Consensus guidelines on managing Rett syndrome across the lifespan
==================================================================

* Cary Fu
* Dallas Armstrong
* Eric Marsh
* David Lieberman
* Kathleen Motil
* Rochelle Witt
* Shannon Standridge
* Paige Nues
* Jane Lane
* Tristen Dinkel
* Monica Coenraads
* Jana von Hehn
* Mary Jones
* Katie Hale
* Bernhard Suter
* Daniel Glaze
* Jeffrey Neul
* Alan Percy
* Timothy Benke

## Abstract

**Background** Rett syndrome (RTT) is a severe neurodevelopmental disorder with complex medical comorbidities extending beyond the nervous system requiring the attention of health professionals. There is no peer-reviewed, consensus-based therapeutic guidance to care in RTT. The objective was to provide consensus on guidance of best practice for addressing these concerns.

**Methods** Informed by the literature and using a modified Delphi approach, a consensus process was used to develop guidance for care in RTT by health professionals.

**Results** Typical RTT presents early in childhood in a clinically recognisable fashion. Multisystem comorbidities evolve throughout the lifespan requiring coordination of care between primary care and often multiple subspecialty providers. To assist health professionals and families in seeking best practice, a checklist and detailed references for guidance were developed by consensus.

**Conclusions** The overall multisystem issues of RTT require primary care providers and other health professionals to manage complex medical comorbidities within the context of the whole individual and family. Given the median life expectancy well into the sixth decade, guidance is provided to health professionals to achieve current best possible outcomes for these special-needs individuals.

*   neurology
*   genetics
*   syndrome
*   rehabilitation
*   gastroenterology

### What is known about the subject?

*   Rett syndrome (RTT) is a multisystem and rare genetic disorder with similarities to other developmental encephalopathies.

*   There is no peer-reviewed, consensus-based therapeutic guidance to care in RTT.

### What this study adds?

*   Primary care providers and other health professionals caring for patients with RTT frequently have limited first-hand experience managing the disorder due to its rare prevalence.

*   A consensus on guidance for health professionals caring for patients with RTT was developed based on literature review and expert opinion.

*   This guidance is applicable to other rare and often severe neurodevelopmental disorders.

## Introduction

Rett syndrome (RTT)1 is a severe neurodevelopmental disorder with an estimated worldwide prevalence of 1 in 20 000–40 000 people. RTT is one of the most common genetic causes of developmental and intellectual impairment in girls,2 affecting up to 1 in 10 000 girls under the age of 12. RTT is not a neurodegenerative condition,3 rather it is a progressive disorder involving multisystem symptom evolution over time. Following demonstration of symptom reversal in mouse models,4 5 there is flourishing hope for further disease-modifying therapies.

Nearly all individuals with RTT have one of >300 distinct loss-of-function mutations in the *MECP2* gene on the X chromosome.6 This gene encodes methyl-CpG binding protein-2, an essential transcriptional regulator in the brain required for normal neurodevelopment.7 Complete genetic testing involves sequencing and methods to detect larger deletions (eg, multiplex ligation-dependent probe amplification) of the *MECP2* gene. Likely owing to the random nature of X chromosome inactivation8 and other genetic modifiers,9–11 genotype–phenotype correlations are imprecise. However, a general pattern exists with some mutations (early truncating mutations such as R168X, R255X and R270X, large deletions and specific point mutations such as R106W) associated with increased severity compared with other mutation groups (R133C, R294X, R306X and C-terminal truncations).12 *MECP2* mutations causing RTT are almost always de novo (spontaneous) and as such are not expected to recur in families.

The presentation is initially subtle in the first 2 years of life, involving developmental delays and hypotonia on examination, but subsequent symptom evolution between 18 and 30 months of age with developmental regression and onset of repetitive, purposeless hand movements is striking.13 The core clinical diagnostic features of RTT (Box 1, typical and atypical)1 include a period of normal (or near normal) development followed by developmental regression with loss of language and hand function skills, impaired gait, and development of hand stereotypies, causing lifelong dependence.14 15 The average age at RTT diagnosis of 2.5 years has been trending downward with increasing availability of diagnostic genetic testing.16 The multisystem nature of the disorder has been documented within multiple observational studies, with symptom risk evolving across the lifespan.

