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Rett Syndrome Differential Diagnoses

  • Author: Bettina E Bernstein, DO; Chief Editor: Caroly Pataki, MD  more...
Updated: Jul 15, 2015

Diagnostic Considerations

Diagnosis of Rett syndrome (RS) is initially difficult; however, the observant pediatrician may note deceleration of head, weight, and height growth. Stereotypies involving separated or joined hands, mouthing, pill-rolling and twisting persist into adulthood and should therefore increase the index of suspicion of RS in adults with otherwise unclassified symptoms.[30]

The differential diagnosis varies according to the clinical stage of RS. Conditions that should receive particular consideration in each of the 4 stages of the syndrome are as follows:

  • Stage I - Benign congenital hypotonia, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and metabolic disorders (eg, fetal alcohol syndrome and trisomy 13)
  • Stage II - Autism spectrum disorder, Angelman syndrome, encephalitis, hearing or visual disturbance, Landau-Kleffner syndrome, psychoses, slow virus panencephalopathy, tuberous sclerosis, metabolic disorders (eg, phenylketonuria and ornithine transcarbamoylase deficiency), and infantile neuronal ceroid lipofuscinosis
  • Stage III - Spastic ataxia, cerebral palsy, spinocerebellar degeneration, leukodystrophies, neuroaxonal dystrophy, Lennox-Gastaut syndrome, and Angelman syndrome (probably not Kabuki makeup syndrome, because patients would have macrocephaly)
  • Stage IV - Other degenerative disorders

Diagnostic criteria

Diagnosis of classic RS requires that patients meet certain necessary, supportive, and exclusionary characteristics. Because of the heterogeneity of the syndrome, atypical or variant instances of RS may occur; primary and supportive criteria for these have also been formulated.

Classic Rett syndrome

Necessary criteria for the diagnosis of classic RS are as follows:

  • Apparently normal prenatal and perinatal period
  • Apparently normal development through at least the first 5-6 months of life
  • Normal head circumference at birth
  • Deceleration of head growth (age, 3 months to 3 years)
  • Loss of acquired skills (age, 3 months to 3 years), including learned purposeful hand skills, acquired babble or learned words, and communicative abilities
  • Appearance of obvious mental deficiency
  • Appearance successively of intense hand stereotypies, including hand wringing or squeezing; hand washing, patting, or rubbing; and hand mouthing or tongue pulling
  • Gait abnormalities among ambulant girls, including gait apraxia, dyspraxia, or both, as well as jerky truncal ataxia, body dyspraxia, or both
  • Diagnosis is tentative until the individual is aged 2-5 years

Supportive criteria for the diagnosis of classic RS are as follows:

  • Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced expulsion of air or saliva
  • Bloating or marked air swallowing
  • Electroencephalographic (EEG) abnormalities, including slow waking background and intermittent rhythmic slowing (3-5 Hz) and epileptiform discharges, with or without clinical seizures
  • Epilepsy (various seizure forms)
  • Spastic signs, later muscle wasting, or dystonic traits
  • Peripheral vasomotor disturbances
  • Neurogenic scoliosis
  • Hypotrophic small and cold feet
  • Growth retardation

Exclusion criteria for the diagnosis of classic RS are as follows:

  • Organomegaly or other signs of storage disease
  • Retinopathy or optic atrophy
  • Microcephaly at birth
  • Presence of identifiable metabolic or other neurodegenerative disorder
  • Acquired neurologic disorder resulting from severe infections, head trauma, or toxic ingestion
  • Evidence of intrauterine growth retardation
  • Evidence of perinatally acquired brain damage

Atypical or variant Rett syndrome

In a girl aged 10 years or older with intellectual disability of unexplained origin who does not demonstrate the exclusion criteria for classic RS (see above), atypical or variant RS can be diagnosed if at least 3 of the 6 primary criteria below are present, along with at least 5 of the 11 supportive criteria.

