Vol. 12/ Núm. 2 2025 pág. 1722
https://doi.org/10.69639/arandu.v12i2.1022
Rett syndrome in a pediatric patient: progressive clinical
presentation and genetic confirmation via mecp2 mutation
Síndrome de Rett en un paciente pediátrico: presentación clínica progresiva y
confirmación genética mediante la mutación mecp2
Hugo Esteban Salazar Lozano
esalazar@uce.edu.ec
https://orcid.org/0009-0005-7128-8376
Universidad Central del Ecuador
Ana Karina Pérez León
akperezl@uce.edu.ec
https://orcid.org/0009-0007-2503-5671
Universidad Central del Ecuador
María Daniela Pérez León
maria.perez.04d03@dpsca.gob.ec
https://orcid.org/0009-0004-7545-7061
Ministerio de Salud Pública, Ecuador
Andrea Carolina Pérez León
acperezl@uce.edu.ec
https://orcid.org/0009-0008-0191-4601
Universidad Central del Ecuador
Diego Fernando Atapuma Madrid
dfatapuma@uce.edu.ec
https://orcid.org/0009-0000-3029-6592
Universidad Central del Ecuador
Artículo recibido: 10 marzo 2025 - Aceptado para publicación: 20 abril 2025
Conflictos de intereses: Ninguno que declarar
ABSTRACT
Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder characterized by an early
phase of apparently normal development, followed by rapid regression in language, motor
coordination, and purposeful hand use. We report the case of a female pediatric patient with
classic RTT confirmed by a de novo pathogenic mutation in the MECP2 gene. The patient
developed typically until 18 months of age, when she began to lose speech, motor function, social
interaction, and developed stereotypic hand movements. Initially misdiagnosed with autism
spectrum disorder and cerebral palsy, genetic testing ultimately provided definitive diagnosis.
The clinical picture included motor apraxia, epilepsy, axial hypotonia, respiratory dysautonomia,
gastrointestinal dysfunction, and neurocognitive impairment. Despite intensive multidisciplinary
care—physical, occupational, speech and respiratory therapy—along with adjunct treatments like
cannabidiol and ozone therapy, her condition progressively deteriorated. She died at age 9 years
and 9 months from rhinovirus pneumonia and acute respiratory failure. This case highlights the
diagnostic delays commonly associated with RTT in resource-limited settings and underscores
Vol. 12/ Núm. 2 2025 pág. 1723
the importance of early clinical suspicion, prompt MECP2 testing in cases of developmental
regression, and comprehensive multidisciplinary management. It also demonstrates the crucial
role of family support in preserving quality of life. This report contributes to the clinical literature
by offering a complete view of the classical RTT trajectory and reinforcing the urgent need for
public health policies ensuring genomic access and long-term specialized care for rare
neurodevelopmental conditions.
Keywords: rett syndrome, mecp2 protein human, genetic testing, neurodevelopmental
disorders, pediatric neurology
RESUMEN
El síndrome de Rett (SR) es un trastorno neurodesarrollativo ligado al cromosoma X,
caracterizado por una fase temprana de desarrollo aparentemente normal seguida de una rápida
regresión del lenguaje, la coordinación motora y el uso intencional de las manos. Presentamos el
caso de una paciente pediátrica femenina con SR clásico confirmado por una mutación patogénica
de novo en el gen MECP2. La paciente alcanzó hitos psicomotores típicos hasta los 18 meses,
momento en el que perdió progresivamente el habla, la función motora y la interacción social, y
desarrolló movimientos estereotipados de las manos. Inicialmente fue diagnosticada
erróneamente con trastorno del espectro autista y parálisis cerebral. La prueba genética
proporcionó el diagnóstico definitivo. El cuadro clínico incluyó apraxia motora, epilepsia,
hipotonía axial, disautonomía respiratoria, disfunción gastrointestinal y deterioro neurocognitivo.
A pesar de un manejo multidisciplinario intensivo —terapia física, ocupacional, del lenguaje y
respiratoria— junto con tratamientos complementarios como cannabidiol y ozonoterapia, la
paciente empeoró de forma progresiva. Falleció a los 9 años y 9 meses por neumonía por rinovirus
e insuficiencia respiratoria aguda. Este caso evidencia los retrasos diagnósticos frecuentes en
entornos con recursos limitados y subraya la importancia de la sospecha clínica temprana, la
realización pronta de la secuenciación de MECP2 en casos de regresión del desarrollo y un
abordaje multidisciplinario integral. Asimismo, destaca el papel esencial del apoyo familiar en el
mantenimiento de la calidad de vida. Este informe contribuye a la literatura clínica al ofrecer una
visión completa de la evolución clásica del SR y refuerza la necesidad urgente de políticas
públicas que garanticen el acceso a pruebas genómicas y una atención especializada continua para
trastornos neurodesarrollativos raros.
Palabras clave: síndrome de rett, proteína mecp2 humana, pruebas genéticas, trastornos
del neurodesarrollo, neurología pediátrica
Todo el contenido de la Revista Científica Internacional Arandu UTIC publicado en este sitio está disponible bajo
licencia Creative Commons Atribution 4.0 International.
the importance of early clinical suspicion, prompt MECP2 testing in cases of developmental
regression, and comprehensive multidisciplinary management. It also demonstrates the crucial
role of family support in preserving quality of life. This report contributes to the clinical literature
by offering a complete view of the classical RTT trajectory and reinforcing the urgent need for
public health policies ensuring genomic access and long-term specialized care for rare
neurodevelopmental conditions.
