Case report
The patient is a full-term Caucasian girl, born after an unremarkable
pregnancy and with no perinatal issues. She was admitted due to an
icterus and a urinary tract infection on the fifth day of life. Hypotony
was remarkable, together with reduced weight gain and recurrent emesis.
Fundus oculi, cranial and abdominal ultrasound were normal; cardiac
ultrasound showed only the persistency of the foramen ovale. She tested
negative for Angelman and Prader-Willi performed due to hypotonia. At
the age of 2 months, brain magnetic resonance (MR) was reported
unremarkable, and she was discharged shortly after.
She came to our attention at the age of 10 months, the psychomotor delay
had become evident, and she scored <70 on the Developmental
Profile-3 test. She did not properly control the head; she reached but
did not grasp objects and fix her gaze just for up to three minutes. The
head circumference was 44 cm (5-10°centile). CGH-array and extensive
metabolic screening, including lumbar puncture, tested negative; evoked
potentials were within normal ranges. Intensive physiotherapy allowed
her to eat semi-liquid foods safely, reach and grab objects with her
hands and maintain ocular contact for several minutes. Despite efforts,
axial hypotonia progressively worsened in the following months, and the
hand’s grip remained poor. At the age of 16 months, she underwent MR
showing a mild bilateral ventricle and subarachnoid spaces widening; MR
spectroscopy was normal. Clinical exome analysis provided a diagnosis of
Rett syndrome 3-months after, identifying a de novo heterozygous
mutation in MECP2 gene (c.396_397insA variant). After that, we
performed polysomnography, showing a not well-organized electrical
activity and diffuse irritating signals at the EEG. PSG was performed
using Somtè PSG (Compumedics, Australia). Cardiorespiratory data
included airflow (nasal pressure transducer and oronasal thermistor if
available), body position, body movements, thoracic and abdominal
movements assessed by respiratory inductance belts, SpO2, and video
recording. The electroencephalographic record was based on the
international 10-20 system with electrodes in positions F1-A2, F2-A1,
C3-A2, C4-A1, O1-A2, O2-A1, recording of eye movements. Transcutaneous
carbon dioxide pressure (PtcCO2) recordings was performed simultaneously
(SenTec Digital Monitor, SenTec Inc, Therwil, Switzerland). Scoring of
respiratory events was performed by an experienced reader, according to
the American Academy of sleep medicine (AASM) criteria: obstructive
apnea was defined as the absence of nasal airflow with continued chest
movements for at least two breaths. Central apnea was defined as the
absence of nasal airflow with the interruption of respiratory effort
lasting more than 20 seconds or associated with arousal and/or a 3%
oxygen desaturation. Periodic breathing was defined as three or more
episodes of central apnea lasting > 3 seconds each and
separated by < 20 seconds of normal breathing. She spent 55%
of her total sleep time (TST) with peripheral oxygen saturation
(SpO2) <90%. Her oxygen desaturations index
(ODI) was 13.9, defined as the number of desaturations >3%
per hour of TST. Periodic breathing (PB) accounted for 25% of TST
matching criteria for persistent periodic breathing (PPB). The mean
percutaneous carbon dioxide partial pressure (PtcCO2)
during bedtime was 50 mmHg, and she spent 57% of the TST above this
limit. Therefore, she fulfilled even the stricter paediatric criteria
for hypoventilation basing on persistent overnight hypercapnia.
Obstructive events were virtually absent with a 0.2 of mixed-obstructive
hypopnea apnoea index (MOHAI), defined as the number of such episodes
per hour of TST. Following the clinical evidence of a huge difference in
breathing patterns between daytime and bedtime, we performed
measurements of SpO2 and PtcCO2 during wakefulness, which were strictly
normal (mean PtcCO2 35 mmHg, range 34-36 mmHg). Therefore, the increase
of PtcCO2 between wakefulness and sleep is greater than 10 mmHg
providing further confirmation of nocturnal hypoventilation.
Non-invasive positive pressure ventilation (NIV) was started during
bedtime. We set spontaneous timed ventilation with shrink spam to
enhance adaptation inspiratory positive airway pressure (IPAP) 8
cmH2O, expiratory positive airway pressure (EPAP) 4
cmH2O, with a respiratory frequency of 23 breaths per
minute (very close to the patient one). Such setting normalized
SpO2 values with minimum SpO2 92% and
an improvement of ODI to 7.2 events/hour. Carbon dioxide even worsened
with a mean PtcCO2 of 51.7 mmHg, and 100% of TST spent
above 50 mmHg. The first attempt was to increase IPAP to 14, reaching a
partial improvement of PtcCO2, lowering the percentage
spent above 50 mmHg to 29% of TST. At the same time, ODI was reduced to
0.5 events/hour. Shifting ventilation mode to adaptive pressure
controlled (APC) mode and slightly increasing IPAP to 16
cmH2O, we finally obtained PtcCO2normalization (peak 49 mmHg). In the few following days, a slight
improvement of the hypotonia and social interaction with the caregiver
was noticed. Due to hypotonia, we performed an x-ray of the column,
revealing extremely precocious scoliosis (T4-L1 Cobb angle 26°).