The Growing Spine in Marfan and Loeys–Dietz Syndromes

Role of nonoperative management

Curves become large at a young age

Brace early or not at all; avoid in low-yield situations

Comprehensive imaging

Image entire spine

MRI before surgery in most cases

CT to define abnormal bony anatomy

Traction films more useful than bending

Medical considerations

Communicate with specialists

Consider genetic consultation

Consult OMIM for information (Online Mendelian Inheritance in Man)

Assess nutrition, respiratory status

Operative considerations

Blood loss likely more

Bone density often lower

Have appropriate size implants

Failure of fixation more likely

Do not “fuse short” in syndromes

Have ICU available postoperatively

Consider rehab needs postoperatively

17.2.1 Role of Nonoperative Management

Patients with syndromic disorders often present with significant curves at a young age. Therefore, they often require more than simply orthotic treatment or spinal fusion near the age of maturity. Syndromic curves can present as early as infancy. There are virtually no studies showing efficacy of orthotic treatment in syndromic curves. In addition, D’Astous and Sanders have shown that Mehta casting is less effective for infants with scoliosis due to syndromes than it is in idiopathic infantile scoliosis [1]. Practically, bracing is commonly recommended in young syndromic patients with curves between 35° and 50°. Orthotic treatment may show in-brace correction but there have been no studies that document an improvement in the expected natural history. The physician should consider refraining from overzealous application of bracing for large curves (over approximately 50°) in young patients at the expense of quality of life.

17.2.2 Comprehensive Evaluation

Another principle of treating patients with syndromic curves is that the whole spine is at risk of developing differently. The cervical, thoracic, and lumbar spine should be examined and imaged as indicated. “Coned” films (focal images centered on area of interest) should be obtained of any area that requires further definition. In addition, there is a greater chance of abnormality of the neuraxis. For this reason, whole-spine magnetic resonance imaging (MRI) should be considered prior to surgical intervention. Findings such as duralectasia, stenosis, spondylolysis, instability, and disk pathology are more likely to be seen than in idiopathic deformity. Computed tomography with multiplanar or three-dimensional reconstruction may be invaluable in defining dystrophic bony features, if suspected. Flexibility is often best assessed with traction films rather than bending films in young patients with syndromes, due to age and curve magnitude.

17.2.3 Medical Considerations

Patients mature at different rates; skeletal maturation in syndromic patients may be earlier or later than in idiopathic deformity. Medical comorbidities are more often seen in syndromic patients. The surgeon should take advantage of pediatric consultants in genetics, pulmonary, and cardiology specialties. A geneticist can be a great help both preoperatively and postoperatively in managing patients with syndromes, tying all of the disparate features together. A good source of genetic information is Online Mendelian Inheritance In Man (OMIM), rapidly available to all on the Entrez Pub Med series of applications. This site allows one to search for diagnoses by listing a series of physical findings. A set of matches, discussion, and references will appear.

Specialists can also provide helpful input in determining the proper role of surgery for a given patient. It is helpful to ask, “what other specialists are you seeing?” so that the orthopedic management plan can be integrated with that of other specialists. Testing prior to surgery may also include echocardiography or sleep study for patients at risk of cardiac or pulmonary difficulties. Specific cardiovascular manifestations of specific syndromes will be discussed further in the subsequent sections. Finally, nutritional and gastrointestinal issues can affect this group of patients as well. Specifically, severe curvatures can cause abdominal compression, including gastric reflux. At least one case of postoperative superior mesenteric syndrome has been reported in literature following scoliosis surgery in a patient with Marfan syndrome (MFS) [2]. Malabsorption has been reported in Ehlers–Danlos syndrome (EDS) and MFS secondary to bacterial overgrowth in large jejunal diverticula. Feeding problems and indigestion have been reported in most syndromic scoliosis disorders. The authors recommend a gastrointestinal consultation if these issues come to light.