Box 1 
### Classic (or typical) and atypical Rett syndrome (RTT) diagnostic criteria1

Classic or typical RTT diagnostic criteria.

A period of regression followed by recovery or stabilisation.

*   Partial or complete loss of acquired purposeful hand skills.

*   Partial or complete loss of spoken language.

*   Gait abnormalities: impaired or absence of ability.

*   Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms.

Atypical RTT diagnostic criteria.

A period of regression followed by recovery or stabilisation.

*   At least two of the four main criteria.

*   Five of eleven supportive criteria.
    
    *   Breathing disturbances while awake.
    
    *   Bruxism while awake.
    
    *   Impaired sleep.
    
    *   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’.

*MECP2* mutations have been identified rarely in boys with neurodevelopmental disorders, termed ‘male RTT encephalopathy’. The resulting developmental outcome is quite variable, although with symptomatology distinct from RTT, and ranges in severity from a severe neonatal encephalopathy with minimal developmental improvement to a mild intellectual disability.17 Male RTT encephalopathy18 and other distinct developmental encephalopathies (historically linked to RTT)19 such as *MECP2* duplication syndrome,20–22 *CDKL5* deficiency disorder23–26 and *FOXG1* syndrome27–30 may have similar approaches (but distinct therapeutics) as more is learnt about specific aspects of their clinical care. Alterations in *MECP2*, *CDKL5* and *FOXG1* should be considered in all individuals, male and female, with developmental delays and intellectual disability.

In the past two decades the natural history of RTT has been extensively studied.31 Perhaps most important to all health professionals managing this complex disorder is the knowledge that with appropriate care, children with RTT will become adults with RTT; 70% live to at least 50 years of age.14 32 As such, health professionals are often presented with the daunting task of effectively managing the evolving medical comorbidities of the disorder throughout a patient’s lifespan. To help address this challenge, based on a review of published literature regarding RTT symptomatology that identified the most relevant primary care concerns through a modified Delphi consensus approach, we developed recommendations regarding guidance for best practice. These recommendations have been organised based on an age-dependent health supervision approach to facilitate the goal of effective and meaningful care for individuals with RTT across all ages.

## Methods

Draft guidance was developed (MJ, KH and PN) and presented and discussed at bimonthly International Rett Syndrome Foundation-sponsored North American Rett Syndrome Clinics Network conference calls between January 2016 and September 2018 with input obtained from 22 clinical sites. An initial draft was presented in January 2017 for external review by the network through September 2018; additional public input was obtained from January 2019 to May 2019 through placement on the RettSyndrome.org website. With supervision by the group leader, the guidance was further refined substantially by eight Rett centres (University of Alabama Birmingham, Vanderbilt University, Children’s Hospital Colorado, Children’s Hospital of Philadelphia, Cincinnati Children’s Hospital, Boston Children’s Hospital, UCSF Benioff Children’s Hospital Oakland and Texas Children’s Hospital) providing multidisciplinary care for individuals with RTT, in partnership with the National Institutes of Health-funded Natural History Study of Rett and Related Disorders (NHS, U54 HD061222; ClinicalTrials.gov: [NCT00299312](http://bmjpaedsopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00299312&atom=%2Fbmjpo%2F4%2F1%2Fe000717.atom)/NCT02738281) and two patient advocacy groups, Rett Syndrome Research Trust and the International Rett Syndrome Foundation. This consensus approach followed a modified Delphi process employed by members of this group previously.33 The partners were chosen based on clinical experience across primary care, multiple subspecialties, healthcare delivery, and importantly patient-family experience with RTT. Conflicts of interest were vetted by the group leader with full knowledge by the group. A consensus led by the group leader surrounding relevant guidance based on published data and clinical opinion was developed through six further rounds of modifications. The results of a literature review were used to inform the guidance (C. Fu et al., BMJ Paediatrics Open, 2020, in press). The recommendations were created based on an age-dependent health supervision approach to assist health professionals in fulfilling the goal of effective and meaningful care for individuals with RTT across all ages (tables 1 and 2). Items are organised by prevalence at each age group. Consistent with the International Classification of Functioning, Disability and Health guidelines (WHO 2001),34 this guidance recognises the inter-relatedness of body function/structure, environment and personal factors to maximise activities and participation (online supplementary table 1). Thus, in addition to routine assessment of medical issues (body function), several psychosocial, environmental and educational concerns need to be assessed frequently to achieve the goal of family-centred service:

