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Rett Syndrome

Overview

Young girl with Rett syndrome wearing a pink fleece jacket looking out of car window from her carseat
Photo by Lexi Luthy
Classic Rett syndrome is an X-linked condition typically characterized by acquired microcephaly, developmental regression at 12-18 months of age, loss of speech and normal hand functions, and hand-wringing. Approximately 90% of children with Rett syndrome will also have epilepsy. [Tarquinio: 2017] Rett syndrome is a severe neurodevelopmental syndrome seen almost exclusively in females and is usually caused by mutations in the MECP2 gene. MeCP2-related disorders include classic Rett syndrome, atypical Rett syndrome, MeCP2-related intellectual disability, and MeCP2 duplication syndrome.
Variants of Rett syndrome, or atypical Rett syndrome, can include preserved speech, early seizures, and FOXG1-related disorder previously known as congenital onset. [Neul: 2010] The validity of the developmental regression in the diagnosis of Rett syndrome is questioned by many, with a possible explanation being that developmental milestones were achieved late or not at all and behavioral characteristics, such as hand movements, appeared without an actual regression. [Cosentino: 2019] [Einspieler: 2019] [Charman: 2002]

Other Names & Coding

Atypical Rett syndrome  disorder RTT
ICD-10 coding

F84.2, Rett syndrome

ICD-10 for Rett Syndrome (icd10data.com) provides further coding details.

Prevalence

The prevalence of Rett syndrome is about 1:9,000-10,000 females. [Laurvick: 2006] [Bienvenu: 2006] Precise estimates are elusive due to lack of recent, large studies that take into consideration the evolving diagnosis criteria for this condition. Rett syndrome affects all racial and ethnic groups. The incidence in males is rare.

Genetics

Most cases of Rett syndrome are due to mutations in the MECP2 gene on the X chromosome, primarily from the paternal side. Different mutation types of the MECP2 gene can affect the age of diagnosis and severity of the clinical course, although 8 “hotspot” mutations are responsible for more than 60% of cases. [Leonard: 2017] Girls with Rett syndrome typically have 1 mutated X chromosome and 1 unaffected chromosome, which helps with their survival. Males with a mutated X chromosome do not have another healthy X chromosome to balance it out (they instead have a Y chromosome), so very few males with Rett syndrome survive past birth.
While Rett syndrome and MECP2-related disorders are often used synonymously, there is not complete overlap between these terms. Up to 5% of girls meeting clinical criteria of typical Rett syndrome will have negative MECP2 testing, and MECP2 mutations are much less common among cases meeting clinical criteria for atypical Rett syndrome. [Neul: 2010] Additionally, MECP2-related disorders encompass many more clinical syndromes than Rett syndrome, including familial Rett syndrome, an asymptomatic female carrier of typical Rett syndrome; atypical Rett syndrome, a severe newborn encephalopathy in males; and X-linked intellectual disability without other clinical features of Rett syndrome.
Atypical Rett syndrome, defined as meeting fewer than 4 of the main criteria for typical Rett syndrrome, is less frequently associated with the MECP2+ mutation, although some are positive for this mutation.
Historically, several disorders have been described as Rett-like, though this term is imprecise. These now distinct and separate disorders include those associated with mutations on the X chromosome on CDKL5 (cyclin-dependent kinase-like 5) or mutations on chromosome 14 on FOXG1. [Olson: 2019] [Fehr: 2013] [Mitter: 2018] Additionally, mutations of the X chromosome WDR45 gene can result in some clinical presentations of similar to Rett syndrome, but it is more commonly implicated in another syndrome known as beta-propeller protein-associated neurodegeneration (BPAD).

Prognosis

Although in classic Rett syndrome significant developmental regression occurs early, regression eventually stops and a plateau, possibly with modest improvements in function, may be obtained in adolescence. Sudden, unexplained death occurs more frequently than in the general population; however, survival into the fifth decade is now typical. In any individual, it is difficult to determine if sudden death is due to Rett syndrome associated autonomic nervous system dysfunction or SUDEP (Sudden Death with Epilepsy), or a combination of the two. [Singh: 2019] Several factors impact individual morbidity and mortality, including cardiorespiratory problems, seizures, immobility, swallowing and aspiration, gastrointestinal function, scoliosis, growth, and nutrition. Frequently Asked Questions (International Rett Syndrome Foundation) provides more details about life quality and expectancy.
The impact on caregiver mental and physical health is similar to that for caregivers of other neurodevelopmental disorders. Feeding difficulties are most highly associated with reduced quality of life for caregivers. [Killian: 2016]

Practice Guidelines

There are currently no evidence-based, expert-consensus practice guidelines for the primary care of individuals with Rett syndrome in the US. The international expert consensus guidelines for the diagnosis of Rett syndrome replaced the original practice guideline [Hagberg: 1989] for diagnosing Rett syndrome:

  • Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen NC, Zappella M, Renieri A, Huppke P, Percy AK.
    Rett syndrome: revised diagnostic criteria and nomenclature.
    Ann Neurol. 2010;68(6):944-50. PubMed abstract / Full Text

Clinical guidelines for specific aspects of care for individuals with Rett syndrome, based on evidence-review and expert-panel consensus, are listed here. Additional material can be found in Helpful Articles, below.

  • Jefferson A, Leonard H, Siafarikas A, Woodhead H, Fyfe S, Ward LM, Munns C, Motil K, Tarquinio D, Shapiro JR, Brismar T, Ben-Zeev B, Bisgaard AM, Coppola G, Ellaway C, Freilinger M, Geerts S, Humphreys P, Jones M, Lane J, Larsson G, Lotan M, Percy A, Pineda M, Skinner S, Syhler B, Thompson S, Weiss B, Witt Engerström I, Downs J.
    Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.
    PLoS One. 2016;11(2):e0146824. PubMed abstract / Full Text

  • Leonard H, Ravikumara M, Baikie G, Naseem N, Ellaway C, Percy A, Abraham S, Geerts S, Lane J, Jones M, Bathgate K, Downs J.
    Assessment and management of nutrition and growth in Rett syndrome.
    J Pediatr Gastroenterol Nutr. 2013;57(4):451-60. PubMed abstract / Full Text

  • Baikie G, Ravikumara M, Downs J, Naseem N, Wong K, Percy A, Lane J, Weiss B, Ellaway C, Bathgate K, Leonard H.
    Gastrointestinal dysmotility in Rett syndrome.
    J Pediatr Gastroenterol Nutr. 2014;58(2):237-44. PubMed abstract

Roles of the Medical Home

A young girl with thick, black hair and a jean jack makes eye contact with an elderly man and displays stereotypical hand behavior
Child with Rett syndrome displaying stereotypic hand behavior
The primary care provider is often the first to recognize clinical signs suggestive of Rett syndrome and initiate the process of formal diagnosis. Once diagnosis occurs, due to the complicated nature of assessment and management of children with Rett syndrome, working with a multi-disciplinary team (genetics, neurology, psychiatry/psychology, speech therapy, occupational therapy, physical therapy, rehabilitation medicine, pulmonology, cardiology, developmental pediatrics, gastroenterology, nutrition, and orthopedics) or a specialized clinic is recommended.
Families with children who have Rett syndrome face many challenges and may be helped by social workers and parent support networks. The primary care clinician makes referrals to these specialists, helps coordinate evaluation and treatments, and provides family support as appropriate. Additionally, the primary care clinician provides immunizations and assists in communication with the family and school, for example, by reviewing the student’s school health plan, seizure action plan, and individualized education plan to provide appropriate accommodations. Inquire at chronic care visits about the many possible new and ongoing problems that frequently occur in children with Rett syndrome.
For clinics, specialists, and other care providers, see Rett Syndrome Clinics (International Rett Syndrome Foundation) and Rett Syndrome.

Clinical Assessment

Overview

The primary care provider should have increased suspicion for classic Rett syndrome in females who have developmental regression around the age of 6-18 months, including loss of speech and decreased motor skills, as well as growth deceleration of the head and loss of purposeful hand movements. The presentations and diagnosis of non-classic types of Rett syndrome are discussed later. The strongest clinical predictors of a pathogenic MECP2 deletion/mutation are partial or complete loss of purposeful hand movements, gait abnormalities, and stereotypic hand movements. [Knight: 2016]
If Rett syndrome is suspected, testing may be performed by the primary care provider with referral to genetics for confirmation and genetic counseling, or the family may be sent directly to genetics for testing. The American College of Medical Genetics recommends that testing for the MECP2 gene mutation should be considered in females with unexplained moderate to severe intellectual disability, even without the other clinical features - see [Moeschler: 2014].

