Two novel mutations in exon 3 of PHOX2B gene: think about congenital central hypoventilation syndrome in patients with Hirschsprung disease

Maria Giovanna Paglietti,Federica Porcaro,Claudio Cherchi,Renato Cutrera,Francesca Petreschi,Alessandra Schiavino,Emanuele Agolini,Antonio Novelli

doi:10.1186/s13052-019-0636-8

Abstract

BackgroundCongenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation increasing during sleep and affected patients are unable to perceive and respond to hypercarbia with increased ventilation and arousal during sleep. PHOX2B gene mutations are considered as responsible for CCHS. Most of patients with CCHS are heterozygous for polyalanine expansion mutations (PARMs) in exon 3, but 10% of patients with classic CCHS are heterozygous for non-polyalanine expansion mutations (NPARMs) of the PHOX2B gene.MethodsData are collected on 3 patients affected by CCHS who referred to the Paediatric Pulmonology Unit of Bambino Gesù Children’s Hospital (Rome, Italy) for a multidisciplinary follow-up program between 2000 and 2017.ResultsWe describe three cases of patients affected by CCHS for which two novel mutations on exon 3 of PHOX2B gene were detected.ConclusionsThe description of these novel mutations and related clinical phenotypes allows to expand the knowledge into NPARM spectrum. Since the presence of Hirschsprung disease is related to NPARMs and the number of alanine repeats, we suggest performing CCHS genetic investigation and periodical assessment also in patients without a clear history of CCHS but affected by Hirschsprung disease.Trial registrationData are retrospectively collected.

Highlights

Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder characterized by autonomic dysregulation and alveolar hypoventilation often requiring lifelong ventilatory assistance
The remaining 10% of patients with classic CCHS are heterozygous for non-polyalanine expansion mutations (NPARMs) founded at the end of exon 2 or in exon 3 of the PHOX2B gene
The purpose of our study is to describe two novel mutations on exon 3 of PHOX2B gene expanding the knowledge into Non-polyalanine repeat expansions mutations (NPARMs) spectrum

Summary

Introduction

Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder characterized by autonomic dysregulation and alveolar hypoventilation often requiring lifelong ventilatory assistance. PHOX2B gene mutations are considered as responsible for CCHS [2] and over 1000 cases of PHOX2B mutation-confirmed CCHS are reported [2]. The normal genotype of PHOX2B gene is reported as 20/20 polyalanine repeat numbers. It encodes a transcription factor responsible for the regulation of genes involved in the development of the autonomic nervous system [4]. Over 90% of CCHS cases are heterozygous for polyalanine expansion mutations (PARMs) in exon 3 of PHOX2B gene producing genotypes of 20/24 to 20/33 [5]. Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation increasing during sleep and affected patients are unable to perceive and respond to hypercarbia with increased ventilation and arousal during sleep. Most of patients with CCHS are heterozygous for polyalanine expansion mutations (PARMs) in exon 3, but 10% of patients with classic CCHS are heterozygous for non-polyalanine expansion mutations (NPARMs) of the PHOX2B gene

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