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Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

ABSTRACT: Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.

SUBMITTER: van Rijn JM

PROVIDER: S-EPMC7662532 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

van Rijn Jorik M JM Werner Lael L Aydemir Yusuf Y Spronck Joey M A JMA Pode-Shakked Ben B van Hoesel Marliek M Shimshoni Elee E Polak-Charcon Sylvie S Talmi Liron L Eren Makbule M Weiss Batia B H J Houwen Roderick R Barshack Iris I Somech Raz R Nieuwenhuis Edward E S EES Sagi Irit I Raas-Rothschild Annick A Middendorp Sabine S Shouval Dror S DS

International journal of molecular sciences 20201102 21

Hyaline fibromatosis syndrome (HFS), resulting from <i>ANTXR2</i> mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious <i>ANTXR2</i> mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-C ...[more]

PMID: 33147779

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Project description:BackgroundCamptodactyly-arthropathy-coxa vara-pericarditis (CACP, OMIM: #208250) syndrome is a rare autosomal recessive disease that can be difficult to recognise not only because of its wide clinical variability but also because of its clinical resemblance to juvenile idiopathic arthritis (JIA). PRG4 is the only gene so far known to be associated with CACP syndrome. Children with CACP syndrome lack the glycoprotein lubricin due to recessive mutations in PRG4. Lubricin serves as a lubricant in joints, tendons and visceral cavities (pleural cavity, pericardium) and inhibits synovial proliferation. Children with CACP syndrome suffer from congenital camptodactyly, arthropathy, coxa vara and sometimes pericarditis. This report concerns a child with CACP syndrome complicated by protein-losing enteropathy (PLE), caused by constrictive pericarditis and so contributes to knowledge of the presentation of CACP syndrome.Case presentationA 10- year-old girl with consanguineous parents suffered from congenital camptodactyly and progressive swollen and painful joints. Her father and his sister had similar childhood-onset joint complaints. Laboratory tests showed no signs of inflammation but showed persistent low protein- and IgG- levels, indicating a secondary immunodeficiency. Increased alpha antitrypsin clearance confirmed PLE. Abdominal ultrasound with Doppler showed hepatomegaly and portal hypertension. Echocardiography suggested constrictive pericarditis. However, heart catheterization could not confirm this. Ultrasound and X-ray examination of the joints combined with a puncture of the synovial fluid were performed. These results, combined with the clinical presentation and the consanguinity, suggested CACP syndrome. Due to excessive enteral protein losses, the patient was treated with Cotrimoxazol prophylaxis and immunoglobulin supplements. These supplements were inadequate to achieve normal IgG values. As constrictive pericarditis with subsequent PLE was the best explanation for the excessive IgG losses, pericardiectomy was performed with good results. Genetic testing in our patient was complicated but revealed a pathogenic mutation within the repeat sequence in exon 7 of the PRG4 gene.ConclusionPLE resulting from constrictive pericarditis can be a complication of CACP syndrome. As serious complications can arise from the resulting secondary immunodeficiency, we recommend regular evaluation of clinical symptoms of constrictive pericarditis and PLE in children with CACP syndrome.

Dataset Information

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

Publications

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

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