Pearls & Alerts for Assessment

When to consider testing for Rett syndrome

Consider referral to genetics for testing for an MECP2 mutation in girls with moderate or severe intellectual disability even without clinical features of Rett syndrome. [Moeschler: 2014] [Kaur: 2019]

Rett syndrome and MECP2+ mutations are not synonymous

MECP2+ mutations of the X chromosome are frequently, but not always, found in children diagnosed with Rett syndrome, and MECP2+ mutations can be found in syndromes other than Rett syndrome.

Abnormal early development should be a “red flag”

Evidence for subtle early developmental abnormalities in girls with Rett syndrome is beginning to mount; however, the average age of diagnosis of typical and atypical Rett syndrome is 2.7 years. [Tarquinio: 2015] Loss of previously attained developmental skills should be a red flag to any clinician to investigate for an underlying cause, such as a genetic or metabolic disorder. [Neul: 2014]

Screening

Of Family Members

In a family with a child with Rett syndrome, typically the mother of the child can be tested to see if she is an asymptomatic carrier of the mutation. If the testing is negative, the family should be counseled about not-yet-reported germ line mosaicism for recurrence risks; siblings would not be recommended for testing. Future pregnancies can be tested prenatally as well; however, over 99% of Rett syndrome cases are sporadic mutations, not inherited. [International: 2020] A genetic counselor is trained to help explain this information to families.

Presentations

In classic Rett syndrome, progression and features may include:
  • Normal development until approximately 6 to 18 months old, followed by developmental regression
  • Loss of purposeful hand movements and onset of characteristic hand wringing
  • Acquired microcephaly: Occipital frontal circumference (OFC) usually normal at birth, true microcephaly within first few years of life
  • Breathing difficulties, including hyperventilation, apnea, and air swallowing
  • Seizures in approximately 90% of individuals
  • Autistic behaviors, including mouthing, stereotypic hand movements, sighing, and decreased verbalization
  • Bruxism, dysphagia
  • Screaming or crying fits, panic attacks, tremors [Christodoulou: 2012]
  • Severe to profound intellectual disability
  • Truncal ataxia and ataxic gait with eventual loss of independent ambulation
  • Dystonia and spasticity in older girls, scoliosis, osteoporosis, and hand and foot deformities
Atypical Rett syndrome occurs less frequently but accounts for approximately 15% of people diagnosed with Rett syndrome.
Presentation in boys with Rett syndrome
Males with the MECP2+ mutation typically associated with Rett syndrome usually have severe neonatal encephalopathy and an early death, without the classic Rett syndrome trajectory. Males with variant sex chromosomes, such as XXY in Klinefelter syndrome, could have male Rett syndrome with more typical Rett syndrome features and longer survival, although this occurs quite rarely. [Neul: 2019]

Diagnostic Criteria

While genetic testing is recommended for suspected typical and atypical Rett syndrome, the diagnosis remains clinical. Diagnosis of typical and atypical Rett syndrome follows expert consensus opinion published in [Neul: 2010], supplanting the diagnostic criteria by [Hagberg: 2002].
Criteria required for a diagnosis of classic or typical Rett syndrome
  • A period of regression followed by recovery or stabilization
  • All main criteria and all exclusion criteria listed in the table (below).
  • Supportive criteria (below) are not required, although often present in typical Rett syndrome.
Criteria required for a diagnosis of atypical or variant Rett syndrome
  • A period of regression followed by recovery or stabilization
  • At least 2 of the 4 main criteria listed in the table below
  • 5 out of 11 supportive criteria (below)
  • Some experts also require age >5
The following is adapted from About the Diagnosis (International Rett Syndrome Foundation).
Main, Supportive, and Exclusion Criteria for Rett Syndrome Diagnosis
Main Criteria
  • Partial or complete loss of acquired purposeful hand skills
  • Partial or complete loss of acquired spoken language
  • Gait abnormalities: Impaired gait (dyspraxia) or absence of ability to ambulate (apraxia)
  • Stereotypic hand movements, such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms
Supportive criteria for atypical Rett syndrome
  • Breathing disturbances when awake
  • Bruxism when awake
  • Impaired sleep pattern
  • Abnormal muscle tone
  • Peripheral vasomotor disturbances
  • Scoliosis/kyphosis
  • Growth retardation
  • Small, cold hands and feet
  • Inappropriate laughing/screaming spells
  • Diminished response to pain
  • Intense eye communication—eye pointing
Exclusion criteria for typical Rett syndrome
  • Brain injury secondary to trauma (perinatal or postnatal), neurometabolic disease, or severe infection that causes neurological problems
  • Grossly abnormal psychomotor development in first 6 months of life

Clinical Classification

Clinical Features and Genetics for Atypical Rett Syndrome in Children (Zappella, Hanefield, and Rolando Variants)
Classic Rett syndrome and atypical Rett syndrome are diagnosed using the criteria listed above. Atypical Rett syndrome may appear in several forms, including congenital onset, early seizure, and preserved speech variants. The algorithm, Differentiating Among Variants of Atypical Rett Syndrome in Children (left), provides information about clinical features and molecular genetics for 3 variant forms of Rett syndrome.

Differential Diagnosis

It is easy to confuse Rett syndrome, autism, and other diagnoses, particularly if the child doesn't have all the typical features. Other causes of similar clinical findings include:
  • Autism spectrum disorder: While stereotypic hand movements, impaired social skills, and lack of speech can occur in both autism and Rett syndrome, girls with Rett syndrome usually have decelerated head growth, hand wringing and lack of purposeful hand movements, and may develop breathing abnormalities or mobility impairments that are not characteristic of autism. Additionally, girls with Rett syndrome tend to prefer people to objects, whereas social connections may be more challenging for children with autism. Autism Spectrum Disorder has further diagnosis information.
  • Angelman syndrome: Children with Angelman syndrome often have speech delay, microcephaly, and seizures, although they do not usually exhibit a developmental regression, and seizures are a more prominent feature. Sometimes, children with Angelman syndrome have positive testing for MECP2 mutations. The Portal's Angelman Syndrome has further diagnosis information.
  • Cerebral palsy: Sometimes older girls with spasticity and intellectual disability that have been previously diagnosed with cerebral palsy are found to have Rett syndrome. The Portal's Cerebral Palsy has further diagnosis information.
  • Infantile form of neuronal ceroid lipofuscinosis (Batten disease): Patients with neuronal ceroid lipofuscinosis demonstrate a continuing progressive course and have ophthalmologic abnormalities, especially electroretinogram abnormalities. See Neuronal Ceroid Lipofuscinosis (GARD) for information about symptoms, treatment, and current research.

Comorbid & Secondary Conditions

Comorbid conditions include:
  • Chewing, swallowing, and dental problems
  • Heart abnormalities
  • Breathing difficulties including hyperventilation, apnea, and air swallowing
  • Constipation, reflux, and other digestive system problems including gallstones
  • Scoliosis, osteoporosis, hip subluxation or dislocation, and hand and foot deformities
  • Seizures
  • Sleep difficulties

