Recurrent apnoea and respiratory failure in an infant: congenital central hypoventilation syndrome with a novel PHOX2B gene variant

Abstract

A 20-day-old term infant presented with recurrent apnoea, lethargy and respiratory failure. Examination revealed episodes of apnoea and desaturation to 85% without any signs of respiratory distress requiring initiation of non-invasive positive pressure ventilation (NPPV). Capillary blood gas was indicative of respiratory acidosis and serum bicarbonate was elevated at 35 mmol/L. Chest radiograph, echocardiogram and evaluations for infectious aetiologies resulted normal. Due to inability to wean off NPPV with ensuing apnoea and desaturation, polysomnogram was performed and showed central and obstructive sleep apnoea, hypoxaemia and hypoventilation. Central apnoeas and hypoventilation were worse in non-rapid eye movement sleep. Paired-like homeobox 2B genetic studies showed a novel non-polyalanine repeat mutation (c.429+1G>A) establishing the diagnosis of congenital central hypoventilation syndrome (CCHS). Our case highlights the utility of polysomnography in the evaluation of term infants with apnoea. Although rare, clinicians should consider a diagnosis of CCHS in the evaluation of infants with apnoea and hypoventilation.

Background

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disease affecting regulation of breathing and the autonomic nervous system (ANS) that is caused by variants in the paired-like homeobox 2B (PHOX2B) gene.¹ Most patients are diagnosed in the newborn period with few cases presenting later in infancy, childhood or adulthood. In the newborn period, the typical presentation is apnoea, hypoventilation, cyanosis or persistent respiratory failure with inability to wean off ventilatory support.^{2 3} Even during wakefulness, patients with CCHS do not manifest the expected clinical features of hypoxaemia and hypoventilation such as tachypnoea, retractions and nasal flaring. This makes the diagnosis of CCHS challenging.^1–3

We report a 20-day-old term male infant with CCHS who presented with recurrent apnoea and respiratory failure. PHOX2B genetic studies showed a previously undescribed variant, c.429+1G>A non-polyalanine repeat mutation (NPARM). Although rare, clinicians should maintain a high index of suspicion for CCHS in infants with apnoea and hypoventilation.

Case presentation

A 20-day-old boy presented with apnoea, lethargy, reduced oral intake and frequent alarms on a home infant cardiorespiratory monitor (CRM). There was no history of fever, cough or emesis.

In the emergency department, he was awake and afebrile, with a respiratory rate of 45/min, oxygen saturation (SpO₂) of 98%, and a normal physical examination. Subsequently, he developed episodes of apnoea and desaturation to 85% when awake without any tachypnoea, nasal flaring or chest retractions. Non-invasive positive pressure ventilation (NPPV) was initiated, and he was admitted to the paediatric intensive care unit for further management. Several attempts to wean off NPPV were unsuccessful, resulting in apnoeas and desaturations without accompanying signs of respiratory distress. In addition, episodic bradypnoea was noted when awake.

Review of newborn history showed that he was born at term by a vaginal delivery and had an uncomplicated nursery course. Maternal pregnancy was complicated by reduced fetal movements and heart rate variability at 39 weeks gestation requiring labour induction. At 6 days of age, he developed episodic shallow breathing and presented to the hospital at 10 days of age with lethargy, poor oral intake and apnoea. Examination only revealed episodes of apnoea lasting about 15 s with associated desaturation to 82%. Despite being awake, he did not develop tachypnoea or other signs of increased work of breathing with desaturations. Supplemental oxygen was initiated by nasal cannula at 0.75 L/min, but apnoeas persisted requiring initiation of NPPV. Capillary blood gas (CBG) prior to initiation of NPPV showed pH of 7.35 and partial pressure of carbon dioxide (P_CO2) of 49 mm Hg. Blood, urine and cerebrospinal fluid cultures resulted negative. Chest radiograph, serum electrolytes, respiratory viral panel, cranial ultrasound, ECG and electroencephalogram resulted normal. He was weaned to room air and discharged home on an infant CRM at 13 days of age.

