Managing Complexity in Rett Syndrome with a Focus on Respiratory Involvement: A Tertiary Center Experience

Abstract

Background: Rett syndrome (RS) is a rare neurodevelopmental disorder primarily affecting females, characterized by severe neurological impairment and complex comorbidities, including epilepsy, scoliosis, and respiratory dysfunction. Respiratory complications, such as recurrent infections and sleep-disordered breathing (SDB), are increasingly recognized as significant contributors to morbidity. This study aimed to evaluate the prevalence, severity, and management of major comorbidities—including epilepsy, scoliosis, respiratory infections, and SDB—in a pediatric cohort with genetically confirmed RS. Methods: We conducted a retrospective review of medical records from 23 female patients under 18 years of age with MECP2 mutations, referred to our tertiary care center from 2021 to 2025. Data on epilepsy, scoliosis, respiratory infections, and nutritional status were collected. The presence of SDB was assessed through overnight home polygraphy (oPG) and transcutaneous carbon dioxide monitoring in selected cases. Results: Epilepsy affected 65% of patients, all with good seizure control. Scoliosis was present in 52%, with two patients requiring spinal surgery. At least one episode of lower respiratory tract infection (LRTI) was presented in 39% of our girls. LRTIs positively correlated with the number of hospitalization and antibiotic treatment. Among patients undergoing oPG, 67% presented obstructive sleep apnea, with its severity positively correlating with the frequency of lower respiratory infections. Severe nocturnal hypercapnia was documented in three patients, leading to non-invasive or invasive ventilation. Conclusions: Our findings highlight the high prevalence of sleep-related respiratory disorders and their association with respiratory infections in children with RS. Systematic respiratory assessment, including sleep studies, and early implementation of airway clearance techniques and ventilatory support are crucial to improving clinical outcomes in this vulnerable population.

1. Introduction

Rett syndrome (RS) is a rare neurodevelopmental disorder primarily affecting females, caused by de novo mutations in the methyl-CoPG-binding protein 2 (MECP2) gene located on the X chromosome [1]. Atypical forms of RS may be caused by mutations in cyclin-dependent kinase-like 5 (CDKL5) [2]. RS is estimated to affect approximately 1 in 10,000 to 15,000 female births worldwide, making it one of the most common causes of intellectual disability in females [3]. The clinical presentation of classic RS is complex and evolves over time; initially, affected individuals experience a period of seemingly normal development for the first 6–18 months of life, this is followed by a rapid regression phase, during which previously acquired skills, such as purposeful hand movements and spoken language, are lost. Subsequently, a period of stabilization usually occurs, followed by further motor deterioration. Loss of intentional hand movements; the emergence of stereotypical hand movements, such hand washing; vocal language loss; aberrant gait; and stunted growth are some of the main clinical characteristics of RS. This condition is associated with relevant medical comorbidities, including seizures, scoliosis, gastrointestinal issues, and breathing abnormalities. Affected people may differ widely in the presentation and intensity of these symptoms, which makes diagnosis and treatment more difficult [4]. There is currently no cure for RS, and its management focuses on symptomatic treatment and supportive care. A multidisciplinary approach involving neurologists, pulmonologists, physiotherapists, speech therapists, and other specialists is essential to address the different needs of the patients [4,5]. They may require variable therapeutic interventions ranging from anticonvulsant medications to physical therapy, nutritional support, and respiratory management [6].

The aim of our study was to analyze the prevalence, severity, and therapeutic management of major comorbidities such as scoliosis, epilepsy, and respiratory infections in a cohort of patients with RS. Moreover, the prevalence and pattern of sleep-related respiratory disorders, as well as their relationship with other comorbidities, were evaluated in our study.

2. Materials and Methods

We retrospectively collected data from female patients with a confirmed diagnosis of RS with MECP2 gene mutation and age <18 years, referred to our academic tertiary care department, Federico II University, Naples, Italy, from April 2021 to April 2025.

