Rett Syndrome

Description

Other Names

Atypical Rett syndrome
MECP2
 disorder
RTT

Diagnosis Coding

ICD-10

F84.2, Rett syndrome

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

Description

Classic Rett syndrome (RTT) 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 caused by mutations in the MECP2 gene. Variants of Rett syndrome, or atypical Rett syndrome, can include preserved speech, early seizures, and congenital onset. [Neul: 2010]

Prevalence

Prevalence estimates for Rett syndrome are about 1:11,364 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. Different mutation types of the MECP2 gene can affect the age of diagnosis and severity of the clinical course. [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.

Atypical Rett syndrome has diagnostic criteria different than classic Rett syndrome
Photo by Lexi Luthy
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 possibly X-linked intellectual disability without other clinical features of Rett syndrome.

Atypical Rett syndrome is less frequently associated with an MECP2+ mutation, although some are positive for this mutation. In atypical Rett syndrome, genetic testing may reveal a mutation of the X chromosome on CDKL5 (cyclin-dependent kinase-like 5).

In the congenital onset variant, there may be mutations on chromosome 14 on FOXG1, although not all people with this mutation have congenital onset of Rett syndrome. Additionally, mutations of the X chromosome WDR45 gene can result in some clinical presentations of Rett syndrome, but it is more commonly implicated in another syndrome known as BPAD (beta-propeller protein-associated neurodegeneration).

Prognosis

Although 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. 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]

Roles Of The Medical Home

The primary care provider is often the first to recognize clinical signs suggestive of Rett syndrome and to initiate the process of formal diagnosis. Due to the complicated nature of assessment and management of children with Rett syndrome, working with a multi-disciplinary team (genetics, neurology, physiatry, speech, occupational therapy, physical therapy, and orthopedics) or a specialized clinic is recommended.
Females with Rett Syndrome Displaying Stereotypical Hand Behavior
Child with Rett syndrome with stereotypic hand behavior

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, specialist, and other care providers, see Rett Syndrome Clinics (International Rett Syndrome Foundation) and Rett Syndrome, Services & Other Resources.

Practice Guidelines

There are currently no evidence-based, expert, consensus practice guidelines for primary care of individuals with Rett syndrome. The international expert consensus guidelines for 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, have been developed:
  • 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

  • Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H.
    Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence.
    Spine (Phila Pa 1976). 2009;34(17):E607-17. PubMed abstract

  • 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

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:

Christodoulou J, Ho G.
MECP2-Related Disorders.
GeneReviews [Internet] University of Washington, Seattle. 2012. PubMed abstract / Full Text

Moeschler JB, Shevell M.
Comprehensive evaluation of the child with intellectual disability or global developmental delays.
Pediatrics. 2014;134(3):e903-18. PubMed abstract / Full Text

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]).

Screening

Of Family Members

In a family with a child with Rett syndrome, female siblings and both parents could be tested to see if they are asymptomatic carriers of the mutation. Future pregnancies can be tested prenatally as well; however, over 99% of Rett syndrome cases are sporadic mutations, not inherited. [International: 2017]

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. Variant Rett syndrome should be considered when a child meets some (not all) of the diagnostic criteria of classic Rett syndrome, but do meet the diagnostic criteria for atypical Rett syndrome (see diagnostic criteria, below). Variants of atypical Rett syndrome generally fall under 3 categories:
  • Congenital onset Rett syndrome (Rolando variant): There is no period of normal development; delay is noted early on, or seizures begin and are followed by developmental regression.
  • Early seizure variant (Hanefeld variant): Seizures start prior to 5 months of age.
  • Preserved speech variant (Zappella variant): There is later onset of less severe symptoms with some expressive language re-obtained in early childhood.
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.

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.

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)
The following is adapted from About the Diagnosis (International Rett Syndrome Foundation).

