Dermatofibrosis Lenticularis (Buschke-Ollendorf Syndrome)

Back

Background

Dermatofibrosis lenticularis (Buschke-Ollendorff syndrome) is a rare hereditary disorder of connective tissue. It is inherited as a pleiotropic autosomal dominant trait with incomplete penetrance. This condition was described for the first time in 1902 and was termed "scleroderma adultorum" by Abraham Buschke, and it has gone by several names since, including dermatofibrosis lenticularis disseminata.  Buschke-Ollendorff syndrome is characterized by the presence of sclerotic bone lesions (osteopoikilosis and melorheostosis) in association with connective-tissue nevi (collagenomas and elastomas).[1, 2, 3, 4, 5, 6, 7]

See image below depicting Buschke-Ollendorff syndrome.



View Image

Plaque of grouped papular eruptions on the thigh.

Pathophysiology

The clinical findings in Buschke-Ollendorff syndrome likely result from abnormal regulation of extracellular matrix components caused by a loss-of-function mutation in the LEM domain–containing protein 3 (LEMD3) gene. LEMD3 normally functions as an inner nuclear membrane protein that antagonizes bone morphogenetic proteins and tumor growth factor-beta signaling pathways.[8] Mutations in LEMD3 lead to abnormal regulation of fibroblasts, which results in an aberrant extracellular matrix with excess elastin and thickened collagen within the dermis.[8] It has been shown that cultured fibroblasts of patients with Buschke-Ollendorff syndrome produce 2-8 times more tropoelastin than fibroblasts of healthy individuals. Elastin production is higher in both involved and uninvolved skin.[9, 10, 11] Elevated elastin mRNA levels support the notion that Buschke-Ollendorff syndrome results from abnormal regulation of extracellular matrix, leading to increased levels of elastin mRNA and increased accumulation of elastin in the dermis. Heterozygous loss-of-function mutations in the LEMD3 gene have been identified in patients with osteopoikilosis without the presence of connective-tissue nevi.[5, 12, 13, 14, 15]

Etiology

This autosomal dominant disorder is caused by a loss of function mutation in LEM domain-containing protein 3 (LEMD3) gene.[1, 4, 5]

Epidemiology

Frequency

Buschke-Ollendorff syndrome is rare syndrome, with an estimated prevalence of 1 in 20,000.[5, 16]

Race

No racial predilection is reported for Buschke-Ollendorff syndrome.[5]

Sex

The incidence is equal for males and females.[5, 16]

Age

Connective-tissue nevi and osteopoikilosis tend to first occur in the preadolescent age (average age, 7 years), but they can be found in neonates just after birth.[16]

Prognosis

In general, Buschke-Ollendorff syndrome follows a benign course. Patients are expected to have a normal lifespan. The associated lesions are generally asymptomatic and begin in childhood. They often persist throughout life and are often found as incidental findings.[17] However, proper diagnosis of this disease and careful documentation of skin and bone lesion locations can help spare the patient from any unnecessary interventions or diagnostic workup.

There have been reports associating Buschke-Ollendorff syndrome with otosclerosis (with resultant hearing impairment), stenosis of the aortae, and diabetes mellitus.[4, 8, 16, 18] Review series have also demonstrated an association of  Buschke-Ollendorff syndrome with cognitive and/or developmental delay, as well as scoliosis and shortened stature.[16]

Patient Education

The patient and/or the patient's family should be educated concerning potential complications and the autosomal dominant inheritance pattern.

History

History findings in dermatofibrosis lenticularis (Buschke-Ollendorff syndrome) are described below.[1, 4, 5, 15, 19, 20]

The coexistence of connective-tissue nevi, such as elastomas or collagenomas, and skeletal changes, such as osteopoikilosis or melorheostosis, characterize  Buschke-Ollendorff syndrome. As the clinical expression is variable, certain individuals within affected families may not exhibit the full phenotype, and skin and skeletal lesions may occur independently.

Cutaneous lesions typically appear in childhood, but they may first appear in infants or in adults.

Connective-tissue nevi are usually located on the trunk, proximal extremities, and skin folds.

The cutaneous and bone lesions are painless, nonpruritic, and enlarge with the growth of the child.