Keywords: rett syndrome, mecp2 protein human, genetic testing, neurodevelopmental
disorders, pediatric neurology
RESUMEN
El síndrome de Rett (SR) es un trastorno neurodesarrollativo ligado al cromosoma X,
caracterizado por una fase temprana de desarrollo aparentemente normal seguida de una rápida
regresión del lenguaje, la coordinación motora y el uso intencional de las manos. Presentamos el
caso de una paciente pediátrica femenina con SR clásico confirmado por una mutación patogénica
de novo en el gen MECP2. La paciente alcanzó hitos psicomotores típicos hasta los 18 meses,
momento en el que perdió progresivamente el habla, la función motora y la interacción social, y
desarrolló movimientos estereotipados de las manos. Inicialmente fue diagnosticada
erróneamente con trastorno del espectro autista y parálisis cerebral. La prueba genética
proporcionó el diagnóstico definitivo. El cuadro clínico incluyó apraxia motora, epilepsia,
hipotonía axial, disautonomía respiratoria, disfunción gastrointestinal y deterioro neurocognitivo.
A pesar de un manejo multidisciplinario intensivo —terapia física, ocupacional, del lenguaje y
respiratoria— junto con tratamientos complementarios como cannabidiol y ozonoterapia, la
paciente empeoró de forma progresiva. Falleció a los 9 años y 9 meses por neumonía por rinovirus
e insuficiencia respiratoria aguda. Este caso evidencia los retrasos diagnósticos frecuentes en
entornos con recursos limitados y subraya la importancia de la sospecha clínica temprana, la
realización pronta de la secuenciación de MECP2 en casos de regresión del desarrollo y un
abordaje multidisciplinario integral. Asimismo, destaca el papel esencial del apoyo familiar en el
mantenimiento de la calidad de vida. Este informe contribuye a la literatura clínica al ofrecer una
visión completa de la evolución clásica del SR y refuerza la necesidad urgente de políticas
públicas que garanticen el acceso a pruebas genómicas y una atención especializada continua para
trastornos neurodesarrollativos raros.
Palabras clave: síndrome de rett, proteína mecp2 humana, pruebas genéticas, trastornos
del neurodesarrollo, neurología pediátrica
Todo el contenido de la Revista Científica Internacional Arandu UTIC publicado en este sitio está disponible bajo
licencia Creative Commons Atribution 4.0 International.
Vol. 12/ Núm. 2 2025 pág. 1724
INTRODUCTION
Rett syndrome (RS) is a neurodevelopmental disorder that predominantly affects females,
with an estimated incidence of 1 in every 10,000 to 15,000 live female births (Neul et al., 2022).
It is characterized by apparently normal early development, followed by a regression in motor
and language skills between 6 and 18 months of age (NINDS, 2024). Clinical features include
loss of purposeful hand use, stereotypic hand movements, gait abnormalities, acquired
microcephaly, and progressive cognitive impairment (NINDS, 2024).
The etiology of RS is primarily attributed to mutations in the MECP2 gene located on the
X chromosome, which encodes the methyl-CpG-binding protein 2 (MeCP2), essential for
regulating gene expression in the central nervous system (Amir et al., 1999). These de novo
mutations alter MeCP2 function, impacting astrocyte maturation and brain bioenergetics (Zoghbi,
2005; Neul et al., 2022).
Diagnosis of RS relies on established clinical criteria supported by genetic testing that
confirms the presence of MECP2 mutations (Rett Syndrome Foundation, 2024). However, early
recognition is challenging due to phenotypic overlap with other neurodevelopmental disorders,
such as autism spectrum disorder and cerebral palsy (NINDS, 2024). This clinical similarity can
result in misdiagnoses or delayed identification, which negatively impacts timely intervention and
management.
RS progression is divided into four clinical stages: early onset, rapid regression,
stabilization, and late motor deterioration (NINDS, 2024). Each stage presents distinct
characteristics that reflect the natural history of the disorder. Understanding these phases is
essential for clinical monitoring and therapeutic planning.
Management of RS requires a multidisciplinary approach focused on symptom relief and
quality of life improvement. Interventions include physical, occupational, and speech therapy,
along with management of comorbidities such as epilepsy and respiratory problems (Rett
Syndrome Foundation, 2024). Although there is no cure, recent advances in gene therapy and
pharmacological research offer hope for more effective treatments (Frontiers in Neuroscience,
2023).
In March 2023, the Food and Drug Administration (FDA) approved trofinetide
(DAYBUE™) as the first targeted treatment for RS in patients aged two years and older, marking
a major milestone in the therapeutic landscape (FDA, 2023). This drug demonstrated significant
symptom improvement in clinical trials, representing a meaningful advancement in RS care
(Glaze et al., 2023).
The heterogeneity in clinical presentation and progression of RS highlights the importance
of detailed case reports that document individual patient trajectories. Such reports enrich clinical
INTRODUCTION
Rett syndrome (RS) is a neurodevelopmental disorder that predominantly affects females,
with an estimated incidence of 1 in every 10,000 to 15,000 live female births (Neul et al., 2022).
It is characterized by apparently normal early development, followed by a regression in motor
and language skills between 6 and 18 months of age (NINDS, 2024). Clinical features include
loss of purposeful hand use, stereotypic hand movements, gait abnormalities, acquired
microcephaly, and progressive cognitive impairment (NINDS, 2024).
The etiology of RS is primarily attributed to mutations in the MECP2 gene located on the
X chromosome, which encodes the methyl-CpG-binding protein 2 (MeCP2), essential for
regulating gene expression in the central nervous system (Amir et al., 1999). These de novo
mutations alter MeCP2 function, impacting astrocyte maturation and brain bioenergetics (Zoghbi,
2005; Neul et al., 2022).
