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Reversible Metaphyseal Dysplasia, a Novel Bone Phenotype, in Two Unrelated Children with Autoimmunepolyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Clinical and Molecular Studies

Department of Endocrinology, Sydney Children’s Hospital (M.H., J.W.), Randwick, New South Wales 2031, Australia; Endocrine Service, Department of Pediatrics, Hôpital Ste-Justine, Université de Montréal (O.K., C.D., J.S.-R.), Montréal, Québec, H3T 1E2, Canada; School of Pathology, University of New South Wales (C.R.H.), Randwick, New South Wales 2031, Australia; Charité, Humbold University (D.D.), Berlin, D-13353, Germany; and Department of Anatomical Pathology, South Eastern Area Laboratory Services at Sydney Children’s Hospital (V.T.), Randwick, New South Wales 2031, Australia

Address all correspondence and requests for reprints to: Dr. Jan Walker, Department of Endocrinology, Sydney Children’s Hospital, High Street, Randwick, New South Wales 2031, Australia. E-mail: jan.walker{at}unsw.edu.au.

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.

This work was supported by the Sydney Children’s Hospital Foundation (to M.H.) and by la Fondation Vaugrenier à Genève and la Fondation Léon Fredericq à Liège (to O.K.).

M.H. and O.K. are equal first authors.

Abbreviations: AIRE, Autoimmune regulator; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; RMD, reversible metaphyseal dysplasia; RR, reference range; TRAP, tartrate-resistant acid phosphatase; VEGF, vascular endothelial growth factor.