Reports in the literature have described other dermatologic conditions associated with Buschke-Ollendorff syndrome, including pyoderma gangrenosum, acne, hypertrophic scarring, and hidradenitis suppurativa.[21]

Physical Examination

Physical findings are described below.[1, 3, 4, 5, 19, 20, 22, 23, 24, 25, 26, 27, 28]

Buschke-Ollendorff syndrome is characterized by the presence of connective-tissue nevi and sclerotic bone lesions (osteopoikilosis or melorheostosis). The dermal lesions are composed of collagen, elastin fibers, and, in some instances, glycosaminoglycans. The cutaneous lesions are usually localized on the trunk, in the sacrolumbar region, or symmetrically on the extremities. Occasionally, lesions may be found on the head. They present with slightly elevated and flattened yellowish papules and nodules grouped together forming plaques several centimeters in diameter, as depicted below. The plaques are of irregular shape and sharply demarcated. They are numerous, painless, nonpruritic, and develop over several years.



View Image

Plaque of grouped papules on the abdominal coat.

Other findings in  Buschke-Ollendorff syndrome include nasolacrimal duct obstruction, amblyopia, strabismus, benign lymphoid hyperplasia, hypopigmentation, otosclerosis, and short stature. There is also some suggestion in the literature that it may be associated with cognitive or developmental delay.[16]

The bones demonstrate osteopoikilosis in the stratum spongiosum of the epiphysis and the metaphysis of the long bones, especially in the fingers, ulna, and radius. Focal bone densities are often present in the carpal bones, metacarpal bones, and phalanges. They also occur in the lumbosacral spine. Each focal area of density may measure from 1-16 mm in length. Other forms of osteosclerosis, including osteopathia striata, melorheostosis, and mixed sclerosis bone dystrophy, may be present. See the image below.



View Image

Small longitudinal lesions of increased bone density in the proximal epiphysis of the left tibial bone and in the distal epiphysis of the right tibial....

Congenital spinal stenosis, disk herniation, clubfoot deformity, and nerve root compression may be present.

Otosclerosis with or without hearing loss may occur. It is caused by bone resorption and redeposition, and it may be clinically asymptomatic; however, otosclerosis is a rare phenomenon in patients with  Buschke-Ollendorff syndrome.

Complications

Complications can include the following[4, 8, 18] :

Laboratory Studies

Patients suspected of having dermatofibrosis lenticularis (Buschke-Ollendorff syndrome) should undergo genetic testing, given the highly variable phenotypic expression.[16]

Imaging Studies

Consider the following the information below with regard to imaging studies.[1, 2, 4, 5, 27, 31]

In Buschke-Ollendorff syndrome, the radiographic appearance of osteopoikilosis is diagnostic. Bone densities are often present in the fingers, carpal and metacarpal bones, lumbosacral spine, and tibial and radial bones. They are sclerotic circular or ovoid lesions symmetrically distributed in a periarticular location, and they may be 1-16 mm in diameter. Lesions can increase or decrease in size and number or even disappear in serial radiographs. The bone densities are caused by condensations of the spongiosa.

Other sclerosing dysplasias, including osteopathia striata, melorheostosis, and focal sclerosis, can be seen. When osteopoikilosis is seen in combination with these sclerosing dysplasias, the term mixed sclerosing bone dystrophy is used.

Lesions do not have increased bone radiotracer uptake.

T1-weighted MRI reveals multiple, well-circumscribed, low-signal foci usually in a symmetric distribution. The differential diagnosis includes blastic metastases, tuberous sclerosis, and mastocytosis. However, symmetry and uniform size of the lesions would be most suggestive of osteopoikilosis.

Histologic Findings

Regarding skin lesions, histopathologic examination reveals numerous thickened collagen fibers in the dermis. Orcein stain of the reticular layer of the dermis reveals numerous elastic fibers with various diameters as depicted below. These fibers are frequently fragmented, and, in some places, they create a net of bundles. Weigert stain of the reticular dermis also reveals numerous elastic fibers with different diameters as shown below.[10] While most lesions have mixed findings, they can be categorized into four subtypes based on their composition: pure collagenoma, pure elastoma, mixed connective-tissue nevi, and cellular connective-tissue nevi.[15]



View Image

Orcein stain of elastic fibers shows the histopathologic features of the skin lesions.



View Image

Weigert stain of the elastic fibers shows the histopathologic features of the skin lesions.



View Image

Hematoxylin and eosin stain shows the histopathologic features of the skin lesions.

Surgical Care

Surgical excision of the dermal lesions is indicated only for cosmetic reasons. In some patients, surgical treatment of deafness is possible. Surgical treatment of associated conditions, such as stenosis of the aortae, should be performed as appropriate.

Consultations

Note the following potential consultations:

Activity

Osteopoikilosis is asymptomatic; however, 15-20% of patients experience pain and joint effusions. Usually, no special restrictions in activity are required.[5]

Long-Term Monitoring

There are no specific follow-up requirements in the case of asymptomatic dermatofibrosis lenticularis (Buschke-Ollendorff syndrome).