Main, Exclusion, and Supportive 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)
  • Stereotypies, such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms
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
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

Clinical Classification

Clinical Features and Genetics for Atypical Rett Syndrome  in Children (Zappella, Hanefield, and Rolando Variants)
[Neul: 2010]
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. How RTT Differs from Autism (International Rett Syndrome Foundation) has more information about differentiating these 2 conditions and the Portal's Autism Spectrum Disorder, Initial Diagnosis 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, Initial Diagnosis 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 Porta's Cerebral Palsy, Ongoing Assessment has further diagnosis information.
  • Infantile form of neuronal ceroid lipofuscinosis (aka 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 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

Pearls & Alerts

When to consider testing for Rett syndrome

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

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.

Predictors of MECP2+ mutations

The strongest clinical predictors of MECP2+ tests are partial or complete loss of purposeful hand movements, gait abnormalities, and stereotypic hand movements. [Knight: 2016]

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]

History & Examination

Family History

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

Pregnancy Or Perinatal History

This history is usually normal.

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. [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 Oral Health (Dental) Screening & Prevention.
  • 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)

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 such as infantile onset.

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 rehab 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.

Maturational Progress

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]

Social & Family Functioning

Assessing family functioning and resources available for family support are an important part of the medical home visit. Ask about behavioral problems and social functioning. Autism can be a feature associated with Rett syndrome. 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. For those unable to stand, use supine measurements. [Leonard: 2013] When kids ≥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.

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

Monitor for microcephaly, eye gaze problems, and esotropia.

Mouth/Teeth

Examine the oral cavity for evidence of bruxism, problems with hygiene, and other dental concerns. Oral Health (Dental) Screening & Prevention provides further examination and prevention tips.

Chest

Look for abnormal breathing patterns, as well 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 is often 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]

Imaging

DEXA
A baseline DEXA scan for assessment of bone density with re-evaluation every 1-2 years is recommended for those who are at increased risk of osteopenia/osteoporosis. Consider risk based on dietary intake of calcium and vitamin D, nutritional status, mobility, routine sun exposure, 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 (see all Bone Densitometry/DEXA services providers (4) in our database). Spine imaging is recommended when scoliosis is initially observed, and then every 6-12 months depending on factors such as degree of the Cobb angle, ambulatory status, and whether the child is in 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]

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 in 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 Writing Letters of Medical Necessity for sample letters to obtain insurance preauthorization for MECP2 testing.

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 see 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 occipital dominant 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 periodically. 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 (see all Swallow Studies services providers (1) in our database).

Sleep study
Consider if there are problems with breathing during sleep, including snoring, frequent awakenings, or excessive daytime sleepiness (see all Sleep Studies/Polysomnography services providers (6) in our database).

pH probe
Consider a pH probe to help evaluate for reflux.

Subspecialist Collaborations & Other Resources

Developmental Assessment (see Services below for relevant providers)

Refer for evaluation of developmental progress and behavioral concerns.

Developmental - Behavioral Pediatrics (see Services below for relevant providers)

Refer for evaluation of developmental progress and behavioral concerns.

Pediatric Genetics (see Services below for relevant providers)

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

Pediatric Genetic Counseling (see Services below for relevant providers)

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

Pediatric Neurology (see Services below for relevant providers)

Referral to a pediatric neurologist familiar with issues of Rett syndrome is recommended. A referral to neurology 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 co-morbid autism spectrum disorder is present.

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

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 Services below for relevant providers)

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: 2017]

Pediatric Gastroenterology (see Services below for relevant providers)

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 Services below for relevant providers)

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

Psychiatrist, Child-18 (MD) (see Services below for relevant providers)

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).

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 because, 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 that 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.

Pearls & Alerts

Evaluate new or increased screaming 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 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.

Systems

Development (general)

Monitor results of hearing screens and annual ophthalmologic exams. If the child does not tolerate wearing hearing aids or eye glasses for example, work with the specialist or an occupation 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 (see all Early Intervention for Children with Disabilities/Delays services providers (207) in our database) 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 to 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. See Augmentative Communication (AAC).

