Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

Abstract

PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood.

Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions

“…In closing, improved clinical recognition of CCHS and access to PHOX2B molecular testing has both facilitated earlier diagnosis and generated an expanded phenotypic spectrum for PHOX2B‐ related disorders. As reported here, these cases illustrate an expanding phenotypic spectrum for PHOX2b NPARMs to include individuals with sufficiently mild respiratory abnormalities that infants may first present with seemingly isolated HD and/or neuroblastoma (Cain et al, ; Kasi et al, ; Unger et al, ). From these cases and collation from the literature, we suggest that initiation of mechanical‐assisted ventilation should not be a forgone conclusion in all patients diagnosed with CCHS in infancy.…”

The genetics of congenital central hypoventilation syndrome: clinical implications

“… 1 However, NPARM mutations have variable expressivity and incomplete penetrance. 13 , 83 , 84 Some patients have been shown to present with central apneas without hypoventilation, 85 mild hypoxemia, 85 or need for assisted ventilation only during sleep 13 , 84 while others are asymptomatic and are identified only by genetic testing through an affected family member. 13 , 83 , 85 Cain et al 84 described two patients with nonsense pathogenic variant in exon 1 of the PHOX2B producing an N terminally truncated protein presenting with milder phenotype (need for ventilatory support only during sleep and without HSCR or peripheral neuroblastic tumors).…”

“…Two siblings had sleep hypoxemia, anisocoria, HSCR, and characteristic facial features (one sibling did also have a congenital heart disease), while their mother had sleep apnea, anisocoria, and a congenital heart disease but without HSCR or malignancy. 85 In 2017, Kasi et al 13 reported a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C>T) with variable phenotypes. Two of the family members were ventilator dependent only during sleep, with one of them requiring a cardiac pacemaker.…”

“… 21 We also recently reported a patient with NPARM who at 21 years developed bradycardia during sleep, in addition to palpitations and dizziness with exercise. 13 Bradycardia and sinus pauses were documented on Holter monitoring, and the patient subsequently had cardiac pacemaker implantation. 13 These findings indicate that CCHS patients with 20/25 PARM and NPARMs require monitoring for arrhythmias as they become older.…”

“… 13 Bradycardia and sinus pauses were documented on Holter monitoring, and the patient subsequently had cardiac pacemaker implantation. 13 These findings indicate that CCHS patients with 20/25 PARM and NPARMs require monitoring for arrhythmias as they become older.…”