History & Examination

Current & Past Medical History

Important components of past and recent history to ask about include:
  • How the diagnosis was made and the genetic testing results
  • Seizure activity and frequency, and side effects of antiepileptic medications. Up to 90% of girls with Rett syndrome have seizures at some time in their lives. [Tarquinio: 2017]
  • Swallowing problems, such as choking or recurrent pneumonia. Swallowing problems are frequent and may be one of the causes of malnutrition and may be linked to premature death due to choking or aspiration-caused pneumonia.
  • Breathing problems, such as disorganized/abnormal breathing episodes with periods of apnea and/or hyperventilation while awake and obstructive or central sleep apnea. Obtain results from any previous sleep studies.
  • Sleep problems, including decreased sleep time, frequent night awakening, bruxism, or breathing, snoring, and breath-holding, which may indicate presence of hypoventilation or apnea. Find out what medications or behavioral methods the caregivers have tried (aromatherapy, white noise, room darkening, etc.) to help manage sleep.
  • Digestive problems that might include constipation, gastroesophageal reflux, air swallowing, abdominal distention, and episodes of abdominal distress. Growth chart patterns may reflect problems with nutrition and/or digestion.
  • Cardiac issues including tachycardia or documented arrhythmias. Due to abnormal development of conduction fibers in the heart, children with Rett syndrome are at increased risk for sinus tachycardia or prolonged QTc interval, as well as sudden death.
  • Bone health, nutritional problems, decreased mobility, calcium and vitamin D intake, and medications affecting bone density. Osteoporosis is common in this population due to underlying nutritional problems and decreased mobility. [Jefferson: 2016] Assess for a history of fractures. Fractures occur in about 30% of people with Rett syndrome and are often an indicator that there may be osteopenia or osteoporosis. [Briggs: 2014]
  • Mobility and orthopedic issues, mobility aids like wheelchairs or walkers (monitor for appropriate fit). Find out if the individual has had prior imaging of spine or hips.
  • Oral health, including brushing or ability to maintain appropriate oral hygiene, access to fluoride, dental visits, and history of dental surgeries. Ask about medications, seizures, bruxism, and acid reflux since these can all impact dental health. See Dental and Oral Health Screening.
  • Vision or eye alignment issues, such as intermittent eye-crossing, and use of eye gaze technology to assist communication. Review results of ophthalmology exams.
  • Hearing and results of a hearing screen (typically performed in the newborn period, but may be repeated during assessment of a language delay)

Family History

A family history of Rett syndrome is unlikely; approximately 99.5% of mutations are sporadic and are not repeated in the family. [Christodoulou: 2012]

Pregnancy/Perinatal History

This history is usually normal.

Developmental & Educational Progress

Developmental history is key. In children with classic Rett syndrome, developmental progress may seem fairly normal until the second year of life, when previously acquired skills are lost. Prior to this, there can be some stagnation of skills, but this may be hard to discern at the time. The period of regression usually lasts between the ages of 1-4 years. After that, there tends to be a plateau that can last many years, during which there can be some modest increase in communication, as well as sustained ambulation. The timing and severity of these stages can vary for individuals and are not representative of other types of Rett syndrome.
Developmental delays in language, fine, and gross motor skills will be present at the time of diagnosis and should be periodically reassessed. Ask about any developmental or rehabilitation/physical medicine services or school-based services the individual already has. Problems with eye gaze and hand use for activities of daily living are expected. Monitor for changes in hearing and vision, and review records of prior evaluations.

Maturationalprogress

The age range that girls enter puberty is wider than in typically developing females. About half of girls with classic Rett syndrome experience puberty on a similar trajectory as typically developing females; however, about a quarter of girls enter thelarche and/or adrenarche earlier, but they may also enter menarche later (median age 13 years). Eighty percent of girls obtain thelarche between the ages of 7.2 and 11.3 years, and adrenarche occurs for most between ages 6.3 and 11.9. [Killian: 2014] Menarche occurred between ages 10-16. [Killian: 2014] For each of these ranges, 10% of girls experience these earlier and 10% later than these age ranges, so there is a lot of variability. [Killian: 2014] Sex hormones are thought to be normal, despite the deviations in timing. [Killian: 2014] Menarche is helpful for bone health.

Social & Family Functioning

Assessing family functioning and resources available for family support is an important part of the medical home visit. Ask about behavioral problems and social functioning. Agitation and screaming fits are common, but before assuming they are behavioral, medical causes (reflux, seizures, caries, etc.) should be considered. Behavior management may be a significant problem and should be inquired about. Feeding difficulties can also be particularly stressful for families. [Killian: 2016] Find out how the family manages these stressors and if they could benefit from additional referrals to community support groups or mental and behavioral health therapists.

Physical Exam

General

Look for overall interaction and use of hands for purposeful movements.

Vital Signs

Heart rate should be monitored for tachycardia. Respiratory rate should be followed for evidence of autonomic dysfunction. Pulse oximetry is useful if episodes of abnormal breathing patterns or hypoventilation are present.

Growth Parameters

Height, weight, and BMI should be followed closely using a standard growth chart so that problems with undernutrition may be identified early. Rett growth charts are also available. [Tarquinio: 2012] For those unable to stand, use supine measurements. [Leonard: 2013]
When kids ages 0-12 years old are unable to stand, estimates in centimeters can be performed using this algorithm:

  • (3.26 × tibial length*) + 30.8, or (2.69 × knee height**) + 24.2. [Haapala: 2015]
*Tibial length is measured from the superior border of the medial tibial condyle to the inferior border of the medial malleolus, with both the knee and the ankle at 90 degrees. **Knee height is measured from the knee joint line to the bottom of the heel.
Occipitofrontal head circumference (OFC) should be monitored as it will usually stagnate over time, resulting in microcephaly.

Skin

Look for signs of vasomotor instability. Check for pressure sores in girls with ankle-foot orthotics or if the girl is not ambulatory.

HEENT/Oral

Monitor for microcephaly, eye gaze problems, and esotropia. Examine the oral cavity for evidence of bruxism, problems with hygiene, and other dental concerns. Dental and Oral Health Screening provides further examination and prevention tips.

Chest

Look for abnormal breathing patterns, as well as onset of thelarche.

Heart

Listen for sinus tachycardia.

Abdomen

Check for abdominal pain, bloating or distension, or palpable stool burden. A gallbladder exam is important when there is significant pain. If there is a G-tube present, examine the opening for infection, granulation tissue, discharge, and fit.

Genitalia

Perform a genital exam and Tanner staging to monitor for hygiene and anticipate menstruation.

Extremities/Musculoskeletal

Assess for difficulties with gait, hypertonicity and ataxia, and spasticity. Look for evidence of hand and foot contractures or deformities. The spine should be physically examined at time of diagnosis and then every 6 months. [Downs: 2009] Look for scoliosis, which can start prior to puberty, advance rapidly, and continue after puberty. Hips should also be routinely examined for subluxation or dislocation. Be vigilant for fractures, especially of the long bones of the arms and legs. Assess for and lean muscle mass.

Neurologic Exam

Check specifically for dystonia and ataxia. Check eye movements and alignment.

Testing

Sensory Testing

Vision and hearing screens should be performed regularly. Intermittent esotropia, cortical visual impairment, and oculomotor apraxia may be observed in girls with Rett syndrome. Due to difficulties with participation and eye gaze, screening in the primary care setting may not be practical. An ophthalmologic exam is recommended annually. [Briggs: 2014]

Laboratory Testing

Monitor vitamin D 25-OH and consider checking total and ionized calcium, magnesium, phosphorus, alkaline phosphatase, and albumin levels based on risk factors for osteoporosis. [Jefferson: 2016] Check ferritin levels when poor sleep quality is suspected as ferritin levels <50-70 µg/L can be associated with restless legs or periodic limb movement disorders.

Imaging

DEXA
Consider a baseline DEXA scan for assessment of bone density with re-evaluation every 1-2 years for those who are at increased risk of osteopenia/osteoporosis depending on perceived risk based on dietary intake of calcium and vitamin D, nutritional status, mobility, routine sun exposure, pubertal status, and history of fractures. Risk is increased for people with the p.R168X, p.R255X, p.R270X, or p.T158M mutations. A lateral spine film may also be useful in assessing bone density. [Jefferson: 2016] Imaging/ Radioloy (see RI providers [0]).
Spine imaging
Spine imaging should be performed if scoliosis is present clinically, and then every 6-12 months depending on the pediatric orthopedic assessment of the child taking into account ambulatory and pubertal status and Cobb angle. [Killian: 2017]
Hip imaging
Based on management recommendations for cerebral palsy, hip imaging is recommended annually for children who are non-ambulatory as well as if there is a concerning physical exam, such as a positive Galeazzi sign. Annual imaging should start at 18 months. [Tay: 2010] Similar to spine management, imaging may be coordinated by the orthopedic specialist.
Brain imaging is not necessary for girls with Rett syndrome unless specific concerns arise.

