Loeys-Dietz syndrome (LDS) is a newly recognized genetic connective tissue disorder often characterized by 3 findings: hypertelorism, bifid uvula with or without cleft palate, and generalized arterial tortuosity with widespread vascular aneurysms.1 It is an autosomal-dominant disorder caused by mutations that influence the transforming growth factor-β signaling pathway, affecting the extracellular matrix and thus connective tissue development and function.
Cervical spine abnormalities and instability have been reported in up to 76% of cases.2 However, the incidence of scoliosis remains less well-studied and has been anecdotally reported to be 25% to 70%.3,4 Erkula et al3 found that 55% of patients with LDS had scoliosis with a mean major curve of 30 degrees. However, the study had a small sample and no data on treatment.3
Several studies have confirmed the benefits of bracing in patients with idiopathic scoliosis.5–8 However, few authors have investigated the effectiveness of bracing in patients with connective tissue disorders.9 The utility of bracing to prevent curve progression in patients with LDS remains unknown, and a consensus regarding how to manage scoliosis in these patients has not been reached. Because bracing is often suggested as part of a spectrum of care, it is important to study its utility in this population. In addition, little is known about operative management of these patients’ spines, including the types of surgery required and the complication and correction rates.
We studied the largest database of patients with LDS to provide the most comprehensive assessment currently possible. Our objectives were to determine the incidence of scoliosis, characterize the spectrum of spinal deformity, determine the results of bracing and surgery, and define surgical complications in patients with LDS.
Patients were identified from a genetic database of 183 LDS patients at our institution.10 There are no widely accepted clinical diagnostic criteria for LDS, so diagnosis is determined by genetic testing.1,11,12 Medical records were drawn from our institution and others when available. One hundred forty-one patients were included in this study; the remaining patients lacked medical records or imaging data required to evaluate the spine.
Spine radiographs were measured for coronal and sagittal alignment, which consisted of proximal thoracic, midthoracic, and thoracolumbar/lumbar (TL/L) curve angles; direction of curvature; apex of curve; Nash-Moe rotation; and sagittal deformity. All measurements were made by 1 trained researcher who was not directly involved in the patients’ care. For patients without upright scoliosis studies, chest radiography, computed tomography, or magnetic resonance images were evaluated. These imaging modalities allowed identification of curves that were not monitored by radiography or an orthopaedic physician, providing a more comprehensive assessment of the total LDS population. If supine image measurements met the criterion for scoliosis (≥10 deg. in the coronal plane), a diagnosis was considered positive under the assumption that the curve would increase if an upright image had been available. We did not convert supine measurements to their upright values but rather conservatively made a positive diagnosis for curves that would meet the diagnostic criterion.
A subset of the 141 patients underwent surgery or bracing for scoliosis. We studied those who were braced according to the following criteria: spinal curvature (15 to 45 deg.); prebracing Risser grade 0, 1, or 2; 1-year minimum follow-up from the start of bracing; and recommended wear of at least 18 h/d. Brace types were Boston or thoracolumbosacral braces, and wear-time was self-reported. Outcome endpoints were skeletal maturity, surgery, or study completion. Postbracing success was defined as curve progression of <5 degrees by maturity and/or prevention of progression to curve magnitudes warranting surgery.
For the surgery study, we evaluated patients who underwent growing rod procedures or definitive fusions. The spine was measured preoperatively and postoperatively for coronal and sagittal alignment, and intraoperative, postoperative, and implant complications were quantified. Blood loss was compared with reported values for mean estimated blood loss associated with idiopathic pediatric scoliosis procedures.13–22 Twenty-four operations were studied, and we reported blood loss as a percentage of estimated total blood volume, which was approximated by 7% of total body weight in kilograms.23,24 Normalized blood loss for fusion procedures was calculated as blood loss per kilogram of body weight per fused level and was compared with reported values for adolescent idiopathic scoliosis.23
Means and SDs were calculated using Microsoft Excel (Microsoft Corp., Redmond, WA), and Student t tests were used to determine if there were significant associations between patient characteristics and bracing outcome. Significance was set as P<0.05.
One hundred forty-one patients were analyzed. Sixty-two percent (88/141) of patients met the criteria for scoliosis, and 55% of these patients were female. Mean curves were 16±12, 20±21, and 21±15 degrees for proximal thoracic, main thoracic, and TL/L curves, respectively. The most common scoliosis curve types were main thoracic (35 patients, 40%) and TL/L (27 patients, 31%). Rotations were largest in the TL/L spine.
