Case Report
The patient was born to Chinese parents whom are first cousins; mother is a 35-year-old Gravida 3 Para 2 (previous two pregnancies were born at term and are currently well). The pregnancy was unremarkable with normal antenatal ultrasound scans, liquor volume and fetal movements. Mother attended our hospital with per vaginal bleeding at 32 weeks gestation, obstetric assessment on admission noted fetal bradycardia and thus concern of abruption placentae was raised. The patient was immediately delivered via a crash caesarean section. The patient was born with a birth weight of 2 kg (52nd centile), length 42.5 cm (39th centile) and occipital-fontal circumference of 31.1 cm (74th centile). He initially required positive pressure ventilation but subsequently transferred to our neonatal intensive care unit (NICU) on continuous positive airway pressure (CPAP) support.
On clinical examination, he was noted to have baseline bradycardia and intermittent bradypnea with good respiratory effort. He did not have myopathic facies nor any dysmorphism. He was slightly hypotonic but had good anti-gravity movements and normal reflexes throughout.
His post-natal course was significant for severe respiratory distress syndrome requiring intubation at one hour of life. He required three doses of surfactant, and this was also complicated by a right pneumothorax requiring chest drain insertion. He was extubated at day 6 of life to CPAP and failed multiple trials of high flow nasal cannula in view of multiple apneas and increased work of breathing. Thus, he was maintained on CPAP 6 cmH2O with a fraction of inspired oxygen at 23 – 25% until he reached term. The 2-dimesional echocardiography showed a small atrial septal defect, patent foramen ovale, and hypertrabeculation of the left ventricle apex and a 12-lead electrocardiogram (ECG) showed sinus bradycardia.
The patient’s clinical course was atypical for bronchopulmonary dysplasia. He was not an extremely low birth weight or low gestation infant and yet, he required significant respiratory support at term. He was also noted to be significantly bradypnoeic at times with respiratory rates 10 – 15 breaths per minute which was also atypical for prematurity. Since birth, he was also noted to be bradycardic with baseline heart rates 70 – 90 beats per minute.
He was referred to the neurology team to investigate for a possible central pathology in view of the significant bradypnea and multiple apneic episodes while on ventilation. A normal magnetic resonance imaging of the brain ruled out a structural central cause and a normal creatinine kinase level 46 U/L was not in keeping with an underlying congenital muscular dystrophy. Electroencephalogram (EEG) did not reveal any seizures.
His serial chest radiographs showed bilateral mild reticular lung markings suggesting mild bronchopulmonary dysplasia. This was also reflected in his capillary blood gases which showed compensated respiratory acidosis with hypercarbia. He underwent an initial pulse oximetry study on CPAP 6 cmH2O which showed a desaturation index of 131.4 events/hour with an oxygen saturation nadir of 58% as illustrated in Figure 1. Thus, he was converted to bi-level positive airway pressure (BiPAP) at settings of 10 cm H2O / 6 cmH2O. Polysomnogram done showed multiple hypopneic and apneic episodes with significant desaturations and thus, it was recommended to continue the adjusted BiPAP settings. Tracheostomy was recommended for a definitive airway and in view of his frequent hypoventilation episodes. A bedside nasoendoscopy did not reveal any upper airway abnormalities. Since he had persistent oxygen requirements, a computed tomography (CT) of the lungs was performed which showed diffuse reticular lung markings in both lungs.
Another possibility was congenital central hypoventilation syndrome and thus, we referred him to our Genetics team. He underwent PHOX2Bgene testing which returned negative. Subsequently, trio whole exome sequencing was done which identified homozygous variants (NM_1777938.2:c.72G>A; p.Trp24*) in P4HTM (prolyl 4-hydroxylase, transmembrane), in keeping with the diagnosis of autosomal recessive HIDEA syndrome. His parents were heterozygous carriers; the pedigree is illustrated in Figure 2. Based on the ACMG-AMP guidelines, this P4HTM variant would be classified as “likely pathogenic” .
His other postnatal issues included pyloric stenosis for which he presented with multiple episodes of vomiting. Ultrasound abdomen confirmed this and he underwent a pylorotomy at a post menstrual age of 44 weeks. He also has hypothyroxinaemia of prematurity for which he currently remains on L-thyroxine replacement. He was also noted to have roving eye movements and ophthalmology will continue to follow up and assess for possible cortical blindness.
He is currently 2.5 months old corrected age and was discharged home when his parents were competent of taking care of his medical needs at home. He was discharged on BiPAP 24 cm H2O / 9 cm H2O, Rate 35 breaths per minute, Oxygen 2 L/min and three hourly bolus nasogastric tube feeding. He was also referred to the community palliative care team in view of the poor prognosis.