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Atypical presentations associated with non-polyalanine repeat PHOX2B mutations.
Am J Med Genet A. 2018 07; 176(7):1627-1631.AJ

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.

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Authors+Show Affiliations

Katwa U
Division of Pulmonology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
D'Gama AM
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Qualls AE
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Donovan LM
Division of Pulmonology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Medicine, Division of Pulmonary and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Heffernan J
Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Shi J
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
Agrawal PB
Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.

MeSH

Child, PreschoolFemaleHomeodomain ProteinsHumansHypoventilationInfant, NewbornMutationPhenotypePrognosisSleep Apnea, CentralTranscription Factors

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29704303

Citation

Katwa, Umakanth, et al. "Atypical Presentations Associated With Non-polyalanine Repeat PHOX2B Mutations." American Journal of Medical Genetics. Part A, vol. 176, no. 7, 2018, pp. 1627-1631.
Katwa U, D'Gama AM, Qualls AE, et al. Atypical presentations associated with non-polyalanine repeat PHOX2B mutations. Am J Med Genet A. 2018;176(7):1627-1631.
Katwa, U., D'Gama, A. M., Qualls, A. E., Donovan, L. M., Heffernan, J., Shi, J., & Agrawal, P. B. (2018). Atypical presentations associated with non-polyalanine repeat PHOX2B mutations. American Journal of Medical Genetics. Part A, 176(7), 1627-1631. https://doi.org/10.1002/ajmg.a.38720
Katwa U, et al. Atypical Presentations Associated With Non-polyalanine Repeat PHOX2B Mutations. Am J Med Genet A. 2018;176(7):1627-1631. PubMed PMID: 29704303.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atypical presentations associated with non-polyalanine repeat PHOX2B mutations. AU - Katwa,Umakanth, AU - D'Gama,Alissa M, AU - Qualls,Anita E, AU - Donovan,Lucas M, AU - Heffernan,Jody, AU - Shi,Jiahai, AU - Agrawal,Pankaj B, Y1 - 2018/04/28/ PY - 2017/09/26/received PY - 2018/02/26/revised PY - 2018/03/29/accepted PY - 2018/4/29/pubmed PY - 2019/5/21/medline PY - 2018/4/29/entrez KW - PHOX2B KW - congenital central hypoventilation syndrome KW - neuroblastoma KW - neurocristopathy KW - non-polyalanine repeat mutations SP - 1627 EP - 1631 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 176 IS - 7 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/29704303/Atypical_presentations_associated_with_non_polyalanine_repeat_PHOX2B_mutations_ DB - PRIME DP - Unbound Medicine ER -