Rett Syndrome

Rett Syndrome is a neurodevelopmental disorder with regression.

• Genetics: X-linked dominant. Mutations in MECP2 gene (Xq28).
• Incidence: 1 in 10,000-15,000 females.
• Sex: Almost exclusively females. Males with MECP2 mutations usually die in utero.
• Natural History: Normal development followed by regression at 6-18 months.

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Why Scoliosis Develops

• Central hypotonia and poor motor control.
• Asymmetric posture and muscle activity.
• Curves are typically long C-shaped thoracolumbar.
• Pelvic obliquity is common.
• Progression is relentless in most.

Hip Dysplasia

• Hypotonia + abnormal posture → subluxation.
• Often asymptomatic.

The topic states the cause is MECP2 and that the protein is "involved in gene regulation" without explaining what MeCP2 does or why the phenotype varies so widely - both examinable.

• What MeCP2 does. MeCP2 (methyl-CpG-binding protein 2) binds methylated CpG dinucleotides and acts as a transcriptional regulator (classically a repressor recruiting histone deacetylase / Sin3A, but it both represses and activates genes). It is most abundant in mature neurons, where it is needed for synaptic maturation and maintenance - not for the initial wiring of the brain.
• Why regression follows a normal period. Because MeCP2 is required for maintaining mature synaptic function rather than building the early nervous system, the infant develops normally for the first 6-18 months, then regresses as the maturing brain fails without functional MeCP2 - the hallmark "normal then lost" course.
• Why females survive and severity varies (X-inactivation). Females are mosaics: each cell randomly inactivates one X, so a female with a heterozygous MECP2 mutation has a mixture of cells expressing the normal or the mutant allele. The degree and pattern of X-inactivation skewing - together with the specific mutation - largely explains the wide phenotypic variability between affected girls.
• Why males are usually not viable, and the exceptions. A hemizygous male has the mutation in every cell (no normal-allele mosaic), so a classic MECP2 mutation is usually lethal or causes severe neonatal encephalopathy. Rare male survivors occur with Klinefelter (47,XXY), somatic mosaicism, or milder mutations.

This molecular picture underpins both the diagnosis (regression-then-stabilisation) and the move toward disease-modifying therapy.

The mnemonics, examination and cheat sheet repeatedly list equinovarus feet as a core orthopaedic problem, but the topic never develops their assessment or management.

• The deformity. The commonest foot deformity is a neuromuscular equinovarus (and sometimes equinus or planovalgus), driven by spasticity/dystonia and muscle imbalance with a relentless tendency to become fixed and rigid in a largely non-ambulatory child; it interferes with footwear, foot positioning on a wheelchair footplate, transfers and skin care rather than with walking.
• Non-operative first. Stretching, ankle-foot orthoses (AFOs) and accommodative footwear maintain a plantigrade, braceable foot; botulinum toxin can reduce dynamic spastic/dystonic deforming force in a flexible foot and delay surgery.
• Surgery for the fixed, problematic foot. When the deformity is fixed and impairs shoeing/positioning or causes skin breakdown, options are soft-tissue releases and tendon lengthening/transfer for a still- correctable foot, and, for a rigid foot in the older child, a bony procedure such as a triple arthrodesis (or osteotomies) to obtain a stable, plantigrade, shoeable foot.
• The realistic goal. In a non-ambulator the aim is a painless, plantigrade, braceable foot for sitting, transfers and skin care - not a normal gait - so intervention is driven by function and skin, not the radiograph. (Operative correction of the spastic equinovarus foot is detailed in our Spastic Equinovarus Foot topic.)

• ICU Monitoring: Respiratory.
• Pain Assessment: Difficult. Use behavioral scales.
• Mobilization: Sitting as tolerated.
• Long-Term: Orthotic support, ongoing medical care.

• Life Expectancy: Variable. Many survive to 40s-50s.
• Scoliosis Surgery: Improves sitting, caregiving ease. May not improve survival.
• QOL: Difficult to assess. Benefits often for caregivers.

Global epidemiology: Classic Rett syndrome affects approximately 1 in 10,000 to 15,000 live female births worldwide, making it one of the commonest genetic causes of severe intellectual disability in girls. Distribution is global with no major ethnic predilection.

Side-by-side guidance:

• Timing and extent of spinal fusion. Registry data (Downs et al. 2015) support fusion of severe early-onset curves for a survival benefit, but the optimal age and Cobb threshold remain debated. Conventional teaching fuses progressive curves over 40 to 50 degrees, yet some advocate earlier intervention in rapidly progressing skeletally immature girls.
• Fusionless vs definitive fusion in the immature spine. Growth-friendly constructs (traditional growing rods, magnetically controlled rods) and minimally invasive bipolar techniques can defer arthrodesis while preserving trunk/thoracic growth, but carry repeated-procedure burden and their own complication profile; the optimal strategy is unsettled.
• Role of bracing. Bracing does not alter the natural history of the curve and is used only for seating/postural support, not curve control - a frequent exam trap.
• Hip surveillance vs intervention. Hip displacement is common, but most hips are pain-free even when subluxated. There is no consensus on a migration-percentage threshold mandating surgery in non-ambulators; management is largely symptom-driven.
• Disease-modifying therapy. Trofinetide (an IGF-1 analogue) is now approved in some jurisdictions for the neurological phenotype; it does not address established orthopaedic deformity, and its long-term impact on scoliosis progression is unknown.