Sixteen patients (11 female) met the inclusion criteria for the bracing study. The mean age at commencement of bracing was 9±3 years, and all were Risser stage 0. One patient was excluded because of incomplete follow-up. Characteristics of the braced population are shown in Table 1. Table 2 shows spinal curve parameters before and after bracing. Bracing failure was defined as curve progression >5 degrees or to magnitudes >50 degrees. Patients reported a mean of 19 (range, 10 to 24) hours of brace wear daily. Curve progression was not significantly different for patients who reported daily brace wear of <18 versus ≥18 hours (P=0.97). For patients whose curves progressed, those who reported daily brace wear of <18 hours had mean curve progression of 21 degrees versus 14 degrees for patients who reported 18 hours of daily brace wear (P=0.34).
Bracing was considered a failure in 11 of 15 patients, with mean bracing time of 2.3±0.9 years. No weaning program was used and, at the time of writing, 10 patients had progressed to major curves >50 degrees, and 7 of these patients had undergone surgery after failed bracing attempts. Patients in whom bracing was successful either reached skeletal maturity with stable curves <50 degrees or were maintained in brace with curve deviation <5 degrees. There were no significant differences in age, sex, curve type, or prebrace curve magnitude between successfully versus unsuccessfully braced patients (P>0.05) (Table 1).
Thirteen patients met the inclusion criteria, and 9 patients (7 female) had medical records with operative notes that included the complication information relevant to this study. Five of these patients were previously included in the bracing study. Three of the 9 were treated with growing rods, whereas 6 underwent posterior spinal fusion. Table 3 shows patient characteristics and results of correction. The 9 patients underwent a total of 24 procedures (16 growing rod procedures, 8 fusions). Mean curve corrections at latest follow-up were 73% for fusion and 61% for growing rods. One patient showed a larger post-treatment thoracolumbar curve. Mean gain in T1-S1 length for growing rods was 1.9 cm/y (3.7 cm following initial instrumentation, and 10.7 cm at latest follow-up). Table 4 details blood loss for spinal surgeries. In 11 of 24 surgeries, blood loss was >20% of estimated total blood volume. Normalized blood loss for fusion procedures was 2.34 mL/kg/level, which compares to a reported mean normalized blood loss for adolescent idiopathic scoliosis of 1.52 mL/kg/level.23 Growing rod fracture occurred in 2 of 3 patients, and recurrent rod fractures were common (9/16 growing rod surgeries were associated with rod fracture). However, no patients had failure of fixation with pulling out of screws or hooks that required revision. Fixation to the sacrum was performed in 5 of the 9 patients (both growing rods and definitive fusions) when the lumbosacral region was severely unbalanced or showed dysplastic changes. Seven of 24 procedures were accompanied by cerebrospinal fluid leak (4/16 growing rod surgeries, 3/8 fusions), and patients often required subsequent extension of fixation to additional vertebral levels (3/3 growing rod patients, 2/8 fusion patients). A radiographic case series is included to highlight challenges associated with spinal instrumentation in these patients (Figs. 1, 2).
Scoliosis was present in nearly two-thirds of the 141 LDS patients, and bracing failed in 11 of 15 patients. Patients had distinct surgical complications, including greater than typical blood loss and cerebrospinal fluid leaks; they required fixation to the sacrum, augmentation of preexisting fixation, or repair of fractured growing rods.
LDS is rare, making it challenging to obtain a large cohort. It is important that optimal management of the patient and the spine be determined according to the phenotypic features of LDS. The literature contains few data on the incidence and characteristics of spinal deformity, and importantly, the role of intervention has not been studied. One preliminary study, conducted with data from 2007 to 2008, was limited by a lack of radiographic data on all patients to adequately study spinal deformity, as well as the inability to study the effectiveness of treatments.3 We believe this is the first report on the results of bracing and surgery in the management of thoracic and lumbar scoliosis for patients with LDS.