A diagnostic and therapeutic care plan is active for patients affected by RS at our department; the management of the patients involves an interdisciplinary team approach, consisting of pediatric pulmonologists, physiatrists, orthopedists, respiratory physiotherapists, gastroenterologists, and neuropsychiatrists. We collected patients’ medical records showing data including age at evaluation, epilepsy, respiratory infections, scoliosis, hospitalizations, therapeutic strategies, nutrition feeding modalities, and sleep-related breathing disorders. Concerning respiratory infections (upper respiratory tract infections, URTIs; lower respiratory tract infections, LRTIs), hospitalizations, and antibiotic treatments, we evaluated events occurring in the previous year. Data from patients were anonymously recorded using a standardized database.

All patients provided written informed consent for the publication of their anonymized clinical and laboratory data.

2.1. Sleep Study by Polygraphy

Data about sleep-related breathing disorder were obtained by an oPG, using a cardiorespiratory device (NoxT3™—PSG System manufactured by NOX Medical, Reykjavík, Iceland).

The sleep study was performed under clinical wellbeing conditions, clinically controlled epilepsy, and absence of respiratory flare-ups. The parents/caregivers of the patients were trained to set up the equipment.

oPG measurements included: nasal airflow (nasal pressure transducer), oxygen saturation (SpO₂) and cardiac rate (pulse oximetry), thoracic and abdominal movements (inductance plethysmography), and body position.

The recordings were manually scored by two pediatricians of the team with expertise in sleep medicine, according to American Academy of Sleep Medicine guidelines [7].

The following cardiorespiratory parameters were evaluated:

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Total sleep time (TST): the total recording time (in minutes) excluding periods of artifacts and gross body movements.

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Snoring time (%): Percentage of the TST spent snoring.

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Apnea–hypopnea index (AHI): The number of apneas and hypopneas per hour of sleep.

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Obstructive apnea–hypopnea index (oAHI): The number of obstructive and mixed apneas/hypopneas per hour of sleep.

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Central apnea–hypopnea index (CAHI): The number of central apneas/hypopneas per hour of sleep.

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Oxygen desaturation index (ODI): The number of ≥ 3% SpO₂ desaturation events per hour of sleep.

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Mean SpO₂.

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Percentage of the TST spent with an SpO₂ < 90% (T90).

Obstructive sleep apnea (OSA) was defined based on an oAHI higher than 1 event/hour. The severity of OSA was graded, based on oAHI, as follows: mild = 1 < oAHI ≤ 5 events/h; moderate = 5 < oAHI < 10 events/h; severe = oAHI ≥ 10 events/h.

As regards central sleep apnea (CSA), a CAHI ≤ 1 event/h was considered normal, whereas a value of CAHI ≥ 5 event/h was considered clinically significant [8].

Patients with severe sleep apnea performed transcutaneous carbon dioxide (PtcCO₂) recording using the SenTec Digital Monitor (SenTecInc, Therwil, Switzerland) during an overnight hospital stay.

Mean and maximum PtcCO₂ and the percentage of TST spent with a PtcCO₂ > 50 mmHg were reordered. Nocturnal hypoventilation was defined as a PtcCO₂ > 50 mmHg for > 25% of TST [7].

2.2. Statistical Analysis

The variables studied had a normal distribution. Comparison between groups was performed using unpaired t-test. Mann–Whitney test was used to analyze non-parametric variables. To correlate variables, we employed the Pearson test. To compare the percentage of positivity, we used the χ² test. Means and standard deviations (SDs) were reported for continuous variables; median and range were reported for non-parametric variables, and frequencies and percentages were reported for categorical variables. A p value < 0.05 was considered statistically significant. We employed GraphPad Prism 2006 Software to assess statistics.

3. Results

3.1. Clinical Data

Twenty-three girls with RS, mean age at enrolment 9.2 ± 4.2 years old, were included in the study. Their clinical features and therapeutic management are summarized in

Table 1. Clinical features and therapeutic management of twenty-three girls with RS.

