- Catherine McCuaig, MD
Catherine McCuaig, MD
- Associate Clinical Professor of Dermatology
- University of Montreal
Buschke-Ollendorff syndrome (BOS) (MIM #166700) is a rare, inherited autosomal-dominant disorder with high penetrance and variable expressivity characterized by the presence of sclerotic bone lesions (osteopoikilosis, "spotted bones") and, rarely, melorheostosis in association with connective tissue nevi (CTN, elastomas and collagenomas) [1,2]. Most patients present both CTN and bone lesions, but some have only skin or skeletal lesions. Both skin and skeletal lesions are usually asymptomatic and in most cases discovered incidentally.
First described in 1928 by Buschke and Ollendorff as dermatofibrosis lenticularis disseminata, the disease has been reported under a variety of names, including dermatofibrosis lenticularis disseminata with osteopoikilosis, dermatofibrosis disseminated with osteopoikilosis, dermato-osteopoikilosis, dermato-osteopoikilosis with melorheostosis (a dripping wax appearance along the outer bone), osteopathia condensans disseminata, and connective tissue nevus syndrome.
BOS is a rare condition. The precise incidence and prevalence are unknown, as both the cutaneous and bone lesions are usually asymptomatic and detected incidentally [2-4]. Males and females are equally affected. Both inherited and sporadic forms have been described .
BOS is an autosomal dominant disorder with high penetrance and variable expressivity caused by loss-of-function germline mutations in the LEM domain-containing protein 3 (LEMD3) gene (also called MAN1) on chromosome 12q14 . More than 125 pathogenic mutations of the LEMD3 gene have been detected, the vast majority of which are point mutations . There is a single report of BOS occurring in a family without an LEMD3 mutation .
LEMD3 encodes an inner nuclear membrane protein that antagonizes the bone morphogenic proteins (BMPs) and transforming growth factor (TGF)-beta signalling pathways through interactions with specific SMAD family proteins. Loss-of-function mutations in LEMD3 result in upregulation of the downstream targets in both of these pathways, leading to alteration of fibroblast function and increased bone formation. Fibroblasts in affected patients produce more tropoelastin and elastin via enhanced TGF-beta and BMP signaling, resulting in the characteristic cutaneous phenotype [8,9].
- Buschke Ollendorff Syndrome. OMIM. www.omim.org/entry/166700 (Accessed on November 07, 2015).
- Pope V, Dupuis L, Kannu P, et al. Buschke-Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol 2016; 174:723.
- Korkmaz MF, Elli M, Özkan MB, et al. Osteopoikilosis: report of a familial case and review of the literature. Rheumatol Int 2015; 35:921.
- Borman P, Ozoran K, Aydoğ S, Coşkun S. Osteopoikilosis: report of a clinical case and review of the literature. Joint Bone Spine 2002; 69:230.
- Yadegari M, Whyte MP, Mumm S, et al. Buschke-Ollendorff syndrome: absence of LEMD3 mutation in an affected family. Arch Dermatol 2010; 146:63.
- Hellemans J, Preobrazhenska O, Willaert A, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet 2004; 36:1213.
- Kratzsch J, Mitter D, Ziemer M, et al. Identification of a Novel Point Mutation in the LEMD3 Gene in an Infant With Buschke-Ollendorff Syndrome. JAMA Dermatol 2016; 152:844.
- Giro MG, Duvic M, Smith LT, et al. Buschke-Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture. J Invest Dermatol 1992; 99:129.
- Uitto J, Santa Cruz DJ, Starcher BC, et al. Biochemical and ultrastructural demonstration of elastin accumulation in the skin lesions of the Buschke-Ollendorff syndrome. J Invest Dermatol 1981; 76:284.
- Woyciechowsky TG, Monticielo MR, Keiserman B, Monticielo OA. Osteopoikilosis: what does the rheumatologist must know about it? Clin Rheumatol 2012; 31:745.
