Are Patients With Loeys- Dietz Syndrome Misdiagnosed With Beals Syndrome? Rebecca Woolnough, MD, a Andrew Dhawan, MD,b Kimberly Dow, MD,a Jagdeep S. Walia, MBBS, FRCPCa

Beals syndrome, also known as congenital contractural arachnodactyly abstract (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, a Department of Pediatrics, and bSchool of Medicine, thereby changing the diagnosis to Loeys-Dietz syndrome. Previously Queen’s University, Kingston, Ontario, Canada published reports have not implicated any mutation of the transforming Dr Woolnough drafted the initial manuscript; growth factor β receptor genes in cases of Beals syndrome. This case Dr Dhawan reviewed and revised the manuscript; underscores that due to significant phenotypic overlap, there is utility in and Drs Dow and Walia conceptualized, edited, and a full panel of testing, including genes for hereditary connective tissue designed the case report. All authors approved FBN2. the fi nal manuscript as submitted and agree to be disorders with vascular involvement, as well as Likewise, young accountable for all aspects of the work. FBN2 patients who have tested negative for should be tested for hereditary DOI: 10.1542/peds.2016-1281 connective tissue disorders with vascular involvement. Accepted for publication Sep 12, 2016 Address correspondence to Jagdeep S. Walia, MBBS, Department of Pediatrics, Kingston General Beals syndrome (Online Mendelian features are limited to mitral valve Hospital, 76 Stuart St, Kingston, ON, Canada, K7L Inheritance in Man [OMIM]: 121050) prolapse, compared with the more 2V7. E-mail: [email protected] is described in the literature as severe cardiac complications typically PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, an autosomal dominant disorder, associated with Marfan syndrome (eg, 1098-4275). typically characterized by congenital aortic root dilation). Copyright © 2017 by the American Academy of contractures and arachnodactyly. 1, 2 Pediatrics The implicated pathogenic mechanism Loeys-Dietz syndrome (OMIM: FINANCIAL DISCLOSURE: The authors have is a mutation in the FBN2 gene, 609192), initially described in 2005, indicated they have no fi nancial relationships relevant to this article to disclose. coding for fibrillin protein, in region is associated with mutations in the 5q23-31.3 This syndrome shares genes coding for the transforming FUNDING: No external funding. a number of clinical features with growth factor β receptors TGFBR1 POTENTIAL CONFLICT OF INTEREST: The authors Marfan syndrome (OMIM: 154700), and TGFBR2. 4 – 6 This syndrome is have indicated they have no potential confl icts of interest to disclose. including a marfanoid body habitus clinically characterized by findings and arachnodactyly. However, of cerebral, thoracic, and abdominal there are a number of differing arterial aneurysms. Common To cite: Woolnough R, Dhawan A, Dow K, et al. Are features, particularly the fact that skeletal abnormalities associated Patients With Loeys-Dietz Syndrome Misdiagnosed Beals syndrome is believed to be a with Loeys-Dietz syndrome include With Beals Syndrome?. Pediatrics. 2017;139(3): e20161281 benign condition in which cardiac pectus deformities, arachnodactyly,

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 3 , March 2017 :e 20161281 CASE REPORT 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. and club feet; common craniofacial pregnancy and perinatal course; he frontal bossing, partial right ptosis, abnormalities include hypertelorism, was initially referred shortly after and malar hypoplasia. There was also bifid uvula, and cleft palate. birth to medical genetics due to microretrognathia and a high arched Aneurysms in this condition occur multiple congenital anomalies (Fig 1). palate. His ears were low-set, with early in life and can have severe The patient’s family history was crumpled helices, normally rotated, complications; the reported mean age negative for any similar medical and with no associated pits ( Fig 1B). of death in these patients is 26.1 years. conditions or birth defects, and there The present article describes the were no craniofacial abnormalities in Initial Investigations case of a patient who was initially the patient’s mother or father. diagnosed with Beals syndrome At the time of initial consultation, General Examination before the recognition of Loeys-Dietz an echocardiogram revealed a syndrome; this diagnosis occurred On general physical examination, at small patent ductus arteriosus that after the development of aortopathy 7 weeks of age, the