Rett syndrome

A systematic review and meta-analysis estimated a global pooled prevalence of approximately 5 to 10 cases per 100,000 females 5 to 10 cases per 100,000 females.

Rett syndrome is inherited in an X-linked dominant manner, affected hemizygous males are rare and the phenotype in males is typically severe or lethal. The vast majority of affected individuals are simplex cases that arise from de novo pathogenic variants in MECP2. The recurrence risk for future
siblings of a simplex case is low but not negligible, e.g. owing to the possibility of parental germline mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of Rett syndrome is established clinically using published by Neul and colleagues on behalf of the RettSearch Consortium. Meeting these consensus criteria constitutes the clinical diagnosis of classic or variant Rett syndrome. Molecular genetic testing of MECP2 can confirm the clinical diagnosis.

Main differential diagnoses include:

• : intellectual disability, severe speech impairment, gait ataxia or limb tremulousness, microcephaly, and seizures, with developmental delay first noted at approximately 6 months.
• CDKL5 deficiency disorder: early-onset severe seizures, facial dysmorphism, and cortical visual impairment in females, with severe to profound intellectual disability in males; CDKL5.
• FOXG1 syndrome (congenital variant): short normal period of development before regression, with postnatal microcephaly, agenesis of the corpus callosum, seizures, and dyskinesia; FOXG1.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic MECP2 variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the representatives of affected individuals.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Kaur S, Christodoulou J. MECP2 disorders. 2001 Oct 3 [updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID:20301670.
• Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S. Global prevalence of Rett syndrome: systematic review and meta-analysis. Syst Rev. 2023;12(1):5. doi:10.1186/s13643-023-02169-6. PMID:.
• Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-50. doi:10.1002/ana.22124. PMID:.
• Fu C, Armstrong D, Marsh E, Lieberman D, Motil K, Witt R, et al. Consensus guidelines on managing Rett syndrome across the lifespan. BMJ Paediatr Open. 2020;4(1). doi:10.1136/bmjpo-2020-000717. PMID:.