Juvenile Idiopathic Arthritis Associated with Combined JP–HHT Syndrome: A Novel Phenotype Associated with a Novel Variant in SMAD4

Juliet Chhay Bishop; Jacquelyn Francis Britton; Anne M. Murphy; Sangeeta Sule; Sally Mitchell; Clifford Takemoto; Joseph M. Collaco; Wikrom Karnsakul; Carmelo Cuffari; Edith Dietz; Joann Bodurtha

doi:10.1055/s-0037-1609060

Journal of Pediatric Genetics, Table of Contents

J Pediatr Genet 2018; 07(02): 078-082
DOI: 10.1055/s-0037-1609060

Case Report

Georg Thieme Verlag KG Stuttgart · New York

Juvenile Idiopathic Arthritis Associated with Combined JP–HHT Syndrome: A Novel Phenotype Associated with a Novel Variant in SMAD4

Juliet Chhay Bishop

¹Department of Medical Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Jacquelyn Francis Britton

¹Department of Medical Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Anne M. Murphy

²Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Sangeeta Sule

³Department of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Sally Mitchell

⁴Department of Interventional Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Clifford Takemoto

⁵Department of Pediatric Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Joseph M. Collaco

⁶Department of Pediatric Pulmonology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Wikrom Karnsakul

⁷Department of Pediatric Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Carmelo Cuffari

⁷Department of Pediatric Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Edith Dietz

⁸Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

,

Joann Bodurtha

¹Department of Medical Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

› Author Affiliations

Abstract

Juvenile polyposis (JP) syndrome is characterized by multiple hamartomatous polyps of the gastrointestinal tract. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectasia in the skin, mucous membranes, and arteriovenous malformations in other organs. Individuals with JP–HHT syndrome have variable features of both rare disorders, attributed to heterozygous mutations in the SMAD4 gene. Systemic juvenile idiopathic arthritis (JIA) is a severe, chronic disease marked by arthritis and systemic inflammation for which the cause remains unknown. JIA has never been described in association with SMAD4-related disease. We describe a case of JP–HHT syndrome with a novel SMAD4 variant, c.1052A > T (p.D351V), in which the child also had JIA manifestation.

Keywords

SMAD4 - juvenile polyposis syndrome - hereditary hemorrhagic telangiectasia - juvenile idiopathic arthritis - TGF-β

Full Text

References

References
1 Larsen Haidle J, Howe JR. Juvenile polyposis syndrome. In: Pagon RA, Adam MP, Ardinger HH. , et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2003
2 O'Malley M, LaGuardia L, Kalady MF. , et al. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum 2012; 55 (08) 886-892
3 Schwenter F, Faughnan ME, Gradinger AB. , et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J Gastroenterol 2012; 47 (07) 795-804
4 Cox KL, Frates Jr RC, Wong A, Gandhi G. Hereditary generalized juvenile polyposis associated with pulmonary arteriovenous malformation. Gastroenterology 1980; 78 (06) 1566-1570
5 Conte WJ, Rotter JI, Schwartz AG, Congleton JE. Hereditary generalized juvenile polyposis, arteriovenous malformations and colonic carcinoma. Clin Res 1982; 30: 93A
6 Jelsig AM, Tørring PM, Kjeldsen AD. , et al. JP-HHT phenotype in Danish patients with SMAD4 mutations. Clin Genet 2016; 90 (01) 55-62
7 Gallione CJ, Repetto GM, Legius E. , et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 2004; 363 (9412): 852-859
8 Baert AL, Casteels-Van Daele M, Broeckx J, Wijndaele L, Wilms G, Eggermont E. Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy. Am J Roentgenol 1983; 141 (04) 661-662
9 Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001; 11 (05) 863-874
10 Adzhubei IA, Schmidt S, Peshkin L. , et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
11 Tavtigian SV, Deffenbaugh AM, Yin L. , et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 2006; 43 (04) 295-305
12 Hersh AO, Prahalad S. Genetics of juvenile idiopathic arthritis. Rheum Dis Clin North Am 2017; 43 (03) 435-448
13 Teekakirikul P, Milewicz DM, Miller DT. , et al. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am J Med Genet A 2013; 161A (01) 185-191
14 Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A 2011; 155A (05) 1165-1169
15 Heald B, Rigelsky C, Moran R. , et al. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia due to SMAD4. Am J Med Genet A 2015; 167A (08) 1758-1762
16 Holm TM, Habashi JP, Doyle JJ. , et al. Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice. Science 2011; 332 (6027): 358-361
17 Wain KE, Ellingson MS, McDonald J. , et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med 2014; 16 (08) 588-593
18 Xiong G, Huang Z, Jiang H, Pan Z, Xie J, Wang S. Inhibition of microRNA-21 decreases the invasiveness of fibroblast-like synoviocytes in rheumatoid arthritis via TGFβ/Smads signaling pathway. Iran J Basic Med Sci 2016; 19 (07) 787-793
19 Xue M, Gong S, Dai J, Chen G, Hu J. The treatment of fibrosis of joint synovium and frozen shoulder by SMAD4 gene silencing in rats. PLoS One 2016; 11 (06) e0158093