Investigations

The evaluations performed in our patient are summarised in table 1. Chest radiograph was normal (figure 1). CBG showed pH of 7.33 and P_CO2 of 62 mm Hg indicative of respiratory acidosis. Serum bicarbonate was elevated at 35 mmol/L. CRM download summary revealed apnoeas up to 21 s and bradycardia to 33 beats/min lasting 31 s. At 24 days of age, a polysomnogram on room air showed central and obstructive sleep apnoea, with central and obstructive Apnoea–Hypopnoea Index of 15 and 16 events/hour, respectively (figure 2). The average SpO₂ was 96%, nadir to 80%, and SpO₂ was less than 90% for 5.3% of the sleep time. Transcutaneous carbon dioxide (Ptc_CO2) ranged from 46 to 58 mm Hg, and Ptc_CO2 was above 50 mm Hg for 83% of the study, diagnostic of sleep-related hypoventilation. Central apnoeas occured more frequently during non-rapid eye movement (NREM) sleep with associated desaturations and hypoventilation. There was no bradycardia, tachycardia, tachypnoea or arousals in response to hypoxaemia and hypoventilation. Initiation of supplemental oxygen led to improvement in oxygenation; however, hypoventilation and intermittent central apnoeas persisted. Brain MRI to assess for structural abnormalities was normal. Nasopharyngolaryngoscopy to assess for upper airway obstruction and echocardiogram were normal. PHOX2B genetic studies showed a heterozygous previously undescribed variant, c.429+1G>A NPARM. The c.429+1G>A intronic variant results from a glycine to alanine substitution one nucleotide after coding exon 2 of the PHOX2B gene that is predicted to cause aberrant splicing resulting in an abnormal protein.

Table 1.

Investigations performed in our patient

Investigation	Result
Chest radiograph	Normal
Complete blood count	Normal
Blood, urine and cerebrospinal fluid cultures	Negative
Respiratory viral panel	Negative
Serum electrolytes	Normal
Cranial ultrasound	Normal
Capillary blood gas	pH 7.33 and PCO2 62 mm Hg
Serum bicarbonate	35 mmol/L
ECG	Normal
Electroencephalogram	Normal
Polysomnography	Central and obstructive sleep apnoea, hypoxaemia and hypoventilation
Brain MRI	Normal
Nasopharyngolaryngoscopy	Normal
Echocardiogram	Normal
PHOX2B genetic test	c.429+1G>A nonpolyalanine repeat mutation
Barium enema	Rectum was smaller in calibre compared with the sigmoid colon
Suction rectal biopsy	Absence of ganglion cells suggestive of short segment Hirschsprung’s disease
Abdominal ultrasound	Normal
Urine catecholamines	Normal

P_CO2, partial pressure of carbon dioxide; PHOX2B, paired-like homeobox 2B.

Figure 1.

Chest radiograph shows clear lungs.

Figure 2.

A portion of polysomnogram during non-rapid eye movement sleep shows central apnoeas (marked in blue), oxygen desaturations and hypoventilation without accompanying changes in heart rate. Central apnoeas are characterised by cessation in air flow without respiratory effort resulting in oxygen desaturation. BPM, heart rate in beats per minute; chest and abdomen, piezoelectric respiratory belts for chest and abdomen, respectively; N: non-rapid eye movement sleep; SpO2: oxygen saturation; TCPCO2, transcutaneous carbon dioxide; Therm, thermistor that measures nasal air flow.

Although there was no history of constipation, barium enema was performed based on the clinical association of Hirschsprung’s disease (HD) with PHOX2B NPARM and showed that the rectum was smaller in calibre compared with the sigmoid colon (figure 3). Because the barium enema was suspicious for HD, suction rectal biopsy was performed and showed absence of ganglion cells suggestive of short segment HD. Abdominal ultrasound and urine catecholamines for neural crest tumours (NCT) screening resulted normal.