CLINICAL FEATURES
Epilepsy [n. (%)]	15/23 (65)
Scoliosis [n. (%)]	12/23 (52)
Oral solid feeding [n. (%)]	16/23(70)
Oral semi-solid feeding [n. (%)]	5/23(21)
URTIs [n. (%)]	13/23 (56)
URTIs/last year [median (range)]	1 (0–12)
LRTIs [n. (%)]	9/23 (39)
LRTIs/last year [median (range)]	0 (0–10)
n. hospitalizations due to respiratory issues/last year [median (range)]	0 (0–3)
n. hospitalizations for non-respiratory-related issues/last year [median(range)]	0 (0–1)
THERAPEUTIC MANAGEMENT
Antiepileptic drugs [n. (%)]	16/23 * (70)
Arthrodesis [n. (%)]	2/12 (16)
PEG [n. (%)]	2/23 (9)
Antibiotic treatment/last year [median (range)]	1 (0–12)
ACT [n. (%)]	4/23 (17)
Nocturnal ventilation [n. (%)]	3/23 (13)
Tracheostomy [n. (%)]	1/3 (1)

Abbreviations: RS, Rett syndrome; URTIs, upper respiratory tract infections; LRTIs, lower respiratory tract infections; PEG, percutaneous endoscopic gastrostomy; ACT, airway clearance technique. * A patient takes antiepileptic treatment based on electroencephalography abnormalities, in the absence of symptomatic epilepsy.

and

Table 2. Demographic and clinical data.

Patient	Age (Years)	Epilepsy	Scoliosis	PEG	URTIs (n/Year)	LRTIs (n/Year)	Antibiotics (n/Year)	H (n/Year)	ACT	Nocturnal Ventilation
1	16	N	Y	N	0	0	0	0	N	N
2	2.6	N	N	N	4	1	3	1	N	N
3	16.8	N	Y	N	0	0	1	0	N	N
4	5.4	Y	N	N	0	0	1	0	N	N
5	5.4	Y	N	N	3	0	2	0	N	N
6	5	N	N	N	10	0	0	0	N	N
7	11.8	Y	Y	N	0	0	1	0	N	N
8	8.2	N	Y	N	2	1	1	0	N	N
9	16	Y	Y	Y	0	1	2	0	Y	N
10	6.9	Y	N	N	0	0	1	0	N	N
11	7.5	Y	Y	N	2	0	2	0	N	N
12	7.6	Y	N	N	4	1	12	0	N	N
13	5.9	N	N	N	1	0	1	0	N	N
14	15.9	Y	Y	N	0	0	0	0	N	N
15	6.9	Y	N	Y	4	4	5	0	Y	Tracheostomy
16	12.5	Y	Y	N	1	1	2	0	N	N
17	9.6	Y	Y	N	0	0	7	0	N	N
18	13.7	Y	Y	N	1	0	1	0	N	N
19	13.5	Y	Y	N	0	0	1	0	N	N
20	6.5	Y	N	N	2	1	2	1	N	N
21	7.6	Y	N	N	0	10	10	3	Y	NIV
22	5.6	Y	Y	N	12	2	2	0	Y	NIV
23	10.1	N	N	N	4	0	0	0	N	N

Abbreviations: PEG, percutaneous endoscopic gastrostomy; URTIs, upper respiratory tract infections; LRTIs, lower respiratory tract infections; H, hospitalization for respiratory issues; ACT, airway clearance technique; n/year, number of events in the previous year; Y, yes; N, no; NIV, non-invasive ventilation.

.

Concerning comorbidities, epilepsy, managed with antiepileptic drugs, was observed in 15/23 (65%) patients.

Additionally, one patient (n. 22) took antiepileptic therapy due to the presence of abundant multifocal interictal epileptiform abnormalities on electroencephalography, without symptomatic epilepsy. All of them had good control of seizures.

Scoliosis, another common comorbidity, was present in 12/23 (52%) patients. One of them (n. 19) underwent arthrodesis surgery at the age of 11 years. Furthermore, 12 out of 23 (52%) patients were wheelchair dependent; 7/12 (58%) had scoliosis, and 5/12 (42%) did not have it. Fisher test analysis did not show statistical significance between the two percentages.