patient was at the resolved spontaneously. The aortic in the patient’s father, who received 25th percentile for weight, the 95th root was found to be dilated with a genetic testing, confirming a percentile for head circumference, diameter of 14 mm (z score, 4.04). diagnosis of Loeys-Dietz syndrome in and the 90th percentile for length. He A karyotype was unremarkable. No himself. This case serves to highlight had an elongated chest, with marked further targeted genetic testing was the fact that due to the significant nonfixed contractural arachnodactyly available at the time of the patient’s clinical overlap between the Beals (Fig 1 C and D). Both feet were noted initial genetic consultation. and Loeys-Dietz syndromes, there to be clubbed from birth ( Fig 1E). is a crucial need for targeted There was normal male genitalia Initial Diagnosis genetic testing to differentiate these and a small umbilical hernia. No syndromes and to assess the need for neurologic deficits or cardiovascular Based on these features, without follow-up of cardiac parameters to abnormalities were noted on the availability of specific genetic improve prognosis for these patients. examination. testing at the time of presentation, a clinical diagnosis of Beals syndrome Craniofacial Abnormalities was made. In particular, the CASE REPORT This patient was found to have a findings of congenital contractural The male patient was born in 1998 number of craniofacial abnormalities. arachnodactyly increased suspicion at term after an uncomplicated In particular, there was prominent for this syndrome.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e2 WOOLNOUGH et al 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 FIGURE 2 echocardiogram, which showed Congenital contractural arachnodactyly. 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. 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 FIGURE 3 remained otherwise well. A, Pedal anomalies. B, Long, contracted toes are evident. He developed a worsening kyphoscoliosis that ultimately aortic dissection, which prompted to re-evaluation and genetic required corrective orthopedic investigation of the study patient testing for a panel of 17 genes for surgery at age 13 years. with echocardiography; this test aortopathies. Genetic testing in our When the study patient was 15 revealed persistent moderate patient confirmed a mutation in years old, his father experienced an aortic dilation. This finding led TGFBR1, consistent with Loeys-Dietz

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.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 3 , March 2017 e3 syndrome type 1. The mutation Marfan syndrome are rarely seen features described as typical for identified was in exon 4, a nucleotide with Beals syndrome. Loeys-Dietz syndrome: strabismus, substitution at c.722C>T, resulting Loeys-Dietz is a recently discovered a high arched palate, a broad uvula, in an amino acid alteration of genetic syndrome that also shares cervical vertebral abnormalities, p.Ser241Leu. Results of genetic features with Beals and Marfan knee laxity, talipes equinovarus, and FBN1 10 testing for Marfan syndrome ( ) syndromes. Described initially an umbilical hernia. This patient FBN2 and Beals syndrome ( ) were in 2005, Loeys-Dietz syndrome did not have hypertelorism, blue negative. Subsequently, the patient’s is characterized by a triad of sclerae, or craniosynostosis, despite father was found to have a de novo hypertelorism, bifid uvula, or cleft these conditions being common mutation that was identical to his palate, as well as arterial tortuosity, features of Loeys-Dietz syndrome in son’s, although the father’s Loeys- aneurysms, or dissections. Three- previously described patients. Within è 12 Dietz syndrome phenotype is milder quarters of patients with Loeys-Dietz the literature, Ad s et al describes 2 than that of the study patient’s. syndrome have the characteristic patients (patients 3 and 4), diagnosed The patient’s father underwent cranial and facial signs of cleft palate, with Loeys-Dietz syndrome, who a surveillance scan of his entire craniosynostosis, or hypertelorism. 4 had the same p.Ser241Leu mutation vasculature 3 years after his initial In a case series from Pediatrics in as the patient presented in this aortic dissection, at which point he 2006, blue sclerae, cervical vertebra case. Neither of the patients had any was found to have a second aortic subluxation, camptodactyly, talipes congenital contractures, but they dissection that required immediate equinovarus, and hernias were other did present with a number of shared surgery. common features. 