American Journal of Medical Genetics 100:122±129 (2001) Infantile Systemic Hyalinosis in Siblings: Clinical Report, Biochemical and Ultrastructural Findings, and Review of the Literature U. Stucki, 1 M.A. Spycher, 2 G. Eich, 3 A. Rossi, 4 P. Sacher, 5 B. Steinmann, 1 and A. Superti-Furga 1 * 1 Division of Metabolism and Molecular Pediatrics, Department of Pediatrics, University of ZuÈrich, Switzerland 2 Electron Microscopy Laboratory, University Hospital, ZuÈrich, Switzerland 3 Division of Radiology, University Children's Hospital, ZuÈrich, Switzerland 4 Department of Biochemistry, University of Pavia, Italy 5 Department of Surgery, University Children's Hospital, ZuÈrich, Switzerland A boy presented at age 3.5 months with joint contractures, restlessness, and pain on handling. His skin was thickened and there were livid-red macular lesions over bony prominences. Infantile systemic hyalinosis (ISH) was diagnosed, a presumably autoso- mal recessive, progressive, and painful dis- order of as yet unknown pathogenesis. Observation over three years con®rmed the diagnosis as typical changes, such as nodules on both ears, pearly papules in the perinasal folds and on the neck, ¯eshy nodules in the perianal region, and gingival hypertrophy, developed. Skin lesions and painful joint contractures progressed in spite of intense physiotherapy, and at age 3, the child had marked motor disability. The central nervous system (CNS) appeared to be intact and the infant showed normal mental development. Radiologic ®ndings included marked generalized osteopenia, osteolytic erosions in the metaphyses of the long bones, and cortical thinning. Elec- tron microscopy of two skin biopsies demon- strated deposition of ¯occular amorphous substance that was abundant around, and appeared to originate from, small blood vessels in the dermis, partially interfering with collagen ®ber formation. Lysosomal inclusions were not seen. Serum acid hya- luronidase activity was within the normal range, and the synthesis of hyaluronic acid and proteoglycans in cultured skin ®bro- blasts was similar to that of control cells. A younger sister presented at age two months with painful joint contractures and discrete livid-red macules over both malleoli, and showed a similar progression of the disorder over the ®rst year of life. The diagnosis of ISH should be considered in infants and children presenting with painful joint con- tractures and skin lesions. The pathogenesis of this disabling and dis®guring disorder remains unclear. Our data con®rm probable autosomal recessive inheritance, and do not support lysosomal storage, hyaluronidase de®ciency, or a primary collagen disorder, but indicate that the amorphous material accumulating in the skin and articular soft tissues may originate from the blood circu- lation. ß 2001 Wiley-Liss, Inc. KEY WORDS: systemic hyalinosis; joint contractures; skin lesions; osteolytic erosions; hyalur- onidase activity INTRODUCTION Infantile systemic hyalinosis (ISH; MIM #236490) is a familial, presumedly autosomal recessive disorder of as yet unknown pathogenesis. Clinical onset is during the ®rst six months of life, and main clinical symptoms include painful joint contractures, generally thickened skin with livid-red hyperpigmentation over bony prominences, small pearly papules predominantly on the head (face, ears, neck), ¯eshy nodules in the perianal region, gingival hypertrophy, and an increas- ed susceptibility to bone fractures and infections. The disorder is progessive, and the course may lead to death The parents of our patient are willing to share experiences with other families affected by this disorder. Contact Andrea Superti- Furga at asuperti@access.unizh.ch Grant sponsor: Swiss National Foundation; Grant number: 31- 57272.99. *Correspondence to: A. Superti-Furga, Division of Metabolic and Molecular Diseases, University Children's Hospital, Stein- wiesstrasse 75, CH-8032 Zurich, Switzerland. E-mail: asuperti@access.unizh.ch Received 12 June 2000; Accepted 15 January 2001 Published online 16 March 2001 ß 2001 Wiley-Liss, Inc.