Down Syndrome


Down syndrome, or Trisomy 21, is the most common genetic disorder due to a chromosomal abnormality. The presence of three copies of chromosome 21, rather than the usual two, leads to characteristic facial features, developmental delay, intellectual disability, and impaired immune function. Down syndrome is also associated with an increased risk of congenital heart defects, epilepsy, leukemia, and other diseases. Approximately 20% of all patients with Down syndrome have an associated musculoskeletal condition. The main effects of Down syndrome on the musculoskeletal systems are due to ligament laxity, excessive joint flexibility, and loss of muscle tone. Beyond generalized laxity and hypotonia, musculoskeletal manifestations of Down syndrome include cervical spine instability, hip subluxation, patellofemoral instability, scoliosis, and foot conditions such as pes planus.

 

 

Structure and Function

Trisomy 21 is usually due to duplication of one of the parental copies of chromosome 21 (most commonly the mother’s). This occurs due to failure of the diploid chromosome to separate during meiosis (termed “nondisjunction”) into haploid gametes. In rare cases, the Down syndrome is due to a chromosomal translocation.

 

The ligament laxity and excessive joint flexibility seen in Down syndrome likely arise from the production of abnormal or excess Type VI collagen. Type VI collagen production is encoded by a gene found on the 21st chromosome.

 

There is an increased incidence of polyarticular rheumatoid factor-negative arthritis in children with Down syndrome. This typically causes erosive changes of the small joints of the hands and wrists. The mechanism of this arthropathy is not known.

 


Patient Presentation

Growth in children with Down syndrome is commonly delayed and stunted, as are many developmental milestones. The typical facial appearance includes flattening of the nasal bridge, with upward-slanting eyes and epicanthal folds. The mouth is typically small with a large tongue, which commonly leads to obstructive sleep apnea. The neck may be stout or shortened, often with redundant skin posteriorly. The hands are shortened with a single palmar crease (Figure 1). The feet are usually flat (pes planus) may have an unusually large space between the 1st and 2nd toes (Figure 2). Classically, the gait is waddling and broad based.


Figure 1: Shown at left is a hand with a single palmar crease (yellow arrow); a normal hand crease pattern is shown at right. (image courtesy Wikipedia)

 

Figure 2: Clinical photograph of the feet of a boy with Down syndrome, showing a large gap between the first and second toes bilaterally. (image courtesy Wikipedia)

 

Most patients with Down syndrome have some degree of intellectual disability. Hearing and vision problems are fairly common, as is the incidence of epilepsy.

 

Congenital heart disease is common in individuals with Down syndrome. This usually takes the form of some type of septal defect, although valve pathology may be seen, and even more serious defects such as tetralogy of Fallot. Hypothyroidism, type 1 diabetes mellitus, and duodenal atresia are also seen in higher prevalence in patients with Down syndrome. Leukemia is also more prevalent in these patients, as is the overall occurrence of infection. This can also lead to higher surgical site infection rates than seen in the general population.

 

Approximately 20% of all patients with Down syndrome have an associated musculoskeletal condition. Occipito-cervical and atlanto-axial instability is common. Atlantoaxial instability can be assessed on lateral cervical spine radiographs or sagittal CT scans by measuring the atlanto-dens interval (Figure 3). This interval should be 5mm or less.


Figure 3: Mid-sagittal slice of a cervical spine CT scan. The image on the left (A) is of a 14-year-old boy with Down syndrome who was experiencing myelopathic symptoms due to atlantoaxial instability. The atlanto-dens interval, indicated by the yellow line, is ~13mm. The image on the right (B) is of a normal C-spine with normal atlanto-dens interval for comparison.
 

Down syndrome is associated with high rates of scoliosis and slipped capital femoral epiphysis (Figure 4).

 

The hypotonia and ligamentous laxity often present also commonly lead to hip instability and recurrent patellofemoral dislocation (Figure 5).


Figure 4: Frog-leg lateral radiographic view of the bilateral hips in a patient with Down syndrome, demonstrating a left slipped capital femoral epiphysis.
 
Figure 5: Anteroposterior radiographic view of the left knee in a patient with Down syndrome, demonstrating lateral dislocation of the patella (red arrow).

  
 

Objective Evidence

Chromosomal analysis in Down syndrome reveals three copies of chromosome 21, which is diagnostic for this syndrome.

 

On an AP pelvis radiograph, the iliac wings are commonly flared, with flat acetabula. Prior to the advent of chromosome analysis for diagnosis, the pelvis radiograph was often used to confirm the diagnosis of Down syndrome.