Primary criteria for the diagnosis of atypical or variant RS are as follows:

  • Partial or subtotal loss of acquired fine finger skills in late infancy or early childhood
  • Loss of acquired single words or phrases or nuanced babble
  • RS hand stereotypies, with hands together or apart
  • Early deviant communicative ability
  • Deceleration of head growth amounting to 2 standard deviations, even when the value is still within the reference range
  • RS disease profile (ie, a regression period [stage II] followed by some recovery of contact and communication [stage III], in contrast to slow neuromotor regression through school age and adolescence)

Supportive criteria for the diagnosis of atypical or variant RS are as follows:

  • Breathing irregularities (hyperventilation or breath holding)
  • Bloating or marked air swallowing
  • Characteristic RS teeth grinding
  • Gait dyspraxia
  • Neurogenic scoliosis or high kyphosis (in ambulant girls)
  • Development of abnormal lower limb neurology
  • Small blue or cold impaired feet, autonomic or trophic dysfunction
  • Characteristic RS findings on EEG
  • Unprompted sudden laughing or screaming spells
  • Impaired or delayed nociception
  • Intensive eye communication with eye pointing


Acquired Epileptic Aphasia

Autism Spectrum Disorder

Cerebral Palsy


Fetal Alcohol Syndrome

Hearing Impairment

Lennox-Gastaut Syndrome

Metachromatic Leukodystrophy

Neuronal Ceroid Lipofuscinosis

Ornithine Transcarbamoylase Deficiency

Patau Syndrome


Prader-Willi Syndrome

Spastic Ataxia

Tuberous Sclerosis

Contributor Information and Disclosures

Bettina E Bernstein, DO Distinguished Fellow, American Academy of Child and Adolescent Psychiatry; Distinguished Fellow, American Psychiatric Association; Clinical Assistant Professor of Neurosciences and Psychiatry, Philadelphia College of Osteopathic Medicine; Clinical Affiliate Medical Staff, Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia; Consultant to theVillage, Private Practice; Consultant PMHCC/CBH at Family Court, Philadelphia

Bettina E Bernstein, DO is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, American Psychiatric Association

Disclosure: Nothing to disclose.


Daniel G Glaze, MD Medical Director, Blue Bird Circle Rett Center; Professor, Departments of Pediatrics and Neurology, Baylor College of Medicine

Daniel G Glaze, MD is a member of the following medical societies: American Clinical Neurophysiology Society, American Neurological Association, Child Neurology Society

Disclosure: Nothing to disclose.

Chief Editor

Caroly Pataki, MD Health Sciences Clinical Professor of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine

Caroly Pataki, MD is a member of the following medical societies: American Academy of Child and Adolescent Psychiatry, New York Academy of Sciences, Physicians for Social Responsibility

Disclosure: Nothing to disclose.


Joseph H Schneider, MD Assistant Professor of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School

Joseph H Schneider, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, Texas Medical Association, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

  1. Kubota T, Miyake K, Hirasawa T. Role of epigenetics in Rett syndrome. Epigenomics. 2013 Oct. 5(5):583-92. [Medline].

  2. Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat Genet. 1999 Oct. 23(2):185-8. [Medline].

  3. Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, et al. MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev. 2007 Jan. 29(1):47-50. [Medline].

  4. Hoffbuhr K, Devaney JM, LaFleur B. MeCP2 mutations in children with and without the phenotype of Rett syndrome. Neurology. 2001 Jun 12. 56(11):1486-95. [Medline].

  5. Huppke P, Laccone F, Kramer N, et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet. 2000 May 22. 9(9):1369-75. [Medline].

  6. Kankirawatana P, Leonard H, Ellaway C, et al. Early progressive encephalopathy in boys and MECP2 mutations. Neurology. 2006 Jul 11. 67(1):164-6. [Medline].

  7. Kerr AM, Archer HL, Evans JC, et al. People with MECP2 mutation-positive Rett disorder who converse. J Intellect Disabil Res. 2006 May. 50(Pt 5):386-94. [Medline].