- Boulet C, Madani H, Lenchik L, et al. Sclerosing bone dysplasias: genetic, clinical and radiology update of hereditary and non-hereditary disorders. Br J Radiol 2016; 89:20150349.
- Gutierrez D, Cooper KD, Mitchell AL, Cohn HI. Novel Somatic Mutation in LEMD3 Splice Site Results in Buschke-Ollendorff Syndrome with Polyostotic Melorheostosis and Osteopoikilosis. Pediatr Dermatol 2015; 32:e219.
- McCuaig CC, Vera C, Kokta V, et al. Connective tissue nevi in children: institutional experience and review. J Am Acad Dermatol 2012; 67:890.
- Socrier Y, Wann AR, Sigal ML, et al. [Buschke-Ollendorff syndrome]. Ann Dermatol Venereol 2014; 141:164.
- Surrenti T, Callea F, De Horatio LT, et al. Buschke-Ollendorff syndrome: sparing unnecessary investigations. Cutis 2014; 94:97.
- Cañueto J, Román C, Santos-Briz Á, et al. Papular elastorrhexis and Buschke-Ollendorff syndrome are different entities. J Am Acad Dermatol 2011; 65:e7.
- Danielsen L, Midtgaard K, Christensen HE. Osteopoikilosis associated with dermatofibrosis lenticularis disseminata. Arch Dermatol 1969; 100:465.
- Zhang Y, Castori M, Ferranti G, et al. Novel and recurrent germline LEMD3 mutations causing Buschke-Ollendorff syndrome and osteopoikilosis but not isolated melorheostosis. Clin Genet 2009; 75:556.
- Foo CC, Kumarasinghe SP. Juvenile elastoma: a forme fruste of the Buschke-Ollendorff syndrome? Australas J Dermatol 2005; 46:250.
- Saussine A, Marrou K, Delanoé P, et al. Connective tissue nevi: an entity revisited. J Am Acad Dermatol 2012; 67:233.
- Hellemans J, Debeer P, Wright M, et al. Germline LEMD3 mutations are rare in sporadic patients with isolated melorheostosis. Hum Mutat 2006; 27:290.
- Schena D, Germi L, Zamperetti MR, et al. Buschke-Ollendorff syndrome. Int J Dermatol 2008; 47:1159.
- Woodrow SL, Pope FM, Handfield-Jones SE. The Buschke-Ollendorff syndrome presenting as familial elastic tissue naevi. Br J Dermatol 2001; 144:890.
- Trattner A, David M, Rothem A, et al. Buschke-Ollendorff syndrome of the scalp: histologic and ultrastructural findings. J Am Acad Dermatol 1991; 24:822.
- Schaffenburg WC, Fernelius C, Arora NS. Buschke-Ollendorff syndrome presenting as a painful nodule. JAAD Case Rep 2015; 1:77.
- Kobus RJ, Lubbers LM, Coleman CR. Connective tissue nevus and osteopoikilosis in the hand: the Buschke-Ollendorff syndrome. J Hand Surg Am 1989; 14:535.
- Reinhardt LA, Rountree CB, Wilkin JK. Buschke-ollendorff syndrome. Cutis 1983; 31:94.
- Benli IT, Akalin S, Boysan E, et al. Epidemiological, clinical and radiological aspects of osteopoikilosis. J Bone Joint Surg Br 1992; 74:504.
- Chigira M, Kato K, Mashio K, Shinozaki T. Symmetry of bone lesions in osteopoikilosis. Report of 4 cases. Acta Orthop Scand 1991; 62:495.
- Kotulska A, Kucharz EJ. Osteopoikilosis and Buschke-Ollendorff syndrome. Case Rep Clin Pract Rev 2002; 3:290.
- Negi RS, Manchanda KL, Sanga S, et al. Osteopoikilosis - Spotted bone disease. Med J Armed Forces India 2013; 69:196.
- Hasan SA, Siddiq AB, Moula A, et al. Osteopoikilosis. Mymensingh Med J 2010; 19:290.
