Medical Management Considerations
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Recognize that Rett Syndrome is a disorder recognized initially in females characterized by developmental stagnation and subsequent loss of acquired developmental skills, with onset usually around 12 months (6-18 mos) of age.
  • Restate the occurrence of Rett Syndrome (1:10,000 to 1:15,000 live female births) and acknowledge that the reoccurrence risk is < 1% for a family with one affected child.
  • List  four characteristic features of Stage I (6-18 mos) onset of Rett Syndrome; e.g.,
    • Normal head circumference at birth with subsequent deceleration of head growth
    • Developmental stagnation
    • Abnormal cry or poor suck
    • Hypotonia (“floppy” body)
  • Delineate two exclusionary criteria relative to a diagnosis of Rett Syndrome; e.g.,
    • Intrauterine growth retardation
    • Microcephaly at birth
  • Discuss the importance of careful neurological and metabolic work-up (to ensure that young girls with hereditary and preventable causes of developmental delay are not mistakenly diagnosed with Rett Syndrome).
  • Refer families to appropriate resources on Rett Syndrome.

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Description and Cause

Rett Syndrome is a disorder recognized initially in females characterized by developmental stagnation and subsequent loss of acquired developmental skills, with onset usually around 12 months (6-18 months) of age. In many cases, children are misdiagnosed as having cerebral palsy or non-specific developmental delay. Within the past several years a number of MECP2 mutations localized to the X chromosome have been identified in up to 79% of patients with classical Rett syndrome and 25% to 33% of those having nonclassical features. The recent identification of mutations in the methyl-CpG-protein 2 gene (MECP2) on the X chromosome in patients with Rett Syndrome has allowed identification of mentally retarded males with similar mutations. This suggests that males may have the deletions but have different phenotype presentations.


  • 1:10,000 to 1:15,000 live female  births
  • 0.5% of Rett Syndrome children have relatives other than a twin with Rett Syndrome.
  • Most cases are Sporadic
  • Recurrence risk is < 1% for a family with one affected child

Characteristic Features

Stage I: Onset: age 6-18 months; Duration: weeks or months

  • Apparently normal prenatal and perinatal psychomotor development until 6 months
  • Normal head circumference at birth with subsequent deceleration of head growth
  • Developmental stagnation
  • Abnormal cry or poor suck
  • Hypotonia (“floppy” body)

Stage II: Onset: age 1-4 years; Duration: weeks or months

  • Developmental regression
  • Deceleration of head growth
  • Stereotypic hand movements (wringing, clapping/tapping, mouthing, waving, etc.)
  • Loss of acquired purposeful hand skills
  • Difficulty crawling from motor dyspraxias
  • Truncal hypotonia, leading to toe-walking
  • Gait apraxia and truncal apraxia-ataxia
  • Impaired expressive and receptive language; loss of previously acquired language
  • Autistic-like behavior (social withdrawal or loss of responsiveness to others)
  • Intermittent strabismus
  • Bruxism and breath-holding
  • Changes in sleep patterns
  • Feeding difficulties
  • Tremulousness
  • Vacant spells (usually not seizures)
  • Profound mental retardation
  • Deterioration of neurological status (usually nonambulatory and nonverbal by late childhood)

Stage III: Onset: age 2-10 years; Duration: months or years

  • Engaging, intense gaze
  • Increasing rigidity
  • Loss of transitional motor skills
  • Seizures
  • Worsening of feeding problems
  • Scoliosis or kyphoscoliosis
  • Hand or foot deformities
  • Dysplasia of the nails

Stage IV: Onset: age 10 years or over; Duration: years

Note: Many girls remain in Stage III for most of their lives; only some reach Stage IV.

  • Further gross motor deterioration
  • Growth retardation
  • Communication through eye contact primarily
  • Trophic changes of the hands and feet
  • Improvements in frequency and intensity of hand movements
  • Hyperventilation
  • Seizures

Common Associations

  • Breathing dysfunction (apnea, hyperventilation, breath-holding, etc.)
  • EEG abnormalities
  • Seizures
  • Spasticity and muscle wasting
  • Peripheral vasomotor disturbances
  • Scoliosis and kyphoscoliosis
  • Osteopenia
  • Aerophagia
  • Chronic constipation

Exclusionary Criteria

  • Intrauterine growth retardation
  • Organomegaly or other storage disease
  • Retinopathy or optic atrophy
  • Microcephaly at birth
  • Perinatally-acquired brain damage
  • Metabolic or other progressive neurologic disorder
  • Acquired neurologic disorder from infection or head trauma

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Note: These considerations are in addition to the normal medical care provided to an individual without Rett Syndrome. All recommendations can be addressed through clinical examination by the primary care provider, unless otherwise noted.

Upon Diagnosis (Birth to 5 years)

Rett Syndrome is characterized by a period of apparently normal early development. As a result, nearly all children with Rett Syndrome are identified in early childhood when they first evidence developmental stagnation or regression. Whether this occurs in infancy or early childhood, the following should be performed:

  • Perform complete physical exam
  • Perform careful neurological and metabolic work-up to ensure that young girls with hereditary and preventable causes of developmental delay are not mistakenly diagnosed with Rett Syndrome
  • Monitor for psychomotor deterioration
  • Recommend physical/occupational therapy evaluation
  • Refer to early intervention programs and Rett Syndrome/disability support groups
  • Discuss possibility of SSI enrollment

Ongoing (all ages)

  • Consider use of augmentive communication systems (e.g., picture cards)
  • Monitor speech and language progress
  • Watch closely for signs of agitation in non-communicative patients
  • Recommend adequate fluid and fiber intake
  • Recommend small, frequent feedings
  • Consider GE reflux if difficulty feeding
  • Refer to registered dietician for nutrition
  • Monitor for seizures; when indicated, refer for appropriate work-up and refer to neurologist
  • Monitor closely for scoliosis; refer periodically to orthopedist if appropriate
  • Recommend passive and active exercise
  • Minimize changes in routine or environment
  • Monitor for constipation

