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\begin{document}

\title{Hypoventilation in a case of congenital Rett syndrome}



\author[1]{Sergio Ghirardo}%
\author[2]{Letizia Sabatini}%
\author[1]{Alessandro Onofri}%
\author[1]{Beatrice Chiarini Testa}%
\author[1]{Maria Giovanna Paglietti}%
\author[3]{Daria Diodato}%
\author[1]{Marta Ciofi degli Atti}%
\author[1]{Claudio Cherchi}%
\author[4]{Renato Cutrera}%
\affil[1]{Bambino Gesù Children's Hospital IRCCS}%
\affil[2]{University of Rome Tor Vergata}%
\affil[3]{Bambino Gesù Children's Hospital, IRCCS}%
\affil[4]{Bambino Gesù  Childrens’ Hospital, IRCCS}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Breathing disturbances are often a major clinical concern during
wakefulness of classic form of Rett syndrome, but data for atypical
forms are lacking. We report the case of a 20-month-old female affected
by the congenital variant of Rett syndrome, that is characterized by
severe hypotonia and neurodevelopment impairment. She presented
hypoventilation, persistent periodic breathing and sustained
desaturation during sleep time, without obstructive nor central events;
pulse oximetry and capnography during wakefulness were strictly normal.
To the best of our knowledge, this is the first case of Rett syndrome
presenting hypoventilation. Hypotonia may play a major role in the
genesis of hypoventilation and hypoxemia in our patient. Non-invasive
ventilation led to quality-of-life improvements. Thus, we suggest
screening patients with congenital Rett variant through transcutaneous
bedtime carbon dioxide and oxygen monitoring. Moreover, in our case,
assisted control mode was a breakthrough to achieve adequate
ventilation.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Rett syndrome (RS) is a severe neurogenetic syndrome, affecting one baby
every 10.000 live-born, almost exclusively female. Its congenital
variant of Rett syndrome (CRS) accounts for just 5-7\% of all cases, and
the clinical picture is characterized by severe hypotonia, often present
at birth, and neurodevelopmental delay since the very firsts few months.
Classic RS leads to remarkably breathing instability, usually even more
pronounced during wakefulness. We report a 20-month-old female affected
by a congenital variant of Rett syndrome, how showed central apneas,
periodic breathing, and persistent hypercapnia only during sleep time.
Such findings were never reported before in a child affected by Rett
syndrome. We present ventilatory and clinical management of this unique
case.

\textbf{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 \textless{}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\selectlanguage{ngerman}°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 \textgreater{} 3 seconds each and
separated by \textless{} 20 seconds of normal breathing. She spent 55\%
of her total sleep time (TST) with peripheral oxygen saturation
(SpO\textsubscript{2}) \textless{}90\%. Her oxygen desaturations index
(ODI) was 13.9, defined as the number of desaturations \textgreater{}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 (PtcCO\textsubscript{2})
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
cmH\textsubscript{2}O, expiratory positive airway pressure (EPAP) 4
cmH\textsubscript{2}O, with a respiratory frequency of 23 breaths per
minute (very close to the patient one). Such setting normalized
SpO\textsubscript{2} values with minimum SpO\textsubscript{2} 92\% and
an improvement of ODI to 7.2 events/hour. Carbon dioxide even worsened
with a mean PtcCO\textsubscript{2} 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 PtcCO\textsubscript{2}, 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
cmH\textsubscript{2}O, we finally obtained
PtcCO\textsubscript{2}normalization (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°).

\textbf{Discussion:}

Rett syndrome-related breathing features, like hyperpnoea followed by
breath-holding, Valsalva efforts, and periodic breathing, are easily
identifiable during wakefulness. Such symptoms usually reduce or even
abruptly disappear at sleep onset{[}1{]}. Among the patients with Rett
syndrome with pathological polygraph, nearly all present obstructive
events during sleep, with a thin minority of central events associated
with severe obstructive ones{[}2{]}. Remarkably, no patient with RS
showed hypoventilation or hypercapnia{[}2{]}. MECP2 gene plays an
important role in autonomic system regulation {[}3{]}. Animal models
showed an important role of MECP2 in breathing centres sensitivity to
CO2, and its mutations may lead to the typical respiratory instability
of RS{[}4{]}. To the best of our knowledge, this is the first case
reporting hypoxemia and hypoventilation in a patient affected by RS. No
articles perform an in-depth analysis of breathing patterns of RS
variants, in particular during sleep-time. Patients with CRS are a
peculiar cohort; they will never walk autonomously and may acquire the
ability to articulate few simple words at best, usually show severe
mental retardation since the very first's months of life. At the
diagnosis, only a few cases present epilepsy (the landmark of the
classic form), but electrical activity alterations are nearly always
identified at the EEG{[}5{]}, {[}6{]}.