Genetic Testing

MECP2 gene mutation testing is important in the diagnostic process, although some children with Rett syndrome have negative MECP2 mutation testing. Working with pediatric genetics helps ensure appropriate testing and accurate interpretation of results. Also, see Working with Insurance Companies for sample letters to obtain insurance preauthorization for MECP2 testing. [Kaur: 2019]

Other Testing

EEG
It is important to get an EEG if seizures are suspected clinically, and possibly if there is an abrupt change in seizure frequency. The EEG should contain both sleep and wake states during the interval recorded. EEGs do not need to be performed routinely if there is no clinical evidence of seizures. An overnight (or longer) video EEG may be needed to determine if particular episodes of concern are associated with EEG change suggestive of seizure. During early stages of Rett syndrome, the EEG will often show slowing of the dominant occipital rhythm with spike or sharp wave activity during sleep in a pattern common for, but not pathognomonic of, Rett syndrome. During later stages, the occipital dominant rhythm and non-REM sleep characteristics often disappear.
EKG
Because of the risk of heart arrhythmias and long QT syndrome, girls with Rett syndrome should have a baseline EKG, and then have it repeated annually. The International Rett Syndrome Association recommends the first EKG should be performed by age 5 and, if normal, repeated every other year. Abnormal results merit referral to a cardiologist.
Echocardiogram
There is little guidance on whether a baseline echo should be performed. One small study examined the echocardiograms in 32 individuals with Rett syndrome and found no structural anomalies or differences in size or function from the healthy control group [Guideri: 2004], so it is not likely that a cardiomyopathy or valve problems will be found. [Acampa: 2006]
Holter monitor
Holter monitoring may be useful in gathering more information about heart rate and rhythm and possibly correlating them with clinical events, but it is not routinely recommended for children with Rett syndrome.
Swallow study
This study is recommended if a child with Rett syndrome has swallowing problems, such as choking with drinking, or if the past medical history includes frequent pneumonia. Occupational or speech therapy (depending on location) can evaluate swallowing function and safety, determine if interventions (e.g., speech therapy, special feeding techniques, improved feeding position) might lead to improvements in function, and determine the safest and most efficient textures for eating. In some cases, the therapist may suggest a fluoroscopic video swallow study (also called a modified barium or cookie swallow) be part of this evaluation (Swallow Study (see RI providers [0])).
Sleep study
Consider if there are problems with breathing during sleep, including snoring, frequent awakenings, or excessive daytime sleepiness. Sleep Study/Polysomnography (see RI providers [1])
pH probe
Consider a pH probe to help evaluate for reflux.

Specialty Collaborations & Other Services

Developmental Assessments (see RI providers [35])

Refer for evaluation of developmental progress and behavioral concerns.

Developmental - Behavioral Pediatrics (see RI providers [12])

Refer for evaluation of developmental progress and behavioral concerns.

Medical Genetics (see RI providers [4])

Refer for diagnosis and guidance regarding prognosis, management, genetic counseling, inheritance risk, and genetic risks to other family members.

Genetic Testing and Counseling (see RI providers [8])

Refer for genetic counseling, education about the condition, and discussion of recurrence risks for family members.

Pediatric Neurology (see RI providers [18])

Referral to a pediatric neurologist familiar with issues of Rett syndrome is recommended. A referral may be especially helpful in differentiating seizures from other types of episodes (such as cardiac events) and for treatment of seizures. Neurologists may also provide information about prognosis and help determine if comorbid autism spectrum disorder is present.

Pediatric Physical Medicine & Rehabilitation (see RI providers [6])

A referral to a rehabilitation team should be considered for evaluation of abilities, development of a program to optimize functioning, and for medical equipment evaluations.

Pediatric Cardiology (see RI providers [17])

Refer for interpretation of EKGs, education, and management of long QT syndrome. The International Rett Syndrome Foundation recommends EKGs starting by age 5 and then every other year if normal. [International: 2020]

Pediatric Gastroenterology (see RI providers [18])

Refer for evaluation of nutritional problems, swallowing problems, reflux, and constipation. A primary care provider might wish to involve a gastroenterologist if these problems have not responded to usual management.

Pediatric Orthopedics (see RI providers [16])

Refer for evaluation of scoliosis, hip problems, fractures, and deformities.

Psychiatry/Medication Management (see RI providers [80])

Refer for evaluation of behavior problems and for consideration of possible treatment with medications. A psychiatrist can assist in determining if autism spectrum disorder is also present.

Treatment & Management

Overview

Due to the complicated nature of assessment and management of children with Rett syndrome, treatment in a multi-disciplinary clinic or with coordinated care is recommended. The International Rett Syndrome Association maintains a list of specialized clinics in the United States, Canada, Europe, and Asia: See Rett Syndrome Clinics (International Rett Syndrome Foundation).

Pearls & Alerts for Treatment & Management

DAYBUE (trofinetide) for the Treatment of Rett Syndrome

Trofinetide (Daybue) is a medication recently approved by the FDA for treatment of Rett Syndrome (RS) that is thought to work by decreasing inflammation in the brain. It should be available by prescription at the end of April 2023 for adults and children 2 and older with RS. In a clinical trial “LAVENDER,” individuals with RS showed fewer symptoms of RS, including repetitive behaviors such as hand-wringing, and improved mood as judged by caregivers and physicians. The most common side effects were vomiting and diarrhea. More information, including prescribing information, is available at DAYBUE (trofinetide) for the Treatment of Rett Syndrome in Adult and Pediatric Patients.

Evaluate new or increased screaming/agitation for an underlying medical issue or pain

Agitation and screaming fits are common in Rett syndrome but, before assuming they are behavioral, medical causes such as reflux, seizures, and caries should be considered. Screaming can occur while awake or asleep. Recurrent illness with coughing may be due to aspiration, rather than infection.

Gallstones and Rett syndrome

Gallstones occur more frequently in those with Rett syndrome and should be considered in girls with intellectual disability presenting with abdominal distress. Conversely, consider testing for Rett syndrome in girls with intellectual disabilities and gallstones. Consider gallstones as well as obstruction in a girl with Rett syndrome who presents with abdominal distress.

Abdominal distention can be dangerous

Distention and increased gas may be caused by air swallowing, which can lead to severe gastrointestinal problems (rupture and peritonitis) if not treated.

Avoid medications that impact respiratory drive, prolong the QT interval, lower seizure threshold, or decrease bone density

Increased monitoring is warranted when these medications are necessary to use. See Pharmacy & Medications, below, for more details.

Bruxism

Bruxism (tooth grinding) is quite common and may be challenging to treat.

Autonomic nervous system dysfunction

Sudden death due to cardiac dysfunction may be as high as 15% of individuals with Rett syndrome and is likely related to autonomic nervous system dysfunction. This should be considered in girls with breathing problems and in cardiology evaluations. [Singh: 2019]

Rett spells

Rett spells appear very similar to seizures and are almost impossible to distinguish unless on EEG. Spells do not involve altered mental status, so a person having a Rett spell can be interrupted or distracted.

How should common problems be managed differently in children with Rett Syndrome?

Growth or Weight Gain

Use a standard growth chart and aim to keep the BMI at the 25%ile. For those who cannot stand, a supine measurement is reasonable. Growth deceleration can start in the first couple of years, and growth failure is a red flag for bone density loss. Weight loss can be associated with swallowing problems, constipation, and malnutrition that can lead to bone loss.

Development (Cognitive, Motor, Language, Social-Emotional)

Be cautious about making assumptions about developmental prognosis; after the developmental regression phase ends, there may be some advancements in skills such as language and mobility. Recognize that social interaction is important and behavioral problems can be hard for the family to manage.

Viral Infections

An increased aspiration risk during respiratory infection is possible.

Prescription Medications

Review medication use and consider possible interactions. Behavioral and seizure medications can interact with antibiotics and other medications. These interactions could potentially lead to diminished effects of one or the other, or to adverse effects.

Systems

Development (general)

Monitor results of hearing screens and annual ophthalmologic exams. If the child does not tolerate wearing hearing aids or eyeglasses, for example, work with the specialist or an occupational therapist to help the child adjust to wearing the sensory supports. [Briggs: 2014]
Children with Rett syndrome under age 3 should be referred to Early Intervention (Early Intervention for Children with Disabilities/Delays (see RI providers [13])) for developmental services, such as speech, occupational, and physical therapy. Guide families to access special education services offered through the public school for children with Rett syndrome ages 3-21 years. The local school district will perform an assessment and develop an Individualized Education Plan (IEP) to help develop the least restrictive environment to educate and provide developmentally appropriate supports, such as speech, physical, and occupational therapies. An IEP might also include a wheelchair or walker, bussing services, augmentative communication systems, such as eye gaze technology, and toileting and feeding assistance. An IEP usually gets updated about every 3 years. School testing may include an evaluation for autism spectrum disorder; if not, consider referring to a neurodevelopmental expert for formal evaluation.
The intensity and frequency of therapies offered through Early Intervention or the public schools may not be adequate for children with Rett syndrome, so private therapy and/or a referral to a physiatrist should be considered. Obtain authorization from the family for two-way communication with the developmental and educational teams to troubleshoot any issues that arise and share information on the child’s progress. Talk with the family and review reports from early intervention and school evaluations to ensure they are accessing appropriate services and to identify gaps. Families may need letters from the medical home to support the family’s request for some accommodations at school, e.g., an evaluation by the augmentative communication team.
Counsel families that therapy that maximizes physical activities should be life-long, as these will minimize long-term complications and maximize long-term potentials.

