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Rett syndrome
Other Resources UpToDate PubMed

Rett syndrome

Contributors: Samantha Marie Helmy, Surya Mundluru MD
Other Resources UpToDate PubMed


Causes / typical injury mechanism: Rett syndrome is an X-linked dominant neurological disorder causing a regression in motor, verbal, and cognitive abilities. The most common mutation that attributes to this is a de novo mutation of MECP2 on the X chromosome. MECP2 is responsible for transcriptional regulation and DNA methylation. The mutations are almost exclusively of paternal origin.

Classic history and presentation: After a short period of normal development, classic presentation of the regression symptoms typically follow, including partial or complete loss of acquired hand skills, delayed acquisition of higher-level fine motor skills, spoken language, gait abnormalities, postnatal deceleration of head growth, ataxia, seizures, and stereotypic hand-wringing. Many individuals with Rett syndrome have random X-inactivation, allowing normal allele expression in some cells, causing a spectrum of clinical presentations.

Patients can be classified into 3 distinct syndromes based on their clinical presentation and specific mutations in their loci.
  • Preserved speech / Zappella variant, associated with the majority of inherited MECP2 mutations, are the least compromised.
  • Congenital / Rolando variant, more closely associated with mutations in FOXG1
  • Early seizure / Hanefeld variant, more closely associated with mutations in CDKL5
  • Age – Symptoms of Rett syndrome appear between the ages of 1-4 years
  • Sex / gender – The disorder is almost exclusively seen in girls. Boys that inherit Rett syndrome typically die in utero or shortly after birth.
  • The prevalence of Rett syndrome is estimated at 1 /10 000 females at an age of 32 years.
Pathophysiology: Rett syndrome is characterized by inactivating mutations of MECP2 resulting in neurotransmitter system abnormalities, manifesting in dysfunctions of breathing, feeding, and alteration of cardiorespiratory coupling.

Grade / classification system: Prior to the discovery of MECP2 and its known mutation to cause the syndrome, a staging system was created to better track the clinical course.
  • Stage I: Onset between ages 6-18 months, consists of developmental arrest; includes less eye contact, reduced play, gross motor delays, nonspecific hand-wringing.
  • Stage II: Onset between ages 1-4 years, consists of rapid deterioration / regression; includes loss of acquired hand use and spoken language, periodic breathing irregularities, hand-wringing, sleep disturbance, autistic behavioral patterns.
  • Stage III: Onset between ages 2-10 years, follows period of rapid deterioration; includes behavioral improvement and some communication and dexterity improvement by using "eye pointing."
  • Stage IV: Onset after 10 years, consists of late motor deterioration; includes increased rigidity, reduced mobility, dystonia, hypomimia, and bradykinesia.


F84.2 – Rett's syndrome

68618008 – Rett syndrome

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Last Reviewed:10/17/2022
Last Updated:11/01/2022
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Rett syndrome
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