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American Academy of Pediatrics
Case Report

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

Rebecca Woolnough, Andrew Dhawan, Kimberly Dow and Jagdeep S. Walia
Pediatrics March 2017, 139 (3) e20161281; DOI: https://doi.org/10.1542/peds.2016-1281
Rebecca Woolnough
aDepartment of Pediatrics, and
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Andrew Dhawan
bSchool of Medicine, Queen’s University, Kingston, Ontario, Canada
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Kimberly Dow
aDepartment of Pediatrics, and
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Jagdeep S. Walia
aDepartment of Pediatrics, and
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Abstract

Beals syndrome, also known as congenital contractural arachnodactyly (Online Mendelian Inheritance in Man: 121050), is an autosomal dominant disorder caused by a mutation in FBN2 that is typically characterized by congenital contractures and arachnodactyly. It shares a number of phenotypic features with Loeys-Dietz syndrome (Online Mendelian Inheritance in Man: 609192). Loeys-Dietz syndrome, initially described in 2005, is associated with mutations for the transforming growth factor β receptor and is characterized by findings of cerebral, thoracic, and abdominal arterial aneurysms. This report describes a 17-year-old male patient with a typical neonatal diagnosis of Beals syndrome. At age 15 years, an echocardiogram conducted in response to an aortic dissection in his father showed moderate aortic root dilation, prompting comprehensive testing for aortopathies, revealing a mutation in TGFBR1, thereby changing the diagnosis to Loeys-Dietz syndrome. Previously published reports have not implicated any mutation of the transforming growth factor β receptor genes in cases of Beals syndrome. This case underscores that due to significant phenotypic overlap, there is utility in a full panel of testing, including genes for hereditary connective tissue disorders with vascular involvement, as well as FBN2. Likewise, young patients who have tested negative for FBN2 should be tested for hereditary connective tissue disorders with vascular involvement.

  • Abbreviation:
    OMIM —
    Online Mendelian Inheritance in Man
  • Beals syndrome (Online Mendelian Inheritance in Man [OMIM]: 121050) is described in the literature as an autosomal dominant disorder, typically characterized by congenital contractures and arachnodactyly.1,2 The implicated pathogenic mechanism is a mutation in the FBN2 gene, coding for fibrillin protein, in region 5q23-31.3 This syndrome shares a number of clinical features with Marfan syndrome (OMIM: 154700), including a marfanoid body habitus and arachnodactyly. However, there are a number of differing features, particularly the fact that Beals syndrome is believed to be a benign condition in which cardiac features are limited to mitral valve prolapse, compared with the more severe cardiac complications typically associated with Marfan syndrome (eg, aortic root dilation).

    Loeys-Dietz syndrome (OMIM: 609192), initially described in 2005, is associated with mutations in the genes coding for the transforming growth factor β receptors TGFBR1 and TGFBR2.4–6 This syndrome is clinically characterized by findings of cerebral, thoracic, and abdominal arterial aneurysms. Common skeletal abnormalities associated with Loeys-Dietz syndrome include pectus deformities, arachnodactyly, and club feet; common craniofacial abnormalities include hypertelorism, bifid uvula, and cleft palate. Aneurysms in this condition occur early in life and can have severe complications; the reported mean age of death in these patients is 26.1 years.

    The present article describes the case of a patient who was initially diagnosed with Beals syndrome before the recognition of Loeys-Dietz syndrome; this diagnosis occurred after the development of aortopathy in the patient’s father, who received genetic testing, confirming a diagnosis of Loeys-Dietz syndrome in himself. This case serves to highlight the fact that due to the significant clinical overlap between the Beals and Loeys-Dietz syndromes, there is a crucial need for targeted genetic testing to differentiate these syndromes and to assess the need for follow-up of cardiac parameters to improve prognosis for these patients.

    Case Report

    The male patient was born in 1998 at term after an uncomplicated pregnancy and perinatal course; he was initially referred shortly after birth to medical genetics due to multiple congenital anomalies (Fig 1). The patient’s family history was negative for any similar medical conditions or birth defects, and there were no craniofacial abnormalities in the patient’s mother or father.

    FIGURE 1
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    FIGURE 1

    Patient photographs taken from birth. A, Facial photo showing right-sided ptosis. B, Facial profile showing crumpled ear helix, low-set ears, microretrognathia, and frontal bossing. C and D, Multiple congenital contractures with arachnodactyly. E, Bilateral talipes equinovarus.