Diagnosis of RS relies on established clinical criteria supported by genetic testing that
confirms the presence of MECP2 mutations (Rett Syndrome Foundation, 2024). However, early
recognition is challenging due to phenotypic overlap with other neurodevelopmental disorders,
such as autism spectrum disorder and cerebral palsy (NINDS, 2024). This clinical similarity can
result in misdiagnoses or delayed identification, which negatively impacts timely intervention and
management.
RS progression is divided into four clinical stages: early onset, rapid regression,
stabilization, and late motor deterioration (NINDS, 2024). Each stage presents distinct
characteristics that reflect the natural history of the disorder. Understanding these phases is
essential for clinical monitoring and therapeutic planning.
Management of RS requires a multidisciplinary approach focused on symptom relief and
quality of life improvement. Interventions include physical, occupational, and speech therapy,
along with management of comorbidities such as epilepsy and respiratory problems (Rett
Syndrome Foundation, 2024). Although there is no cure, recent advances in gene therapy and
pharmacological research offer hope for more effective treatments (Frontiers in Neuroscience,
2023).
In March 2023, the Food and Drug Administration (FDA) approved trofinetide
(DAYBUE™) as the first targeted treatment for RS in patients aged two years and older, marking
a major milestone in the therapeutic landscape (FDA, 2023). This drug demonstrated significant
symptom improvement in clinical trials, representing a meaningful advancement in RS care
(Glaze et al., 2023).
The heterogeneity in clinical presentation and progression of RS highlights the importance
of detailed case reports that document individual patient trajectories. Such reports enrich clinical
Vol. 12/ Núm. 2 2025 pág. 1725
understanding and may identify patterns that inform better care and intervention strategies (Neul
et al., 2022).
In this context, we present the case of a pediatric patient with genetically confirmed RS,
highlighting her clinical evolution, diagnostic challenges, and the interdisciplinary strategies
implemented. This report aims to contribute to the clinical knowledge of RS and emphasize the
importance of accurate and timely diagnosis.
METHODOLOGY
This case report was conducted in accordance with the CARE (CAse REport) guidelines to
ensure completeness and transparency in clinical documentation. All data were retrospectively
collected from the patient’s medical records, specialist reports, genetic studies, therapeutic
evaluations, and caregiver interviews. The patient was followed from birth until her death at 9
years and 9 months of age. Clinical observations, symptom progression, and therapeutic responses
were documented by a multidisciplinary team, including pediatric neurology, medical genetics,
pulmonology, gastroenterology, physical therapy, occupational therapy, and speech-language
pathology.
The diagnosis of Rett syndrome was confirmed through next-generation sequencing (NGS)
identifying a de novo pathogenic variant in the MECP2 gene. Functional assessments were
compiled using standardized instruments such as the Sensorium profile (for sensory modulation)
and institutional neuromuscular evaluation protocols to document changes in posture, mobility,
and communication. Supporting documentation included the metabolic screening report, genetic
confirmation file, and clinical summaries of orthotic and respiratory management strategies. All
personally identifiable information was anonymized in accordance with ethical publication
standards, and written consent was obtained from the patient’s family for the use of medical
information and for the publication of this report.
Case Presentation
We present the case of a female patient born in Ecuador by cesarean section at 38 weeks
of gestation, following an uneventful pregnancy. Apgar scores were 8 at one minute and 9 at five
minutes. No immediate neonatal complications were reported, and exclusive breastfeeding was
provided during the first months. The patient lived in a stable, middle-income household with no
family history of neurological or genetic disorders. No perinatal risk factors were identified, and
her early development was considered normal until 18 months of age.
During the first year of life, the patient reached developmental milestones within expected
ranges: head control at 2 months, sitting at 6 months, crawling at 11 months, and independent
walking by 14 months. Babbling began at 6 months, and her first words were spoken by 11
months. She demonstrated appropriate social interaction, sustained eye contact, and functional
play. However, from 18 months onward, a progressive regression was noted, starting with loss of
understanding and may identify patterns that inform better care and intervention strategies (Neul
et al., 2022).
In this context, we present the case of a pediatric patient with genetically confirmed RS,
highlighting her clinical evolution, diagnostic challenges, and the interdisciplinary strategies
implemented. This report aims to contribute to the clinical knowledge of RS and emphasize the
importance of accurate and timely diagnosis.
METHODOLOGY
This case report was conducted in accordance with the CARE (CAse REport) guidelines to
ensure completeness and transparency in clinical documentation. All data were retrospectively
collected from the patient’s medical records, specialist reports, genetic studies, therapeutic
evaluations, and caregiver interviews. The patient was followed from birth until her death at 9
years and 9 months of age. Clinical observations, symptom progression, and therapeutic responses
were documented by a multidisciplinary team, including pediatric neurology, medical genetics,
pulmonology, gastroenterology, physical therapy, occupational therapy, and speech-language
pathology.
The diagnosis of Rett syndrome was confirmed through next-generation sequencing (NGS)
identifying a de novo pathogenic variant in the MECP2 gene. Functional assessments were
compiled using standardized instruments such as the Sensorium profile (for sensory modulation)
and institutional neuromuscular evaluation protocols to document changes in posture, mobility,
and communication. Supporting documentation included the metabolic screening report, genetic
confirmation file, and clinical summaries of orthotic and respiratory management strategies. All
personally identifiable information was anonymized in accordance with ethical publication
standards, and written consent was obtained from the patient’s family for the use of medical
information and for the publication of this report.
