Musculoskeletal Findings of Loeys-Dietz Syndrome

Erkula, Gurkan MD; Sponseller, Paul D. MD; Paulsen, Laura C. BS; Oswald, Gretchen L. MS; Loeys, Bart L. MD, PhD; Dietz, Harry C. MD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.I.01140
Scientific Articles

Background: Loeys-Dietz syndrome is a recently recognized multisystemic disorder caused by mutations in the genes encoding the transforming growth factor-beta receptor. It is characterized by aggressive aneurysm formation and vascular tortuosity. We report the musculoskeletal demographic, clinical, and imaging findings of this syndrome to aid in its diagnosis and treatment.

Methods: We retrospectively analyzed the demographic, clinical, and imaging data of sixty-five patients with Loeys-Dietz syndrome seen at one institution from May 2007 through December 2008.

Results: The patients had a mean age of twenty-one years, and thirty-six of the sixty-five patients were less than eighteen years old. Previous diagnoses for these patients included Marfan syndrome (sixteen patients) and Ehlers-Danlos syndrome (two patients). Spinal and foot abnormalities were the most clinically important skeletal findings. Eleven patients had talipes equinovarus, and nineteen patients had cervical anomalies and instability. Thirty patients had scoliosis (mean Cobb angle [and standard deviation], 30° ± 18°). Two patients had spondylolisthesis, and twenty-two of thirty-three who had computed tomography scans had dural ectasia. Thirty-five patients had pectus excavatum, and eight had pectus carinatum. Combined thumb and wrist signs were present in approximately one-fourth of the patients. Acetabular protrusion was present in approximately one-third of the patients and was usually mild. Fourteen patients had previous orthopaedic procedures, including scoliosis surgery, cervical stabilization, clubfoot correction, and hip arthroplasty. Features of Loeys-Dietz syndrome that are important clues to aid in making this diagnosis include bifid broad uvulas, hypertelorism, substantial joint laxity, and translucent skin.

Conclusions: Patients with Loeys-Dietz syndrome commonly present to the orthopaedic surgeon with cervical malformations, spinal and foot deformities, and findings in the craniofacial and cutaneous systems.

Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Author Information

1c/o Elaine P. Henze, BJ, ELS, Medical Editor and Director, Editorial Services, Department of Orthopaedic Surgery, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, #A665, Baltimore, MD 21224-2780. E-mail address for P.D. Sponseller:

Article Outline

Loeys-Dietz syndrome is a recently identified autosomal dominant syndrome with aortic-arterial aneurysms and craniofacial and musculoskeletal involvement1,2. The syndrome is characterized by the triad of vascular aneurysms and tortuosity, hypertelorism (Fig. 1), and bifid uvula or cleft palate2. Affected patients have a high risk of early rupture of vascular aneurysms. The syndrome is caused by mutations in the transforming growth factor-beta receptor 1 (TGF-βR1) or 2 (TGF-βR2) genes1-7.

Patients with Loeys-Dietz syndrome may present with vascular (e.g., aortic and arterial aneurysms and dissections) and skeletal (e.g., pectus anomalies and scoliosis) characteristics that are similar to those found in Ehlers-Danlos syndrome, Marfan syndrome, or Shprintzen-Goldberg syndrome. Loeys-Dietz syndrome can be differentiated from these and other syndromes by its distinctive facial features, including craniosynostosis, hypertelorism, and cleft palate or bifid uvula, and by its associated extremity contractures, talipes equinovarus, and cervical congenital malformations and instability. A substantial number of patients with Loeys-Dietz syndrome also present with cutaneous features (e.g., translucent skin and easy bruising) and joint hypermobility. Thus, the observation of any of these skeletal, craniofacial, or cutaneous features should prompt referral for an echocardiogram to assess for aortic dilation and for genetic testing to assess for mutations in the TGF-βR1 or TGF-βR2 genes. Because early diagnosis allows for institution of medication to lower blood pressure, proper guidance for imaging surveillance, and surgical treatment of aneurysms, it is important to recognize patients with Loeys-Dietz syndrome as early as possible2.

The goal of this study was to report the musculoskeletal findings and other evident features of sixty-five patients with Loeys-Dietz syndrome seen at one institution as a means to promote its early recognition and awareness and to facilitate management of the associated musculoskeletal and vascular problems.

