PHOX2B mutations in patients with Ondine–Hirschsprung disease and a review of the literature

Abstract

Congenital central hypoventilation syndrome (CCHS), also known as Ondine's curse, is characterized by idiopathic failure of autonomic breathing and is often associated with neurocristopathies such as Hirschsprung disease (HSCR). CCHS is caused by mutations in the paired-like homeobox 2B (PHOX2B) gene, often manifest as polyalanine repeat expansions. Herein, we report the cases of two unrelated Korean patients with Ondine-Hirschsprung disease. 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. Intestinal biopsies were performed and the absence of ganglion cells in the colon was consistent with HSCR. We performed direct sequencing analysis in the PHOX2B and RET genes and fluorescence polymerase chain reaction in order to determine the polyalanine tract expansion in exon 3 of the PHOX2B gene. Expansion mutations were detected in both patients; one had 20/24 repeats and the other had 20/27 repeats. The 20/24 genotype has not been previously described in severe CCHS phenotypes and associated HSCR. We believe that the information in this report will improve our understanding of the phenotypic and genotypic heterogeneities of CCHS and HSCR.

Heterozygous 24-polyalanine repeats in the PHOX2B gene with different manifestations across three generations

“…The third report is of a full‐term newborn with a 20/24 genotype who had apnea and cyanosis immediately after birth. This infant, with associated Hirschsprung disease, failed extubation because of apnea episodes while asleep, and eventually required tracheostomy and mechanical ventilation . Even though this baby had a severe presentation, complete sequencing of the PHOX2B gene detected no additional non‐polyalanine repeat expansion mutations (NPARMs) .…”

“…Patients with 20/25 genotype have milder hypoventilation and usually require ventilatory support only at night, while individuals with 20/26 to 20/33 often require daytime support . The 20/24 and 20/25 genotypes may be “presymptomatic,” with late‐onset during childhood or adulthood, often after a triggering event (i.e., anesthesia, sedation, and respiratory illness) …”

“…Although CCHS is usually diagnosed during the newborn period, later‐onset CCHS has been reported with the 20/25 genotype and rarely with the 24‐alanine repeat expansion. There are two published reports of the 20/24 genotype and one of 24/24 genotype …”

Molecular genetics of congenital central hypoventilation syndrome and Haddad syndrome

“…2). In Korea, there are few reports describing CCHS and Haddad syndrome [11,[17][18][19]. Further data on patients with CCHS and Haddad syndrome in Korea should be gathered.…”

“…The combination is referred to as Haddad syndrome In Korea, Ahn et al [15] reported the first case of CCHS in 1993. Several additional cases have been reported to date [11,[16][17][18][19]. With early diagnosis and immediate intervention, the prognosis of CCHS patients has improved in the last decade.…”