frequent complications, as in previous reports, and should be carefully monitored for various complications, including neural crest-derived tumor.