17.2.4 Operative and Postoperative Management

Implant size may be a problem in young patients with poor nutrition, such as infantile Marfan patients. A range of implant diameters should be available. Osteopenia and increased blood loss may affect surgery. Failure of fixation is another complication commonly seen in syndromic patients following spinal instrumentation. The number and types of anchors should be chosen to minimize this risk. Because of balance and connective tissue factors, principles of instrumentation and fusion that apply to idiopathic patients may not apply to syndromic patients. Attempts to “save levels” do not always work as predictably as in idiopathic deformity. Patients with syndromes often require more involved postoperative care and intensive care stay may be appropriate. Return to function may also be significantly slower than in idiopathic patients. Inpatient rehabilitation may occasionally be indicated after discharge from hospital.

17.3 Specific Syndromes

17.3.1 Marfan Syndrome

MFS is one of the most common connective tissue disorders. It is characterized by its classical involvement of the skeletal, ocular, and cardiovascular organ systems due to its effect on microfibril formation.

17.3.1.1 Etiology/Genetics

MFS has been linked to heterozygous mutations of the FBN1 gene on chromosome 15 that encodes the fibrillin-1 protein, which undergoes polymerization to produce micofibrils [3]. Therefore, fibrillin-1 is an essential component of elastic connective tissue. Additionally, fibrillin-1 plays a role in transforming growth factor beta (TGF-β) binding by stabilizing latent growth factor β-binding proteins, which hold TGF-β in the inactivated state [3]. It was previously hypothesized that the mutations in FBN1 cause structural abnormalities in the microfibrils that lead to the Marfan phenotype; however, it is now accepted that the faulty regulation of TGF-β by fibrillin-1 may be the dominant mechanism [4].

Family history of MFS should be considered significant, as it is a heritable disorder, however it has been approximated that up to 27 % of cases arise from a de novo mutation [4].

17.3.1.2 Presentation/Diagnosis

A diagnosis of MFS may be considered in a young patient who is tall and thin, with long arms and digits, pectus deformities, scoliosis, and other skeletal features [5] (see Table 17.2). The Ghent Nosology is the most widely accepted diagnostic criteria. A Revised Ghent Nosology was published in 2010 [6]. Under the new criteria, cardiovascular manifestations of MFS receive greater attention and, as demonstrated in Table 17.3, aortic root aneurysms and ectopialentis are considered principle features for diagnosis. When no family history is noted, a combination of aortic root aneurysms and ectopialentis are sufficient to establish a positive diagnosis. If these features are not present, demonstration of a FBN1 mutation or a number of systemic features (see Table 17.2) may establish the diagnosis [6]. Under the Revised Ghent Nosology by Loeys et al. [6], a new scoring system has been devised to and is summarized in Table 17.3.

Table 17.2

Systemic features scoring for Marfan syndrome

Scoring for systemic features in Marfan syndrome
Feature	Points
Combined wrist and thumb sign	3
Wrist or thumb sign	1
Pectus carinatum deformity	2
Pectus excavatum or chest asymmetry	1
Hindfoot deformity	2
Plain pes planus	1
Pneumothorax	2
Dural ectasia	2
Protrusio acetabula	2
Reduced upper segment/lower segment ratio + increased arm/height + no severe scoliosis	1
Scoliosis or thoracolumbar kyphosis	1
Reduced elbow extension	1
Facial features (3/5): olichocephaly, enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia	1
Skin striae	1
Myopia >3 diopters	1
Mitral valve prolapse	1

Table 17.3

Diagnosis of Marfan syndrome

No family history	Family history
1. Aortic root dilation Z score ≥ 2 + Ectopia lentis	1. Ectopia lentis + family history of Marfan syndrome
2. Aortic root dilation Z score ≥ 2 + Causal FBN1 mutation	2. Systemic features score ≥ 7 + family history of Marfan syndrome
3. Aortic root dilation Z score ≥ 2 + systemic features score ≥ 7	3. Aortic root dilatation Z score ≥ 2 (if above 20 years old), ≥ 3 (if below 20 years old) + Family History of Marfan syndrome
4. Ectopia lentis + causal FBN1 mutation + aortic root dilation	–