Figure 3.

Barium enema shows a smaller calibre of the rectum compared with the sigmoid colon suspicious for Hirschsprung’s disease.

Differential diagnosis

Recurrent apnoea and hypoventilation in a term infant can be a challenging clinical scenario since it can be caused by a multitude of aetiologies. The differential diagnoses and suggested evaluations for apnoea and hypoventilation in term infants are (1) perinatal events such as hypoxia–ischaemia: obtaining a thorough maternal, prenatal, intrapartum and resuscitation history and cranial ultrasound, (2) infections such as meningitis, pneumonia and sepsis: chest radiograph, complete blood count, cultures of blood, urine and cerebrospinal fluid, (3) inborn errors of metabolism and metabolic causes such as abnormalities in electrolytes, calcium and glucose: newborn screening test, serum glucose, electrolytes and calcium, and evaluation by paediatric genetics and (4) central nervous system abnormalities such as seizures, haemorrhage, and structural lesions of the brain or brainstem: electroencephalogram, MRI scan of the brain and brainstem, lumbar puncture and evaluation by a paediatric neurologist, (5) upper airway obstruction: endoscopic airway evaluation and evaluation by a paediatric otolaryngologist, (6) genetic disorders such as CCHS: blood gas analysis, polysomnography, PHOX2B genetic test and evaluation by paediatric genetics, (7) cardiac disease: ECG and echocardiogram and (8) pulmonary disease: chest radiograph and potentially chest CT scan.^{1 4 5} These evaluations are generally performed in consultation with a paediatric pulmonologist and neurologist.

When the diagnosis of CCHS is suspected, in addition to a thorough history and examination, PHOX2B genetic studies should be performed. In our patient, the clinical features of recurrent apnoea, hypoxaemia and hypoventilation without accompanying signs of respiratory distress in conjunction with a PHOX2B gene variant confirmed the diagnosis of CCHS.

Treatment

During the hospitalisation, our patient remained on NPPV until the diagnosis of CCHS was confirmed with PHOX2B genetic studies. Nasogastric tube feeds were initiated for nutrition. At 1 month of age, tracheostomy was performed to deliver continuous PPV.

Outcome and follow-up

At 2 months of age, the patient was discharged home on continuous PPV via tracheostomy. Home monitoring with pulse oximetry and end tidal carbon dioxide monitor were recommended. Home care nursing was arranged prior to discharge. At the time of this writing, parental PHOX2B genetic studies were recommended, but not yet completed. Follow-up with paediatric pulmonology, cardiology and gastroenterology was established. At 3 months of age, the patient was evaluated in the paediatric pulmonology clinic where he was noted to be doing well on his home ventilator without any hypoxaemia or hypercapnia.

Discussion

CCHS is a rare, generalised disorder of the ANS and control of breathing. Gas exchange abnormalities in common sleep-disordered breathing conditions such as obstructive sleep apnoea is typically worse in REM sleep. In patients with CCHS, central apnoea, hypoxaemia and hypoventilation are generally worse during NREM sleep but may also be present during REM sleep and wakefulness.^{1 6} In addition to gas exchange abnormalities during sleep, patients also have abnormal or absent arousal and heart rate responses to hypoxaemia, as seen in our patient.⁶ Hence, polysomnography may be a valuable test in the evaluation of infants with apnoea and hypoventilation. Other associated clinical features in CCHS include HD, NCT, cardiac rhythm abnormalities and temperature dysregulation. Studies have reported infants with CCHS and PHOX2B NPARM presenting with central sleep apnoea and hypoventilation.^{7 8}

The PHOX2B gene plays a vital role in the development of the ANS and contains a repeat sequence of 20 alanines in exon 3. PHOX2B gene variants are classified as (1) PARMs which are more common (90% cases) and cause an increase in the alanine repeats and (2) NPARM that include missense, nonsense and frameshift mutations.^{1 9} There is a genotype and phenotype correlation wherein patients with NPARM generally have a more severe phenotype with continuous ventilator dependence and increased risk for NCT and HD.¹⁰ Although some PHOX2B gene variants can occur de novo, an autosomal dominant inheritance pattern has been described.^{1 11} In our patient, PHOX2B full gene sequence analysis was performed in a commercial laboratory by polymerase chain reaction-based double-stranded automated sequencing in exons 1–3 of the PHOX2B gene and at least five bases into the 5’ and 3’ ends of all the introns. On our review of the literature, we did not find any published reports of the novel PHOX2B variant identified in our patient.