Subspecialist Collaborations & Other Resources

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

A pediatric physiatrist and team is helpful 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 Services below for relevant providers)

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

Occupational Therapy, Pediatric (see Services below for relevant providers)

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

Speech Therapy (see Services below for relevant providers)

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

Audiology (see Services below for relevant providers)

Evaluate hearing and fit the individual with appropriate hearing devices.

Pediatric Ophthalmology (see Services below for relevant providers)

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

Early Intervention for Children with Disabilities/Delays (see Services below for relevant providers)

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 is 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.

Subspecialist Collaborations & Other Resources

Speech Therapy (see Services below for relevant providers)

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

Pediatric Ophthalmology (see Services below for relevant providers)

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, and most start by age 13. Seizures are generally grand mal or partial complex; less commonly, myoclonic seizures, atonic seizures, or infantile spasms occur. (See Types of Generalized Seizures for general descriptions.) 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 the neurologist regarding seizure activity, seizure frequency, and 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, Treatment & Management also has further management information.

Subspecialist Collaborations & Other Resources

Pediatric Neurology (see Services below for relevant providers)

Evaluation and management of seizures in girls with Rett syndrome is 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. or 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 other 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 and Gastrostomies.

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, Treatment & Management 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 causes 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  Thickening Liquids & Pureeing Foods. Ask about family concerns regarding feeding, as 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].

Subspecialist Collaborations & Other Resources

Pediatric Gastroenterology (see Services below for relevant providers)

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

Speech Therapy (see Services below for relevant providers)

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

Swallow Studies (see Services below for relevant providers)

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.

Subspecialist Collaborations & Other Resources

Pediatric Dentistry (see Services below for relevant providers)

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. (Childhood Obesity Screening & Prevention 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 (see all Nutrition Assessment Services services providers (175) in our database) .

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, Power Packing, and supplementation with formulas. Comprehensive lists of formulas can be found at: General information about formulas and formula funding can be found at Formulas. Nutrition and Growth in Children with CP 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] Also see Osteopenia Pathologic Fractures for more information. 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.

Obtain a baseline DEXA scan for assessment of bone density with re-evaluation every 1-2 years. [Jefferson: 2016] A diagnosis of osteoporosis requires both a history of fracture in combination with low bone densitometry findings. [Jefferson: 2016] Consider risk based on dietary intake of calcium and vitamin D, nutritional status, mobility, routine sun exposure, 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]

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.

Subspecialist Collaborations & Other Resources

Pediatric Gastroenterology (see Services below for relevant providers)

A visit with gastroenterology 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 Services below for relevant providers)

Refer for assistance in monitoring musculoskeletal health and addressing fractures.

Nutrition Assessment Services (see Services below for relevant providers)

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

Pediatric Endocrinology (see Services below for relevant providers)

If bone density is low, and there has been a fracture history, consider referral to endocrinology.

Bone Densitometry/DEXA (see Services below for relevant providers)

Obtain for baseline and re-evaluation.

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. Acetyl-L-carnitine may also be helpful; however, large safety studies have not been performed. [Briggs: 2014] 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.

Subspecialist Collaborations & Other Resources

Pediatric Cardiology (see Services below for relevant providers)

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.

Subspecialist Collaborations & Other Resources

Pediatric Orthopedics (see Services below for relevant providers)

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.

Subspecialist Collaborations & Other Resources

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

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, Pediatric (see Services below for relevant providers)

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

Speech Therapy (see Services below for relevant providers)

Refer for assistance with communication and augmentative devices.

Physical Therapy (see Services below for relevant providers)

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

Speech Therapy (see Services below for relevant providers)

Refer for assistance with communication and augmentative devices.

Mental Health/Behavior

Agitation, self-injurious behavior, and other behavior 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.

Young Girl with Rett Syndrome Participating in Support Group Event
Connect families with resources, such as International Rett Syndrome Association (IRSA) 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 anti-epileptics.

