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. [34]
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:
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Stage I - Benign congenital hypotonia, cerebral palsy, Prader-Willi syndrome, Angelman syndrome, and metabolic disorders (eg, fetal alcohol syndrome and trisomy 13)
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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
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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)
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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:
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Apparently normal prenatal and perinatal period
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Apparently normal development through at least the first 5-6 months of life
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Normal head circumference at birth
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Deceleration of head growth (age, 3 months to 3 years)
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Loss of acquired skills (age, 3 months to 3 years), including learned purposeful hand skills, acquired babble or learned words, and communicative abilities
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Appearance of obvious mental deficiency
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Appearance successively of intense hand stereotypies, including hand wringing or squeezing; hand washing, patting, or rubbing; and hand mouthing or tongue pulling
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Gait abnormalities among ambulant girls, including gait apraxia, dyspraxia, or both, as well as jerky truncal ataxia, body dyspraxia, or both
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Diagnosis is tentative until the individual is aged 2-5 years
Supportive criteria for the diagnosis of classic RS are as follows:
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Breathing dysfunction, including periodic apnea during wakefulness, intermittent hyperventilation, breath-holding spells, and forced expulsion of air or saliva
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Bloating or marked air swallowing
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Electroencephalographic (EEG) abnormalities, including slow waking background and intermittent rhythmic slowing (3-5 Hz) and epileptiform discharges, with or without clinical seizures
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Epilepsy (various seizure forms)
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Spastic signs, later muscle wasting, or dystonic traits
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Peripheral vasomotor disturbances
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Neurogenic scoliosis
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Hypotrophic small and cold feet
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Growth retardation
Exclusion criteria for the diagnosis of classic RS are as follows:
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Organomegaly or other signs of storage disease
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Retinopathy or optic atrophy
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Microcephaly at birth
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Presence of identifiable metabolic or other neurodegenerative disorder
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Acquired neurologic disorder resulting from severe infections, head trauma, or toxic ingestion
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Evidence of intrauterine growth retardation
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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:
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Partial or subtotal loss of acquired fine finger skills in late infancy or early childhood
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Loss of acquired single words or phrases or nuanced babble
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RS hand stereotypies, with hands together or apart
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Early deviant communicative ability
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Deceleration of head growth amounting to 2 standard deviations, even when the value is still within the reference range
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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:
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Breathing irregularities (hyperventilation or breath holding)
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Bloating or marked air swallowing
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Characteristic RS teeth grinding
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Gait dyspraxia
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Neurogenic scoliosis or high kyphosis (in ambulant girls)
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Development of abnormal lower limb neurology
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Small blue or cold impaired feet, autonomic or trophic dysfunction
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Characteristic RS findings on EEG
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Unprompted sudden laughing or screaming spells
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Impaired or delayed nociception
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Intensive eye communication with eye pointing
Differential Diagnoses