Patients with CCHS require assisted ventilation throughout their life. Supplemental oxygen alone is insufficient for the management of hypoventilation in CCHS. Some patients require ventilatory support only during sleep, whereas others may require continuous ventilatory support.¹ The duration of ventilator requirement generally correlates with the PHOX2B genotype.¹⁰ At initial diagnosis, the current guideline recommends PPV via tracheostomy to ensure optimal ventilation, oxygenation and neurocognitive outcomes. Later in childhood, other modalities of ventilatory support such as diaphragm pacing (DP) and NPPV can be considered.¹ DP activates inspiration using the patient’s own diaphragm by electrical stimulation of the phrenic nerves via implanted phrenic nerve electrodes. Since patients lack the typical responses to hypoxaemia and hypoventilation, they should be monitored with continuous pulse oximetry and capnography (using end tidal carbon dioxide monitor) during sleep and periodic checks during wakefulness. In addition, home care nursing is recommended for continuous monitoring and management of patients on ventilatory support.¹ An annual assessment of oxygenation and ventilation both when awake and during sleep on ventilatory support (generally by polysomnography) is recommended to assess and titrate ventilator settings to achieve optimal gas exchange. Impaired gas exchange can lead to pulmonary hypertension and may adversely affect neurodevelopmental outcomes.¹

Individuals with CCHS are at risk for developing complications such as pulmonary hypertension, cardiac rhythm abnormalities, NCTs and neurocognitive impairment. An echocardiogram and Holter monitor study are recommended annually to assess for pulmonary hypertension and cardiac pauses. A cardiac pacemaker may be indicated for sinus pauses of 3 s or longer.^{1 12 13} In children with constipation, consultation with a gastroenterologist is recommended to assess for HD. CCHS management guidelines recommend evaluations for HD in patients with constipation and recommends against systematic evaluations for HD in asymptomatic patients.^{1 5} On our review of the literature, we were unable to identify any reports of infants with CCHS and HD without gastrointestinal symptoms.¹⁴ Our case highlights the importance of evaluating children with PHOX2B NPARM for HD despite the absence of symptoms. Serial chest and abdominal imaging in patients with 20/29 PARM and higher, and NPARMs are recommended for NCT surveillance. Neurocognitive evaluation is recommended annually to identify and treat any developmental delays. Since CCHS can be inherited in an autosomal dominant pattern, genetic counselling and parental PHOX2B genetic tests are recommended.¹ With advances in multidisciplinary care, the outcomes are promising for patients with CCHS who are now surviving into adulthood and have families of their own.²

Learning points.

• Apnoea in term infants is clinically challenging due to a wide range of potential aetiologies that may require several investigations to determine appropriate therapies.

• Although rare, clinicians should maintain a high index of suspicion for congenital central hypoventilation syndrome (CCHS) in infants with apnoea and hypoventilation.

• CCHS is caused by variants in the paired-like homeobox 2B gene. Affected patients have abnormal control of breathing and require assisted ventilation throughout life.

• Patients with CCHS lack the typical clinical features of hypoxaemia and hypoventilation such as nasal flaring, tachypnoea and retractions. Hence clinicians must rely on objective measures of gas exchange such as pulse oximetry and capnography.

• All the clinical features of CCHS may not manifest at birth. Some clinical features such as cardiac rhythm abnormalities, pulmonary hypertension, neural crest tumours and neurocognitive delays can manifest during variable age ranges in children with CCHS.