Subspecialist Collaborations & Other Resources

Psychologist, Child-18 (PhD, PsyD) (see Services below for relevant providers)

Refer for medical management of behavior problems and expertise regarding behavior management issues, although not all psychologists 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, topiramate, lamotrigine, and others [Vignoli: 2017] [Briggs: 2014]
  • Seizure rescue meds: Diazepam and lorazepam
  • Antacids: H2 blockers and PPIs
  • Promotility: Low-dose erythromycin (EES)
  • Menstrual suppression: Levonorgestrel-releasing intrauterine system (Mirena). [Jefferson: 2016]
  • Osteoporosis: Bisphosphonates (limited evidence for use in Rett syndrome). [Jefferson: 2016] As with administration of bisphosphonate to anyone, the child needs to have an empty stomachs and be able to sit upright (or be positioned in an upright fashion) for 30 minutes after ingestion. The medication can be given with a small spoon of applesauce to allow it to be swallowed. Episodes of heartburn and known uncontrolled reflux are relative contraindications.
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] Ongoing monitoring of tolerance and for side effects and drug interactions is important. Be aware that many medications have significant side effects. 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.

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 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: 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
  • 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]

Subspecialist Collaborations & Other Resources

Psychiatrist, Child-18 (MD) (see Services below for relevant providers)

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 Services below for relevant providers)

Consult for expert advice on diagnosis and treatment of seizures.

Respiratory

Due to problems with the autonomic nerve 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 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.

Subspecialist Collaborations & Other Resources

Pediatric Pulmonology (see Services below for relevant providers)

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 interventions/sleep hygiene. 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 Medications for Sleep 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.

Subspecialist Collaborations & Other Resources

Pediatric Sleep Medicine (see Services below for relevant providers)

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 Children and Adolescents with Developmental Disabilities.

Subspecialist Collaborations & Other Resources

Gynecology (Ped/Adol, Special Needs) (see Services below for relevant providers)

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.

Frequently Asked Questions

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 mutation 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].

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. Multidisciplinary 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.

Issues Related to Rett Syndrome

Development (general)

Augmentative Communication

Resources

Information for Clinicians

MECP2-Related Disorders (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; sponsored by the U.S. National Center for Biotechnology Information, U.S. National Library of Medicine.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

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:

Christodoulou J, Ho G.
MECP2-Related Disorders.
GeneReviews [Internet] University of Washington, Seattle. 2012. PubMed abstract / Full Text

Moeschler JB, Shevell M.
Comprehensive evaluation of the child with intellectual disability or global developmental delays.
Pediatrics. 2014;134(3):e903-18. PubMed abstract / Full Text

Clinical Tools

Patient Education & Instructions

International Rett Syndrome Association (IRSA)
A non-profit organization that invests in research, provides support to families, and raises awareness about Rett syndrome.

Other

Variant Forms of RTT that Meet Criteria for Atypical RTT (PDF Document 140 KB)
Clinical and genetic criteria for preserved speech variant (Zapppella variant), early seizure variant (Hanefeld variant), and congenital variant (Rolando variant) of RTT; Table 2 of Neul JL, Kaufmann WE, et al for the RettSearch Consortium. 2010. Rett Syndrome: Revised Diagnostic Criteria and Nomenclature. Ann Neurol.

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.

Information & Support for Families

Family Diagnosis Page

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.

International Rett Syndrome Association (IRSA)
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 (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Support National & Local

International Rett Syndrome Association (IRSA)
A non-profit organization that invests in research, provides support to families, and raises awareness about Rett syndrome.

Studies/Registries

Rett Syndrome (clinicaltrials.gov)
Lists clinical studies that have an active, recruiting, and completed status; National Institutes of Health.

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

Audiology

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Occupational Therapy, Pediatric

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Pediatric Cardiology

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Pediatric Dentistry

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Pediatric Sleep Medicine

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Psychiatrist, Child-18 (MD)

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Sleep Studies/Polysomnography

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Authors

Reviewing Author: Clint Nelson, MD - 9/2017
Content Last Updated: 9/2017

Bibliography

Acampa M, Guideri F.
Cardiac disease and Rett syndrome.
Arch Dis Child. 2006;91(5):440-3. PubMed abstract / Full Text

Arora E, Singh H, Gupta YK.
Impact of antiepileptic drugs on bone health: Need for monitoring, treatment, and prevention strategies.
J Family Med Prim Care. 2016;5(2):248-253. 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
Evidence-based expert consensus recommendations for GERD, constipation, and bloating in the context of Rett syndrome.