### Supplementary data

[[bmjpo-2020-000717supp001.pdf]](pending:yes)

View this table:
[Table 1](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T1)

Table 1 
Health supervision guidance as a checklist for individuals and primary care providers (PCP)

View this table:
[Table 2](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T2)

Table 2 
Detailed approaches to management and therapy for RTT: genetics, neurology, cardiology, respiratory and urology

View this table:
[Table 3](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T3)

Table 3 
Detailed approaches to management and therapy for RTT: gastroenterology and nutrition

View this table:
[Table 4](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T4)

Table 4 
Detailed approaches to management and therapy for RTT: orthopaedics, rehabilitation, skin, endocrine and hospitalisation

View this table:
[Table 5](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T5)

Table 5 
Detailed approaches to management and therapy for RTT: psychological, behavioural, sleep, pain and screenings

View this table:
[Table 6](http://bmjpaedsopen.bmj.com/content/4/1/e000717/T6)

Table 6 
Detailed approaches to management and therapy for RTT: development, education, therapies, social and alternative medications

*   The financial, emotional and physical impact on the family as a whole: sibling well-being, parent physical and mental health (sleep, grief, anxiety, depression), quality of life, and marital impact.35 36

*   Vigilance regarding signs and symptoms of abuse and neglect of an at-risk individual.

*   Educational support programmes for which the individual may be eligible.

*   Government-sponsored income and other support benefits.

*   Personal financial, community and emotional support available to the family.

### Patient and public involvement

Patient family groups (International Rett Syndrome Foundation and Rett Syndrome Research Trust), represented by parents of individuals with RTT (PN and MC), were involved in the development of the patient care guidance and writing of this manuscript. Their organisations will assist with dissemination of the guidance.

## Results

The guidance was formulated into a checklist (table 1) with further details and references (tables 2–6) that informed the checklist and the consensus process. The guidance for management by health professionals was grouped by relevant features and therapeutic approaches at different ages. The checklist (table 1) is suitable for use by health professionals as well as the family as part of their healthcare records, with tables 2–6 providing further detailed guidance.

### Diagnosis to 5 years old: early childhood

Most features of RTT may emerge during this age period. Feeding difficulties and growth failure37–39 begin during this age. Additional treatable gastrointestinal issues, including dysmotility, gastro-oesophageal reflux, constipation and gas bloating, often presenting as irritability or apparent discomfort, manifest commonly at this age.37 40 The development of microcephaly or head growth stagnation (as early as 1.5 months)39 is a common feature, although macrocephaly has also been seen.41 Tone issues at this age are typically characterised by hypotonia42; early referral to therapists (physical, occupational, speech language including augmentative communication43) and establishment of an individualised education programme44 are necessary. Severe hearing loss is uncommon in RTT,45 but there may be delayed auditory processing46 47 that mimics hearing impairment. There is increased risk of cortical visual impairment and ocular apraxia in RTT.48 There is evidence suggesting increased risk for prolonged QTc interval that may be present from a young age49–51 and may develop with time.52 The frequency of epileptic and non-epileptic spells53 54 waxes and wanes throughout the course.53 55 Individuals with RTT generally respond to anticonvulsants,53 55 56 but there have been no randomised controlled trials of specific anticonvulsants for RTT. If hospitalised, it is important to inform hospital staff of important issues in individuals with RTT that could potentially confound or complicate care. These include a heightened sensitivity to the effects of anaesthetics, potentially requiring lower doses of anaesthetic medications to achieve sedation,57 58 or longer time to awaken from general anaesthesia.59 Although response to pain is altered in RTT,60 the approach to analgesia should not be altered. Hospital staff should also be aware of cold extremities,61 irregular and disordered breathing with oxygen desaturations,62 63 impaired proprioception, lack of hand use, inability to change position, and increased fall risk.