Case Presentation
We present the case of a female patient born in Ecuador by cesarean section at 38 weeks
of gestation, following an uneventful pregnancy. Apgar scores were 8 at one minute and 9 at five
minutes. No immediate neonatal complications were reported, and exclusive breastfeeding was
provided during the first months. The patient lived in a stable, middle-income household with no
family history of neurological or genetic disorders. No perinatal risk factors were identified, and
her early development was considered normal until 18 months of age.
During the first year of life, the patient reached developmental milestones within expected
ranges: head control at 2 months, sitting at 6 months, crawling at 11 months, and independent
walking by 14 months. Babbling began at 6 months, and her first words were spoken by 11
months. She demonstrated appropriate social interaction, sustained eye contact, and functional
play. However, from 18 months onward, a progressive regression was noted, starting with loss of
Vol. 12/ Núm. 2 2025 pág. 1726
language and social interaction. By 20 months, gait instability emerged, with a wide base and
frequent falls. At 22 months, hand stereotypies appeared, including wringing, rubbing, and
flapping movements. She lost purposeful hand use, fine motor skills, and eventually gross motor
function.
Neurological symptoms progressed rapidly. At 2 years and 4 months, she developed severe
motor apraxia, frequent backward falls, and difficulty maintaining posture. A protective helmet
was required. At 3 years and 3 months, she had her first generalized tonic-clonic seizure, marking
a significant decline: she lost independent ambulation and required orthotic support.
Subsequently, she developed episodic hyperventilation, progressive scoliosis, and hypotonia. Her
sleep remained relatively stable, with occasional nighttime awakenings. The use of cannabidiol
was cited as a possible factor in her sleep regulation by the family, who denied any persistent
sleep disturbances.
At 4 years and 4 months, she began experiencing persistent postprandial vomiting and
coughing, with suspected gastroesophageal reflux. However, diagnostic studies were negative,
and neurological dysphagia was suspected. Four choking episodes required home resuscitation
by caregivers. Consequent weight loss resulted in alopecia, partially managed with
supplementation and local ozone therapy. Nutritional strategies were implemented, including
high-fiber diets and fruits such as pitahaya and prunes, to manage intermittent but significant
constipation.
Neurological examination by multiple pediatric neurologists revealed axial hypotonia, mild
spasticity, hyperreflexia, and positive Babinski sign. Neuropsychological assessments included
partial administration of the Vineland scale; CARS and ADOS were not performed. Sensory
assessment indicated generalized hyposensitivity. Multisensory therapy began at 22 months,
leading to partial improvements in visual contact and auditory responsiveness. Cognitively, she
demonstrated severe expressive language delay and nonverbal communication limited to gaze
signaling. She did not develop sphincter control or functional autonomy.
The initial differential diagnosis included autism spectrum disorder, cerebral palsy,
generalized epilepsies, and nonspecific genetic syndromes. Complementary studies included EEG
showing frontal spikes and generalized slowing, brain MRI with no significant atrophy, and
normal visual and auditory evoked potentials. Expanded metabolic panels, both national and
international, ruled out inborn errors of metabolism. At age 3, a geneticist recommended MECP2
sequencing using NGS, which confirmed a pathogenic mutation (Figure 1). Maternal carrier
testing was negative, and the mutation was classified as de novo.
language and social interaction. By 20 months, gait instability emerged, with a wide base and
frequent falls. At 22 months, hand stereotypies appeared, including wringing, rubbing, and
flapping movements. She lost purposeful hand use, fine motor skills, and eventually gross motor
function.
Neurological symptoms progressed rapidly. At 2 years and 4 months, she developed severe
motor apraxia, frequent backward falls, and difficulty maintaining posture. A protective helmet
was required. At 3 years and 3 months, she had her first generalized tonic-clonic seizure, marking
a significant decline: she lost independent ambulation and required orthotic support.
Subsequently, she developed episodic hyperventilation, progressive scoliosis, and hypotonia. Her
sleep remained relatively stable, with occasional nighttime awakenings. The use of cannabidiol
was cited as a possible factor in her sleep regulation by the family, who denied any persistent
sleep disturbances.
At 4 years and 4 months, she began experiencing persistent postprandial vomiting and
coughing, with suspected gastroesophageal reflux. However, diagnostic studies were negative,
and neurological dysphagia was suspected. Four choking episodes required home resuscitation
by caregivers. Consequent weight loss resulted in alopecia, partially managed with
supplementation and local ozone therapy. Nutritional strategies were implemented, including
high-fiber diets and fruits such as pitahaya and prunes, to manage intermittent but significant
constipation.
Neurological examination by multiple pediatric neurologists revealed axial hypotonia, mild
spasticity, hyperreflexia, and positive Babinski sign. Neuropsychological assessments included
partial administration of the Vineland scale; CARS and ADOS were not performed. Sensory
assessment indicated generalized hyposensitivity. Multisensory therapy began at 22 months,
leading to partial improvements in visual contact and auditory responsiveness. Cognitively, she
demonstrated severe expressive language delay and nonverbal communication limited to gaze
signaling. She did not develop sphincter control or functional autonomy.
The initial differential diagnosis included autism spectrum disorder, cerebral palsy,
generalized epilepsies, and nonspecific genetic syndromes. Complementary studies included EEG
showing frontal spikes and generalized slowing, brain MRI with no significant atrophy, and
normal visual and auditory evoked potentials. Expanded metabolic panels, both national and
international, ruled out inborn errors of metabolism. At age 3, a geneticist recommended MECP2
sequencing using NGS, which confirmed a pathogenic mutation (Figure 1). Maternal carrier
testing was negative, and the mutation was classified as de novo.