Bassett E, Heinle R, Johnston D.
Sleep Apnea in Patients With Rett Syndrome: Roles for Polysomnography and Adenotonsillectomy.
J Child Neurol. 2016;31(14):1633-1634. PubMed abstract

Bienvenu T, Philippe C, De Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Feingold J, Chelly J, Villard L.
The incidence of Rett syndrome in France.
Pediatr Neurol. 2006;34(5):372-5. PubMed abstract

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:

Carotenuto M, Esposito M, D'Aniello A, Rippa CD, Precenzano F, Pascotto A, Bravaccio C, Elia M.
Polysomnographic findings in Rett syndrome: a case-control study.
Sleep Breath. 2013;17(1):93-8. PubMed abstract

Castro J, Garcia RI, Kwok S, Banerjee A, Petravicz J, Woodson J, Mellios N, Tropea D, Sur M.
Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome.
Proc Natl Acad Sci U S A. 2014;111(27):9941-6. PubMed abstract / Full Text

Christodoulou J, Ho G.
MECP2-Related Disorders.
GeneReviews [Internet] University of Washington, Seattle. 2012. PubMed abstract / Full Text

De Filippis B, Chiodi V, Adriani W, Lacivita E, Mallozzi C, Leopoldo M, Domenici MR, Fuso A, Laviola G.
Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome.
Front Behav Neurosci. 2015;9:86. PubMed abstract / Full Text

Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H.
Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence.
Spine (Phila Pa 1976). 2009;34(17):E607-17. PubMed abstract
Specific clinical guidelines based on evidence review and expert panel consensus.

Ellaway C, Williams K, Leonard H, Higgins G, Wilcken B, Christodoulou J.
Rett syndrome: randomized controlled trial of L-carnitine.
J Child Neurol. 1999;14(3):162-7. PubMed abstract

Fuertes-González MC, Silvestre FJ, Almerich-Silla JM.
Oral findings in Rett syndrome: a systematic review of the dental literature.
Med Oral Patol Oral Cir Bucal. 2011;16(1):e37-41. PubMed abstract

Goyal M, O'Riordan MA, Wiznitzer M.
Effect of topiramate on seizures and respiratory dysrhythmia in Rett syndrome.
J Child Neurol. 2004;19(8):588-91. PubMed abstract

Guideri F, Acampa M, Matera MR, Zappella M, Hayek Y.
Echocardiographic evaluation in Rett children with cardiac dysautonomia.
Journal of Pediatric Neurology. 2004;Vol. 2(No. 3, July-):pp. 145-. / Full Text

Hagberg B, Hagberg G, Olow I, von Wendt L.
The changing panorama of cerebral palsy in Sweden. V. The birth year period 1979-82.
Acta Paediatr Scand. 1989;78(2):283-90. PubMed abstract

Hagberg B, Hanefeld F, Percy A, Skjeldal O.
An update on clinically applicable diagnostic criteria in Rett syndrome. Comments to Rett Syndrome Clinical Criteria Consensus Panel Satellite to European Paediatric Neurology Society Meeting, Baden Baden, Germany, 11 September 2001.
Eur J Paediatr Neurol. 2002;6(5):293-7. PubMed abstract
International expert consensus guidelines related to diagnosis.

Herrera JA, Ward CS, Pitcher MR, Percy AK, Skinner S, Kaufmann WE, Glaze DG, Wehrens XH, Neul JL.
Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs.
Dis Model Mech. 2015;8(4):363-71. PubMed abstract / Full Text

International Rett Syndrome Foundation.
Frequently Asked Questions.
(2017) https://www.rettsyndrome.org/about-rett-syndrome/faq. Accessed on May 2017.