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Materials and Methods

We obtained a Continuing Review Waiver of Consent for this study from our institutional review board. We retrospectively reviewed the demographic, clinical, and imaging data for sixty-five patients with identified Loeys-Dietz syndrome at the McKusick-Nathans Institute of Genetic Medicine. All patients had molecular confirmation of Loeys-Dietz syndrome with a mutation in the TGF-βR1 or TGF-βR2 genes. Most patients had undergone much of their treatment elsewhere because this is a newly recognized disorder. Patients were generally referred for testing after their initial treatments had been completed. Clinical records from those outside sources were requested, but they did not uniformly describe all previous orthopaedic problems and treatments. The presence of the syndrome was confirmed with genetic testing.

Data from the patient records included age, sex, facial findings (shape and placement of eyes, presence or absence of cleft palate, uvular manifestations, dolichocephaly, retrognathia or micrognathia, malar hypoplasia, and color of the sclera), joint laxity or contractures, wrist and thumb signs, ratio of arm span to height, congenital abnormalities of the extremities (camptodactyly, dolichostenomelia, and arachnodactyly), foot manifestations (talipes equinovarus, pes planus, and medially displaced medial malleolus), developmental delay, history of developmental dysplasia of the hip, type of previous orthopaedic procedures performed, presence or absence of a family history of Loeys-Dietz syndrome, and the type of TGF-β receptor mutation.

From the imaging examinations, Cobb angles, cervical abnormalities (malrotation, off-center location of the odontoid, dislocation, or defects in formation), junctional kyphosis or spondylolisthesis, dural ectasia, and acetabular protrusion were noted.

Some of the patients in this study did not undergo any imaging studies so the results are reported according to availability. Whole-body computed tomography scans, performed to detect aneurysms, were the most commonly available imaging modality. Although not all patients were examined by an orthopaedic surgeon, all were examined by a geneticist and all had TGF-β receptor analysis. Clinical data on some of the skeletal features were not available for all patients.

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Statistical Analysis

All results were calculated on the basis of the numerator representing the data on the presence or absence of a specific finding and the denominator representing the total number of patients with available data on that finding. Statistical software was used to generate means and standard deviations for the genetic findings.

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Source of Funding

There was no external source of funding for this study.

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Demographic and Previous Findings

Our sixty-five patients had a mean age (and standard deviation) of 21.4 ± 16.6 years, and thirty-six (55%) were less than eighteen years old. Fifty-two percent were male.

Some patients had a previous diagnosis of Marfan syndrome (sixteen), Ehlers-Danlos syndrome (two), or Shprintzen-Goldberg syndrome (one). Family history was positive for Loeys-Dietz syndrome in 60% (eighteen) of thirty patients or for vascular abnormalities, including aortic aneurysms, in eighteen of thirty patients. Delays in motor milestones were reported for 38% (nine) of twenty-four patients.

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Cervical Spine Findings

The greatest number of spinal problems involved congenital upper cervical abnormalities and instability. All computed tomography scans were made at our institution with the head of the patient in the neutral position. Nineteen (51%) of thirty-seven patients had cervical formation defects or instability, or both. Formation defects included six anterior (Fig. 2) and four posterior arch defects at C1. Five patients had lateral off-center location of the odontoid within the ring of the atlas (Fig. 3), three had atlantoaxial rotatory subluxation of C1 on C2 with a centered odontoid, one had anterior C1-C2 subluxation, and one had anterior C2-C3 subluxation.

The patient who had C2-C3 subluxation, which was diagnosed when he presented with respiratory compromise, had been treated with a posterior arthrodesis that demonstrated delayed healing. The patient with C1-C2 subluxation had been treated with a C1 laminectomy and posterior cervical arthrodesis of C1-C2 with allograft placement and wiring. Because of delayed union, she had successful repeat surgery with posterior cervical arthrodesis and instrumentation. One patient with a posterior arch defect and C1-C2 atlantoaxial rotatory subluxation was treated with an occipitocervical arthrodesis from the occiput to C4, and, in another patient, the atlantoaxial rotatory instability was reduced with traction and did not require surgical treatment. One patient with C1-C2 atlantoaxial rotatory subluxation was treated with posterior cervical arthrodesis from the occiput to C3. A pseudarthrosis resulted, and it was treated with anterior and posterior cervical arthrodesis with use of allograft. He again developed a pseudarthrosis and required a third operation with posterior instrumentation and a local injection of bone morphogenetic protein. At the time of the latest follow-up, this patient was wearing a brace and had no evidence of union.