Vol. 12/ Núm. 2 2025 pág. 1727
Figure 1
Shows the official genetic report confirming the de novo pathogenic variant in the MECP2 gene
Following genetic confirmation, the therapeutic plan was restructured. The patient received
intensive interdisciplinary care, involving pediatric neurology, genetics, orthopedics,
pulmonology, gastroenterology, physical, occupational, language, respiratory, and sensory
therapy. Home-based special education was integrated, with school attendance before the
COVID-19 pandemic. Prescribed medications included anticonvulsants, antispasmodics,
nutritional supplements, and cannabidiol. The family also pursued complementary therapies such
as homeopathy, ozone therapy, and multisensory stimulation, which they reported as helpful in
stabilizing symptoms.
The clinical course was marked by phases of relative stability followed by gradual decline.
She remained fully dependent for mobility, feeding, and self-care. Despite continuous
interventions, her functional prognosis remained poor. The family provided consistent support,
using adaptive equipment, orthotic devices, passive respiratory aids, and daily stimulation. At 9
years and 9 months, the patient developed a hospital-acquired pneumonia caused by rhinovirus
that proved refractory to treatment, resulting in acute respiratory failure and death, consistent with
the terminal stage of classical Rett syndrome.
DISCUSSION
Rett syndrome (RTT) is recognized as one of the most complex epigenetic
encephalopathies of neurodevelopment, where early identification remains a substantial clinical
challenge (Lyst & Bird, 2015). Multicenter studies have indicated that the diagnostic interval
from the onset of initial signs to genetic confirmation can exceed two to three years on average
(Tarquinio et al., 2015). In this case, the diagnostic delay and initial confusion with disorders such
as autism spectrum disorder (ASD) or cerebral palsy reflect a pattern commonly described in the
Figure 1
Shows the official genetic report confirming the de novo pathogenic variant in the MECP2 gene
Following genetic confirmation, the therapeutic plan was restructured. The patient received
intensive interdisciplinary care, involving pediatric neurology, genetics, orthopedics,
pulmonology, gastroenterology, physical, occupational, language, respiratory, and sensory
therapy. Home-based special education was integrated, with school attendance before the
COVID-19 pandemic. Prescribed medications included anticonvulsants, antispasmodics,
nutritional supplements, and cannabidiol. The family also pursued complementary therapies such
as homeopathy, ozone therapy, and multisensory stimulation, which they reported as helpful in
stabilizing symptoms.
The clinical course was marked by phases of relative stability followed by gradual decline.
She remained fully dependent for mobility, feeding, and self-care. Despite continuous
interventions, her functional prognosis remained poor. The family provided consistent support,
using adaptive equipment, orthotic devices, passive respiratory aids, and daily stimulation. At 9
years and 9 months, the patient developed a hospital-acquired pneumonia caused by rhinovirus
that proved refractory to treatment, resulting in acute respiratory failure and death, consistent with
the terminal stage of classical Rett syndrome.
DISCUSSION
Rett syndrome (RTT) is recognized as one of the most complex epigenetic
encephalopathies of neurodevelopment, where early identification remains a substantial clinical
challenge (Lyst & Bird, 2015). Multicenter studies have indicated that the diagnostic interval
from the onset of initial signs to genetic confirmation can exceed two to three years on average
(Tarquinio et al., 2015). In this case, the diagnostic delay and initial confusion with disorders such
as autism spectrum disorder (ASD) or cerebral palsy reflect a pattern commonly described in the
Vol. 12/ Núm. 2 2025 pág. 1728
literature (Kaufmann et al., 2021), underscoring the necessity of including RTT in the differential
diagnosis of psychomotor regression in girls during the first two years of life (Neul et al., 2014).
The age of regression onset in this patient—around 18 months—is consistent with cohorts
reported in Europe, Asia, and America, where over 80% of classic cases begin between 12 and
24 months (Neul et al., 2010). The abrupt loss of language, visual contact, fine and subsequently
gross motor skills, followed by the emergence of hand stereotypies, aligns with the typical
sequence documented in multiple international clinical registries (Leonard et al., 2017; Laurvick
et al., 2006). This progressive phenotypic evolution is one of the most robust characteristics
distinguishing RTT from other neurodevelopmental disorders.
The neurological manifestations observed in the patient—particularly hand stereotypies,
motor apraxia, axial hypotonia, epileptic seizures, and ataxic gait—have been described as
cardinal signs of classic RTT (Percy et al., 2022). EEG studies have confirmed characteristic
patterns such as slow waves and frontal spikes, also found in this patient, supporting the diagnosis
(Buchanan et al., 2021). The onset of epilepsy around the age of three coincides with reports
indicating its initiation between 2 and 5 years in over 60% of cases, with a tendency toward
pharmacoresistant epilepsy in 30–40% of affected girls (Tarquinio et al., 2017).
The gastrointestinal and respiratory symptoms observed—such as postprandial vomiting,
coughing, bronchoaspiration, pharyngolaryngeal hypotonia, and episodic hyperventilation—
represent a frequently underestimated phenotype in RTT. Studies like that of Motil et al. (2012)
have indicated that up to 70% of girls with RTT develop autonomic digestive and respiratory
dysfunction, which is one of the main causes of morbidity and mortality in adolescents with the
syndrome. The progression to fatal rhinovirus pneumonia with acute respiratory failure, as
occurred in this patient, aligns with international reports on mortality due to respiratory causes in
RTT (Killian et al., 2020).
Regarding neuropsychological evaluations, the literature acknowledges that many standard
scales such as ADOS, WISC, or Vineland fail to fully capture the cognitive profile of girls with
RTT, given the severe motor and communicative impairment. However, eye-gaze
communication, recognized as a form of adaptive communication, has been validated as a
functional assessment strategy (Townend et al., 2016). In this case, the early initiation of sensory
therapies and nonverbal language may have contributed to preserving minimal social responses
despite progressive deterioration.
