Rett Syndrome

Rett syndrome is a neurodevelopmental disorder with regression. It is X-linked dominant, caused by mutations in the MECP2 gene at Xq28, and affects about 1 in 10,000-15,000 females. Development is normal for the first 6-18 months, then stalls and is lost, in the sequence the Hagberg stages describe.

Who. Almost exclusively girls: males with MECP2 mutations usually die in utero. Most patients are non-ambulatory and use a wheelchair.

What the orthopaedic surgeon sees. Scoliosis, which is nearly universal and often severe, hip subluxation, and equinovarus feet.

What MeCP2 does. MeCP2 (methyl-CpG-binding protein 2) binds methylated CpG dinucleotides and acts as a transcriptional regulator. It is classically described as a repressor that recruits histone deacetylase and 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 maintains mature synaptic function rather than building the early nervous system, the infant develops normally for the first 6-18 months and then regresses as the maturing brain fails without functional MeCP2. This "normal then lost" course is the hallmark of the disease. The molecular picture underpins both the diagnosis, which rests on regression followed by stabilisation, and the move toward disease-modifying therapy.

Why girls survive, and why they differ. Females are mosaics. Each cell randomly inactivates one X, so a girl heterozygous for an 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 boys usually do not. A hemizygous male has the mutation in every cell and no normal-allele mosaic, so a classic MECP2 mutation is usually lethal or causes a severe neonatal encephalopathy. Rare male survivors occur with Klinefelter syndrome (47,XXY), somatic mosaicism or milder mutations.

Why the spine curves. Central hypotonia and poor motor control, with asymmetric posture and muscle activity, produce scoliosis in 80-90%. The curve is typically a long C-shaped thoracolumbar curve, pelvic obliquity is common, and progression is relentless in most.

Why the hips sublux. Hypotonia and abnormal posture lead to subluxation, which is often asymptomatic.

The Hagberg clinical stages trace the course from stagnation through regression to a plateau and late motor deterioration.

History. Establish the age of regression, current mobility and communication, the seizure history, respiratory status and any feeding problems.

Examination. The girl is non-communicative and may be agitated. Look for the hand stereotypies, hand-wringing and hand-mouthing, and for breathing irregularities such as hyperventilation and breath-holding. Then examine the spine for scoliosis, the hips for subluxation and the feet for equinovarus.

Genetic testing. An MECP2 mutation is confirmatory. Rett syndrome nonetheless remains a clinical diagnosis, and the consensus criteria in the Evidence Base stand independent of molecular findings.

Imaging. Spine radiographs assess the scoliosis and hip radiographs the subluxation.

Cardiac and respiratory. QT prolongation can occur, so an ECG is part of the work-up. A sleep study is added if needed.

Scoliosis. Mild curves are observed. Bracing, used as seating support, does not prevent progression but aids sitting. Progressive curves greater than 40-50° are treated by posterior spinal fusion, usually from T2 to the pelvis.

Hips. Most are asymptomatic and are observed. Surgery is rarely indicated, and then as salvage for painful subluxation.

General care. Seizures are managed by neurology. Gastrostomy is often needed for nutrition, and breathing is monitored, with BiPAP if needed.

Posterior spinal fusion. Through a posterior approach, a pedicle-screw construct spans a long fusion from T2 to the pelvis, with pelvic fixation by iliac or S2-alar-iliac screws.

Why the operation is demanding. The complication rate is high and respiratory compromise is common. These patients are non-communicative, so pain is difficult to assess afterwards. The case for surgery rests on quality of life, through sitting balance and ease of caregiving (see Outcomes and Prognosis).

The deformity. The commonest foot deformity is a neuromuscular equinovarus, sometimes equinus or planovalgus, driven by spasticity or dystonia and muscle imbalance. In a largely non-ambulatory child it has a relentless tendency to become fixed and rigid, and it interferes with footwear, foot positioning on a wheelchair footplate, transfers and skin care rather than with walking. Its assessment and management therefore follow a different logic from idiopathic clubfoot.

Non-operative first. Stretching, ankle-foot orthoses (AFOs) and accommodative footwear maintain a plantigrade, braceable foot. Botulinum toxin can reduce the dynamic spastic or dystonic deforming force in a flexible foot and delay surgery.

Surgery for the fixed, problematic foot. Operate when a fixed deformity impairs shoeing or positioning or causes skin breakdown. A still-correctable foot is treated with soft-tissue releases and tendon lengthening or transfer. For a rigid foot in the older child the option is a bony procedure such as a triple arthrodesis, or osteotomies, to obtain a stable, plantigrade, shoeable foot. Operative correction of the spastic equinovarus foot is detailed in the Spastic Equinovarus Foot topic.

She is monitored in ICU for her breathing. Pain is judged on behavioural scales, and she is mobilised to sitting as tolerated. In the long term she needs orthotic support and ongoing medical care.

Life expectancy. Variable, and many survive into their 40s and 50s.

What scoliosis surgery is proven to do. Improve sitting balance, weight distribution, ease of caregiving and cosmesis. These are the outcomes demonstrated in prospective follow-up, and they are the honest basis for consent.

What it is associated with but not proven to do. In a population-based cohort of girls with severe scoliosis, fusion was associated with lower mortality (adjusted HR 0.30, 95 percent CI 0.12-0.74). This is observational and open to confounding by indication: the girls selected for major spinal surgery are by definition those judged fit to survive it, so some of the apparent benefit reflects who was chosen rather than what was done. Quote it as an association with a plausible mechanism, a collapsing thorax impairing respiratory function, not as a proven survival gain.

Quality of life. Difficult to measure in a non-verbal patient. Much of the demonstrated benefit is in ease of care and comfort, which matters to the family and to the girl but is not the same as prolonging life.

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:

• Whether fusion actually prolongs life. Registry data (Downs et al. 2015) show fusion of severe early-onset curves is associated with markedly lower mortality, but the study is observational and cannot exclude confounding by indication: the girls offered a long fusion are those judged fit for it, and unfitness for surgery and early death share the same causes (poor respiratory reserve, seizure burden, nutritional state). No randomised comparison exists and none is feasible, so this will not be resolved - which is precisely why the operation should be justified on the outcomes that are proven, namely sitting balance and ease of care. The optimal age and Cobb threshold remain debated for the same reason. 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.