Investigating respiratory issues, 13/23 (56%) patients presented at least one episode of URTI, and 9/23 (39%) presented at least one episode of LRTI. The URTI number (median = 1; range 0–12) did not differ from the LRTI one (0; 0–10). The median value of antibiotic administration was 1 (range 0–12). LRTIs, but not URTIs, showed a strong positive correlation with antibiotic therapy (Pearson r = 0.6, p < 0.005). Furthermore, the LRTI number positively correlated with the number of hospitalizations due to respiratory issues (Pearson r = 0.8, p < 0.0001) (Figure 1a, b); this correlation was not found for the URTI number.

The number of LRTIs and URTIs was not statistically different in the presence of comorbidities such as epilepsy or scoliosis.

Four patients (17% n. 9, 15, 21, 22) underwent an airway clearance technique (ACT) with cough assistance.

Two patients (n. 19, 22) underwent an intensified ACT program with cough assistance to prevent respiratory infections during the post-operation period. One of these patients underwent arthrodesis surgery for severe scoliosis; the other one had a laparoscopic left salpingo-ovariectomy for an immature cystic teratoma. Both required invasive ventilation through endotracheal intubation (ET-IV) for about 3 h. Successively, admitted to an ordinary pediatric ward, they received non-invasive ventilatory support using high-flow nasal cannula oxygen therapy (HFNC) for 24 h and ACT by mechanical cough assistance three times/day for seven days. They did not present any post-operative complications.

3.2. Polygraphy Data

Fifteen patients (65%), mean age 9.8 ± 4.4 years old, underwent oPG as they presented one or more of the following symptoms: snoring, obstructive apnea, hypotonia, and scoliosis. All data of oPG are summarized in

Table 3. Polygraphic data.

	Patient	TST (Minutes)	Snoring Time (%)	AHI (Events/h)	oAHI (Events/h)	CAHI (Events/h)	ODI (Events/h)	Mean SpO2 (%)	T90 (%)	PtcCO2 > 50 mmHg (%)
NO OSA oAHI < 1	23	240	10.9	0.5	0	0	4.6	97	1.5	-
	17	297	1.6	0.8	0.2	0.6	1.2	97	0.1	-
	14	423	4.1	1.4	0.4	0.1	1.3	97	0.2	-
	18	449	9.5	0.4	0.4	0	0.5	97	0	-
	10	336	9.7	1.4	0.9	0.4	1.1	96	0	-
MILD OSA 1 < oAHI ≤ 5	22	480	N/A	10.2	2.8	7.2	37	95	N/A	91
	16	335	7.3	5.9	3.4	2.5	0.4	95	1.8	-
	11	467	50	5.1	3.7	1.3	8.7	94	0.6	-
	5	382	19.7	4.7	3.8	0.9	3.5	97	0.2	-
	19	240	3.1	6.8	3.8	2.7	9.2	95	0.1	-
	9	394	0.3	4.5	4.5	0	3.1	96	1.4	-
MODERATE OSA 5 < oAHI < 10	4	291	N/A	7.4	7.4	0	26.6	92	2.9	-
	3	466	11.1	8.2	7.6	0.6	4.2	96	1.9	-
SEVERE OSA oAHI≥ 10	15	240	N/A	11.5	10.7	0.4	18	95	N/A	100
	21	285	28.1	15.8	11.1	3.4	10.3	94	1.3	91
Mean ± DS		355 ± 88.2
Median; range			9.6; 0.3–50	4.9; 0.4–15.8	3.7; 0–11.1	0.4; 0–7.2	3.8; 0.4–37	96; 92–97	0.6; 0–2.9	91; 91–100

Abbreviations: TST, total sleep time; snoring time (%): percentage of the TST spent snoring; AHI, apnea–hypopnea index; oAHI, obstructive apnea–hypopnea index; CAHI, central apnea–hypopnea index; ODI, oxygen desaturation index; SpO₂, oxygen saturation by pulse oximetry; T90 (%), percentage of the TST spent with an SpO₂ < 90%; tcPCO₂ > 50 mmHg (%): the percentage of TST spent with a PtcCO₂ > 50 mmHg; PtcCO₂, transcutaneous carbon dioxide; N/A, not available.