In determining the incidence of scoliosis and characterizing the typical spinal deformity in LDS patients, we needed to evaluate supine images as well as upright scoliosis radiographs because erect spine radiographs are available only in a subset of patients (those with larger curves) and therefore not reflective of the entire population. However, spinal curves tend to be smaller when supine than when upright. In addition, although a conversion of measurements from supine magnetic resonance imaging to erect correlates has been proposed for idiopathic scoliosis,25 we reasoned that this conversion would not be relevant for patients with LDS because of the laxity of the spine resulting from connective tissue malformation. Instead, we conservatively considered a diagnosis to be positive only if the supine curve measurements met the criteria for scoliosis. We did not use these supine measurements to create a precise quantitative index of spinal deformity for the LDS population, but rather used them to acquire a more accurate prevalence of scoliosis. The mean reported curve magnitudes therefore represent a conservative estimate of deformity, with a primary aim of identifying incidental scoliosis that was not followed or addressed by an orthopaedic physician. This enabled us to study the spines of 141 patients. We found that scoliosis is present in most patients with LDS, thoracic and lumbar curves are common, and prevalence of scoliosis is approximately equal for male and female patients, which is in contrast to adolescent idiopathic scoliosis, though similar to what is seen in Marfan syndrome.26 Therefore, physicians treating patients with LDS should be vigilant for spinal deformity and refer to an orthopaedic physician when curves are large or rapidly changing.
In 2013, the Bracing in Adolescent Idiopathic Scoliosis Trial established, with a high level of evidence, that bracing significantly reduces the risk of curve progression and need for surgery.8,27,28 Conversely, bracing was deemed successful in only 27% of patients with LDS, and >60% of patients progressed to surgical curve magnitudes, with 47% having undergone surgery at latest follow-up. We found that age, sex, curve type, and prebraced curve magnitude did not predict bracing success. The study included children and adolescents, although there was no significant difference between the mean ages of successfully versus unsuccessfully braced patients. A possible explanation for the high rates of bracing failure is that many patients in our database presented with substantial curves at young ages. Moreover, connective tissue challenges reduce corrective forces throughout the spine. However, it is possible that bracing slowed the increase in spinal curves and allowed useful delays in surgery until closer to maturity.
Therefore, bracing should be studied to define scenarios in which it has the highest likelihood of success. Possible outcomes should be discussed with patients to determine whether these probabilities, for them, justify the physical and social/psychological morbidity associated with bracing.
Overall, both growing rod surgery and definitive spinal fusion were able to correct and control deformity to a substantial degree. We further examined the high rates of complications. High blood loss, most notably seen with spinal fusion procedures, may perhaps be explained by vascular fragility in patients with LDS secondary to connective tissue malformation.4,27,29 Cerebrospinal fluid leaks were also common and may have been caused by high prevalence of dural ectasia.28 Deformity control challenges were also seen in this population and manifest in several ways, including high rates of pelvic fixation and subsequent “adding-on” of vertebral levels to the fusion. Recurrent growing rod fractures were also seen.17,30–32 Many patients had severely dysplastic pedicles and osteopenia, which compromised fixation strength. We believe this, as well as ligamentous laxity, caused the need for more extensive fixation. Furthermore, posterior osteotomies were required in some cases because of severe curves, which may have resulted in more bleeding and made the dura more susceptible to leaking.
Interestingly, although TL/L curves tended to show the greatest median curves in patients with LDS, midthoracic curves tended to be largest in the surgically treated patients.
We did not include a control group of matched LDS patients who did not undergo bracing because bracing was regularly recommended, with the prevailing belief that it may prevent progression of curves to ranges warranting surgery. Therefore, it is unknown whether bracing reduced the rate of curve progression. It is possible that bracing allowed a delay in surgery until a more skeletally mature age.
In addition, some patients lacked radiographic data to permit evaluation of the spine, and some treatment records were received from outside institutions. Some information was incomplete or unable to be located; therefore, 23% of 183 patients in our LDS database were excluded from this study. Our sample may also be skewed by referral of more severely affected patients to our specialty center. However, such tendencies may apply more to cardiovascular disorders than spinal ones.
The major limitation is the small sample size of treated patients. However, we believe important observations and clinically relevant implications guiding care of these patients are shown. Scoliosis was common in our database of patients with LDS, progression occurred during bracing, and surgery resulted in satisfactory curve correction, though the surgeon must anticipate fixation challenges and remain vigilant for surgical complications, many of which may be attributed to unique expressions of this connective tissue disorder. Furthermore, because this is a syndrome involving multiple body systems, it is incumbent upon the treating physician to look beyond scoliosis and remain vigilant for instability and deformity of the cervical spine, as well as vascular compromise that could lead to large vessel dissection.
The authors thank Sara Fuhrhop, MD, for her help with data collection in patients with Loeys-Dietz syndrome and for her pioneering work on the cervical spine.
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