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Thoracolumbar Spinal Findings

Scoliosis was present in thirty (55%) of fifty-five patients, and the average Cobb angle was 29.6° ± 17.9°. The most common curve pattern was thoracic (twenty patients), followed by double-major (five), thoracolumbar (three), lumbar (one), and triple (one) curves. Some of these patients were treated with orthoses, but complete data on indications and results were not available. Three of these patients underwent posterior spine arthrodesis with instrumentation, and one was treated with growing spinal instrumentation. One patient had a 68° thoracic kyphosis, and four patients had an average thoracolumbar kyphosis of 28° ± 16°.

One patient had grade-I spondylolisthesis, and one had grade-II spondylolisthesis at the level of L5-S1. Four patients with an average age in the mid-thirties had degenerative changes involving L3 to L5, including decreased height of the vertebrae, anterior bone-bridging, and calcification of the intervertebral disc. Two of the patients with degenerative changes had back pain and used pain medications daily.

Dural ectasia was found in twenty-two (67%) of the thirty-three patients who had computed tomography scans, and it was diagnosed by the presence of thinning or erosion of the pedicles, widening of the central canal, dilatation of the neural foramina, and the evidence of dural expansion out of the central canal.

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Other Extraspinal Findings

Pectus excavatum was more common (63%; thirty-five of fifty-six patients) than pectus carinatum (14%; eight of fifty-six patients). Four of the patients with severe pectus excavatum deformity had surgical correction of the deformity with satisfactory results.

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Foot and Ankle Findings

Severe hindfoot valgus was present in twelve (39%) of thirty-one patients, and flatfoot was present in twenty-two (58%) of thirty-eight patients. Twelve (55%) of twenty-two patients with flatfoot had a severe hindfoot valgus (Fig. 4, Table I).

Eleven patients had a history of talipes equinovarus (seven of forty-eight had unilateral and four of forty-eight had bilateral involvement). The medical records described more extreme deformity in Loeys-Dietz syndrome than is typically seen with idiopathic talipes equinovarus, although no objective rating had been performed. Most of these patients had undergone serial casting, and three patients required surgery for clubfoot correction, including complete subtalar release. One patient later required a calcaneal osteotomy for correction of hindfoot valgus. All three patients had valgus of the hindfoot or metatarsus adductus after the operation. However, they had no pain.

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Extremity Findings

Dolichostenomelia (unusually long limbs) was seen in 17% (four) of twenty-four patients, and arachnodactyly was seen in 53% (eighteen) of thirty-four patients. The mean arm span-to-height ratio for the group was 1.03 ± 0.03, and 68% (twenty-five) of thirty-seven patients had a ratio of <1.05. This finding is in contrast to that of Marfan syndrome, in which an arm span-to-height ratio of >1.05 is a major skeletal feature. Camptodactyly was present in nine patients, and three patients had generalized proximal interphalangeal contractures of the hand, which were treated by exercise and application of a cast after birth. Although most of the patients had hypermobility (Fig. 5), two patients had elbow flexion contractures, one patient had a knee flexion contracture, and one patient had multiple joint contractures.

The Steinberg (thumb) sign8 was present in 32% (ten) of thirty-one patients. The Steinberg sign is positive when the entire distal phalanx protrudes beyond the ulnar border of the clenched fist8. The Walker-Murdoch (wrist) sign9 was positive in 26% (eight) of thirty-one patients. This sign is positive if the thumb can cover the entire nail of the fifth finger when wrapped around the contralateral wrist9. Combined Steinberg and Walker-Murdoch signs were seen in 26% (eight) of thirty-one patients. Although the prevalence of these findings was higher than that in the general population, they were lower than that in patients with Marfan syndrome8-10.

Two patients had developmental dysplasia of the hip, which was treated with varus derotation osteotomy combined with iliac osteotomy. Another patient had hip replacement surgery when she was in her mid-thirties because of idiopathic osteonecrosis of both femoral heads.

One patient had an unseparated femoral neck fracture after minor trauma at the age of three years and was managed with immobilization in a hip spica cast for six weeks. Six months after the removal of the cast, the patient refractured the femoral neck and was placed in a hip spica cast for six weeks. The fracture healed completely with no further complications.