Author

Vernon J Forrester, MD, Resident Physician, Department of Dermatology, UVA Health System, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Barbara B Wilson, MD, Edward P Cawley Associate Professor, Department of Dermatology, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Krista Roncone, University of Virginia School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Grazyna Szybejko-Machaj, MD, PhD, Assistant Professor, Department of Dermatology, Wroclaw Medical University

Disclosure: Nothing to disclose.

Jacek C Szepietowski, MD, PhD, Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

Lukasz Matusiak, MD, PhD, Assistant, Department and Clinic of Dermatology, Venereology and Allergology, Medical University of Wroclaw

Disclosure: Nothing to disclose.

Acknowledgements

Mark A Crowe, MD Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine

Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society

Disclosure: Nothing to disclose.

Mieczyslawa Miklaszewska, MD, PhD Professor, Department of Dermatology, Medical University in Wroclaw, Poland

Disclosure: Nothing to disclose.

References

  1. Benli IT, Akalin S, Boysan E, Mumcu EF, Kis M, Türkoglu D. Epidemiological, clinical and radiological aspects of osteopoikilosis. J Bone Joint Surg Br. 1992 Jul. 74(4):504-6. [View Abstract]
  2. Crivellato E. Disseminated nevus anelasticus. Int J Dermatol. 1986 Apr. 25(3):171-3. [View Abstract]
  3. Dahan S, Bonafe JL, Laroche M, et al. [Iconography of Buschke Ollendorff syndrome: x ray computed tomography and nuclear magnetic resonance of osteopoikilosis]. Ann Dermatol Venereol. 1989. 116(3):225-30. [View Abstract]
  4. Lin F, Morrison JM, Wu W, Worman HJ. MAN1, an integral protein of the inner nuclear membrane, binds Smad2 and Smad3 and antagonizes transforming growth factor-beta signaling. Hum Mol Genet. 2005 Feb 1. 14(3):437-45. [View Abstract]
  5. de la Salmonière P, Janier M, Chemlal K, Lazareth I, Carlotti A, Charasson I, et al. [Buschke-Ollendorff syndrome]. Ann Dermatol Venereol. 1994. 121(10):718-20. [View Abstract]
  6. Umaretiya PJ, Miest RY, Tollefson MM. A 5-year-old with connective tissue nevi: Buschke-Ollendorff syndrome. J Pediatr. 2014 Jul. 165(1):206. [View Abstract]
  7. Boyaci A, Boyaci N, Tutoglu A. Familial osteopoikilosis. J Back Musculoskelet Rehabil. 2013. 26(3):247-50. [View Abstract]
  8. Giro MG, Duvic M, Smith LT, Kennedy R, Rapini R, Arnett FC, et al. Buschke-Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture. J Invest Dermatol. 1992 Aug. 99(2):129-37. [View Abstract]
  9. Ehrig T, Cockerell CJ. Buschke-Ollendorff syndrome: report of a case and interpretation of the clinical phenotype as a type 2 segmental manifestation of an autosomal dominant skin disease. J Am Acad Dermatol. 2003 Dec. 49(6):1163-6. [View Abstract]
  10. Hellemans J, Preobrazhenska O, Willaert A, Debeer P, Verdonk PC, Costa T, et al. Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet. 2004 Nov. 36(11):1213-8. [View Abstract]
  11. Trattner A, David M, Rothem A, Ben-David E, Sandbank M. Buschke-Ollendorff syndrome of the scalp: histologic and ultrastructural findings. J Am Acad Dermatol. 1991 May. 24(5 Pt 2):822-4. [View Abstract]
  12. Ben-Asher E, Zelzer E, Lancet D. LEMD3: the gene responsible for bone density disorders (osteopoikilosis). Isr Med Assoc J. 2005 Apr. 7(4):273-4. [View Abstract]
  13. Grimer RJ, Davies AM, Starkie CM, Sneath RS. [Chondrosarcoma in a patient with osteopoikilosis. Apropos of a case]. Rev Chir Orthop Reparatrice Appar Mot. 1989. 75(3):188-90. [View Abstract]
  14. Lagier R, Mbakop A, Bigler A. Osteopoikilosis: a radiological and pathological study. Skeletal Radiol. 1984. 11(3):161-8. [View Abstract]
  15. Saussine A, Marrou K, Delanoé P, et al. Connective tissue nevi: An entity revisited. J Am Acad Dermatol. 2011 Oct 18. [View Abstract]