    General Examination

    On general physical examination, at 7 weeks of age, the patient was at the 25th percentile for weight, the 95th percentile for head circumference, and the 90th percentile for length. He had an elongated chest, with marked nonfixed contractural arachnodactyly (Fig 1 C and D). Both feet were noted to be clubbed from birth (Fig 1E). There was normal male genitalia and a small umbilical hernia. No neurologic deficits or cardiovascular abnormalities were noted on examination.

    Craniofacial Abnormalities

    This patient was found to have a number of craniofacial abnormalities. In particular, there was prominent frontal bossing, partial right ptosis, and malar hypoplasia. There was also microretrognathia and a high arched palate. His ears were low-set, with crumpled helices, normally rotated, and with no associated pits (Fig 1B).

    Initial Investigations

    At the time of initial consultation, an echocardiogram revealed a small patent ductus arteriosus that resolved spontaneously. The aortic root was found to be dilated with a diameter of 14 mm (z score, 4.04). A karyotype was unremarkable. No further targeted genetic testing was available at the time of the patient’s initial genetic consultation.

    Initial Diagnosis

    Based on these features, without the availability of specific genetic testing at the time of presentation, a clinical diagnosis of Beals syndrome was made. In particular, the findings of congenital contractural arachnodactyly increased suspicion for this syndrome.

    Clinical Course

    The noteworthy features in this patient that evolved over time included childhood myopia, with ophthalmologic assessments not revealing ectopia lentis at any point. Because Beals syndrome was believed to be unrelated to persistent cardiac issues, in view of the moderately dilated aortic root at birth, cardiac monitoring was arranged as a 1-year follow-up echocardiogram, which showed a normal aortic root. No further follow-up was arranged until his father was diagnosed with aortic dissection. The patient’s dysmorphic features persisted (Figs 2–4), notably with significant craniofacial dysmorphism and arachnodactyly.

    FIGURE 2
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    FIGURE 2

    Congenital contractural arachnodactyly.

    FIGURE 3
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    FIGURE 3

    A, Pedal anomalies. B, Long, contracted toes are evident.

    FIGURE 4
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    FIGURE 4

    Craniofacial appearance. Abnormalities include: A, partial right eye ptosis; B and C, microretrognathia; B and C, low-set ears; and C, malar hypoplasia and crumpled ear helices.

    The patient grew to become the tallest member of his family with a height of 187 cm (mid-parental height, 184.3 cm). Developmentally, he displayed a mild learning disability but remained otherwise well. He developed a worsening kyphoscoliosis that ultimately required corrective orthopedic surgery at age 13 years.

    When the study patient was 15 years old, his father experienced an aortic dissection, which prompted investigation of the study patient with echocardiography; this test revealed persistent moderate aortic dilation. This finding led to re-evaluation and genetic testing for a panel of 17 genes for aortopathies. Genetic testing in our patient confirmed a mutation in TGFBR1, consistent with Loeys-Dietz syndrome type 1. The mutation identified was in exon 4, a nucleotide substitution at c.722C>T, resulting in an amino acid alteration of p.Ser241Leu. Results of genetic testing for Marfan syndrome (FBN1) and Beals syndrome (FBN2) were negative. Subsequently, the patient’s father was found to have a de novo mutation that was identical to his son’s, although the father’s Loeys-Dietz syndrome phenotype is milder than that of the study patient’s. The patient’s father underwent a surveillance scan of his entire vasculature 3 years after his initial aortic dissection, at which point he was found to have a second aortic dissection that required immediate surgery.

    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.

    Ethics Statement and Consent

    Written informed consent was obtained from the patient and family members for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.

    Acknowledgments

    We thank the patient and the patient’s family for allowing us to publish their clinical case and presentation. We are grateful for the clinical assistance provided by the genetic counselors involved in this case.

    Footnotes

      • Accepted September 12, 2016.
    • Address correspondence to Jagdeep S. Walia, MBBS, Department of Pediatrics, Kingston General Hospital, 76 Stuart St, Kingston, ON, Canada, K7L 2V7. E-mail: waliaj{at}kgh.kari.net
    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: No external funding.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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    Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome?
    Rebecca Woolnough, Andrew Dhawan, Kimberly Dow, Jagdeep S. Walia
    Pediatrics Mar 2017, 139 (3) e20161281; DOI: 10.1542/peds.2016-1281

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    Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome?
    Rebecca Woolnough, Andrew Dhawan, Kimberly Dow, Jagdeep S. Walia
    Pediatrics Mar 2017, 139 (3) e20161281; DOI: 10.1542/peds.2016-1281
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