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.
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.
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).
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.
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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