Figure 6: Pelvic radiograph showing “flaring” of the iliac wing, outlined in red, with the normal contour outlined in yellow. (Case courtesy of Radiopaedia.org, rID: 43579)
 

 

 

Epidemiology

Down syndrome is the most common chromosomal abnormality, occurring about once per 700 to 1000 live births. This occurrence, however, varies with the mother’s age at conception, with the risk increasing with maternal age. Down syndrome does not have a predilection for certain races or geographic regions. Life expectancy for patients with Down syndrome averages around 50-60 years. Individuals with Down syndrome also suffer premature aging, with a high prevalence of Alzheimer’s disease in those who reach mid-adulthood.

 

 

Differential Diagnosis

Diagnosis can usually be made based on typical phenotypic characteristics described above. Other conditions that may have overlapping phenotypes include hypotonia due to other causes. When the diagnosis is in question, a chromosomal analysis may provide confirmation.

 

 

Red Flags

Down syndrome is itself a red flag for atlantoaxial instability. This must be considered before any surgical procedure for which intubation is contemplated. Many clinicians recommend radiographic evaluation of the cervical spine before patients with Down syndrome may be cleared to play sports, though this is not universally accepted.

 

When evaluating a Down syndrome patient with a limb or vague complaints of lower extremity pain, especially knee pain, pelvis radiographs must be studied closely with a discerning eye for a subtle slipped capital femoral epiphysis of the hip, as these patients may have trouble articulating their symptoms.

 

 

Treatment Options and Outcomes

When treating musculoskeletal manifestations in Down syndrome, non-operative modalities should be exhausted prior to surgical intervention as complication rates tend to be higher in this population.

 

Pes planovalgus and patellar subluxation can be treated initially with stabilization braces and physical therapy Hip subluxation can be treated initially with hip abduction braces. When non-operative treatments fail, any surgical strategy must consider that patients with Down syndrome have generalized hypotonia and ligamentous laxity and thus typical soft-tissue stabilization procedures alone often ineffective. Osteotomies, such as tibial tubercle osteotomies for patellar instability or acetabular osteotomies for hip dislocation are needed.

 

If a slipped capital femoral epiphysis occurs in a Down syndrome patient, pinning the unaffected side prophylactically is usually undertaken at the same time.

 

The treatment of various degrees of atlantoaxial instability is controversial. Although the normal atlanto-dens interval is 5 mm or less, asymptomatic patients with an interval measuring between 5–10 mm can be simply observed with surgical fusion and stabilization reserve for when symptoms develop.

 

Fusion options include C1-C2 fusion, or even occiput to C2 or C3 if greater instability exists. However, it should be cautioned that complication rates of fusion in Down syndrome patients are high, with overall complication rates approaching 50%, and mortality rates quoted as high as 25%.

 

The scoliosis that occurs in many patients with Down syndrome often resembles idiopathic scoliotic curves and treatment is similar: bracing and observation for small curves and surgical fusion for larger curves (Figure 7).


Figure 7: preoperative (left) and post-operative (right) views of a patient with Down syndrome and scoliosis. (image courtesy Scoliosis 10, 14 (2015). https://doi.org/10.1186/s13013-015-0035-x)
 

Although the life expectancy for individuals with Down syndrome is shorter than normal, many patients routinely live into their 6th decade of life. Reasons for earlier mortality include cardiac disease and infections.

 

The orthopedist can also play a significant role in affecting quality of life in this patient population, by helping to manage the mange musculoskeletal conditions that are commonly seen with Down. The treating surgeon must be aware, however, that many treatment strategies that rely on muscle tone or tissue quality may fail, given the hypotonia and ligamentous laxity present. Additionally, with any surgical endeavor, complication rates and infection rates are higher in patients with Down syndrome.

 


Risk Factors and Prevention

The most well-known risk factor for Down syndrome is advanced maternal age. This risk is < 0.1% when the mother is < 30 years old at conception, and increases more than 10-fold as the mother reaches her late 30s to early 40s. Parents of a child with Down syndrome are at increased risk of a subsequent child being affected. There is no known modifiable risk factor other than maternal age at which prevention can be aimed. For rare cases of Down syndrome due to a translocation, parents who carry the translocation are at an increased risk of passing the translocation to their offspring.

 


Miscellany

Down syndrome is named after John Langdon Down, who first described the condition in 1862. However, it wasn’t until the late 1950s that the genetic cause of the condition was identified, after the advent of technology to make karyotyping possible.