Late-onset congenital central hypoventilation syndrome and a rare PHOX2B gene mutation

Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Cain

Kim

Quast

et al. 2017

“…To date she is doing well developmentally, and she will continue to require close follow up in case respiratory support is needed during future respiratory illnesses. Evidence from Patient 1 and others suggest that CCHS is not always associated with a severe respiratory phenotype, and in fact can be later diagnosed in patients who are asymptomatic at birth (Cain et al, ; Lombardo et al, ; Magalhaes et al, ; Parodi et al, ; Trochet et al, ; Weese‐Mayer et al, ). For example, the majority of NPARMs reported to date are frameshift variants.…”

Section: Discussionmentioning

confidence: 99%

“…For the nonsense NPARMs reported to date, the location of the mutation appears to be associated with the phenotypic severity. Although a severe clinical presentation was reported in a patient with p.K155*, milder clinical presentations are reported for patients carrying nonsense mutations upstream of p.M18/M21, likely due to translational reinitiation at p.M18 or p.M21 (Cain et al, ; Lombardo et al, ; Magalhaes et al, ; Parodi et al, ; Trochet et al, ). In the future, additional research is needed on patients with NPARMs to further understand and characterize the variety of associated clinical presentations and disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…However, the genotype–phenotype correlation for NPARMs is not as well described. While there is evidence that NPARMs are associated with a more severe CCHS phenotype, several studies have identified novel NPARMs in CCHS patients who have a milder clinical presentation and delayed diagnosis, suggesting that NPARM‐associated phenotypes may depend on the type and location of the mutation (Cain et al, ; Lombardo et al, ; Magalhaes et al, ; Parodi et al, ; Trochet et al, ). In this clinical report, we present two patients with NPARMs who have distinct differences in phenotype severity with mild and atypical presentations.…”

Section: Introductionmentioning

confidence: 99%

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Atypical presentations associated with non‐polyalanine repeat PHOX2B mutations

Katwa

D’Gama

Qualls

et al. 2018

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.

Variable phenotype in a novel mutation in PHOX2B

Lombardo

Kramer

Cnota

et al. 2017

We evaluated a family with three siblings, two of whom ages 2 years and 19 months, had long segment colonic agangliosis and anisocoria. The mother also had anisocoria. All three affected family members were mildly dysmorphic with a flat facial profile, square appearance to the face, depressed nasal bridge, and anteverted nares. Genetic testing identified a novel heterozygous mutation, c.234C>G, resulting in a premature stop codon in exon 1 of the PHOX2B gene. Screening for neural crest tumors was performed in the siblings and to date has been negative. This family supports a strong association between non polyalanine tract mutations, autonomic dysfunction, and Hirschsprung disease, but suggests mutation outside of the polyalanine tract may not dictate severe phenotype with significant respiratory compromise. A unique finding in this family is the association of congenital heart disease in two of the affected patients. These malformations may be a sporadic isolated finding or the result of environmental factors or a modifying allele. Given the association between congenital heart disease and aberrant neural crest cell development, however, findings are suggestive that congenital heart disease may be a rare feature of PHOX2B mutation which has not been previously reported.