Notable exceptions to Table 17.3 include when a patient presents distinguishing features that suggest LDS (described in this chapter), Shprintzen–Goldberg syndrome, or EDS (described in this chapter that follows). These syndromes often demonstrate significant overlap with MFS. Additionally, molecular testing for TGFBR1/2, collagen biochemistry, and COL3A1 may be required before a positive diagnosis of MFS can be made [6].

Table 17.2 shows the scoring system for systemic features, as defined for the Revised Ghent Nosology [6]. A score of ≥7 is required to fulfill the criteria for systemic involvement.

The early assessment of patients with a suspected diagnosis of MFS should include a detailed personal and family history, due to the age-dependent and heritable patterns of this disorder. Furthermore, an ophthalmological examination and transthoracic echocardiogram are warranted to identify ocular and cardiovascular criteria. Molecular genetic testing may be indicated; however, testing for FBN1 mutations has not proven definitive by itself due to the fact that FBN1 mutations may not be unique to MFS, and 5–10 % of patients may not demonstrate mutations via current testing methods [7–9].

MFS cannot be ruled out in young patients via the Ghent Nosology due to the age-dependent development of its features. If MFS is on the differential diagnosis, children should be kept under clinical review until age 18 or until a positive diagnosis has been made [4].

17.3.1.3 Skeletal/Spine Manifestations

Skeletal manifestations include pectus deformity, spinal deformity (scoliosis, spondylolisthesis, kyphosis, reduced lumbar pedicle, and laminar thickness), joint hypermobility, dolichostenomelia, arachnodactyly, highly arched palate with crowding of teeth, and abnormalities in facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures).

Scoliosis exists in two-thirds of MFS patients. The curve patterns resemble that of idiopathic curves, but with earlier onset, and may be associated with pain in the region of curvature. There appears to be no familial pattern and the scoliosis shows approximately equal prevalence in male and female patients, as opposed to larger idiopathic curves, which tend to be more common in females. Similar to idiopathic causes, scoliosis in MFS tends to demonstrate right-side thoracic curvature and left-side lumbar curvature. The curvature in Marfan infants tends to progress most rapidly, at approximately 20° per year, followed by the curvature of adolescents, which progress at approximately 6° per year (which is not dissimilar to the rate of idiopathic curves during growth spurts). Curves of magnitude greater than 20° are likely to progress during growth and curves greater than 30°–40° tend to progress during adulthood. In general, curves of more than 30° demonstrate mild progression, while curves of more than 50° demonstrate more rapid progression.

The incidence of spondylolisthesis does not appear to be increased. However, the amount of slip tends to be approximately double that of patients without MFS [5]. There is also a tendency for thoracolumbar kyphosis. Dural ectasia, while rare in the general population, is present in at least 60 % of Marfan patients and is often associated with back pain. Patients with duralectasia demonstrate increased rates of bony erosion and anterior or posterior meningoceles [10]. Lumbar pedicle widths and laminar thicknesses tend to be significantly reduced in patients with MFS and may be associated with duralectasia and vertebral scalloping [11]. Additionally, bone mineral density tends to be lower in the spine and pelvis. However, an increase in fracture rate has not been demonstrated [12, 13].

17.3.1.4 MFS and Sports

Patients with MFS are not recommended to participate in high-intensity static exercises, such as weight lifting and hill climbing exercises, due to their effects on blood pressure and vascular resistance. Regular non-strenuous and noncompetitive aerobic activity should be encouraged. Contact sports should be avoided due to risk of damage to the aorta and eyes, and scuba diving should be avoided due to increased risk of pneumothorax [4].

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