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°).