Diagnostic confirmation through MECP2 gene sequencing—as occurred in this case—
constitutes the gold standard. The most frequent mutations are located in the coding regions of
the methyl-binding domain (MBD) and the transcriptional repression domain (TRD), and certain
variants have been shown to be associated with more severe phenotypes (Neul et al., 2014; Bao
et al., 2021). Although the exact mutation is not specified in this case, the finding of a de novo
literature (Kaufmann et al., 2021), underscoring the necessity of including RTT in the differential
diagnosis of psychomotor regression in girls during the first two years of life (Neul et al., 2014).
The age of regression onset in this patient—around 18 months—is consistent with cohorts
reported in Europe, Asia, and America, where over 80% of classic cases begin between 12 and
24 months (Neul et al., 2010). The abrupt loss of language, visual contact, fine and subsequently
gross motor skills, followed by the emergence of hand stereotypies, aligns with the typical
sequence documented in multiple international clinical registries (Leonard et al., 2017; Laurvick
et al., 2006). This progressive phenotypic evolution is one of the most robust characteristics
distinguishing RTT from other neurodevelopmental disorders.
The neurological manifestations observed in the patient—particularly hand stereotypies,
motor apraxia, axial hypotonia, epileptic seizures, and ataxic gait—have been described as
cardinal signs of classic RTT (Percy et al., 2022). EEG studies have confirmed characteristic
patterns such as slow waves and frontal spikes, also found in this patient, supporting the diagnosis
(Buchanan et al., 2021). The onset of epilepsy around the age of three coincides with reports
indicating its initiation between 2 and 5 years in over 60% of cases, with a tendency toward
pharmacoresistant epilepsy in 30–40% of affected girls (Tarquinio et al., 2017).
The gastrointestinal and respiratory symptoms observed—such as postprandial vomiting,
coughing, bronchoaspiration, pharyngolaryngeal hypotonia, and episodic hyperventilation—
represent a frequently underestimated phenotype in RTT. Studies like that of Motil et al. (2012)
have indicated that up to 70% of girls with RTT develop autonomic digestive and respiratory
dysfunction, which is one of the main causes of morbidity and mortality in adolescents with the
syndrome. The progression to fatal rhinovirus pneumonia with acute respiratory failure, as
occurred in this patient, aligns with international reports on mortality due to respiratory causes in
RTT (Killian et al., 2020).
Regarding neuropsychological evaluations, the literature acknowledges that many standard
scales such as ADOS, WISC, or Vineland fail to fully capture the cognitive profile of girls with
RTT, given the severe motor and communicative impairment. However, eye-gaze
communication, recognized as a form of adaptive communication, has been validated as a
functional assessment strategy (Townend et al., 2016). In this case, the early initiation of sensory
therapies and nonverbal language may have contributed to preserving minimal social responses
despite progressive deterioration.
Diagnostic confirmation through MECP2 gene sequencing—as occurred in this case—
constitutes the gold standard. The most frequent mutations are located in the coding regions of
the methyl-binding domain (MBD) and the transcriptional repression domain (TRD), and certain
variants have been shown to be associated with more severe phenotypes (Neul et al., 2014; Bao
et al., 2021). Although the exact mutation is not specified in this case, the finding of a de novo
Vol. 12/ Núm. 2 2025 pág. 1729
pathogenic variant is consistent with 99% of non-familial cases reported globally (Hagberg et al.,
2018).
Regarding therapeutic management, the interdisciplinary approach applied to this patient—
including physical, speech, occupational, and respiratory therapies—is consistent with the clinical
recommendations of the International Rett Syndrome Foundation (IRSF) and the American
Academy of Pediatrics (Glaze et al., 2010). The complementary use of cannabidiol has been
recently explored with promising results for controlling epilepsy and sleep disorders, although it
is still under systematic evaluation (Devinsky et al., 2019). Non-conventional interventions such
as homeopathy or ozone therapy should be ethically reported but lack support in the scientific
literature, and their use should be contextualized within family autonomy and the pursuit of
symptomatic relief.
In terms of prognosis, it has been documented that life expectancy in classic RTT can reach
young adulthood in patients with good control of comorbidities, although respiratory infections,
epilepsy, and malnutrition represent lethal risks (Anderson et al., 2014). The role of the family
environment is fundamental: various studies have demonstrated that the commitment of the
primary caregiver improves treatment adherence, emotional stability, and the functional quality
of life of the patient (Mahdi et al., 2018). In this case, active family intervention was a key pillar
in sustaining the patient's quality of life until her death.
This clinical case provides relevant evidence on the natural course of classic RTT,
documenting in detail its onset, progression, applied therapies, and outcome. When compared
with the scientific literature, the case stands out for its illustrative value in countries with limited
access to early genetic diagnosis and for the clear clinical sequence that justifies its publication.
In regions of low prevalence and scarce training in pediatric neurogenetics, reports like this are
essential to promote early clinical suspicion protocols and comprehensive functional monitoring.
CONCLUSION
This clinical case precisely illustrates the typical progression of classic Rett syndrome,
highlighting the importance of early clinical surveillance in girls under two years of age who
present with psychomotor regression. The trajectory of this patient—from seemingly normal early
development to progressive neurological deterioration and eventual fatal outcome—reflects the
ongoing diagnostic and therapeutic challenges, especially in settings with limited access to
genetic testing. Molecular confirmation through MECP2 gene mutation allowed for definitive
diagnosis and a more tailored therapeutic approach, although the functional prognosis followed a
severe course. This case supports the need to consider early MECP2 sequencing in the presence
of early-onset language regression, motor skill loss, and hand stereotypies, to improve diagnostic
accuracy and timely intervention.
pathogenic variant is consistent with 99% of non-familial cases reported globally (Hagberg et al.,
2018).