Specialty Collaborations & Other Services

Pediatric Physical Medicine & Rehabilitation (see RI providers [6])

Refer for help in managing disability issues and providing private therapies for speech, occupational, and physical therapies. A primary care provider can consult a physiatrist on a one-time basis or for ongoing management if the child with Rett syndrome has complicated problems. See Resources for listings of therapies.

Physical Therapy (see RI providers [6])

Refer for assistive devices, such as walkers and standers, as well as exercises and orthotics to prevent and manage spasticity.

Occupational Therapy (see RI providers [21])

Refer to an occupational therapist for assistance with fine motor skills and adaptive strategies for activities of daily life.

Speech - Language Pathologists (see RI providers [33])

Refer to a speech therapist for assistance with communication and augmentative devices.

Audiology (see RI providers [24])

Evaluate hearing and fit the individual with appropriate hearing devices.

Pediatric Ophthalmology (see RI providers [8])

Perform detailed vision exams, prescribe glasses and other interventions, and perform surgery when necessary.

Early Intervention for Children with Disabilities/Delays (see RI providers [13])

Children with Rett syndrome under age 3 should be referred for developmental services such as speech, occupational, and physical therapy.

Eyes/Vision

Monitor for changes in vision or eye alignment. Intermittent esotropia, cortical visual impairment, and oculomotor apraxia are not uncommon. Ensure routine follow up with a pediatric ophthalmologist to help evaluate for vision problems. Individuals with Rett syndrome characteristically have a strong eye gaze with good eye contact and visual tracking. Due to this, non-verbal communication, such as eye gaze technology could be helpful.

Specialty Collaborations & Other Services

Speech - Language Pathologists (see RI providers [33])

Refer to a speech therapist for assistance with communication and augmentative devices.

Pediatric Ophthalmology (see RI providers [8])

Perform detailed vision exams, prescribe glasses and other interventions, and perform surgery when necessary.

Neurology

Educate parents about what to watch for and be sure they know that the course may be relapsing or remitting. Up to 90% of girls with Rett syndrome have seizures at some time in their lives. Most start by age 13, although some start as late as age 28. Seizures are generally grand mal or partial complex; less commonly, myoclonic seizures, atonic seizures, or infantile spasms occur. Staring episodes, which may include eye-rolling or myoclonic jerks, usually are not absence seizures. [Tarquinio: 2017] Behavioral events may be difficult to distinguish from seizures, and seizures in Rett syndrome may be difficult to control. Abnormal random discharges on EEG not correlated with seizure activity clinically do not need to be treated with antiepileptic medication.
Children with Rett syndrome should be referred to pediatric neurology for seizure diagnosis and an ongoing treatment plan. Most common medications used to treat seizures in individuals with Rett syndrome include levetiracetam, valproic acid, oxcarbazepine, and lamotrigine.
The medical home should routinely talk with the family and neurologist regarding seizure activity, seizure frequency, and the side effects of antiepileptic medications. Some seizures may be managed completely within the medical home model, whereas others may need frequent neurology consultation. Either the medical home or the neurologist should provide a seizure action plan for the home and for the school, including instructions on using any rescue medications. See Prescription Medications below for more information on seizure medications. Seizures/Epilepsy also has further management information.

Specialty Collaborations & Other Services

Pediatric Neurology (see RI providers [18])

Evaluation and management of seizures in girls with Rett syndrome are often difficult, and if possible, referral should be made to a pediatric neurologist. Since girls with Rett syndrome may have seizure-like events that aren't truly seizures, it is important to have a diagnostic evaluation before treatment. The neurologist also may assist in recognizing comorbid autism spectrum disorder.

Gastro-Intestinal & Bowel Function

Reflux
Girls with Rett syndrome have a high frequency of gastroesophageal reflux, possibly due to their difficulties with muscle coordination. Reflux may present as arching, irritability, or food refusal (rather than vomiting). Treatment can be started empirically with referral to gastroenterology if symptoms continue. Medications typical include H2 blockers or proton pump inhibitors, and duration of treatment should be limited if at all possible. For detailed treatment information, see Gastroesophageal Reflux Disease.
Treatment may be augmented by the use of a motility agent (e.g., low-dose erythromycin), but the clinician must monitor closely for side effects. When medical therapy is not successful, Nissen or another type of fundoplication may be recommended and can be performed laparoscopically in some cases, which shortens hospital and recovery time. For children who do not feed orally and are poor surgical candidates, another option is moving the distal end of the feeding tube to the small intestine (i.e., GJ-tube or J-tube). See Feeding Tubes & Gastrostomies in Children.
Air swallowing and abdominal distention
If problematic, behavioral treatment, such as decreasing the length of mealtimes, keeping the child in a sitting position to maximize burping, and avoiding constipation, may be adequate. In severe cases, gastrostomy tubes or Nissen fundoplication may be necessary. 
Constipation
Constipation is common in girls with Rett syndrome and can cause weight loss and discomfort. Ask about bowel patterns at visits to the medical home. Dietary intake should be optimized for the control of constipation (high-fluid and high-fiber foods). Treatment should be as needed. See the Constipation for detailed behavioral and pharmaceutical management information and for patient educational materials.
Swallowing problems
Swallowing problems may result in drooling, malnutrition, aspiration, and dental caries. If swallowing problems cause aspiration, a referral to gastroenterology or pediatric surgery for feeding tube placement should be made. If dysphagia is determined to be a problem, diets using pureed foods and thickened liquids or feeding with a gastrostomy tube may be necessary to decrease aspiration and to help with nutrition. See Thickened Liquids & Modified Foods. Ask about family concerns regarding feeding difficulties are common and impact the family’s quality of life.
Gallstones
Gallstones are more common in girls with Rett syndrome than in typically developing children and can be an easily overlooked source of pain. For a helpful article about gastroenterology needs and nutrition in girls with Rett syndrome, see [Baikie: 2014].

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see RI providers [18])

Refer for management of reflux and constipation when necessary, as well as nutritional issues; may do feeding tube placements.

Speech - Language Pathologists (see RI providers [33])

Refer for assessment and treatment of swallowing disorders, such as dysphagia and aspiration.

Swallow Study (see RI providers [0])

Refer for assessment and treatment of swallowing disorders such as dysphagia and aspiration.

Dental

Monitor for dental problems that can be exacerbated by use of certain medications, seizures, difficulties in maintaining appropriate oral hygiene, mouthing, reflux, and bruxism. [Fuertes-González: 2011] Refer to a pediatric dentist who is skilled in managing children with special health care needs.

Specialty Collaborations & Other Services

Pediatric Dentistry (see RI providers [54])

Refer for oral health evaluation, treatment, and preventive care.

