PHOX2B 20/27 polyalanine repeat mutation (PARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally associated with full-time ventilator dependence, Hirschsprung disease, and increased risk for cardiac asystole. We follow a 14-year-old boy with CCHS PHOX2B 20/27 PARM who is full-time ventilator dependent via tracheostomy and has Hirschsprung disease. His mother, age 52 years, has a history of prolonged recovery from anesthesia and an elevated serum bicarbonate level of 45 mEq/L discovered on routine blood chemistry. PHOX2B gene mutation analysis was performed and showed an identical 20/27 PARM, diagnostic of CCHS. Late-onset CCHS has been reported in those with 20/24, 20/25 PHOX2B PARM, and in nonpolyalanine repeat mutations. This is the first report of a patient with PHOX2B 20/27 PARM with a mild phenotype diagnosed during adulthood. This unusual presentation supports the screening for PHOX2B mutations in parents of children with CCHS.
Kasi AS, Kun SS, Keens TG, Perez IA. Adult with PHOX2B mutation and late-onset congenital central hypoventilation syndrome. J Clin Sleep Med. 2018;14(12):2079–2081.
Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder of the autonomic nervous system due to a mutation in the paired-like homeobox 2B (PHOX2B) gene.1 Most patients with CCHS present in the neonatal period with apnea or hypercapnia requiring assisted ventilation. CCHS has been diagnosed beyond the newborn period and as late as during adulthood where the presentation is respiratory compromise following general anesthesia or respiratory infections.1 In these reported cases, patients have 20/24, 20/25 polyalanine repeat mutations (PARM), and nonpolyalanine repeat mutations (NPARM) of the PHOX2B gene.1,2 A few asymptomatic adults with 20/27 PARM PHOX2B mutation with mosaicism have also been reported in the literature.3,4 Most PHOX2B mutations occur de novo but can be inherited in an autosomal dominant pattern, although with variable penetrance. The current recommendation is to screen parents of children with CCHS for PHOX2B gene mutations. The reported cases were identified by screening the parents of patients with CCHS.
We report a 52-year-old woman with 20/27 PARM PHOX2B mutation expected to have a more severe phenotype.
REPORT OF CASE
The patient in the index case, now 14 years of age, was born at term by caesarean section. He had abdominal distension and hypoxemia at birth requiring intubation with mechanical ventilation. He failed extubation trials with resultant hypoxemia and hypercapnia requiring re-intubation with ventilatory support. A rectal biopsy confirmed the diagnosis of Hirschsprung disease, and a colectomy was performed. After extensive inpatient evaluation, the clinical diagnosis of CCHS was made. A gastrostomy tube was placed for swallowing dysfunction. Subsequently, tracheostomy was performed, and he was discharged home on full-time positive pressure ventilation (PPV) via tracheostomy. When the patient was 6 years old, PHOX2B gene mutation analysis became available and showed a 20/27 PARM that is diagnostic of CCHS. Strabismus developed during the patient's early childhood that required surgical correction. He continues to require full-time ventilatory support with PPV via tracheostomy. Periodic echocardiograms and Holter monitoring were normal. The patient attends regular school and does not have neurocognitive delays.
The patient's mother, age 52 years, was healthy until age 32 years. She was born at term by an uncomplicated normal vaginal delivery and had an uneventful neonatal course. She denied childhood seizures, constipation, or respiratory infections requiring oxygen or ventilatory support. She noted the ability to voluntarily hold her breath longer than others during her childhood. At 32 years of age, following surgery for a knee injury, she required inpatient hospitalization and oxygen therapy for 3 days. Attempts to wean from oxygen led to headache and desaturations on pulse oximetry. A similar pattern was noted in the following four surgeries requiring anesthesia. She had a routine blood chemistry performed by her physician that showed elevated serum bicarbonate of 45 mEq/L. She noticed desaturations during sleep using a pulse oximeter after her son received a diagnosis of CCHS. Her body mass index was 27 kg/m2. Family history is significant for several first cousins in whom sleep apnea was diagnosed and required continuous positive airway pressure therapy (CPAP).
PHOX2B gene sequence analysis was performed on the mother and was positive for 20/27 PARM, diagnostic of CCHS. Blood tests showed normal levels of hemoglobin of 14.2 g/dL and hematocrit 42.7%. Arterial blood gas showed pH 7.42, PCO2 37 mmHg, PO2 58 mmHg, and bicarbonate of 24 mmol/L while awake breathing room air. Pulmonary function test was normal. Echocardiogram showed normal right heart size and pulmonary artery pressure. Holter recording was normal. She reports an overnight polysomnography without capnography that showed obstructive sleep apnea (OSA) and sleep-related hypoxemia. A subsequent overnight polysomnography was performed as a split-night study, which consisted of a diagnostic portion and positive airway pressure titration (Figure 1). The diagnostic portion of the sleep study showed OSA with apnea-hypopnea index (AHI) of 14.4 events/h, baseline SpO2 94% to 95%, minimum SpO2 of 80%, and 2.5% sleep time with SpO2 < 90%. During the remainder of the sleep study, CPAP was initiated and titrated to 9 cmH2O without any residual OSA or hypoxemia. However, CO2 monitoring was not performed during the sleep studies. Her first son, age 16 years, did not have any mutations in the PHOX2B gene.
Split-night sleep study shows OSA and episodic hypoxemia during the diagnostic portion and subsequent CPAP titration.
