Abiri, Maryam

Aghighi, Yahya

Uitto, Jouni

Vahidnezhad, Hassan

Youssefian, Leila

Zeinali, Sirous

Ziaee, Vahid

Acta Dermato-Venereologica

English

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Hyaline Fibromatosis Syndrome: A Novel Mutation and Recurrent Founder Mutation in the CMG2/ANTXR2 Gene.

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Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Dermatology and CutaneousBiology Faculty PapersDepartment of Dermatology and CutaneousBiology1-4-2017Hyaline Fibromatosis Syndrome: A NovelMutation and Recurrent Founder Mutation in theCMG2/ANTXR2 Gene.Leila YoussefianThomas Jefferson University; Tehran University of Medical Sciences, leila.youssefian@jefferson.eduHassan VahidnezhadThomas Jefferson University; Pasteur Institute of Iran, hassan.vahidnezhad@jefferson.eduYahya AghighiTehran University of Medical SciencesVahid ZiaeeTehran University of Medical SciencesSirous ZeinaliPasteur Institute of Iran; Kawsar Human Genetics Research CenterSee next page for additional authorsLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/dcbfpPart of the Dermatology CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Dermatology and Cutaneous Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For moreinformation, please contact: JeffersonDigitalCommons@jefferson.edu.Recommended CitationYoussefian, Leila; Vahidnezhad, Hassan; Aghighi, Yahya; Ziaee, Vahid; Zeinali, Sirous; Abiri,Maryam; and Uitto, Jouni, "Hyaline Fibromatosis Syndrome: A Novel Mutation and RecurrentFounder Mutation in the CMG2/ANTXR2 Gene." (2017). Department of Dermatology andCutaneous Biology Faculty Papers. Paper 66.https://jdc.jefferson.edu/dcbfp/66AuthorsLeila Youssefian, Hassan Vahidnezhad, Yahya Aghighi, Vahid Ziaee, Sirous Zeinali, Maryam Abiri, and JouniUittoThis article is available at Jefferson Digital Commons: https://jdc.jefferson.edu/dcbfp/66SHORT COMMUNICATIONdoi: 10.2340/00015555-2459Journal Compilation © 2017 Acta Dermato-Venereologica. ISSN 0001-5555This is an open access article under the CC BY-NC license. www.medicaljournals.se/actaActa Derm Venereol 2017; 97: 108–109108Hyaline Fibromatosis Syndrome (HFS) is a rare auto-somal recessive disorder affecting primarily skin and mucous membranes. Skin appears thickened with subcu-taneous nodules, associated with swollen joint contrac-tures, red hyperpigmentation and gingival hyperplasia. Additional findings include osteopenia and osteoporosis, and the affected children are susceptible to infections and protein losing enteropathy (1). Histopathology of skin lesions shows proliferation of spindle-shaped cells, embedded in a homogeneous hyaline-like material, and biochemical alterations in type I and VI collagens as well as in glycosaminoglycans have been reported (2, 3).Initially, infantile systemic hyalinosis and juvenile systemic hyalinosis were considered as two distinct en-tities on the basis of time of onset. However, subsequent work demonstrated that both forms of hyalinosis were caused by mutations in the CMG2 gene (also known as ANTXR2), indicating that these disorders are allelic and part of the same phenotypic spectrum, now known as HFS (4, 5). The CMG2 gene encodes a 55-kDa type I transmem-brane protein known as capillary morphogenesis protein 2. While the precise physiologic function of this protein is currently unknown, its expression is upregulated in endothelial cells during capillary formation. This protein also serves as the main receptor of the anthrax toxin (6). The gene is expressed in all tissues with exception of the brain, a finding consistent with normal cognitive development of the affected individuals (6, 7).CASE REPORTSThis study examines 4 cases with clinical features of HFS, all resulting from consanguineous marriages (Fig. 1 and Fig. S11). The clinical features of these patients are presented in Appendix