Nutrition/Growth/Bone

Growth
Monitor for appropriate weight, height, and BMI using a standard growth chart. Aim to keep the BMI at least at the 25th percentile on a standard growth chart and avoid excessive weight gain. (Obesity in Children &Teens has links to BMI charts and contains detailed screening information.) Referrals to a nutrition specialist early in the course of Rett syndrome should be considered. Dieticians and Nutritionists (see RI providers [3]).
Monitor for growth deceleration, which can occur starting in the first couple of years and may be indicative of loss of bone mass and poor nutrition. [Jefferson: 2016] Treatment options for poor growth include small frequent meals, Boosting Calories for Babies, Toddlers, and Older Children, and supplementation with formulas. Comprehensive lists of formulas can be found at: General information about formulas and formula funding can be found at Formulas and Affording Formula. Feeding & Nutrition may also be helpful for clinicians. If the girl is still underweight, consider feeding tube placement.
Osteopenia and osteoporosis
Be vigilant for fractures, particularly in the long bones of the arms and legs, even without a significant inciting event. Fractures occur in 30-40% of people with Rett syndrome and are often an indicator that there may be osteopenia or osteoporosis. [Jefferson: 2016] [Briggs: 2014] Encourage non-pharmacological interventions that improve bone health, including increased vitamin D-25-OH and calcium (preferably from dietary sources), and increased physical activity. Pharmacological interventions such as bisphosphonates are discussed in Prescription Medications, below. Also, see Osteoporosis and Pathologic Fractures for more information.
Obtain a baseline DEXA scan for assessment of bone density with re-evaluation every 1-2 years depending on dietary intake of calcium and vitamin D, nutritional status, mobility, routine sun exposure, and history of fractures. [Jefferson: 2016] A diagnosis of osteoporosis requires both a history of fracture in combination with low bone densitometry findings. [Jefferson: 2016] Risk is increased for people with p.R168X, p.R255X, p.R270X, or p.T158M mutations. A lateral spine film may also be useful in assessing bone density. [Jefferson: 2016]
Vitamin D
Assess vitamin D-25-OH status annually for children with increased risk factors, such as non-ambulatory status and osteoporosis). [Jefferson: 2016] Monitoring calcium (including ionized), magnesium, phosphorus, alkaline phosphatase, albumin, and other secondary markers of nutritional status and bone health can also be helpful; however, the evidence for routine monitoring is low. [Jefferson: 2016] Please see Calcium and Vitamin D for information about recommended daily allowances and supplementation.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see RI providers [18])

A visit may be helpful if the child is having trouble gaining weight or swallowing, or if a gastrostomy tube placement is being considered.

Pediatric Orthopedics (see RI providers [16])

Refer for assistance in monitoring musculoskeletal health and addressing fractures.

Dieticians and Nutritionists (see RI providers [3])

Consider a visit, especially if the child is having difficulty gaining weight.

Pediatric Endocrinology (see RI providers [12])

Obtain DEXA scan for baseline and re-evaluation. If bone density is low and there has been a fracture history, consider referral.

Gynecology: Pediatric/Adolescent; Special Needs (see RI providers [3])

Cessation of menses may be desired for hygiene purposes, affiliation with seizure intensity, etc. Avoid Depo-Provera due to bone health concerns. Consider Adolescent Gynecology for IUD placement.

Cardiology

Due to frequent cardiac problems related to abnormal development of conduction fibers in the heart, including prolonged QTc interval and sinus tachycardia and bradycardia, individuals with Rett syndrome should have regular EKGs, and if abnormal, be evaluated by a pediatric cardiologist (or a cardiologist familiar with pediatric cardiac disease). Valve problems or cardiac myopathies are not associated with Rett syndrome. [Briggs: 2014] Families who have a child with Rett syndrome and prolonged QT syndrome should know which medications to avoid (see Prescription Medications below). In some cases of prolonged QT, beta-blockers may be helpful. Heart arrhythmias may be one of the causes of the rare cases of sudden death in girls with Rett syndrome. Sudden death occurs more frequently in Rett syndrome than in the general population, but the cause is not well understood. [Briggs: 2014] Even in girls without symptoms of heart disease, a baseline visit with cardiology and periodic follow-up is reasonable.

Specialty Collaborations & Other Services

Pediatric Cardiology (see RI providers [17])

Refer for assessment and management of cardiac problems, including formal review of EKGs and Holter monitoring.

Musculoskeletal

Girls with Rett syndrome should be followed for hand and foot contractures and deformities, fractures, hip subluxation or dislocation, and scoliosis. Monitor mobility aids like wheelchairs or walkers for appropriate fit.
Scoliosis
Scoliosis can start prior to puberty, advance rapidly, and continue after puberty. [Downs: 2009] By age 16, 85% of girls with Rett syndrome develop scoliosis to some extent, and many undergo spine surgery. [Killian: 2017] Spine imaging is recommended when scoliosis is initially observed and then every 6-12 months depending on the degree of the Cobb angle, ambulatory status, and stage of puberty. Because of the complexity of the detailed guidelines for the management of scoliosis in Rett syndrome, spinal imaging may be coordinated by the child’s orthopedic surgeon. [Downs: 2009]
Hips
Hip subluxation or dislocation is also common, but not painful (so it could be easily overlooked). In one study, hip problems were noted in 50% of girls with Rett syndrome by age 15.6 years. [Tay: 2010] Hip imaging is recommended annually starting at age 18 months for children who are non-ambulatory and if there is a positive Galeazzi sign or other concerning physical exam findings. [Tay: 2010] Similar to spine management, imaging may be coordinated by the orthopedic specialist.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see RI providers [16])

Refer for ongoing surveillance and management of musculoskeletal issues.

Mobility/Function/ADLs/Adaptive

Children with Rett syndrome usually need developmental and rehabilitative therapies, including physical, occupational, and speech therapies, and may benefit from an augmentative communication device. For family education, see Augmentative Communication (AAC).
Since it takes time to evaluate a child for a wheelchair, get insurance approval, and order the wheelchair (possibly as long as 6 months), this needs to be done before the child is having great difficulty walking. Parents generally find that having a wheelchair available is helpful, although sometimes initially raising the issue of a child needing a wheelchair can be emotionally difficult. If families would like to learn more, they can be directed to Wheelchairs and Adapted Strollers. Good positioning in a wheelchair with postural support and availability of a tray for toys and food may be helpful with developmental tasks, and also in preventing scoliosis.

Specialty Collaborations & Other Services

Pediatric Physical Medicine & Rehabilitation (see RI providers [6])

Refer for non-surgical management of musculoskeletal issues, prevention and treatment of spasticity, and if walkers, wheelchairs, or standers are needed. The rehab specialists coordinate care with physical and occupational therapists and seating specialists.

Occupational Therapy (see RI providers [21])

Refer for assistance with fine motor skills and adaptive strategies for activities of daily life.

Speech - Language Pathologists (see RI providers [33])

Refer for assistance with communication and augmentative devices.

Physical Therapy (see RI providers [6])

Refer for assistive devices and for exercises and orthotics to prevent and manage spasticity.

Speech - Language Pathologists (see RI providers [33])

Refer for assistance with communication and augmentative devices.

Mental Health/Behavior

Agitation, self-injurious behavior, and other behavioral abnormalities are frequent in children with Rett syndrome and often overwhelming for their families. Behavioral counseling and medications may be necessary to manage these problems, especially agitation. Before visiting professionals for help, families should keep a brief record of problem behaviors, frequency, triggers, and factors that help. See [Peebles: 2012] for a theoretical explanation of why self-injurious behavior occurs in individuals with intellectual disability. See Self-injurious Behavior for further clinical information.
Young Girl displaying Rett Syndrome features looks at the camera while standing by adults
Connect families with resources, such as Rettsyndrome.org and Family Voices state chapters. If behavior management or family stress are significant concerns, the medical home provider can help identify psychiatrists who specialize in mental health for children with special health care needs, although these can be hard to come by. The medical home clinician may prescribe psychiatric medications to help treat agitation when necessary, yet the medications may have unwanted side effects (see Pharmacy & Medications, below).
Consult with a psychiatrist if prescribing unfamiliar or high-risk medications like atypical antipsychotics. For individuals on seizure medications, consult the child’s neurologist to ensure the psychiatric medications do not alter seizure threshold or interact with the antiepileptics.

Specialty Collaborations & Other Services

Psychiatry/Medication Management (see RI providers [80])

Refer for medical management of behavior problems and expertise regarding behavior management issues, although not all psychiatrists have experience treating behavioral issues in the context of developmental disabilities.