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
Specific clinical guidelines based on evidence review and expert panel consensus.

Kaufmann WE, Stallworth JL, Everman DB, Skinner SA.
Neurobiologically-based treatments in Rett syndrome: opportunities and challenges.
Expert Opin Orphan Drugs. 2016;4(10):1043-1055. PubMed abstract / Full Text

Killian JT Jr, Lane JB, Lee HS, Pelham JH, Skinner SA, Kaufmann WE, Glaze DG, Neul JL, Percy AK.
Caretaker Quality of Life in Rett Syndrome: Disorder Features and Psychological Predictors.
Pediatr Neurol. 2016;58:67-74. PubMed abstract / Full Text

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

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

Knight VM, Horn PS, Gilbert DL, Standridge SM.
The Clinical Predictors That Facilitate a Clinician's Decision to Order Genetic Testing for Rett Syndrome.
Pediatr Neurol. 2016;63:66-70. PubMed abstract

Kumar A, Jaryal A, Gulati S, Chakrabarty B, Singh A, Deepak KK, Pandey RM, Gupta N, Sapra S, Kabra M, Khajuria R.
Cardiovascular Autonomic Dysfunction in Children and Adolescents With Rett Syndrome.
Pediatr Neurol. 2017;70:61-66. PubMed abstract

Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, Williamson S, Leonard H.
Rett syndrome in Australia: a review of the epidemiology.
J Pediatr. 2006;148(3):347-52. PubMed abstract

Leonard H, Cobb S, Downs J.
Clinical and biological progress over 50 years in Rett syndrome.
Nat Rev Neurol. 2017;13(1):37-51. PubMed abstract

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
Specific clinical guidelines based on evidence review and expert panel consensus.

Lopez LM, Grimes DA, Schulz KF, Curtis KM, Chen M.
Steroidal contraceptives: effect on bone fractures in women.
Cochrane Database Syst Rev. 2014(6):CD006033. PubMed abstract

March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J.
Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial.
JAMA. 2004;292(7):807-20. PubMed abstract

Moeschler JB, Shevell M.
Comprehensive evaluation of the child with intellectual disability or global developmental delays.
Pediatrics. 2014;134(3):e903-18. PubMed abstract / Full Text

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

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

Peebles KA, Price TJ.
Self-injurious behaviour in intellectual disability syndromes: evidence for aberrant pain signalling as a contributing factor.
J Intellect Disabil Res. 2012;56(5):441-52. PubMed abstract / Full Text

Percy AK, Glaze DG, Schultz RJ, Zoghbi HY, Williamson D, Frost JD Jr, Jankovic JJ, del Junco D, Skender M, Waring S.
Rett syndrome: controlled study of an oral opiate antagonist, naltrexone.
Ann Neurol. 1994;35(4):464-70. PubMed abstract

Schaevitz LR, Nicolai R, Lopez CM, D'Iddio S, Iannoni E, Berger-Sweeney JE.
Acetyl-L-carnitine improves behavior and dendritic morphology in a mouse model of Rett syndrome.
PLoS One. 2012;7(12):e51586. PubMed abstract / Full Text

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

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.
Age of diagnosis in Rett syndrome: patterns of recognition among diagnosticians and risk factors for late diagnosis.
Pediatr Neurol. 2015;52(6):585-91.e2. PubMed abstract / Full Text

Tay G, Graham H, Graham HK, Leonard H, Reddihough D, Baikie G.
Hip displacement and scoliosis in Rett syndrome - screening is required.
Dev Med Child Neurol. 2010;52(1):93-8. PubMed abstract

Vignoli A, Savini MN, Nowbut MS, Peron A, Turner K, La Briola F, Canevini MP.
Effectiveness and tolerability of antiepileptic drugs in 104 girls with Rett syndrome.
Epilepsy Behav. 2017;66:27-33. PubMed abstract

Williamson SL, Christodoulou J.
Rett syndrome: new clinical and molecular insights.
Eur J Hum Genet. 2006;14(8):896-903. PubMed abstract