  16. Pope V, Dupuis L, Kannu P, Mendoza-Londono R, Sajic D, So J, et al. Buschke-Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol. 2016 Apr. 174 (4):723-9. [View Abstract]
  17. Blum AE, Hatter A, Honda K, Lu K. An unusual presentation of Buschke-Ollendorff syndrome. J Am Acad Dermatol. 2011 Jul. 65(1):e25-6. [View Abstract]
  18. Ayling RM, Evans PE. Giant cell tumor in a patient with osteopoikilosis. Acta Orthop Scand. 1988 Feb. 59(1):74-6. [View Abstract]
  19. Morrison JG, Jones EW, MacDonald DM. Juvenile elastoma and osteopoikilosis (the Buschke--Ollendorff syndrome). Br J Dermatol. 1977 Oct. 97(4):417-22. [View Abstract]
  20. Schorr WF, Optiz JM, Reyes CN. The connective tissue nevus-osteopoikilosis syndrome. Arch Dermatol. 1972 Aug. 106(2):208-14. [View Abstract]
  21. Gracia-Cazaña T, Frias M, Roselló R, Vera-Álvarez J, Gilaberte Y. PASH syndrome associated with osteopoikilosis. Int J Dermatol. 2015 Sep. 54 (9):e369-71. [View Abstract]
  22. Al Attia HM, Sherif AM. Buschke-Ollendorff syndrome in a grande multipara: a case report and short review of the literature. Clin Rheumatol. 1998. 17(2):172-5. [View Abstract]
  23. Atherton DJ, Wells RS. Juvenile elastoma and osteopoikilosis (the Buschke-Ollendorf syndrome). Clin Exp Dermatol. 1982 Jan. 7(1):109-13. [View Abstract]
  24. Cantatore FP, Carrozzo M, Loperfido MC. Mixed sclerosing bone dystrophy with features resembling osteopoikilosis and osteopathia striata. Clin Rheumatol. 1991 Jun. 10(2):191-5. [View Abstract]
  25. Miklaszewska M, Szybejko-Machaj G, Szepietowski J. [Buschke-Ollendorf syndrome - case report with a literature review.]. Dermatol Klin Zabieg. 1999. 2:85-9.
  26. Schnur RE, Grace K, Herzberg A. Buschke-Ollendorff syndrome, otosclerosis, and congenital spinal stenosis. Pediatr Dermatol. 1994 Mar. 11(1):31-4. [View Abstract]
  27. Woodrow SL, Pope FM, Handfield-Jones SE. The Buschke-Ollendorff syndrome presenting as familial elastic tissue naevi. Br J Dermatol. 2001 Apr. 144(4):890-3. [View Abstract]
  28. Surrenti T, Callea F, De Horatio LT, Diociaiuti A, El Hachem M. Buschke-Ollendorff syndrome: sparing unnecessary investigations. Cutis. 2014 Aug. 94(2):97-100. [View Abstract]
  29. Cañueto J, Román C, Santos-Briz Á, Ciria S, González R, Unamuno P. Papular elastorrhexis and Buschke-Ollendorff syndrome are different entities. J Am Acad Dermatol. 2011 Jul. 65 (1):e7-9. [View Abstract]
  30. Kennedy JG, Donahue JR, Aydin H, Hoang BH, Huvos A, Morris C. Metastatic breast carcinoma to bone disguised by osteopoikilosis. Skeletal Radiol. 2003 Apr. 32(4):240-3. [View Abstract]
  31. Holbrook KA, Byers PH. Structural abnormalities in the dermal collagen and elastic matrix from the skin of patients with inherited connective tissue disorders. J Invest Dermatol. 1982 Jul. 79 Suppl 1:7s-16s. [View Abstract]

Plaque of grouped papular eruptions on the thigh.

Plaque of grouped papules on the abdominal coat.

Small longitudinal lesions of increased bone density in the proximal epiphysis of the left tibial bone and in the distal epiphysis of the right tibial bone.

Orcein stain of elastic fibers shows the histopathologic features of the skin lesions.

Weigert stain of the elastic fibers shows the histopathologic features of the skin lesions.

Hematoxylin and eosin stain shows the histopathologic features of the skin lesions.

Plaque of grouped papular eruptions on the thigh.

Hematoxylin and eosin stain shows the histopathologic features of the skin lesions.

Small longitudinal lesions of increased bone density in the proximal epiphysis of the left tibial bone and in the distal epiphysis of the right tibial bone.

Orcein stain of elastic fibers shows the histopathologic features of the skin lesions.

Weigert stain of the elastic fibers shows the histopathologic features of the skin lesions.

Plaque of grouped papules on the abdominal coat.