Acetabular protrusion was seen on pelvic radiographs or computed tomography scans of ten (29%) of thirty-four patients and was usually mild. Acetabular protrusion was identified on computed tomography scans when the acetabular line crossed the normal oval shape formed by the two iliopectineal lines.

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Facial Findings

Some of the most distinctive features of the syndrome were the facial findings. Hypertelorism was present in 64% (sixteen) of twenty-five patients11, and many patients (55%; twelve of twenty-two) had blue sclera. Forty percent (twelve of thirty patients) had down-slanting palpebral fissures. Dolichocephaly (a relatively long head) was found in four of twenty patients12. The prevalence of a high arched palate was 76% (thirty-one of forty-one patients), and cleft palate was present in 36% (eight) of twenty-two patients. Additional common findings of the syndrome were retrognathia, which was seen in 63% (twenty-two) of thirty-five patients, and malar hypoplasia, which was seen in 73% (twenty-two) of thirty patients13. Although dolichocephaly, down-slanting palpebral fissures, retrognathia, and malar hypoplasia are also seen in Marfan syndrome and a variety of connective tissue disorders, hypertelorism, blue sclera, and cleft palate are more suggestive of a Loeys-Dietz syndrome diagnosis.

Uvular findings were also frequent in this series and may aid in recognition. Changes in the uvula could be classified with regard to severity as broad-shaped with raphe or as bifid. Overall, most (thirty-six) of the forty-two patients with data available had malformations of the uvula, with the most frequent malformation being a bifid uvula (twenty-one patients), followed by a broad-shaped uvula with raphe (fifteen patients).

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Statistical Results

Comparison of the means for independent groups of TGF-βR1 and TGF-βR2 revealed no significance for musculoskeletal findings (Table II). Both groups had the same proportional distribution of the musculoskeletal findings; all of the variables collected for the study were compared in the analysis.

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In 1996, De Paepe et al.10 identified what appeared to be a subgroup of patients with Marfan syndrome with slightly different diagnostic criteria. Their in-depth analysis of the records of the “atypical” or undiagnosed patients with Marfan-like criteria revealed some common characteristics, including the findings of hypertelorism, cleft palate, and uvular abnormalities. Echocardiography and computed tomography angiography also showed vascular tortuosity and widespread aneurysms that did not resemble those of Marfan syndrome. Further investigation revealed that this newly described syndrome was caused by mutations in the TGF-βR1 and TGF-βR2 genes1.

Although Loeys-Dietz syndrome has many findings in common with those of Marfan syndrome, the two syndromes have more differences than similarities. Both may include scoliosis, but our preliminary impression is that it is less frequently severe in Loeys-Dietz syndrome. Cervical formation defects and anomalies are an important and potentially pathognomonic feature, at times leading to cervical instability. Along with the cardiac and vascular abnormalities, cervical instability can be a silent risk of undiagnosed Loeys-Dietz syndrome. The cause of the developmental anomalies in the cervical region is unclear.

We had two patients with pronounced lumbar degenerative changes, including loss of vertebral height, intervertebral bridge formation, decreased intervertebral space, and degeneration of the disc. Most patients in the study group were pediatric patients, and it is not yet known how common degenerative changes are in adults with Loeys-Dietz syndrome. Dural ectasia is common in patients with Loeys-Dietz syndrome, but we have not observed changes as severe as those in Marfan syndrome. The clinical importance of the dural ectasia is not clear, but it may pose an increased risk of cerebrospinal fluid leakage if spinal surgery or lumbar puncture is performed.

The presence of talipes equinovarus or extremity contractures in conjunction with hyperextensibility in the same patient is unusual, but is commonly seen in Loeys-Dietz syndrome. In our study, 23% (eleven) of forty-eight patients had talipes equinovarus, and most responded to early serial casting. These patients experienced undercorrection or overcorrection and had a tendency toward final hindfoot valgus deformity. In the patients we were able to examine, residual deformities of the forefoot and hindfoot, which may require reoperation later, were noted.

Patients with Loeys-Dietz syndrome may also present with extremity or hand contractures. The management of these patients to date has been nonoperative, with stretching, physical therapy, and serial cast application used whenever necessary. Many of the digital contractures improved, and no patient required operative treatment.

Two patients in our series had hip dysplasia and required treatment with varus derotation and iliac osteotomies. Both patients were treated at outside institutions with satisfactory results and without recurrence or complications.

