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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Fibromatosis | Research

Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome

Authors: Claudia Cozma, Marina Hovakimyan, Marius-Ionuț Iurașcu, Nawal Makhseed, Laila A. Selim, Amal M. Alhashem, Tawfeg Ben-Omran, Iman G. Mahmoud, Nihal M. Al Menabawy, Mariam Al-Mureikhi, Magi Martin, Laura Demuth, Zafer Yüksel, Christian Beetz, Peter Bauer, Arndt Rolfs

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

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Abstract

Background

Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder.

Results

We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13–17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients.

Conclusions

Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder.
Appendix
Available only for authorised users
Literature
1.
Shieh JTC, Hoyme HE, Arbour LT. Hyalinosis, Inherited Systemic. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993.
2.
Landing BH, Nadorra R. Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis. Pediatr Pathol. 1986;6(1):55–79.PubMedCrossRef
3.
Nofal A, Sanad M, Assaf M, Nofal E, Nassar A, Almokadem S, et al. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: a unifying term and a proposed grading system. J Am Acad Dermatol. 2009;61(4):695–700.PubMedCrossRef
4.
Denadai R, Raposo-Amaral CE, Bertola D, Kim C, Alonso N, Hart T, et al. Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system. Am J Med Genet Part A. 2012;158A(4):732–42.PubMedCrossRef
5.
Hanks S, Adams S, Douglas J, Arbour L, Atherton DJ, Balci S, et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73(4):791–800.PubMedPubMedCentralCrossRef
6.
Dowling O, Difeo A, Ramirez MC, Tukel T, Narla G, Bonafe L, et al. Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73(4):957–66.PubMedPubMedCentralCrossRef
7.
Deuquet J, Lausch E, Superti-Furga A, van der Goot FG. The dark sides of capillary morphogenesis gene 2. EMBO J. 2012;31(1):3–13.PubMedCrossRef
8.
Casas-Alba D, Martinez-Monseny A, Pino-Ramirez RM, Alsina L, Castejon E, Navarro-Vilarrubi S, et al. Hyaline fibromatosis syndrome: clinical update and phenotype-genotype correlations. Hum Mutat. 2018;39(12):1752–63.PubMedCrossRef
9.
Bell SE, Mavila A, Salazar R, Bayless KJ, Kanagala 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, cellular differentiation and G-protein signaling. J Cell Sci. 2001;114(Pt 15):2755–73.PubMed
10.
Scobie HM, Rainey GJ, Bradley KA, Young JA. Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor. Proc Natl Acad Sci U S A. 2003;100(9):5170–4.PubMedPubMedCentralCrossRef
11.
Burgi J, Kunz B, Abrami L, Deuquet J, Piersigilli A, Scholl-Burgi S, et al. CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome. Nat Commun. 2017;8:15861.PubMedPubMedCentralCrossRef
12.
13.
Dyment DA, Bennett SAL, Medin JA, Levade T. ASAH1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle: University of Washington; 1993.
14.
Koch J, Gartner S, Li CM, Quintern LE, Bernardo K, Levran O, et al. Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease J Biol Chem. 1996;271(51):33110–5.PubMed
15.
16.
Cozma C, Iurascu MI, Eichler S, Hovakimyan M, Brandau O, Zielke S, et al. C26-ceramide as highly sensitive biomarker for the diagnosis of Farber disease. Sci Rep. 2017;7(1):6149.PubMedPubMedCentralCrossRef
17.
Youssefian L, Vahidnezhad H, Aghighi Y, Ziaee V, Zeinali S, Abiri M, et al. Hyaline fibromatosis syndrome: a novel mutation and recurrent founder mutation in the CMG2/ANTXR2 gene. Acta Derm Venereol. 2017;97(1):108–9.PubMedCrossRef
18.
Coban-Akdemir Z, White JJ, Song X, Jhangiani SN, Fatih JM, Gambin T, et al. Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. Am J Hum Genet. 2018;103(2):171–87.PubMedPubMedCentralCrossRef
19.
Deuquet J, Abrami L, Difeo A, Ramirez MC, Martignetti JA, van der Goot FG. Systemic hyalinosis mutations in the CMG2 ectodomain leading to loss of function through retention in the endoplasmic reticulum. Hum Mutat. 2009;30(4):583–9.PubMedCrossRef
20.
Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24(6):1006–13.PubMedPubMedCentralCrossRef
21.
22.
Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet. 1998;77(2):155–61.PubMedCrossRef
23.
Mitne-Neto M, Kok F, Beetz C, Pessoa A, Bueno C, Graciani Z, et al. A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large Brazilian pedigree. Eur J Hum Genet. 2007;15(12):1276–9.PubMedCrossRef
24.
van Capelle CI, van der Meijden JC, van den Hout JM, Jaeken J, Baethmann M, Voit T, et al. Childhood Pompe disease: clinical spectrum and genotype in 31 patients. Orphanet J Rare Dis. 2016;11(1):65.PubMedPubMedCentralCrossRef
25.
Yu Z, Zhai G, Singmann P, He Y, Xu T, Prehn C, et al. Human serum metabolic profiles are age dependent. Aging Cell. 2012;11(6):960–7.PubMedCrossRef
26.
Ishikawa M, Maekawa K, Saito K, Senoo Y, Urata M, Murayama M, et al. Plasma and serum lipidomics of healthy white adults shows characteristic profiles by subjects' gender and age. PLoS One. 2014;9(3):e91806.PubMedPubMedCentralCrossRef
27.
Hertel J, Friedrich N, Wittfeld K, Pietzner M, Budde K, Van der Auwera S, et al. Measuring biological age via Metabonomics: the metabolic age score. J Proteome Res. 2016;15(2):400–10.PubMedCrossRef
28.
Beger RD, Dunn W, Schmidt MA, Gross SS, Kirwan JA, Cascante M, et al. Metabolomics enables precision medicine: “a White paper, community perspective”. Metabolomics. 2016;12(10):149.PubMedPubMedCentralCrossRef
29.
Kim SH, Weiss C, Hoffmann U, Borggrefe M, Akin I, Behnes M. Advantages and limitations of current biomarker research: from experimental research to clinical application. Curr Pharm Biotechnol. 2017;18(6):445–55.PubMedCrossRef
30.
Temtamy SA, Aglan MS, Otaify GA, Abdel-Hamid M, Ismail S, Makhrytanasis P, et al. Exome sequencing in the diagnosis of an atypical phenotypeof infantile hyalinosis. Middle East J Med Genet. 2015;4:18–23.CrossRef
31.
Sugita M, Dulaney JT, Moser HW. Ceramidase deficiency in Farber's disease (lipogranulomatosis). Science. 1972;178(4065):1100–2.PubMedCrossRef
32.
Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018;46(W1):W486–W94.PubMedPubMedCentralCrossRef
Metadata
Title
Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome
Authors
Claudia Cozma
Marina Hovakimyan
Marius-Ionuț Iurașcu
Nawal Makhseed
Laila A. Selim
Amal M. Alhashem
Tawfeg Ben-Omran
Iman G. Mahmoud
Nihal M. Al Menabawy
Mariam Al-Mureikhi
Magi Martin
Laura Demuth
Zafer Yüksel
Christian Beetz
Peter Bauer
Arndt Rolfs
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1183-5

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