title: Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies.
abstract: We report the association of an undescribed, reversible metaphyseal dysplasia (RMD) with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in two patients, one homozygous and one heterozygous for a 13-bp deletion in exon 8 of the autoimmune regulator (AIRE) gene. One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a STOP codon in exon 10. Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiological examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiological resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. RMD may constitute a rare phenotypic variation of APECED, possibly resulting from autoimmunity directed against skeletal proteins. We also demonstrated AIRE expression in chondrocytes derived from human fetal growth plates, primary culture of human chondrocytes, and two chondrosarcoma cell lines, suggesting a potential role for abnormal AIRE expression in the development of RMD.
authors.affiliation: Department of Endocrinology, Sydney Children's Hospital, Randwick, New South Wales 2031, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
authors.forename: Ouafae
authors.initials: O
authors.lastname: Kecha
authors.forename: Cheri
authors.initials: C
authors.lastname: Deal
authors.forename: C Rolfe
authors.initials: CR
authors.lastname: Howlett
authors.forename: Dorothee
authors.initials: D
authors.lastname: Deiss
authors.forename: Vivienne
authors.initials: V
authors.lastname: Tobias
authors.forename: Judith
authors.initials: J
authors.lastname: Simoneau-Roy
authors.forename: Jan
authors.initials: J
authors.lastname: Walker
mesh_terms: D000328:Adult; D001706:Biopsy; D002648:Child; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D002813:Chondrosarcoma; D004252:DNA Mutational Analysis; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D017353:Gene Deletion; D015870:Gene Expression; D006228:Hand Deformities, Congenital / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D010009:Osteochondrodysplasias / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011859:Radiography; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D000096927:AIRE Protein
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; D000096927:AIRE Protein