Facial features of the syndrome are an important guide to recognition. A patient with Marfanoid extremity features, abnormalities in the uvula, cleft palate, or hypertelorism should be evaluated for cervical malformations and instability, as well as scoliosis.

Early diagnosis of this syndrome allows for appropriate intervention, including the institution of medications to lower blood pressure, most commonly beta-blockers or angiotensin receptor blockers. Accurate diagnosis is also important because the vascular imaging surveillance in Loeys-Dietz syndrome differs from that seen in other disorders such as Marfan syndrome. Specifically, because of the risk of aneurysms seen throughout the arterial tree in Loeys-Dietz syndrome, routine head-through-pelvis imaging is obtained. Additionally, the vascular phenotype appears more aggressive than that seen in Marfan syndrome, and surgical intervention of aortic enlargement is typically undertaken at smaller dimensions and at younger ages.

Aortic and arterial dissection and cervical spine instability can be seen at presentation, with substantial morbidity and mortality, in undiagnosed individuals. Because many patients may first present to orthopaedic clinics for their skeletal concerns, orthopaedists play a key role in the recognition and referral of those individuals who may be affected by Loeys-Dietz syndrome.

The main weakness of our study is the lack of availability of radiographic imaging data or patient records for the entire cohort, a common deficit of retrospective studies. We plan to report on the different system findings and treatment options in future prospective studies.

Orthopaedic surgeons should be alert for a diagnosis of this syndrome. Key skeletal elements include clubfeet, scoliosis, upper cervical deformity, and knee or elbow hyperextensibility. Findings of hypertelorism, cleft palate, or bifid uvula should prompt referral to a geneticist.

Investigation performed at the Department of Orthopaedic Surgery and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, Maryland

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

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1. Loeys BL Schwarze U Holm T Callewaert BL Thomas GH Pannu H De Backer JF Oswald GL Symoens S Manouvrier S Roberts AE Faravelli F Greco MA Pyeritz RE Milewicz DM Coucke PJ Cameron DE Braverman AC Byers PH De Paepe AM Dietz HC. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98.
2. Loeys BL Chen J Neptune ER Judge DP Podowski M Holm T Meyers J Leitch CC Katsanis N Sharifi N Xu FL Myers LA Spevak PJ Cameron DE De Backer J Hellemans J Chen Y Davis EC Webb CL Kress W Coucke P Rifkin DB De Paepe AM Dietz HC. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81.
3. Lee RS Fazel S Schwarze U Fleischmann D Berry GJ Liang D Miller DC Mitchell RS. Rapid aneurysmal degeneration of a Stanford type B aortic dissection in a patient with Loeys-Dietz syndrome. J Thorac Cardiovasc Surg. 2007;134:242–3, 243.e1.
4. LeMaire SA Pannu H Tran-Fadulu V Carter SA Coselli JS Milewicz DM. Severe aortic and arterial aneurysms associated with a TGFBR2 mutation. Nat Clin Pract Cardiovasc Med. 2007;4:167–71.
5. Singh KK Rommel K Mishra A Karck M Haverich A Schmidtke J Arslan-Kirchner M. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006;27:770–7.
6. Viassolo V Lituania M Marasini M Dietz H Benelli F Forzano F Faravelli F. Fetal aortic root dilation: a prenatal feature of the Loeys-Dietz syndrome. Prenat Diagn. 2006;26:1081–3.
7. Yetman AT Beroukhim RS Ivy DD Manchester D. Importance of the clinical recognition of Loeys-Dietz syndrome in the neonatal period. Pediatrics. 2007;119:e1199–202.
8. Feingold M. The thumb sign in children. Clin Pediatr (Phila). 1968;7:423–4.
9. Walker BA Murdoch JL. The wrist sign. A useful physical finding in the Marfan syndrome. Arch Intern Med. 1970;126:276–7.
10. De Paepe A Devereux RB Dietz HC Hennekam RC Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62:417–26.
11. Costaras M Pruzansky S Broadbent BH Jr. Bony interorbital distance (BIOD), head size, and level of the cribriform plate relative to orbital height: I. Normal standards for age and sex. J Craniofac Genet Dev Biol. 1982;2:5–18.
12. Hadlock FP Deter RL Carpenter RJ Park SK. Estimating fetal age: effect of head shape on BPD. AJR Am J Roentgenol. 1981;137:83–5.
13. Chaisrisookumporn N Stella JP Epker BN. Cephalometric profile evaluations in patients with cleft lip and palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80:137–44.
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