Pharmacy & Medications

Often-prescribed medications
Certain medications are prescribed more commonly in treating issues related to Rett syndrome, below is a list of some of the issues with the often-prescribed medications:
  • Agitation: SSRIs (fluoxetine and other psychiatric medications); buspirone may also help with autonomic dysfunction [Briggs: 2014] [Kumar: 2017]
  • Cardiac arrhythmias and dysautonomia: Beta-blockers (propranolol) [Herrera: 2015] [Kumar: 2017]
  • Antiepileptics: Valproic acid, oxcarbazepine, levetiracetam (may not be a good fit for many with irritability side effects), topiramate, lamotrigine, clobazam, and others [Vignoli: 2017] [Briggs: 2014]
  • Seizure rescue meds: Diazepam and lorazepam, intranasal midazolam
  • Antacids: H2 blockers and PPIs
  • Promotility: Low-dose erythromycin (EES); however, this can affect the QT interval
  • Menstrual suppression: Levonorgestrel-releasing intrauterine system (Mirena) [Jefferson: 2016]
  • Osteoporosis: Bisphosphonates (limited evidence for use in Rett syndrome) [Jefferson: 2016] usually via IV infusion in conjunction with an endocrinologist
Neuromodulators (e.g., growth factors and glutamate modulators) are undergoing clinical study. There are novel medications for treatment of behavioral symptoms and other aspects of Rett syndrome, but these studies are mostly in animal models. [Kaufmann: 2016] [De: 2015] [Castro: 2014]
Be aware that many medications have significant side effects, and ongoing monitoring for tolerance, side effects, and drug interactions is important.
Prescription medications to avoid [Williamson: 2006] [Acampa: 2006] [Arora: 2016]
Certain medications that could be used to treat associated issues may be problematic for children with Rett syndrome. Medications that impact respiratory drive, prolong the QT interval, lower seizure threshold, or reduce bone density should be avoided when possible. Increase monitoring when these medications are used:
  • Medications that can affect QT interval: Prokinetics (e.g., cisapride), antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine), antiarrhythmics (e.g., quinidine, sotalol, amiodarone), and certain antibiotics (e.g., erythromycin, ketoconazole)
  • Medications that can lower seizure threshold: Antibiotics (e.g., penicillin, metronidazole), anticholinergics, antidepressants (rarely), antihistamines, antiasthmatics (e.g., theophylline), anesthetics (local and general), baclofen, hormones (e.g., estrogen, prednisone, insulin), immunosuppressants, narcotics, neuroleptics, stimulants, and others.
  • Medications that can affect bone density: Antiepileptics (e.g., valproate, phenytoin, phenobarbital, and carbamazepine), glucocorticoids, proton pump inhibitors (e.g., omeprazole, lansoprazole), progesterone-only medications (e.g., medroxyprogesterone (Depo-Provera), etonogestrel (Nexplanon) (conflicting evidence) [Lopez: 2014], and thyroid hormone
  • Medications that can depress respiratory function: Benzodiazepines (may be used in seizure control), opioids, and sedatives
Additionally, the medical home clinician should discuss black box warnings, such as the increased risk of suicidality with SSRIs. Families should also know that the basis for this warning came from the Treatment of Adolescents with Depression Study (TADS) [March: 2004], which excluded teens with intellectual disability, pervasive developmental disorder, and confounding medical conditions.
Over-the-counter medications to consider
  • Bone health: Vitamin D3 (cholecalciferol) and sometimes calcium [Briggs: 2014]
  • Sleep: Melatonin for sleep onset difficulties, iron supplements for restless leg symptoms - see Sleep Medications
  • Behavior: Acetyl-l-carnitine - may also alleviate some cardiac dysautonomia [Schaevitz: 2012] [Briggs: 2014] and possibly may improve hand apraxia to some degree. [Ellaway: 1999]

Specialty Collaborations & Other Services

Psychiatry/Medication Management (see RI providers [80])

Refer for assistance in diagnosis and treatment of complicated medication management. May provide brief consultation or routine follow-up, depending on the needs and preferences of the primary care clinician and family. The patient may see a nurse practitioner or physician assistant who is supervised by the psychiatrist. Frequency of visits is usually a few times per year.

Pediatric Neurology (see RI providers [18])

Consult for expert advice on diagnosis and treatment of seizures.

Respiratory

Due to problems with the autonomic nervous system, girls with Rett syndrome typically have episodes of abnormal breathing when they are awake. These episodes consist of disorganized breathing with periods of apnea and/or hyperventilation that can result in oxygen desaturation and clinical cyanosis. During sleep, hypoventilation or sleep apnea (obstructive or central) can occur. [Briggs: 2014] Although episodes of abnormal breathing may appear dangerous, they usually consist of hyperventilation followed by normal breathing, and treatment is usually not required. Breathing problems become less noticeable with age and should not be confused with seizures.
Older studies offer limited evidence that topiramate (sometimes prescribed for girls with Rett syndrome for seizures) may help with breathing problems. [Goyal: 2004] Naltrexone, an opiate antagonist, may help control irregular breathing, but it is known to have significant adverse side effects in the Rett syndrome population. [Percy: 1994] Novel medications are undergoing clinical trials, mostly in animal models.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see RI providers [6])

In some cases of very frequent abnormal breathing patterns, a visit with a pediatric pulmonologist may be helpful.

Sleep

Sleep problems are common and often difficult to manage in girls with Rett syndrome, but they should be treated if they are causing disruption to the family. Sleep problems may be noted as early as a few months of age. Sleep disturbances include abnormal circadian rhythm, excessive napping during the day, night terrors, bruxism, and frequent awakenings that may include laughing, crying, and/or screaming. Medical problems disrupting sleep, such as reflux and nocturnal seizures, need to be ruled out. Treatment should begin with Behavioral Techniques to Improve Sleep.
If not successful, medications that might be helpful include melatonin, iron supplementation (for restless sleep associated with ferritin levels <50), trazodone, gabapentin, and clonidine. The effect of these supplements and medications specifically in children with Rett syndrome are not well studied. See Sleep Medications for more information.
Be aware that hypoventilation, as well as central or obstructive sleep apnea, can occur. Obtain a sleep study (polysomnography) and consider adenotonsillectomy or positive pressure ventilation if there is a problem. [Bassett: 2016] See [Carotenuto: 2013] for a description of polysomnography in Rett syndrome.

Specialty Collaborations & Other Services

Sleep Disorders (see RI providers [2])

Consultation with a sleep specialist may be helpful.

Maturation/Sexual/Reproductive

About half of girls with classic Rett syndrome experience puberty on a similar trajectory as typically developing females; however, there can be a wider range in timing for the other percentage of girls. Menarche primarily occurs between ages 10-16. [Killian: 2014] Sex hormones are thought to be normal. [Killian: 2014] Menstrual periods may be difficult to manage for girls who have difficulty using their hands and for girls with intellectual disability. As a result, menstrual suppression may be important for quality of life for the patient as well as her caregivers. Despite both of the following being progestin-only contraceptives, most bone health experts strongly support the Mirena (levonorgestrel-releasing intrauterine system) implant for menstrual regulation and strongly encourage avoidance of Depo-Provera (medroxyprogesterone injection). Nexplanon (newer generation etonogestrel implant) has less data regarding effects in the Rett syndrome population (and even less information about use of the older Implanon implant). Of note, none of these methods are 100% reliable for menstrual suppression, and some individuals may experience heavier or irregular bleeding. See also Sexuality Education for Those with Developmental Disabilities (Florida Developmental Disabilities Council) and Sexuality & Children with Disabilities.

Specialty Collaborations & Other Services

Gynecology: Pediatric/Adolescent; Special Needs (see RI providers [3])

Refer to providers who are comfortable providing gynecologic care for girls with special needs.

Transitions

As the child matures, the medical home provider should monitor for family preparedness and supports for transitions in legal status, medical care in an adult setting, and housing and support of the young adult. Information about the role of the medical home in helping with transitions can be found at Transition Issues. Information for families can be found at Transition to Adulthood.
No Related Issues were found for this diagnosis.

Ask the Specialist

If I suspect Rett syndrome, what testing should I send?

Testing may be performed by the primary care provider with referral to genetics for confirmation and genetic counseling, or the family may be sent directly to genetics for testing. The American College of Medical Genetics recommends that testing for the MECP2 gene sequencing and separate deletion/duplication analysis should be considered In females with moderate to severe intellectual disability and non-diagnostic neuroimaging, even without other typical clinical features. For more information about the testing of the child with intellectual disability or global developmental delays, see [Moeschler: 2014] and [Kaur: 2019].

What common problems and/or subspecialty care does this patient need?

Monitor for gastrointestinal problems (oral health, bruxism, aspiration, gastroesophageal reflux, constipation, etc.), cardiac arrhythmia, irregular breathing, sleep dysregulation, seizures, musculoskeletal problems (wheelchair need, scoliosis, osteopenia), vision problems, growth and nutritional issues, and behavioral problems. Multi-disciplinary care is essential.

What is the risk of seizure in Rett syndrome?