Childhood (1 to 13 years)

  • Monitor neurological functioning
  • Monitor head growth
  • Monitor hand coordination
  • Recommend evaluation by speech therapist
  • Recommend ongoing physical and/or occupational therapy with periodic re-evaluations
  • Recommend and arrange for dental care

Adolescence and Adulthood (13 years and over)

  • Continue to monitor growth and motor skills
  • Discuss long-term financial plans
  • Discuss alternative community living resources
  • Discuss community-supported employment opportunities
  • Monitor prevocational training and vocational activities (may not apply to those who are severely impaired)

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Peer-reviewed Journal Articles/Academies

Amir, R. et al. (2000). Candidate Gene Analysis in Rett Syndrome and the Identification of 21 SNPs in Xg. American Journal of Human Genetics, 90(1), 69-71.

Auranen M. et al. (2001). MECP2 Gene Analysis in Classical Rett Syndrome and in Patients with Rett-like Features. Neurology, 56(5), 611-617.

Bienvenu T. et al. (2000). MECP2 Mutations Account for Most Cases of Typical Forms of Rett Syndrome. Human Molecular Genetics, 9(9), 1377-1384.

Budden, S.S. (1995). Management of Rett Syndrome: A Ten Year Experience. Neuropediatrics, 26(2), 75-77.

Budden, S.S. (1997). Understanding, Recognizing, and Treating Rett Syndrome. Medscape Women’s Health, 2(3), 3.

Hagberg, B. (2005). Long-term Clinical Follow-up Experiences over Four Decades. Journal of Child Neurology, 20(9), 722-727.

Ham, A.L. (2005). Does Genotype Predict Phenotype in Rett Syndrome? Journal of Child Neurology, 20(9), 718-721.

Huppke, P., Gartner, J. (2005). Molecular Diagnosis of Rett Syndrome. Journal of Child Neurology, 20(9), 732-736.

Lebo, R,V. et al. (2001). Rett Syndrome from Quintuple and Triple Deletions within MECP2 Deletion Hotspot Region. Clinical Genetics, 59(6), 406-417.

Moog, U. et al. (2006). MECP2 Mutations are an Infrequent Cause of Mental Retardation Associated with Neurological Problems in Male Patients. Brain & Development, 28(5), 305-310.

Meloni, I. et al. (2000). A Mutation in the Rett Syndrome Gene, MECP2, Causes X-linked Mental Retardation and Progressive Spasticity in Males. American Journal of Human Genetics, 67(4), 982-985.

Percy, A.K., Lane, J.B. (2005). Rett Syndrome: Model of Neurodevelopmental Disorders, Journal of Child Neurology, 20(9), 718-721.

Robertson, L. et al. (2006). The Association between Behavior and Genotype in Rett Syndrome Using the Australian Rett Syndrome Database. American Journal of Medical Genetics, Part B. Nueropsychiatric Genetics, 141(2), 177-183.

Trappe, R. et al. (2001). MECP2 Mutations in Sporadic Cases of Rett Syndrome are Almost Exclusively of Paternal Origin. American Journal of Human Genetics, 68(5), 1093-1101.

Von Tetzchner, S. et al. (1996). Vision, Cognition and Developmental Characteristics of Girls and Women with Rett Syndrome. Developmental Medicine and Child Neurology, 38(3), 212-225.

Wan, M. et al. (1999). Rett syndrome and Beyond: Recurrent Spontaneous and Familial MECP2 Mutations at CpG Hotspots. American Journal of Human Genetics 65(6), 1520-1529.

Special Interest Groups/Other Publications

Batshaw, M.L. & Perret, Y.M. (1992). Children with Disabilities. Baltimore: Paul H. Brookes.

Capute, A.J. & Accardo, P.J. (1996). Developmental Disabilities in Infancy and Childhood vol. I: Neurodevelopmental Diagnosis and Treatment. Baltimore: Paul H. Brookes Publishing.

Capute, A.J. & Accardo, P.J. (1996). Developmental Disabilities in Infancy and Childhood vol II: The Spectrum of Developmental Disabilities. Baltimore: Paul H. Brookes Publishing Co.

Hagberg, B. (1993). Rett Syndrome – Clinical & Biological Aspects. London: MacKeith Press.

Kastner, T. et al. (1992). Rett Syndrome and Metabolic Disorder” (letter to the editor). Journal of the American Academy of Child and Adolescent Psychiatry, 31(3), 567-568.

Lee, J. (1999). Coping with Rett Syndrome. Agricultural Research, 47(2), 20.

Menkes, J.H. (1995). Textbook of Child Neurology (5th Ed.). Baltimore: Lippincott, Williams & Wilkins.

Rubin, I,L. &  Crocker, A.C. (1989). Developmental Disabilities: Delivery of Medical Care for Children and Adults. Philadelphia: Lea & Febiger.

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Baylor College of Medicine Rett Center

California Department of Developmental Services

California Regional Centers


Exceptional Parent Magazine

Indiana Rett Syndrome Page

International Rett Syndrome Association, Inc.

Kennedy-Krieger Institute Rett Program

March of Dimes Birth Defects Foundation

National Institute of Neurological Disorders and Stroke

Northwest Rett Syndrome Foundation

Research for Rett Foundation, Inc.

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Theodore A. Kastner, M.D., M.S.
Felice Weber Parisi, M.D., M.P.H.
Romie H. Holland, M.D.
Joan M. Reese, M.D., M.P.H.

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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.