Variable phenotype in a novel mutation in PHOX2B

Abstract

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.

Atypical presentations associated with non‐polyalanine repeat PHOX2B mutations

“…The test revealed a normal number of polyalanine repeats (20/20) in exon 3 and identified a nonsense heterozygous NPARM, p.Y78* (c.234C > G) in exon 1. This variant has been recently reported in another family (Lombardo et al, ) and is expected to result in loss of PHOX2B function via premature protein truncation or nonsense‐mediated mRNA decay.…”

“…In contrast to Patient 1, Patient 2 presented at birth with a more severe clinical course characterized by persistent severe desaturations, severe hypercarbia while awake and asleep, OSA, and oropharyngeal airway collapse requiring tracheostomy and placement of a gastrostomy tube. PHOX2B genetic testing revealed a normal number of polyalanine repeats and identified a pathogenic nonsense NPARM recently reported in a different family (Lombardo et al, ). In that family, the mutation was maternally inherited in two siblings and was associated with a variable phenotype.…”

“…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.…”

“…CCHS can occur in isolation or in association with Hirschsprung disease and/or neural crest tumors (Croaker, Shi, Simpson, Cartmill, & Cass, ; Ramanantsoa & Gallego, ). Compared to patients with PARMs, patients with NPARMs have been shown to have an increased incidence of both Hirschsprung disease (87–100% in patients with NPARMs versus 13–20% in patients with PARMs) (Weese‐Mayer et al, ) and neuroblastoma (50% versus 1%) (Lombardo, Kramer, Cnota, Sawnani, & Hopkin, ).…”

“…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.…”