Regarding therapeutic management, the interdisciplinary approach applied to this patient—
including physical, speech, occupational, and respiratory therapies—is consistent with the clinical
recommendations of the International Rett Syndrome Foundation (IRSF) and the American
Academy of Pediatrics (Glaze et al., 2010). The complementary use of cannabidiol has been
recently explored with promising results for controlling epilepsy and sleep disorders, although it
is still under systematic evaluation (Devinsky et al., 2019). Non-conventional interventions such
as homeopathy or ozone therapy should be ethically reported but lack support in the scientific
literature, and their use should be contextualized within family autonomy and the pursuit of
symptomatic relief.
In terms of prognosis, it has been documented that life expectancy in classic RTT can reach
young adulthood in patients with good control of comorbidities, although respiratory infections,
epilepsy, and malnutrition represent lethal risks (Anderson et al., 2014). The role of the family
environment is fundamental: various studies have demonstrated that the commitment of the
primary caregiver improves treatment adherence, emotional stability, and the functional quality
of life of the patient (Mahdi et al., 2018). In this case, active family intervention was a key pillar
in sustaining the patient's quality of life until her death.
This clinical case provides relevant evidence on the natural course of classic RTT,
documenting in detail its onset, progression, applied therapies, and outcome. When compared
with the scientific literature, the case stands out for its illustrative value in countries with limited
access to early genetic diagnosis and for the clear clinical sequence that justifies its publication.
In regions of low prevalence and scarce training in pediatric neurogenetics, reports like this are
essential to promote early clinical suspicion protocols and comprehensive functional monitoring.
CONCLUSION
This clinical case precisely illustrates the typical progression of classic Rett syndrome,
highlighting the importance of early clinical surveillance in girls under two years of age who
present with psychomotor regression. The trajectory of this patient—from seemingly normal early
development to progressive neurological deterioration and eventual fatal outcome—reflects the
ongoing diagnostic and therapeutic challenges, especially in settings with limited access to
genetic testing. Molecular confirmation through MECP2 gene mutation allowed for definitive
diagnosis and a more tailored therapeutic approach, although the functional prognosis followed a
severe course. This case supports the need to consider early MECP2 sequencing in the presence
of early-onset language regression, motor skill loss, and hand stereotypies, to improve diagnostic
accuracy and timely intervention.
Vol. 12/ Núm. 2 2025 pág. 1730
This report contributes to the medical literature by thoroughly documenting the
multisystemic clinical manifestations of RTT, the response to various therapeutic strategies, and
the essential role of family support in maintaining quality of life. We emphasize the importance
of strengthening clinical suspicion protocols and early genetic referral, as well as the integration
of multidisciplinary teams including rehabilitation, respiratory and nutritional support, and
psychosocial guidance for families. Case reports like this not only enhance clinical understanding
of RTT but also highlight the urgent need for public policies that ensure timely diagnostic access
and continuous specialized care.
Acknowledgments
The authors would like to express their heartfelt gratitude to the Altuna Cousin Family
for their invaluable trust, generosity, and consent in allowing the clinical trajectory of their
daughter to be documented and shared. Their openness and support have made it possible to
contribute meaningfully to the scientific and medical understanding of Rett syndrome. This case
report is not only a contribution to clinical literature, but also a tribute to the strength and dignity
of a family that accompanied their daughter with love, perseverance, and unwavering care.
This report contributes to the medical literature by thoroughly documenting the
multisystemic clinical manifestations of RTT, the response to various therapeutic strategies, and
the essential role of family support in maintaining quality of life. We emphasize the importance
of strengthening clinical suspicion protocols and early genetic referral, as well as the integration
of multidisciplinary teams including rehabilitation, respiratory and nutritional support, and
psychosocial guidance for families. Case reports like this not only enhance clinical understanding
of RTT but also highlight the urgent need for public policies that ensure timely diagnostic access
and continuous specialized care.
Acknowledgments
The authors would like to express their heartfelt gratitude to the Altuna Cousin Family
for their invaluable trust, generosity, and consent in allowing the clinical trajectory of their
daughter to be documented and shared. Their openness and support have made it possible to
contribute meaningfully to the scientific and medical understanding of Rett syndrome. This case
report is not only a contribution to clinical literature, but also a tribute to the strength and dignity
of a family that accompanied their daughter with love, perseverance, and unwavering care.
Vol. 12/ Núm. 2 2025 pág. 1731
REFERENCES
Anderson, A., Wong, K., Jacoby, P., Downs, J., & Leonard, H. (2014). Twenty years of
surveillance in Rett syndrome: what does this tell us? Orphanet Journal of Rare Diseases,
9(1), 87. https://doi.org/10.1186/1750-1172-9-87
Bao, X., Downs, J., Wong, K., et al. (2021). Genotype–phenotype relationships in RTT: a
systematic review. Neurology Genetics, 7(4), e603.
https://doi.org/10.1212/NXG.0000000000000603
Buchanan, C. B., Stallworth, J. L., Scott, A. E., et al. (2021). Epilepsy in Rett syndrome: Clinical
characteristics and response to therapy. Pediatric Neurology, 118, 10–18.
Devinsky, O., Patel, A. D., Thiele, E. A., et al. (2019). Effect of cannabidiol on drop seizures in
the Lennox–Gastaut syndrome. The New England Journal of Medicine, 378(20), 1888–1897.
Glaze, D. G., Percy, A. K., Skinner, S., et al. (2010). Guidelines for the management of Rett
syndrome problems. Pediatric Neurology, 43(3), 153–165.