### 5 years to the prepubescent stage: late childhood

During the early school years, children with RTT typically have stabilised developmentally; the regression phase has ended.39 Overall, many of the multisystem issues that arose during the first 5 years of life persist. Preventing undernutrition and maintaining a healthy body mass index are important, as these have been associated with better functioning.38 64 Surveillance for scoliosis becomes an important preventive measure; some children (~20%) ultimately require spinal surgery for this comorbidity.65 Longitudinal assessment of pubertal development indicates an increased prevalence of early thelarche and adrenarche but delayed menarche.66 Difficulties with abnormal tone in this age range typically are characterised by hypotonia evolving to rigidity.67 68

### Postpuberty to the end of school (~21 years old): postpuberty

Surveillance for scoliosis continues to be an important preventive measure, although this lessens with completion of puberty.66 Surveillance for urinary retention is important.69 70 Biliary tract disease is seen in young adulthood at rates similar to the general population, but due to communication impairment in RTT the presenting symptoms may be limited to irritability, weight loss and vomiting.71 72 Studies of longevity in RTT demonstrate survival of many into middle age, underscoring the need for the early development of a comprehensive, thoughtful plan for transitioning to adulthood.73 Longitudinal supervision is required in RTT as physical, behavioural and cognitive limitations will not allow for independent living.14 15 This may include day programmes and respite care.

### 21 years and older: adulthood

Overall, individuals with RTT tend to stabilise clinically in young adulthood.74–76 Frequent causes of hospitalisation for women with RTT include pneumonia, respiratory distress, status epilepticus, rectal bleeding, decline in ambulation or refusal/inability to eat or drink.15 While one-third of individuals may have a gastrostomy tube, half of these continue to have some oral intake.32 With age, concern for low bone mineral mass coupled with long-term use of particular anticonvulsants raises the risks for osteoporosis and bone fractures,77–79 necessitating continued supplementation and monitoring of 25-OH vitamin D status.80 81 Musculoskeletal problems and gross motor function may worsen overall,75 possibly due to more parkinsonian features,67 but with overall preservation of intellect and memory15; additional study is needed due to relatively low numbers studied. Physical limitations, parkinsonian features and high prevalence of social withdrawal behaviours lead to abnormal or decreased social interactions consistent with anxiety or depression.82 Although the majority of women with RTT in the USA live at home,14 in other countries only about one-third of women over age 16 with RTT live at home (either full time or part-time), with the majority living in a residential facility.15 Long-term and individually tailored care that provides social interactions and physical activity should be provided at all ages to reduce age-related deterioration.83

## Discussion

Management of RTT requires input or expertise related to multiple specialties, often necessitating referrals to many providers in addition to the primary care provider. The above health guidance will evolve with further research into the longitudinal course of RTT by the NHS and others. However, there are limitations to the current proposed health guidance, specifically with respect to the lack of needed randomised clinical trials in a rare condition where interventions, such as physical and other therapies, are rarely standardised. While evaluation of annual ECG for prolonged QT appears supported by the literature,49–52 the impact and outcomes of such surveillance need further study. At this time, longitudinal prognostic details are not well understood in certain areas of evaluation, such as affect, displayed emotion and its meaning, the most appropriate manner to assess intelligence and how it evolves, or the lifespan of gynaecological concerns. Additional studies should also address the role and utility of palliative care and banking of postmortem tissue. From this breadth of information, quality metrics with benchmarks can be defined to ensure standards of care with best outcomes for individuals with RTT.

With the relative paucity of older individuals in the NHS and related studies, further study into the care of older individuals is needed to better address guidance more extensively for both older women with RTT and for those more severely affected who are not routinely captured in most studies.76 Additionally, with current and future clinical trials, the disease course for individuals with RTT may be more modifiable with severity of symptoms and disease progression very different from our current understanding. There is considerable ongoing research in the field of specific RTT therapeutics.84 It is therefore important for families, caregivers and health professionals to reach out to Rett centres and family support group resources to stay up-to-date on clinical trials, drug approvals and how this impacts this current care guidance. While a primary care provider may not be able to counsel on the suitability of different clinical trials, actively engaging individuals with RTT and their families and referring to clinical trials at specialty centres are necessary for the development of improved therapeutics.

With the advances in healthcare and technology, improved and earlier genetic testing, robust research in RTT, and active patient advocacy from families and clinicians, individuals with RTT are surviving well into adulthood while living more healthy and meaningful lives. With the vast amount of medical knowledge emerging from research in RTT today and knowing the complexity of care RTT often requires, this proposed guidance can facilitate delivery of more thorough and well-rounded management and comprehensive surveillance by primary care providers and other health professionals caring for individuals with RTT. Importantly, the guidance also helps to outline considerations in which health professionals may want to refer the individual with RTT for more specialised management.