Approximately 90% of children with Rett syndrome will also have epilepsy. [Tarquinio: 2017]

What type of therapies are most beneficial for patients with Rett syndrome?

Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards or communication boards) are beneficial. Anticipate the need for mobility devices and home adaptations, such as specialized bed, bath chair, and toilet.

Resources for Clinicians

On the Web

MECP2-Related Disorders (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

PubMed search for Rett syndrome in children, last 3 years

Briggs A.
Primary care of a child with Rett syndrome.
J Am Assoc Nurse Pract. 2014;26(9):471-80. PubMed abstract
This clinical guide published through the American Association of Nurse Practitioners provides the most current evidence-based recommendations based on literature review, but it is not a consensus guideline:

Killian JT, Lane JB, Lee HS, Skinner SA, Kaufmann WE, Glaze DG, Neul JL, Percy AK.
Scoliosis in Rett Syndrome: Progression, Comorbidities, and Predictors.
Pediatr Neurol. 2017;70:20-25. PubMed abstract

Moeschler JB, Shevell M.
Comprehensive evaluation of the child with intellectual disability or global developmental delays.
Pediatrics. 2014;134(3):e903-18 (reaffirmed 2020). PubMed abstract / Full Text
An AAP Clinical Report that provides guidance for primary care clinicians assisting families in preparing for a genetic evaluation; reaffirmed 2020.

Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, Tarquinio DC, Glaze DG, McGwin G, Kaufmann WE, Percy AK, Neul JL, Olsen ML.
Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome.
J Med Genet. 2014;51(3):152-8. PubMed abstract / Full Text
This study confirmed that MECP2 mutation type is a strong predictor of disease severity.

Halbach NS, Smeets EE, Steinbusch C, Maaskant MA, van Waardenburg D, Curfs LM.
Aging in Rett syndrome: a longitudinal study.
Clin Genet. 2013;84(3):223-9. PubMed abstract
This is the first longitudinal cohort study about aging in RTT.

Killian JT, Lane JB, Cutter GR, Skinner SA, Kaufmann WE, Tarquinio DC, Glaze DG, Motil KJ, Neul JL, Percy AK.
Pubertal development in Rett syndrome deviates from typical females.
Pediatr Neurol. 2014;51(6):769-75. PubMed abstract / Full Text
Examines pubertal trajectories in females with Rett syndrome including the relationship of body mass index to timing of puberty onset.

Neul JL, Lane JB, Lee HS, Geerts S, Barrish JO, Annese F, Baggett LM, Barnes K, Skinner SA, Motil KJ, Glaze DG, Kaufmann WE, Percy AK.
Developmental delay in Rett syndrome: data from the natural history study.
J Neurodev Disord. 2014;6(1):20. PubMed abstract / Full Text

Tarquinio DC, Motil KJ, Hou W, Lee HS, Glaze DG, Skinner SA, Neul JL, Annese F, McNair L, Barrish JO, Geerts SP, Lane JB, Percy AK.
Growth failure and outcome in Rett syndrome: specific growth references.
Neurology. 2012;79(16):1653-61. PubMed abstract / Full Text
The study aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.

Glaze DG, Percy AK, Skinner S, Motil KJ, Neul JL, Barrish JO, Lane JB, Geerts SP, Annese F, Graham J, McNair L, Lee HS.
Epilepsy and the natural history of Rett syndrome.
Neurology. 2010;74(11):909-12. PubMed abstract / Full Text
Seizures are common in Rett syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity.

Percy AK, Neul JL, Glaze DG, Motil KJ, Skinner SA, Khwaja O, Lee HS, Lane JB, Barrish JO, Annese F, McNair L, Graham J, Barnes K.
Rett syndrome diagnostic criteria: lessons from the Natural History Study.
Ann Neurol. 2010;68(6):951-5. PubMed abstract / Full Text
Analysis of 819 participants enrolled in the Rett syndrome (RTT) Natural History Study validated recently revised diagnostic criteria.

Kirby RS, Lane JB, Childers J, Skinner SA, Annese F, Barrish JO, Glaze DG, Macleod P, Percy AK.
Longevity in Rett syndrome: analysis of the North American Database.
J Pediatr. 2010;156(1):135-138.e1. PubMed abstract / Full Text
This analysis provides strong evidence for significant longevity in RTT and indicates the need for careful planning for long-term care of these women.

Tarquinio DC, Hou W, Berg A, Kaufmann WE, Lane JB, Skinner SA, Motil KJ, Neul JL, Percy AK, Glaze DG.
Longitudinal course of epilepsy in Rett syndrome and related disorders.
Brain. 2017;140(Pt 2):306-318. PubMed abstract / Full Text
This study summarizes the findings of the Rett syndrome Natural History study in regards to the longitudinal course of epilepsy and the patterns of seizure onset and remission.

Tarquinio DC, Hou W, Neul JL, Berkmen GK, Drummond J, Aronoff E, Harris J, Lane JB, Kaufmann WE, Motil KJ, Glaze DG, Skinner SA, Percy AK.
The course of awake breathing disturbances across the lifespan in Rett syndrome.
Brain Dev. 2018;40(7):515-529. PubMed abstract / Full Text
Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.

Tarquinio DC, Hou W, Neul JL, Kaufmann WE, Glaze DG, Motil KJ, Skinner SA, Lee HS, Percy AK.
The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders.
Pediatr Neurol. 2015;53(5):402-11. PubMed abstract / Full Text

Clinical Tools

Letters of Medical Necessity

Rett Syndrome / MECP2 Testing - Letter of Medical Necessity / Preauthorization (Word Document 19 KB)

Angelman & Rett / CGH Microarray - Letter of Medical Necessity / Preauthorization.docx (Word Document 18 KB)

Other

About the Diagnosis (International Rett Syndrome Foundation)
Explains the requirements for the diagnosis of classic and atypical Rett syndrome, including genetic testing for various mutations.

Patient Education & Instructions

Rettsyndrome.org
A non-profit organization that invests in research, provides support to families, and raises awareness about Rett syndrome.

Resources for Patients & Families

Information on the Web

For Parents & Families (Medical Home Portal)
Information for parents to help them better care for their child with Rett syndrome (and other complex conditions) from diagnosis through their child's transition to adult care.

Rettsyndrome.org
A non-profit organization that invests in research, provides support to families, and raises awareness about Rett syndrome.

Síndrome de Rett (NINDS)
Spanish language overview of Rett syndrome; National Institute of Neurological Disorders and Stroke.

Rett Syndrome (MedlinePlus)
Excellent, detailed review of condition for patients and families; National Library of Medicine and National Institutes of Health.

National & Local Support

Rettsyndrome.org
A non-profit organization that invests in research, provides support to families, and raises awareness about Rett syndrome.

Studies/Registries

Rett Syndrome (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Rare Diseases Clinical Research Network Registry
A place for patients with rare diseases, such as Rett syndrome, MECP2 Duplication, and Rett-Related Disorders Consortium, can register and be contacted about clinical research opportunities and updates on the progress of research projects. The registry is anonymous and free of charge.

Services for Patients & Families in Rhode Island (RI)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: June 2013; last update/revision: June 2020
Current Authors and Reviewers:
Author: Jennifer Goldman, MD, MRP, FAAP
Contributing Author: Lynne M. Kerr, MD, PhD
Reviewer: Timothy Benke, MD, PhD
Authoring history
2017: update: Jennifer Goldman, MD, MRP, FAAPA; Clint Nelson, MDR
2013: first version: Karin Dent, MS, CGCA; Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

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Longitudinal course of epilepsy in Rett syndrome and related disorders.
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The course of awake breathing disturbances across the lifespan in Rett syndrome.
Brain Dev. 2018;40(7):515-529. PubMed abstract / Full Text
Awake breathing dysfunction is common in RTT, more so than seizures, and is associated with function, quality of life and risk for cardiac dysrhythmia.

Tarquinio DC, Hou W, Neul JL, Kaufmann WE, Glaze DG, Motil KJ, Skinner SA, Lee HS, Percy AK.
The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders.
Pediatr Neurol. 2015;53(5):402-11. PubMed abstract / Full Text

Tarquinio DC, Hou W, Neul JL, Lane JB, Barnes KV, O'Leary HM, Bruck NM, Kaufmann WE, Motil KJ, Glaze DG, Skinner SA, Annese F, Baggett L, Barrish JO, Geerts SP, Percy AK.
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