  8. Moog U, Smeets EE, van Roozendaal KE, et al. Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediatr Neurol. 2003. 7(1):5-12. [Medline].

  9. Moretti P, Zoghbi HY. MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev. 2006 Jun. 16(3):276-81. [Medline].

  10. Philippe C, Villard L, De Roux N, et al. Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update. Eur J Med Genet. 2006 Jan-Feb. 49(1):9-18. [Medline].

  11. Wan M, Lee SS, Zhang X, et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet. 1999 Dec. 65(6):1520-9. [Medline].

  12. Zeev BB, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology. 2009 Apr 7. 72(14):1242-7. [Medline].

  13. Temudo T, Ramos E, Dias K, Barbot C, Vieira JP, Moreira A, et al. Movement disorders in Rett syndrome: an analysis of 60 patients with detected MECP2 mutation and correlation with mutation type. Mov Disord. 2008 Jul 30. 23(10):1384-90. [Medline].

  14. Nectoux J, Bahi-Buisson N, Guellec I, Coste J, De Roux N, Rosas H, et al. The p.Val66Met polymorphism in the BDNF gene protects against early seizures in Rett syndrome. Neurology. 2008 May 27. 70(22 Pt 2):2145-51. [Medline].

  15. Percy AK, Neul JL, Glaze DG, et al. Rett syndrome diagnostic criteria: lessons from the Natural History Study. Ann Neurol. 2010 Dec. 68(6):951-5. [Medline]. [Full Text].

  16. Suter B, Treadwell-Deering D, Zoghbi HY, Glaze DG, Neul JL. Brief Report: MECP2 Mutations in People Without Rett Syndrome. J Autism Dev Disord. 2013 Aug 7. [Medline].

  17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 5th. Arlington, VA: American Psychiatric Association; 2013. 57.

  18. Monteggia LM, Kavalali ET. Rett syndrome and the impact of MeCP2 associated transcriptional mechanisms on neurotransmission. Biol Psychiatry. 2009 Feb 1. 65(3):204-10. [Medline].

  19. Zhang Y, Minassian BA. Will my Rett syndrome patient walk, talk, and use her hands?. Neurology. 2008 Apr 15. 70(16):1302-3. [Medline].

  20. Maezawa I, Swanberg S, Harvey D, LaSalle JM, Jin LW. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J Neurosci. 2009 Apr 22. 29(16):5051-61. [Medline].

  21. Bebbington A, Downs J, Percy A, Pineda M, Zeev BB, Bahi-Buisson N, et al. The phenotype associated with a large deletion on MECP2. Eur J Hum Genet. 2012 Apr 4. [Medline].

  22. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A. 2009 Feb 10. 106(6):2029-34. [Medline].

  23. Glaze DG, Schultz RJ. Rett Syndrome: Meeting the Challenge of This Gender-Specific Neurodevelopmental Disorder. Medscape Womens Health. 1997 Jan. 2(1):3. [Medline].

  24. Sampieri K, Meloni I, Scala E, et al. Italian Rett database and biobank. Hum Mutat. 2007 Apr. 28(4):329-35. [Medline].

  25. Terai K, Munesue T, Hiratani M, Jiang ZY, Jibiki I, Yamaguchi N. The prevalence of Rett syndrome in Fukui prefecture. Brain Dev. 1995 Mar-Apr. 17(2):153-4. [Medline].

  26. Huppke P, Maier EM, Warnke A, et al. Very mild cases of Rett syndrome with skewed X inactivation. J Med Genet. 2006 May 11. [Medline].

  27. Kozinetz CA, Skender ML, MacNaughton N, et al. Epidemiology of Rett Syndrome: a population-based registry. Pediatrics. 1993. 91(2):445-50. [Medline].

  28. Hagberg B, Berg M, Steffenburg U. Rett Syndrome - an odd handicap afffecting girls. A current 25-year follow-up in western Sweden. Lakartidningen. 1999. 96(49):5488-90. [Medline].