S11. Following acquisition of informed consent in accordance with the Declaration of Helsinki Principles, DNA was extracted from peripheral blood samples taken from patients and family mem-bers (if available) using QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA, USA). PCR amplification of the CMG2 gene was performed using 17 pairs of primers spanning all 17 exons and the flanking intronic sequencing, followed by bidirectional Sanger sequencing. For haplotype analysis and homozygosity mapping, additional primers were designed for typing of 13 informed SNPs within and flanking the CMG2 gene. In Family 1, DNA was not available for mutation analysis from the deceased proband but both parents were heterozygous car-riers of a previously unreported splice junction mutation (c.946-2A→G in intron 11) in CMG2, which by Human Splicing Finder program (www.umd.be/HSF/#) is predicted to result in aberrant splicing and a subsequent premature termination codon. Thus, the proband was deduced to be homozygous for this mutation. In Family 2, the proband had an insertion mutation, c.1073_1074insC (p.Pro358ProfsX13), which has been previously reported (8). This mutation in exon 13 causes a frameshift and results in premature termination of translation. In Family 3, a homozygous mutation, c.1074delT (p.Pro358ProfsX50) in exon 13, was detected; this re-current mutation has been reported in a number of cases. In Family 4, no mutations in the CMG2 gene were noted, and subsequent homozygosity mapping excluded this gene locus at chromosomal region 4q21 (Fig. S11).Since the mutation c.1074delT has been encountered in a number of cases, we examined the possibility that this mutation is either a result of “founder effect” or is a “hotspot” mutation. For this purpose, haplotype analysis with 13 SNPs within and flanking the CMG2 gene was performed with DNA from the proband in Family 2 as well as from another patient with HFS that we have recently described (9). The results revealed a 2 Mb conserved block within a 3 Mb region of the genome which included CMG2 in these pro-bands and suggesting a founder effect in these two Iranian cases of different ethnicity and language group.DISCUSSIONThus far, 37 distinct mutations have been identified in CMG2 in ~150 HFS patients. This study adds a previous-ly unreported mutation to this database. Furthermore, one of our patients demonstrated the same, recurrent mutation c.1074delT, which has previously been repor-ted in a number of cases (9, 10). Haplotype analysis in the families reported here suggests that this mutation is a result of founder effect rather than being a hotspot mutation. Finally, extensive sequencing of the CMG2 gene failed to reveal any pathogenic mutations in one family and homozygosity mapping excluded this gene. It should be noted that the latter patient had characteristic features of HFS, phenotypically similar to the other 4 cases, but also had additional features not present in other cases examined. These include immunodeficiency Hyaline Fibromatosis Syndrome: A Novel Mutation and Recurrent Founder Mutation in the CMG2/ANTXR2 Gene Leila YOUSSEFIAN1,2#, Hassan VAHIDNEZHAD1,3#, Yahya AGHIGHI4#, Vahid ZIAEE4,5#, Sirous ZEINALI3,6, Maryam ABIRI2,3 and Jouni UITTO11Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 S. 10th Street, Suite 450 BLSB, Philadelphia, PA 19107, Pennsylvania, USA, 2Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, 3Biotechnology Research Center, Department of Molecular Medicine, Pasteur Institute of Iran, 4Department of Pediatrics, Imam Khomeini Hospital, Tehran University of Medial Sciences, 5Rheumatology Research Center, School of Medicine, Tehran University of Medical Sciences, and 6Kawsar Human Genetics Research Center, Tehran, Iran. Tehran, Iran. E-mail: Jouni.Uitto@Jefferson.edu#These authors contributed equally to this work.Accepted May 11, 