In conclusion, RTT is a medically complex neurodevelopmental disorder impacting multiple organ systems in an evolving fashion from childhood through the sixth decade of adulthood. Primary care providers and other health professionals tasked with coordinating care play an essential role in ensuring the long-term health and well-being of these individuals through effective screening practices, active management and thoughtful coordination of subspecialty requirements. The accumulating knowledge regarding the natural history of RTT serves as a vital resource to help providers anticipate the complexities of this disorder.

### Web links to regional RTT clinics for health professionals

*   [https://www.rettsyndrome.org/about-rett-syndrome/clinics](https://www.rettsyndrome.org/about-rett-syndrome/clinics)

*   [https://reverserett.org/newly-diagnosed/%23clinics-map](https://reverserett.org/newly-diagnosed/%23clinics-map)

*   [https://www.rettsyndrome.eu/](https://www.rettsyndrome.eu/)

### Useful web links for families

*   [https://www.rettsyndrome.org/](https://www.rettsyndrome.org/)

*   [https://reverserett.org/](https://reverserett.org/)

*   [https://www.rettsyndrome.org/for-families/resources-for-families](https://www.rettsyndrome.org/for-families/resources-for-families)

*   [https://www.rettsyndrome.eu/](https://www.rettsyndrome.eu/)

## Acknowledgments

We sincerely thank all of the individuals and families who have participated in this research. Thanks to Dr Walter Kaufmann for comments on a later stage of this manuscript.

## Footnotes

*   Contributors PN, EM, MJ, JN, AP and TB conceptualised and designed the literature search and guidance. PN and MJ initiated the first draft of tables 1 and 2. CF, DA, DL, EM and RW initiated the search and the first draft of the guidance. All authors contributed to subsequent drafts of the figure and guidance as described. TB, as group leader, supervised and moderated the search and consensus process, initial drafts, and the overall collation of the figure, tables, manuscript and guidance. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

*   Funding CF: International Rett Syndrome Foundation; DA: Rett Syndrome Research Trust; EM: NIH U54 HD061222, Rett Syndrome Research Trust; RW: Rett Syndrome Research Trust; DL: Rett Syndrome Research Trust, NIH U54 HD061222; JL: NIH U54 HD061222, Rett Syndrome Research Trust, International Rett Syndrome Foundation; PN: International Rett Syndrome Foundation; KM: International Rett Syndrome Foundation; BS: Blue Bird Circle, NIH U54 HD061222; DG: Blue Bird Circle, NIH U54 HD061222; JN: NIH U54 HD061222, U54 HD461222, Rett Syndrome Research Trust; AP: NIH U54 HD061222, Rett Syndrome Research Trust; TB: International Rett Syndrome Foundation, Rett Syndrome Research Trust, NIH U54 HD061222, Children’s Hospital Colorado Foundation Ponzio Family Chair in Neurology Research.

*   Competing interests EM: funding from the NIH and International Rett Syndrome Foundation; clinical trials with GW Pharmaceuticals, Zogenix and Marinus; consultancy to Stoke Therapeutics. DL: consultancy for AveXis; clinical trials with Acadia, Anavex and GW Pharmaceuticals. SS: speaker bureau for GW Pharmaceuticals. BS: funding from the NIH and Blue Bird Circle; clinical trials with Acadia. DG: funding from the NIH and Blue Bird Circle; clinical trials with GW Pharmaceuticals, Acadia, Anavex and Newron; consultancy for Acadia and Trend Community Pharmaceuticals. JN: funding from the NIH; consultancy with Acadia, AveXis, Biohaven, GW Pharmaceuticals, Kurro, Neuren, Newron, Ovid, Takeda and Teva. JL: funding from NIH; consultancy from International Rett Syndrome Foundation and GW Pharmaceuticals. AP: funding from the NIH; consultancy for Anavex, AveXis, Acadia and GW Pharmaceuticals; clinical trials with Anavex, Acadia, GW Pharmaceuticals and RSRT. TB: funding from the NIH, International Foundation for CDKL5 Research and Loulou Foundation; consultancy for AveXis, Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda and Marinus; clinical trials with Acadia, Ovid, GW Pharmaceuticals, Marinus and RSRT; all remuneration has been made to his department.

*   Patient consent for publication Not required.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Data availability statement No data are available.

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