Congenital central hypoventilation syndrome: a life-threatening cause of neonatal apnoea

Background

Congenital central hypoventilation syndrome (CCHS), previously referred to with the expression ‘Ondine’s curse’, is a rare life-threatening disease, first described in infants in 1970 by Mellins et al.1 2 With no gender preference and an estimated incidence of 1 in 50 000–200 000 live births, it is defined by an autonomic nervous system (ANS) failure.1 3 4

The hallmark manifestation of this disorder is the alveolar hypoventilation that consists of a diminished or absent response to hypoxia and hypercapnia that is more severe during sleep.3 5 These patients can manifest a multiorgan autonomic dysfunction affecting mainly the heart, the gastrointestinal system and the central nervous system (CNS).4 6 7

Mutations in the paired-like homeobox 2B (PHOX2B) gene are implicated in the pathophysiology of this disease. Its recognition is essential for the diagnosis and predicts disease severity.1 6 8

The authors present a clinical report of CCHS diagnosed in a term newborn with persistent apnoea in the first hours of life.

Case presentation

We present a case of a female newborn delivered by caesarean section at 38 weeks’ gestation to a 29-year-old (gravida 2, para 1) Caucasian woman. The parents were non-consanguineous and already had a healthy 4-year old daughter.

A family history review revealed a case of sudden infant death syndrome (SIDS) in a first-degree maternal cousin.

Complications of the pregnancy included, at 37 weeks, maternal influenza B infection treated with oseltamivir. At 38 weeks, the mother was admitted to the emergency department (ED) with dyspnoea and cough. Due to her previous history of thrombophlebitis, pulmonary embolism was suspected and it was decided that an elective caesarean section be performed. Angio-CT performed later did not confirm this diagnosis, and she had clinical improvement with ceftriaxone.

Prenatal screening showed no signs of active maternal infection. The newborn’s birth weight was 3500 g, and the Apgar score was 8 at both 1 and 5 min. Non-vigorous crying, shallow breathing movements, and lip cyanosis were noted in the first minutes, having reversed with stimulation and oxygen. Mydriatic pupils with diminished photoreaction were also evident.

At 20 min of life, the newborn presented with an apnoeic event with lip cyanosis that motivated admission to a level III neonatal intensive care unit. Shortly after, she had another event now with desaturation up to 70%. In the physical examination, shallow, periodic breathings with decreased tone and responsiveness stood out. At this time, oxygen therapy through nasal cannulas was started, and a sepsis workup was conducted, including blood exams (normal complete blood count and blood chemistry and negative C reactive protein), blood cultures, venous blood gas analysis (pH 7.31, pCO₂ 57 mm Hg, pO₂ 27 mm Hg, HCO₃ 28.7 mmol/L, base excess 2.4, lactate 3.7 mmol/L) and chest radiography (showing symmetrical bilateral interstitial infiltrate). Despite not showing any major changes, she was treated with antibiotics for 7 days because of clinical presentation and maternal infection. The herpes simplex virus workup was also negative, as well as the respiratory virus panel.

Approximately 20 hours after birth, due to persistent apnoea with hypercapnia, hypoxia and severe respiratory acidosis, and after the failure of non-invasive respiratory support, high-flow cannulas and bilevel continuous positive airway pressure (positive end expiratory pressure (PEEP)1 6 cmH₂O, PEEP2 8 cmH₂O, T High 1 s, respiratory rate (RR) 10 breaths/min, fraction of inspired oxygen (FiO₂) 35%); the newborn was intubated and placed on conventional synchronised intermittent mandatory ventilation (PEEP 4 cmH₂O, peak inspiratory pressure 24 cmH₂O, RR 35 breaths/min, FiO₂ 40%).

Furthermore, she manifested thermal and glycaemic instability with a tendency to hyperglycaemic up to day of life (DOL) 3, and arterial hypotension requiring aminergic support with dopamine until DOL 4.

Investigations

Secondary to unexplained apnoea and mild axial hypotonia with decreased responsiveness, a head ultrasound was performed, which revealed enlargement of the pellucid septum cavum but otherwise was unremarkable. An MRI of the newborn’s head performed on the DOL 4 was also unremarkable.

An ophthalmology consultant done on DOL 4, because of mydriatic pupils present since DOL 1, found that the pupils were reactive to pilocarpine, despite their diminished response to the light.

In the face of these manifestations, the aetiological investigation was extended, including ammonia levels; blood and cerebrospinal fluid (CSF) cultures; screening blood and urine tests for metabolic disease; CSF neurotransmitter studies; and ECG, which were all negative or normal.

These facts, difficulties in extubation and evidence of hypercapnia during sleep raised the suspicion of CCHS.

On DOL 6, a genetic consultation was done and a next-generation sequencing panel of six genes related to CCHS was requested but was negative. The genetic study continued in the reference laboratory with the study of the PHOX2B gene, including PCR amplification of all three coding exons followed by fragment analysis and sequencing. The results revealed a heterozygous polyalanine repeat mutation (PARM) of 33 repeats in exon 3, consistent with the diagnosis of CCHS.

Polysomnography performed later was also suggestive of central hypoventilation, evidencing hypercapnia, especially in non-rapid eye movement (NREM) sleep, and decreased cardiorespiratory response to respiratory events.

On DOL 9, after clinical worsening with desaturation, tachycardia and hypotension, with an elevation of C reactive protein, a Staphylococcus hominis sepsis was identified and treated with vancomycin.

From DOL 9–11, she presented two episodes of generalised hypertonia associated with ocular retroversion, desaturation, cyanosis and bradycardia. These short-duration episodes reversed after ventilation with manual autoinsufflator and motivated neuropaediatrics evaluation. The electroencephalogram (sleep–wake cycle) performed exhibited a normal wave pattern.

An echocardiogram was also performed on DOL 12 for an audible murmur. The murmur was found to be consistent with patent oval foramen with a left–right shunt. A holter was also done but did not show changes in pace or conduction.

Outcome and follow-up

The infant was under invasive ventilation until DOL 13, with elective extubation for non-invasive positive pressure ventilation (NIPPV).

Throughout hospitalisation, she maintained feeding difficulties, having been fed with breast milk supplemented with infant formula exclusively by nasogastric tube. There was some improvement in food progression tolerance over time and with the institution of a proton pump inhibitor.

The infant was discharged home at 2 months old on NIPPV through a nasal mask during sleep.

After discharge, she still requires multidisciplinary follow-up with pulmonology, neurology, paediatric nutrition, cardiology, speech therapy, occupational therapy and physical therapy. The infant has not yet had complications that motivated observation in the ED. The parents were also referred for genetic consultation and were tested for CCHS mutations.

At her 6-month follow-up visit, the infant was ventilator dependent only on the night shift, without reported cyanosis or desaturations. Currently, the infant continues to be fed through a nasogastric tube with good weight progression.