Protein-losing enteropathy and joint contractures caused by a novel homozygous ANTXR2 mutation

Abstract

Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in the ANTRX2 gene encoding the transmembrane anthrax toxin receptor 2. Its main features include characteristic skin lesions, joint contractures, persistent diarrhea, and failure to thrive due to accumulation of hyaline material in multiple organs. The resulting severe malnutrition can cause death in early infancy. Because of its rarity and high fatality rate, timely diagnosis is difficult and ISH may be underdiagnosed. In this report, we describe a 10-month-old male with severe protein-losing enteropathy, skin lesions, and painful joint contractures, diagnosed with ISH based on skin his-topathology and identification of a novel homozygous ANTRX2 mutation, c.1127_1128delTG (p.V376Gfs*14). While its clinical outcome is poor without curative treatment, establishing a diagnosis of ISH starting from clinical suspicion to molecular analysis is important for appropriate medical management and for risk and carrier assessment of family members.

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

“…The ANTXR2-deficient patients described here, and multiple patients reported before [8,12,13], suffer from PLE. However, the pathogenesis of the intestinal phenotype has not been defined.…”

“…However, the pathogenesis of the intestinal phenotype has not been defined. Some HFS patients were reported to suffer from intestinal lymphangiectasia based on histological analysis [8,[10][11][12][13], but it is unclear whether ANTXR2 deficiency leads to a primary defect of the epithelium as well. We generated intestinal organoids from Patient 1 in order to study the intrinsic properties of ANTXR2-mutant epithelial cells in an isolated system.…”

“…In the severe forms of HFS, protein losing enteropathy (PLE) has been reported, and several patients were noted to suffer from intestinal lymphangiectasia [8,[10][11][12][13]. Diverse mechanisms can lead to development of PLE, including aberrant lymphatic formation, mucosal damage or loss of barrier function of the intestinal epithelium [14].…”

Converging physiological roles of the anthrax toxin receptors

“…Both HFS and GAPO patients have issues with the skin: skin thickening in HFS and alopecia in GAPO. Although few histopathological analyses have been reported for patients with GAPO 37 , the dermis of one patient with GAPO was shown to have abundant hyaline material with increased collagenous fibers 48 , suggesting that, like HFS (the earliest histopathological analyses 72 to the latest 73 ), GAPO is a disease of the connective tissue. This increased ECM could interfere in the development and cycling of the hair follicles 74 but this is still unproven.…”

Síndrome de fibromatosis hialina: reporte de un caso y revisión bibliográfica

“…6 Las manifestaciones iniciales aparecen en los primeros meses de vida, 6,7 con contracturas articulares y lesiones pápulo-nodulares aperladas en el cuello y la región periorificial (oral, nasal y anal), acompañadas de hipertrofia gingival progresiva. 12,13 El diagnóstico de síndrome de fibromatosis hialina se establece mediante hallazgos clínicos, con apoyo del examen histopatológico de tejido cutáneo o intestinal, en el que se identifica la acumulación de material hialino 14,15 y se confirma con el análisis molecular del gen ANTXR2 (único gen identificado, hasta hoy, asociado con la enfermedad). 2,4,15 Se han descrito cerca de 50 variantes patogénicas del gen y en aproximadamente 80% de los casos los genotipos son homocigotos.…”