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Am J Med Genet A. 2018 Jul;176(7):1627-1631. doi: 10.1002/ajmg.a.38720. Epub 2018 Apr 28.

Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.

Author information

1
Division of Pulmonology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
2
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
3
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
4
The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
5
Department of Medicine, Division of Pulmonary and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
6
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.

Abstract

Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations.

KEYWORDS:

PHOX2B; congenital central hypoventilation syndrome; neuroblastoma; neurocristopathy; non-polyalanine repeat mutations

PMID:
29704303
PMCID:
PMC6117218
DOI:
10.1002/ajmg.a.38720
[Indexed for MEDLINE]
Free PMC Article

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