Hagberg, B., Hanefeld, F., Percy, A., & Skjeldal, O. H. (2018). An update on clinically applicable
criteria for the Rett syndrome. Brain & Development, 23(7), 708–711.
Kaufmann, W. E., Tierney, E., Rohde, C. A., et al. (2021). Timeliness of diagnosis in Rett
syndrome: A retrospective analysis. Journal of Child Neurology, 36(8), 662–668.
Killian, J. T., Lane, J. B., Lee, H. S., et al. (2020). Mortality in Rett syndrome: Insights from the
US natural history study. Neurology, 95(10), e1285–e1292.
Laurvick, C. L., Christensen, D., et al. (2006). Rett syndrome in Australia: A review of current
data and future research directions. Journal of Paediatrics and Child Health, 42(1‐2), 9–16.
Leonard, H., Bower, C., English, D., et al. (2017). The Australian Rett Syndrome Database:
Progress and trends over 20 years. Journal of Paediatrics and Child Health, 53(1), 4–8.
Lyst, M. J., & Bird, A. (2015). Rett syndrome: A complex disorder with simple roots. Nature
Reviews Genetics, 16(5), 261–275. https://doi.org/10.1038/nrg3897
Mahdi, S., Balcioglu, A., et al. (2018). Caregiver perspectives in Rett syndrome: Quality of life
and resilience. Orphanet Journal of Rare Diseases, 13(1), 205.
Motil, K. J., Caeg, E., Barrish, J. O., et al. (2012). Gastrointestinal and nutritional problems occur
frequently throughout life in girls and women with Rett syndrome. Journal of Pediatric
Gastroenterology and Nutrition, 55(3), 292–298.
Neul, J. L., Kaufmann, W. E., Glaze, D. G., et al. (2010). Rett syndrome: Revised diagnostic
criteria and nomenclature. Annals of Neurology, 68(6), 944–950.
Percy, A. K., Neul, J. L., Glaze, D. G., et al. (2022). Rett syndrome diagnostic and management
update. Pediatric Neurology, 126, 1–10.
Tarquinio, D. C., Hou, W., et al. (2015). Age of diagnosis in Rett syndrome: Patterns of
recognition among different clinical specialties. Pediatric Neurology, 52(6), 585–591.
REFERENCES
Anderson, A., Wong, K., Jacoby, P., Downs, J., & Leonard, H. (2014). Twenty years of
surveillance in Rett syndrome: what does this tell us? Orphanet Journal of Rare Diseases,
9(1), 87. https://doi.org/10.1186/1750-1172-9-87
Bao, X., Downs, J., Wong, K., et al. (2021). Genotype–phenotype relationships in RTT: a
systematic review. Neurology Genetics, 7(4), e603.
https://doi.org/10.1212/NXG.0000000000000603
Buchanan, C. B., Stallworth, J. L., Scott, A. E., et al. (2021). Epilepsy in Rett syndrome: Clinical
characteristics and response to therapy. Pediatric Neurology, 118, 10–18.
Devinsky, O., Patel, A. D., Thiele, E. A., et al. (2019). Effect of cannabidiol on drop seizures in
the Lennox–Gastaut syndrome. The New England Journal of Medicine, 378(20), 1888–1897.
Glaze, D. G., Percy, A. K., Skinner, S., et al. (2010). Guidelines for the management of Rett
syndrome problems. Pediatric Neurology, 43(3), 153–165.
Hagberg, B., Hanefeld, F., Percy, A., & Skjeldal, O. H. (2018). An update on clinically applicable
criteria for the Rett syndrome. Brain & Development, 23(7), 708–711.
Kaufmann, W. E., Tierney, E., Rohde, C. A., et al. (2021). Timeliness of diagnosis in Rett
syndrome: A retrospective analysis. Journal of Child Neurology, 36(8), 662–668.
Killian, J. T., Lane, J. B., Lee, H. S., et al. (2020). Mortality in Rett syndrome: Insights from the
US natural history study. Neurology, 95(10), e1285–e1292.
Laurvick, C. L., Christensen, D., et al. (2006). Rett syndrome in Australia: A review of current
data and future research directions. Journal of Paediatrics and Child Health, 42(1‐2), 9–16.
Leonard, H., Bower, C., English, D., et al. (2017). The Australian Rett Syndrome Database:
Progress and trends over 20 years. Journal of Paediatrics and Child Health, 53(1), 4–8.
Lyst, M. J., & Bird, A. (2015). Rett syndrome: A complex disorder with simple roots. Nature
Reviews Genetics, 16(5), 261–275. https://doi.org/10.1038/nrg3897
Mahdi, S., Balcioglu, A., et al. (2018). Caregiver perspectives in Rett syndrome: Quality of life
and resilience. Orphanet Journal of Rare Diseases, 13(1), 205.
Motil, K. J., Caeg, E., Barrish, J. O., et al. (2012). Gastrointestinal and nutritional problems occur
frequently throughout life in girls and women with Rett syndrome. Journal of Pediatric
Gastroenterology and Nutrition, 55(3), 292–298.
Neul, J. L., Kaufmann, W. E., Glaze, D. G., et al. (2010). Rett syndrome: Revised diagnostic
criteria and nomenclature. Annals of Neurology, 68(6), 944–950.
Percy, A. K., Neul, J. L., Glaze, D. G., et al. (2022). Rett syndrome diagnostic and management
update. Pediatric Neurology, 126, 1–10.
Tarquinio, D. C., Hou, W., et al. (2015). Age of diagnosis in Rett syndrome: Patterns of
recognition among different clinical specialties. Pediatric Neurology, 52(6), 585–591.