As previously stressed, the congenital variant is deeply impacted by
hypotonia that is as severe as to cause scoliosis within the very first
years of life{[}7{]}. Therefore, in CRS, hypotony maybe, per se, cause
desaturation and hypoventilation as for other neuromuscular diseases in
children{[}8{]}, suggesting different pathogenesis than for classic form
of RS. The normality of PtcCO2 during waketime (when muscle strength is
relatively increased) supports this suggestion. Of particular interest
is the persistent periodic breathing of this patient. Breathing centres
homeostasis is very fragile in RS due to MECP2mutation{[}4{]}, with a
consequent high gain loop causing periodic breathing. Such events may be
boosted by repeated desaturations caused by CRS-related
hypotonia{[}9{]}, {[}10{]}. Therefore, although a ST mode of ventilation
is usually preferred to maximize patient comfort, an assisted
pressure-controlled mode could be necessary to overcome the lack of
appropriate respiratory centres control. Providing an adequate
ventilation in such patients could contribute to the daytime quality of
life and hypotonia improvement, as already reported for other hypotonic
diseases{[}8{]}.

In conclusion, we think that this single case suggests the need for a
very early polygraph or at least pulse oximetry plus capnography in each
patient affected by the congenital variant of Rett syndrome. Broadly
speaking, we suggest considering a diagnosis of congenital Rett syndrome
patients with hypotonia without a diagnosis.

{[}1{]} J. Gallego, ``Genetic diseases: Congenital central
hypoventilation, rett, and prader-willi syndromes,'' \emph{Compr.
Physiol.} , vol. 2, no. 3, pp. 2255--2279, 2012, doi:
10.1002/cphy.c100037.

{[}2{]} K. M. Sarber, J. J. M. Howard, T. J. Dye, J. E. Pascoe, and N.
Simakajornboon, ``Sleep-disordered breathing in pediatric patients with
Rett syndrome,'' \emph{J. Clin. Sleep Med.} , vol. 15, no. 10, pp.
1451--1457, 2019, doi: 10.5664/jcsm.7974.

{[}3{]} G. Pini \emph{et al.} , ``Rett syndrome: a wide clinical and
autonomic picture,'' \emph{Orphanet J. Rare Dis.} , vol. 11, no. 1, pp.
1--16, 2016, doi: 10.1186/s13023-016-0499-7.

{[}4{]} and Y. W. Chun Jiang, Ningren Cui, Weiwei Zhong, Christopher M.
Johnson, ``Breathing abnormalities in animal models of Rett syndrome a
female neurogenetic disorder,'' \emph{Respir Physiol Neurobiol} , vol.
176, no. 5, pp. 139--148, 2017, doi:
10.1016/j.resp.2016.11.011.Breathing.

{[}5{]} C. Keogh \emph{et al.} , ``Clinical and genetic Rett syndrome
variants are defined by stable electrophysiological profiles 11 Medical
and Health Sciences 1109 Neurosciences,'' \emph{BMC Pediatr.} , vol. 18,
no. 1, pp. 1--15, 2018, doi: 10.1186/s12887-018-1304-7.

{[}6{]} J. N. Saby, S. U. Peters, T. P. L. Roberts, C. A. Nelson, and E.
D. Marsh, ``Evoked Potentials and EEG Analysis in Rett Syndrome and
Related Developmental Encephalopathies: Towards a Biomarker for
Translational Research,'' \emph{Front. Integr. Neurosci.} , vol. 14, no.
May, pp. 1--12, 2020, doi: 10.3389/fnint.2020.00030.

{[}7{]} F. Ariani \emph{et al.} , ``FOXG1 Is Responsible for the
Congenital Variant of Rett Syndrome,'' \emph{Am. J. Hum. Genet.} , vol.
83, no. 1, pp. 89--93, 2008, doi: 10.1016/j.ajhg.2008.05.015.

{[}8{]} B. Fauroux, S. Khirani, L. Griffon, T. Teng, A. Lanzeray, and A.
Amaddeo, ``Non-invasive Ventilation in Children With Neuromuscular
Disease,'' \emph{Front. Pediatr.} , vol. 8, no. November, pp. 1--9,
2020, doi: 10.3389/fped.2020.00482.

{[}9{]} J. A. Dempsey \emph{et al.} , ``The ventilatory responsiveness
to CO 2 below eupnoea as a determinant of ventilatory stability in sleep
Sleep effects on ventilatory control stability,'' \emph{J Physiol} ,
vol. 560, pp. 1--11, 2004, doi: 10.1113/jphysiol.2004.072371.

{[}10{]} J. A. Dempsey, S. C. Veasey, B. J. Morgan, and C. P. O'Donnell,
``Pathophysiology of sleep apnea,'' \emph{Physiol. Rev.} , vol. 90, no.
1, pp. 47--112, 2010, doi: 10.1152/physrev.00043.2008.

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