10 Orthopedic phenotypic features, such as a high findings of Loeys-Dietz syndrome arched palate, umbilical herniae, include oligo-articular issues, such and arachnodactyly. Furthermore, DISCUSSION as bilateral club feet, acetabular the clinical course of each of these 3 patients shared progressively As discussed earlier, Beals protrusion, and contractures, worsening kyphoscoliosis of the spine, syndrome is a rare autosomal typically in the fingers, as opposed to through the thoracolumbar regions, to dominant disorder characterized by major joints. 11 In contrast, patients varying degrees of severity. multiple clinical findings, including with Beals syndrome typically exhibit arachnodactyly, narrow body habitus, contractures of the knees and ankles The patients described by Yetman scoliosis, congenital contractures, at the time of birth, which improve et al 10 were diagnosed between and external ear deformities. The with time. 1 2 days and 9 years of age; in syndrome is typically suspected At presentation as a neonate, our comparison, our patient was clinically at birth based on the patient demonstrated the classic diagnosed with Loeys-Dietz presence of the following: knee, phenotype of Beals syndrome. At syndrome relatively late, at age 15 ankle, and fist-like hand contractures; that time, targeted genetic testing years. It is crucial to identify patients arachnodactyly; and crumpled ear was not available, and Loeys- with Loeys-Dietz syndrome early helices. 1 Beals syndrome results Dietz syndrome had not yet been to allow for monitoring of their from a mutation in fibrillin-2 (FBN2), described. Appropriately, Marfan cardiovascular status with routine which codes for fibrillin glycoprotein, syndrome was considered in the echocardiography; these patients are a protein related to that affected in differential, but because this patient at high risk of rapid aortic dilation Marfan syndrome (FBN1). Mutation initially lacked any major cardiac and of aortic dissection or rupture. 13 uptake rates for the FBN2 gene are or ocular disease, this scenario lent As reported in the literature, the reported at 39% to 75%. 7, 8 further confirmation to the clinical mean age of death in patients with Loeys-Dietz is 26.1 years, with aortic Beals syndrome and Marfan diagnosis of Beals syndrome. In disease being the major cause of syndrome share many common particular, according to the Ghent their early mortality. 4 An article features, including tall stature, nosology for Marfan syndrome (as by MacCarrick et al 14 provides dolichostenomelia, arachnodactyly, revised in 2010), the absence of a guidelines on the monitoring and progressive kyphosis or scoliosis, family history in our patient, and the management of the vascular effects and pectus excavatum or lack of ectopia lentis, even with an and other complications of Loeys- carinatum. 9 Beals syndrome was echocardiogram showing moderate Dietz syndrome. first differentiated from Marfan aortic root dilation, was insufficient syndrome in 1971. The prognosis of reason to confirm the diagnosis of We note that although aortic root Beals syndrome is more favorable Marfan syndrome. involvement is uncommon in Beals than Marfan syndrome because the The study patient shares a number syndrome,15 screening for aortic cardiovascular complications of of clinical features with those root dilation in Beals syndrome has

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e4 WOOLNOUGH et al been suggested. In fact, a 2004 report to publish their clinical case and the molecular pathogenesis and shows that aortic root dilation may presentation. We are grateful for the clinical phenotype. Hum Mutat. occur and persist in this disorder. 16 clinical assistance provided by the 2002;19(1):39–48 The 2007 recommendation by genetic counselors involved in this 8. De Coninck S, Meersschaut I, Garcia Yetman et al 10 to routinely perform case. Miñaur S, et al. Congenital contractural echocardiography on patients with arachnodactyly: delineation of clinical Beals syndrome was not followed criteria. Eur Soc Human Genetics. in this patient because this case ABBREVIATION 2016;Abstract P04.020 predated that recommendation. One OMIM: Online Mendelian 9. Jones JL, Lane JE, Logan JJ, wonders if this simple screening Inheritance in Man Vanegas ME. Beals-Hecht syndrome. measure could have detected the South Med J. 2002;95(7): patient’s, and even the patient’s 753–755 father’s, aortic dilation earlier and REFERENCES 10. Yetman AT, Beroukhim RS, Ivy DD, if this course may have reduced Manchester D. Importance of the 1. Tun çbilek E, Alanay Y. Congenital morbidity and surgeries. clinical recognition of Loeys-Dietz contractural arachnodactyly (Beals syndrome in the neonatal period. The present case underscores the syndrome). Orphanet J Rare Dis. Pediatrics. 