Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome?

Discussion

As discussed earlier, Beals syndrome is a rare autosomal dominant disorder characterized by multiple clinical findings, including arachnodactyly, narrow body habitus, scoliosis, congenital contractures, and external ear deformities. The syndrome is typically suspected clinically at birth based on the presence of the following: knee, ankle, and fist-like hand contractures; arachnodactyly; and crumpled ear helices.¹ Beals syndrome results from a mutation in fibrillin-2 (FBN2), which codes for fibrillin glycoprotein, a protein related to that affected in Marfan syndrome (FBN1). Mutation uptake rates for the FBN2 gene are reported at 39% to 75%.^7,8

Beals syndrome and Marfan syndrome share many common features, including tall stature, dolichostenomelia, arachnodactyly, progressive kyphosis or scoliosis, and pectus excavatum or carinatum.⁹ Beals syndrome was first differentiated from Marfan syndrome in 1971. The prognosis of Beals syndrome is more favorable than Marfan syndrome because the cardiovascular complications of Marfan syndrome are rarely seen with Beals syndrome.

Loeys-Dietz is a recently discovered genetic syndrome that also shares features with Beals and Marfan syndromes. Described initially in 2005, Loeys-Dietz syndrome is characterized by a triad of hypertelorism, bifid uvula, or cleft palate, as well as arterial tortuosity, aneurysms, or dissections. Three-quarters of patients with Loeys-Dietz syndrome have the characteristic cranial and facial signs of cleft palate, craniosynostosis, or hypertelorism.⁴ In a case series from Pediatrics in 2006, blue sclerae, cervical vertebra subluxation, camptodactyly, talipes equinovarus, and hernias were other common features.¹⁰ Orthopedic findings of Loeys-Dietz syndrome include oligo-articular issues, such as bilateral club feet, acetabular protrusion, and contractures, typically in the fingers, as opposed to major joints.¹¹ In contrast, patients with Beals syndrome typically exhibit contractures of the knees and ankles at the time of birth, which improve with time.¹

At presentation as a neonate, our patient demonstrated the classic phenotype of Beals syndrome. At that time, targeted genetic testing was not available, and Loeys-Dietz syndrome had not yet been described. Appropriately, Marfan syndrome was considered in the differential, but because this patient initially lacked any major cardiac or ocular disease, this scenario lent further confirmation to the clinical diagnosis of Beals syndrome. In particular, according to the Ghent nosology for Marfan syndrome (as revised in 2010), the absence of a family history in our patient, and the lack of ectopia lentis, even with an echocardiogram showing moderate aortic root dilation, was insufficient reason to confirm the diagnosis of Marfan syndrome.

The study patient shares a number of clinical features with those features described as typical for Loeys-Dietz syndrome: strabismus, a high arched palate, a broad uvula, cervical vertebral abnormalities, knee laxity, talipes equinovarus, and an umbilical hernia.¹⁰ This patient did not have hypertelorism, blue sclerae, or craniosynostosis, despite these conditions being common features of Loeys-Dietz syndrome in previously described patients. Within the literature, Adès et al¹² describes 2 patients (patients 3 and 4), diagnosed with Loeys-Dietz syndrome, who had the same p.Ser241Leu mutation as the patient presented in this case. Neither of the patients had any congenital contractures, but they did present with a number of shared phenotypic features, such as a high arched palate, umbilical herniae, and arachnodactyly. Furthermore, the clinical course of each of these 3 patients shared progressively worsening kyphoscoliosis of the spine, through the thoracolumbar regions, to varying degrees of severity.

The patients described by Yetman et al¹⁰ were diagnosed between 2 days and 9 years of age; in comparison, our patient was diagnosed with Loeys-Dietz syndrome relatively late, at age 15 years. It is crucial to identify patients with Loeys-Dietz syndrome early to allow for monitoring of their cardiovascular status with routine echocardiography; these patients are at high risk of rapid aortic dilation and of aortic dissection or rupture.¹³ As reported in the literature, the mean age of death in patients with Loeys-Dietz is 26.1 years, with aortic disease being the major cause of their early mortality.⁴ An article by MacCarrick et al¹⁴ provides guidelines on the monitoring and management of the vascular effects and other complications of Loeys-Dietz syndrome.

We note that although aortic root involvement is uncommon in Beals syndrome,¹⁵ screening for aortic root dilation in Beals syndrome has been suggested. In fact, a 2004 report shows that aortic root dilation may occur and persist in this disorder.¹⁶ The 2007 recommendation by Yetman et al¹⁰ to routinely perform echocardiography on patients with Beals syndrome was not followed in this patient because this case predated that recommendation. One wonders if this simple screening measure could have detected the patient’s, and even the patient’s father’s, aortic dilation earlier and if this course may have reduced morbidity and surgeries.

The present case underscores the importance of considering Loeys-Dietz and of performing definitive genetic testing, even in seemingly clinically classic cases of Beals syndrome, because of the significant degree of clinical overlap; doing so ensures that appropriate screening examinations for these patients are instituted. Overall, due to significant phenotypic overlap, panel testing for hereditary connective tissue disorders with vascular involvement should include testing for FBN2 and, conversely, young patients with negative FBN2 test results should undergo testing for genes related to hereditary connective tissue disorders with vascular involvement.