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.