2007;119(5). Available at: importance of considering Loeys- 2006;1:20 www.pediatrics. org/ cgi/ content/ full/ Dietz and of performing definitive 2. Hecht F, Beals RK. “New” syndrome 119/ 5/ e1199 genetic testing, even in seemingly of congenital contractural 11. Erkula G, Sponseller PD, Paulsen clinically classic cases of Beals arachnodactyly originally described LC, Oswald GL, Loeys BL, Dietz HC. syndrome, because of the significant by Marfan in 1896. Pediatrics. Musculoskeletal fi ndings of Loeys- degree of clinical overlap; doing so 1972;49(4):574–579 Dietz syndrome. J Bone Joint Surg Am. ensures that appropriate screening 3. Nishimura A, Sakai H, Ikegawa S, 2010;92(9):1876–1883 examinations for these patients are et al. FBN2, FBN1, TGFBR1, and TGFBR2 12. Ad ès LC, Sullivan K, Biggin A, instituted. Overall, due to significant analyses in congenital contractural et al. FBN1, TGFBR1, and the Marfan- phenotypic overlap, panel testing arachnodactyly. Am J Med Genet A. craniosynostosis/mental retardation for hereditary connective tissue 2007;143A(7):694–698 disorders revisited. Am J Med Genet A. disorders with vascular involvement 4. Van Hemelrijk C, Renard M, Loeys B. 2006;140(10):1047–1058 should include testing for FBN2 and, The Loeys-Dietz syndrome: an update 13. Ha JS, Kim YH. A sporadic case of conversely, young patients with for the clinician. Curr Opin Cardiol. Loeys-Dietz syndrome type I with two negative FBN2 test results should 2010;25(6):546–551 novel mutations of the TGFBR2 gene. undergo testing for genes related 5. Loeys BL, Chen J, Neptune ER, et al. Korean J Pediatr. 2011;54(6): to hereditary connective tissue A syndrome of altered cardiovascular, 272–275 disorders with vascular involvement. craniofacial, neurocognitive and 14. MacCarrick G, Black JH III, Bowdin S, skeletal development caused by et al. Loeys-Dietz syndrome: a Ethics Statement and Consent mutations in TGFBR1 or TGFBR2. Nat primer for diagnosis and Genet. 2005;37(3):275–281 management. Genet Med. 2014;16(8): Written informed consent was é 576–587 obtained from the patient and family 6. Stheneur C, Collod-B roud G, Faivre L, et al. Identifi cation of 23 TGFBR2 15. Robinson PN, Arteaga-Solis E, members for the publication of and 6 TGFBR1 gene mutations and Baldock C, et al. The molecular this case report and accompanying genotype-phenotype investigations in genetics of Marfan syndrome and images. A copy of the written consent 457 patients with Marfan syndrome related disorders. J Med Genet. is available for review by the Editor type I and II, Loeys-Dietz syndrome 2006;43(10):769–787 of this journal. and related disorders. Hum Mutat. 16. Gupta PA, Wallis DD, Chin TO, et al. 2008;29(11):E284–E295 FBN2 mutation associated with ACKNOWLEDGMENTS 7. Gupta PA, Putnam EA, Carmical SG, manifestations of Marfan syndrome et al. Ten novel FBN2 mutations and congenital contractural We thank the patient and the in congenital contractural arachnodactyly. J Med Genet. patient’s family for allowing us arachnodactyly: delineation of 2004;41(5):e56

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 3 , March 2017 e5 Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome? Rebecca Woolnough, Andrew Dhawan, Kimberly Dow and Jagdeep S. Walia Pediatrics 2017;139; DOI: 10.1542/peds.2016-1281 originally published online February 16, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/139/3/e20161281 References This article cites 15 articles, 5 of which you can access for free at: http://pediatrics.aappublications.org/content/139/3/e20161281#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genetics http://www.aappublications.org/cgi/collection/genetics_sub Dysmorphology http://www.aappublications.org/cgi/collection/dysmorphology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 Are Patients With Loeys-Dietz Syndrome Misdiagnosed With Beals Syndrome? Rebecca Woolnough, Andrew Dhawan, Kimberly Dow and Jagdeep S. Walia Pediatrics 2017;139; DOI: 10.1542/peds.2016-1281 originally published online February 16, 2017;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/139/3/e20161281

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2017 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 1, 2021