APAP = autotitrating positive airway pressure, ASV = adaptive servoventilation, CPAP = continuous positive airway pressure, EPAP = expiratory pressure, IPAP = inspiratory pressure, PLM = periodic limb movement, REM = rapid eye movement sleep, RERA = respiratory effort-related arousal.
Split-night sleep study shows OSA and episodic hypoxemia during the diagnostic portion and subsequent CPAP titration.
Based on the mother's PHOX2B gene mutation, a repeat polysomnogram was recommended with end-tidal CO2 monitoring and noninvasive PPV titration. Because her PHOX2B gene mutation is associated with life-threatening sinus pauses, annual Holter monitoring was recommended. Annual echo-cardiogram to assess for pulmonary hypertension was recommended as well. Because PHOX2B gene mutations are inherited in an autosomal dominant pattern, PHOX2B gene mutation testing was recommended for immediate family members and her siblings.
We present the case of a 52-year-old woman with 20/27 PARM PHOX2B mutation with a mild clinical phenotype, whereas the expected clinical phenotype with a similar genotype requires full-time ventilatory support, has Hirschsprung disease, and is at risk for sudden cardiac death from arrhythmias. This patient was evaluated and CCHS was subsequently diagnosed primarily by the presence of a family history of CCHS.
CCHS is characterized by hypercapnia and/or hypoxemia, which is worse during sleep than during wakefulness. Patients with CCHS have absent or negligible ventilatory sensitivity to hypercapnia and hypoxemia, and do not exhibit signs of respiratory distress when challenged with hypercarbia or hypoxia.5,6 This explains our patient's ability to hold her breath longer than others during early childhood. These subtle symptoms in childhood have been described in adults in whom CCHS was diagnosed.1,3,7
The diagnosis of CCHS must be confirmed with PHOX2B gene mutation. Different mutations in the PHOX2B gene lead to different levels of cellular dysfunction, influencing the phenotype of an individual patient with CCHS. In general, milder disease courses are expected with fewer PARM (20/25 or 20/26) and are not usually associated with neural crest tumors or Hirschsprung disease.1 Patients with genotypes 20/27 to 20/33 usually require continuous ventilatory support and have clinical manifestations of autonomic dysfunction including Hirschsprung disease, strabismus, etc. as seen in our 14-year-old patient. Autosomal dominant inheritance with variable penetrance of the PHOX2B mutation could explain the mild phenotype seen in our patient's mother.1 This phenotypic variability may be due to unknown modifier genes or environmental factors.1,3 In this family, there is autosomal dominant inheritance, incomplete penetrance, and variability in phenotype.
Most patients with CCHS present during the newborn period. Some are asymptomatic until older childhood, adolescence, or adulthood when they present with unanticipated respiratory failure, seizures, pulmonary hypertension, or polycythemia following stressors such as viral illness, pneumonia, or exposure to anesthesia.1,8 Thus, in these age groups, the diagnosis of CCHS should be considered in cases of unexplained alveolar hypoventilation, apnea, cyanosis, or seizures after administration of anesthetics or central nervous system depressants, or with relatively mild respiratory infections.1 Because of the rare incidence of this disease as well as presentation at a later age, this diagnosis can be missed by many clinicians who are unaware of CCHS.
Late-onset CCHS (beyond the newborn period) has been reported in patients with the milder 20/24, 20/25 PARM PHOX2B and in NPARMs.1,2,7,8 Adults with 20/27 PARM PHOX2B mutation have been identified by testing parents of patients with CCHS. These adults had mosaicism of the 20/27 PARM PHOX2B mutation.3,9,10 Our patient's mother was heterozygous for the 20/27 PARM PHOX2B mutation consistent with a diagnosis of CCHS. This case study is the first to demonstrate the 20/27 PARM PHOX2B mutation in an adult that is not attributed to somatic mosaicism.
PHOX2B mutations are inherited in an autosomal dominant pattern, but with incomplete penetrance. Thus, it is important to test both parents of an affected child for the PHOX2B mutation.1 Early identification of parents with PHOX2B mutations can facilitate prompt evaluation and interventions to improve long-term outcomes, as well as genetic counseling for familial recurrence in parents planning to have offspring.
Our case study shows that relatively asymptomatic individuals with PHOX2B gene mutations can manifest later in life as suggested by the elevated serum bicarbonate seen in our patient's mother. Hence, periodic evaluation of cardiac and respiratory function in asymptomatic individuals with PHOX2B gene mutations are essential, and patients should be counseled on ventilatory disturbances that can be induced by anesthesia, alcohol, and respiratory infections.
Our study also highlights the importance of incorporating capnography in adult polysomnography protocols in individuals with PHOX2B mutations. Overnight polysomnography without monitoring for CO2, as was performed in this case will not detect the alveolar hypoventilation that is present in individuals with CCHS.
Our case represents an atypical familial presentation of CCHS in an adult with 20/27 PARM PHOX2B mutation and emphasizes the importance of screening for PHOX2B gene mutations in relatively asymptomatic parents of children with CCHS.
Work for this study was performed at the Children's Hospital Los Angeles. All authors have reviewed and approved the manuscript. The authors report no conflicts of interest.
congenital central hypoventilation syndrome
continuous positive airway pressure therapy
nonpolyalanine repeat mutations
obstructive sleep apnea
polyalanine repeat mutations
positive pressure ventilation
The authors thank the patient and his mother for their participation in this report.
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