2016; Epub ahead of print May 13, 20161https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2459ActaDVActaDVAdvances in dermatology and venereologyActa Dermato-Venereologica109Short communicationActa Derm Venereol 2017and infantile pyloric stenosis, features also present in the Jacobsen syndrome, known as 11q terminal dele-tion syndrome (11). Identification of mutations in the CMG2 gene in families with HFS can be used to confirm clinical diagnosis and will form the basis for identifica-tion of heterozygous carriers in extended families with previous history of affected children. Finally, know-ledge of the specific mutations allows prenatal testing and preimplantation genetic diagnosis to prevent the reoccurrence of HFS in consanguineous families with history of this disease. ACKNOWLEDGEMENTSThe authors thank Sara Afsharaalam, Fatemeh Golnabi, and Zahra Motezaker for contributing to this study. Carol Kelly assisted in manuscript preparation, and Dr. Andrew P. South made help-ful suggestions.The authors declare no conflict of interest.REFERENCES1. Deuquet J, Lausch E, Superti-Furga A, van der Goot FG. The dark sides of capillary morpho-genesis gene 2. EMBO J 2012; 31: 3–13.2. Tanaka K, Ebihara T, Kusubata M, Adachi E, Arai M, Kawaguchi N, et al. Abnormal colla-gen deposition in fibromas from patient with juvenile hyaline fibromatosis. J Dermatol Sci 2009; 55: 197–200.3. Tzellos TG, Dionyssopoulos A, Klagas I, Ka-rakiulakis G, Lazaridis L, Papakonstantinou E. Differential glycosaminoglycan expression and hyaluronan homeostasis in juvenile hy-aline fibromatosis. J Am Acad Dermatol 2009; 61: 629–638.4. Hanks S, Adams S, Douglas J, Arbour L, Atherton DJ, Balci S, et al. Mutations in the gene encoding capillary morphogenesis pro-tein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet 2003; 73: 791–800.5. Nofal A, Sanad M, Assaf M, Nofal E, Nassar A, Almokadem S, et al. Juvenile hyaline fibro-matosis and infantile systemic hyalinosis: a unifying term and a proposed grading system. J Am Acad Dermatol 2009; 61: 695–700.6. Scobie HM, Rainey GJ, Bradley KA, Young JA. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc Natl Acad Sci USA 2003; 100: 5170–5174.7. Bell SE, Mavila A, Salazar R, Bayless KJ, Ka-nagala S, Maxwell SA, et al. Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cel-lular differentiation and G-protein signaling. J Cell Sci 2001; 114: 2755–2773.8. Deuquet J, Lausch E, Guex N, Abrami L, Salvi S,  Lakkaraju A, et al.  Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors. EMBO Mol Med 2011; 3: 208–221.9. Vahidnezhad H, Ziaee V, Youssefian L, Li Q, Sotoudeh S, Uitto J. Infantile systemic hyalinosis in an Iranian family with a mutation in the CMG2/ANTXR2 gene. Clin Exp Dermatol 2015; 40: 636–639.10. El-Kamah GY, Fong K, El-Ruby M, Afifi HH, Clements SE, Lai-Cheong JE, et al. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis. Br J Dermatol 2010; 163: 213–215.11. Favier R, Akshoomoff N, Mattson S, Grossfeld P. Jacobsen syndrome: Advances in our knowledge of phenotype and genotype. Am J Med Genet C Semin Med Genet 2015; 169: 239–250.Fig. 1. Clinical features of patients with hyaline fibromatosis syndrome. Note a tumor on the right parietal area (a) and multiple nuchal papules (b) in Patient 3. Patient 4 had extensive perianal rash with subcutaneous nodules (c). Patient 2 had characteristic findings of HFS, including flexural contracturs of the joints (“frog-leg position”) (f), multiple reddish pearly papules on the face and neck (e, g), prominent low-set ears (e), and hyperpigmentation shown on lateral malleoli (d).ActaDVActaDVAdvances in dermatology and venereologyActa Dermato-Venereologica

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Hyaline Fibromatosis Syndrome: A Novel Mutation and Recurrent Founder Mutation in the CMG2/ANTXR2 Gene.

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