- Debeer P, Pykels E, Lammens J, et al. Melorheostosis in a family with autosomal dominant osteopoikilosis: report of a third family. Am J Med Genet A 2003; 119A:188.
- Greenspan A, Azouz EM. Bone dysplasia series. Melorheostosis: review and update. Can Assoc Radiol J 1999; 50:324.
- Dawson AL, Schulman JM, Jordan RC, North JP. Ossifying fibroma in Buschke-Ollendorff syndrome. J Cutan Pathol 2014; 41:740.
- Fernández-Faith E, Kress D, Piliang M, et al. Buschke-Ollendorff syndrome and bilateral cutaneous syndactyly. Pediatr Dermatol 2012; 29:661.
- Schnur RE, Grace K, Herzberg A. Buschke-Ollendorff syndrome, otosclerosis, and congenital spinal stenosis. Pediatr Dermatol 1994; 11:31.
- Korekawa A, Nakano H, Toyomaki Y, et al. Buschke-Ollendorff syndrome associated with hypertrophic scar formation: a possible role for LEMD3 mutation. Br J Dermatol 2012; 166:900.
- Gracia-Cazaña T, Frias M, Roselló R, et al. PASH syndrome associated with osteopoikilosis. Int J Dermatol 2015; 54:e369.
- Buysse K, Reardon W, Mehta L, et al. The 12q14 microdeletion syndrome: additional patients and further evidence that HMGA2 is an important genetic determinant for human height. Eur J Med Genet 2009; 52:101.
- Verbov J. Buschke--Ollendorff syndrome (disseminated dermatofibrosis with osteopoikilosis). Br J Dermatol 1977; 96:87.
- Tuncel M, Caner B. Osteopoikilosis: a major diagnostic problem solved by bone scintigraphy. Rev Esp Med Nucl Imagen Mol 2012; 31:93.
- Sharma R, Verma P, Singal A, Sharma S. Eruptive collagenoma. Indian J Dermatol Venereol Leprol 2013; 79:256.
- McClung AA, Blumberg MA, Huttenbach Y, et al. Development of collagenomas during pregnancy. J Am Acad Dermatol 2005; 53:S150.
- Uitto J, Santa-Cruz DJ, Eisen AZ. Familial cutaneous collagenoma: genetic studies on a family. Br J Dermatol 1979; 101:185.
- Park MY, Choi YJ, Lee JY, et al. A case of familial cutaneous collagenoma. Ann Dermatol 2011; 23 Suppl 1:S119.
- Hershkovitz D, Amitai B, Sprecher E. Familial cutaneous collagenomas resulting from a novel mutation in LEMD3. Br J Dermatol 2007; 156:375.
- Vidal A, Iglesias MJ, Fernández B, et al. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. J Eur Acad Dermatol Venereol 2008; 22:835.
- Ozdemirel AE, Cakit BD, Erdem HR, Koc B. A rare benign disorder mimicking metastasis on radiographic examination: a case report of osteopoikilosis. Rheumatol Int 2011; 31:1113.
- Rossini M, Zanotti R, Viapiana O, et al. Bone involvement and osteoporosis in mastocytosis. Immunol Allergy Clin North Am 2014; 34:383.
- Alpay Kanıtez N, Erer B, Doğan Ö, et al. Osteoporosis and osteopathy markers in patients with mastocytosis. Turk J Haematol 2015; 32:43.
- Skin lesions
- Bone lesions
- CLINICAL MANIFESTATIONS
- Connective tissue nevi
- Skeletal lesions
- - Osteopoikilosis
- Radiologic findings
- - Melorheostosis
- Associated conditions
- Diagnostic workup
- - History and physical examination
- - Skin biopsy
- - Radiologic imaging
- - Genetic testing
- DIFFERENTIAL DIAGNOSIS
- Connective tissue nevi
- PROGNOSIS AND FOLLOW-UP
- SUMMARY AND RECOMMENDATIONS