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Median oAHI was 3.7 events/h (range 0–11.1); median CAHI was 0.4 events/h (0–7.2). No correlation was found between oAHI or CAHI and age of girls.

The median ODI was 3.8 (range 0.4–37); the median value of mean SpO₂ and T90 were 96 (range 92–97) and 0.6 (0–2.9), respectively.

According to oAHI, 10/15 (67%) patients had OSA: 6 of them (60%) mild OSA, 2 (20%) moderate OSA, and 2 (20%) severe OSA. One patient (n. 22) had clinically significant CSA (CAHI ≥ 5 events/h) (Figure 2a,b).

Comparing the oPG data to respiratory problems, we showed that 50% of patients with OSA presented at least one LRTI in comparison to the group without OSA who did not have LRTIs (p < 0.0001) (Figure 3).

Moreover, oAHI positively correlated with episodes of LRTIs (Pearson r = 0.7, p < 0.01) (Figure 4) but not with URTIs.

In the case of comorbidities such as epilepsy and scoliosis, we found that the same percentage of patients had scoliosis and/or epilepsy, independent from the presence of OSA.

Three patients with severe apnea syndrome (patients n. 15, 21 OSA; patient n. 22 CSA; Table 3) underwent PtcCO₂ recording. Mean values of mean and maximum PtcCO₂ were 54.8 ± 2.16 mmHg and 60.86 ± 2.52 mmHg, respectively. They showed nocturnal hypercapnia, with a median value of % of TST with PtcCO₂ > 50 mmHg of 91 (range 91–100). For this reason, patients 21 and 22 received non-invasive ventilatory support, and patient 15 underwent invasive ventilation via tracheostomy.

4. Discussion

Patients with RS present a complex and multifaceted clinical profile, with comorbidities affecting virtually every organ system [5]. The most frequently observed complications are neurological manifestations such as epilepsy and movement disorders; orthopedic problems, including scoliosis; and gastrointestinal and nutritional issues [9]. In our retrospective study, we first described the prevalence and therapeutic management of major comorbidities in a cohort of children and adolescents with RS. We found a high prevalence of epilepsy with more than two-thirds (70%) of our girls taking antiepileptic medications at the time of enrolment, as described in adults [9]. Our data also confirmed that scoliosis, which occurred in about half of our patients, is a common comorbidity, although with a lower prevalence, especially as regards corrective surgery, than that in a previous paper [9]. This could be explained by the average age of our population (mean age at enrolment 9.2 ± 4.2 years old); in fact, it is described that 75% of RS patients develop scoliosis by the age of 15 years and that severe conditions requiring surgery are rare before age 9 years [10]. So, in conclusion, both epilepsy and scoliosis are early-onset comorbidities that should be recognized and treated appropriately. Indeed, early therapeutic interventions have shown improvement in survival as well as in the control of other comorbidities, such as respiratory infections [10]. About nutritional issues, almost all the patients of our pediatric population received food orally (solid or semi-solid feeding), showing a good weigh gain and no reported symptoms and signs of aspiration. Only 9% had enteral nutrition exclusively through a PEG for documented risk of aspiration. The risk of inhalation seems to increase with age; in fact, the percentage of patients in our study with a PEG is lower than that of adults (27%) [9].

Our data showed that respiratory involvement, particularly respiratory infection, was an important condition with significant consequences such as use of antibiotic therapy and hospitalization. These data are consistent with the results of a recent study that underlines the risk of severe healthcare-associated infections, commonly sustained by antimicrobial-resistant microorganisms, in patients with complex and chronic conditions like RS [5]. Moreover, it is known that the hospitalization of children with complex disease affects the quality of life of patients and their families, due to the detachment from their place of origin, economic issues, and work difficulties for parents. In addition, the management of these patients requires highly specialized healthcare structures and several subspecialists. However, these centers are not always near the patients’ residences, due to the non-homogeneous geographical distribution of healthcare resources, worsening the discomfort of hospitalizations [11].