  29. Kerr AM, Julu PO. Recent insights into hyperventilation from the study of Rett syndrome. Arch Dis Child. 1999 Apr. 80(4):384-7. [Medline].

  30. Vignoli A, La Briola F, Canevini MP. Evolution of stereotypies in adolescents and women with Rett syndrome. Mov Disord. 2009 Jul 15. 24(9):1379-83. [Medline].

  31. Amir RE, Sutton VR, Van den Veyver IB. Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol. 2005 Sep. 20(9):779-83. [Medline].

  32. Ham AL, Kumar A, Deeter R. Does genotype predict phenotype in Rett syndrome?. J Child Neurol. 2005 Sep. 20(9):768-78. [Medline].

  33. Ellaway CJ, Sholler G, Leonard H, et al. Prolonged QT interval in Rett syndrome. Arch Dis Child. 1999 May. 80(5):470-2. [Medline].

  34. Glaze DG, Schultz RJ, Frost JD. Rett syndrome: characterization of seizures versus non-seizures. Electroencephalogr Clin Neurophysiol. 1998 Jan. 106(1):79-83. [Medline].

  35. Glaze DG, Percy AK, Motil KJ, Lane JB, Isaacs JS, Schultz RJ, et al. A study of the treatment of Rett syndrome with folate and betaine. J Child Neurol. 2009 May. 24(5):551-6. [Medline].

  36. Wilfong AA, Schultz RJ. Vagus nerve stimulation for treatment of epilepsy in Rett syndrome. Dev Med Child Neurol. 2006 Aug. 48(8):683-6. [Medline].

  37. Chung JC, Lai CK, Chung PM, French HP. Snoezelen for dementia. Cochrane Database Syst Rev. 2002. CD003152. [Medline].

  38. Lavie E, Shapiro M, Julius M. Hydrotherapy combined with Snoezelen multi-sensory therapy. Int J Adolesc Med Health. 2005 Jan-Mar. 17(1):83-7. [Medline].

  39. Lotan M. Management of Rett syndrome in the controlled multisensory (Snoezelen) environment. A review with three case stories. ScientificWorldJournal. 2006. 6:791-807. [Medline].

  40. Downs J, Young D, de Klerk N, Bebbington A, Baikie G, Leonard H. Impact of scoliosis surgery on activities of daily living in females with Rett syndrome. J Pediatr Orthop. 2009 Jun. 29(4):369-74. [Medline].

  41. Hartman AL. Does the effectiveness of the ketogenic diet in different epilepsies yield insights into its mechanisms?. Epilepsia. 2008 Nov. 49 Suppl 8:53-6. [Medline].

  42. Motil KJ, Schultz RJ, Browning K, et al. Oropharyngeal dysfunction and gastroesophageal dysmotility are present in girls and women with Rett syndrome. J Pediatr Gastroenterol Nutr. 1999 Jul. 29(1):31-7. [Medline].

  43. Leonard H, Thomson MR, Glasson EJ, et al. A population-based approach to the investigation of osteopenia in Rett syndrome. Dev Med Child Neurol. 1999 May. 41(5):323-8. [Medline].

  44. PapiniAM, Nuti F, Real-Fernandez F, Rossi G, Tiberi C, Sabatino G, et al. Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N (Glc) IgM Antibody Fraction. J of Immunology Research. 2014. 1-6.

  45. Gadalla KKE, Ross PD, Riddell JS, Bailey MES, Cobb SR. Knockout Mouse Model of Rett Syndrome Reveals Early-Onset and Progressive Motor Deficits. PLoS One. 2014. 9(11):1-5.

  46. Zhang W, Peterson M, Beyer B, Frankel WN, Zhang ZW. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures. J of Neuroscience. Feb 2014. Feb 12:2754-2763.

  47. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome. Am J Respir Cell Mol Biol. 2014 Jun. 50 (6):1031-9. [Medline].

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