Although this topic is not addressed by currently available guidelines [12], an early daily physiotherapy program could be useful to prevent respiratory infections. As in other complex chronic conditions, the use of airway clearance techniques, such as mechanical cough assistance, could be useful for RS patients; therefore, we recommend intensifying the ACT program in case of a respiratory flare-up or during the post-operation period.

Regarding respiratory involvement, SDB is another important issue. It may be easily overlooked due to the clinical heterogeneity of RS and the high burden of other comorbidities that often dominate the clinical picture. However, the potential consequences of unrecognized SDB, including poor sleep quality, daytime somnolence, impaired cognitive functioning, and even cardiopulmonary complications, underscore the importance of systematically screening for these disturbances. In our study we performed oPG in 65% of the RS population; we recognize that this is a limitation. However, it is important to consider that the sleep study is poorly tolerated by patients and their caregivers, especially in the absence of symptoms. Finally, this method is expensive and time consuming. According to the recent Italian experts’ consensus [5], patients in our cohort presenting at least one symptom, such as snoring, obstructive apnea, hypotonia, and scoliosis, underwent sleep study. Although polysomnography (PSG) is the gold standard for the diagnosis of sleep-disordered breathing, it is an expensive, poorly tolerated, and time-consuming tool. Polygraphy is more affordable than PSG, showing good sensitivity and specificity in the presence of moderate–severe sleep apnea. In order to reduce the burden of hospitalizations, our patients underwent home oPG. This tool provides several benefits for the diagnosis of OSA, especially for pediatric populations, such as increasing diagnostic accuracy and simplifying the diagnostic process, with no significant difference in results compared with PSG [13].

Most of our patients (67%) had a diagnosis of OSA—moderate to severe in almost half of them. Central sleep apnea was found in only one patient (7%) with mild OSA. These data confirm the higher prevalence of obstructive respiratory events than central events in patients with RS [14,15].

Interestingly, no correlation was found between oAHI or CAHI and age, suggesting that severity may be independent of age. Regarding comorbidities, the presence of sleep apnea was not related to epilepsy, consistent with previous reports [15], and scoliosis.

However, our three patients with hypoventilation (n. 15, 21, 22) had scoliosis, in agreement with Hagebeuk et al. [16]. These data suggest that patients with RS and scoliosis should be carefully evaluated, in particular before surgery, by means of a polygraphy study along with non-invasive carbon dioxide monitoring [17].

Although the increased vulnerability to lower respiratory infection in patients with RS is known, and its relationship with age, mutation type, feeding, and walking status has already been investigated [18], to the best of our knowledge, our study for the first time evaluated the relationship between respiratory infections and sleep apnea. A significant positive correlation between OSA and LRTIs was observed, indicating that a greater severity of obstructive sleep apnea is associated with a higher frequency of respiratory infections. This finding could be explained by the potential role of sleep apnea in worsening airway inflammation and the mismatch in ventilation and perfusion, already known in subjects with RS [19].

Given the potential impact of SDB on overall health, we strongly support the inclusion of sleep-focused respiratory assessment in the routine clinical evaluation of patients with RS. While full polysomnography remains the gold standard, simplified tools such as oPG represent a feasible and informative alternative, particularly in fragile and uncooperative patients.

Notably, in our sample, respiratory events were often not associated with significant oxygen desaturation, underscoring the role of CO₂ monitoring in detecting subtle hypoventilation that might otherwise go unnoticed. It would therefore be desirable to perform a sleep study using transcutaneous CO₂ recording in addition to polygraphy. This is a limitation of our study due to the unavailability of home transcutaneous CO₂ equipment, which was therefore reserved for the most severe cases.

Our findings highlight the high prevalence of sleep-related respiratory disorders and their association with respiratory infections in children with RS. Multidisciplinary services and programs are necessary to optimize health and wellbeing in this vulnerable population with enhancement of systematic respiratory assessments, including sleep studies, and implementation of early airway clearance techniques and ventilatory support.