Dermatology

Buschke-Ollendorff syndrome (dermatofibrosis lenticularis disseminata, connective tissue nevus with osteopoikilosis)

Are You Confident of the Diagnosis?

Buschke-Ollendorff syndrome (BOS) describes an autosomal dominant condition that encompasses connective tissue nevi and osteopoikilosis. The skin findings of BOS are primarily skin-colored to yellow papules, which may coalesce into plaques. As these cutaneous findings are not unique to the syndrome, both osteopoikilosis and a positive family history are required for a confident diagnosis.

Characteristic findings on physical examination

The initial diagnosis may be made as an incidental finding or in a patient who presents with multiple papules or plaques suggestive of BOS. On physical examination the findings are varied, likely reflecting genetic diversity. Skin-colored to yellowish papules may be symmetrical and widespread, forming plaques that are several centimeters in diameter; or, sparse and asymmetric with a predilection for the arms and buttocks. A segmental variant has been reported. Often described as minimally elevated, the eruption has been compared to wrinkled, “pigskin” (Figure 1).

Figure 1.

BOS. A. Yellowish papules and nodules coalescing into cobbelstoned plaques. B. Close-up, notice the irregular shape, smooth surface,and sharp demarcation from unaffected areas of skin.

Other variations include streaked and deep nodular lesions, typically in flexures. The majority of cases present in adulthood; however, skin lesions of BOS have been reported in the first year of life.

The bone involvement of BOS is termed osteopoikilosis. Osteopoikilosis is a hyperostotic bone disorder characterized by ectopic foci of calcification appearing on x-ray as round or oval focal densities, 1 to 10mm in diameter (Figure 2). These lesions are most often located in the long bones, hands, feet, and pelvis. Generally, there is a predilection for the epiphyses and metaphyses of bone; however, the ribs, skull, and spine are almost never involved. These lesions are considered non-pathologic and asymptomatic, with no increased propensity towards fracture. While osteopoikilosis is usually an incidental finding, reports have indicated that the condition may begin in childhood, with characteristic lesions attaining their final form during puberty.

Figure 2.

Radiograph highlighting the isolated sclerotic lesions of osteopoikilosis. Arrowheads indicate prominent lesions (classic for osteopoikilosis) whereas the asteriks denote more subtle changes (more irregular areas of sclerosis).

The association of skin and bone findings was referred to as dermatofibrosis lenticularis disseminata by Abraham Buschke and Helene Ollendorff Curth in their original report of 1928. The posthumous eponym was not proposed until 1979 by Schimpf et al. There are considerable discrepancies in terminology for BOS in the literature. Dermatofibrosis lenticularis disseminata is invoked most frequently to describe the collagenous form of skin lesions found in the syndrome, whereas juvenile elastoma is used for lesions where elastic tissue predominates. Some reports propose that the skin lesions of BOS are elastic-type connective tissue nevi exclusively.

At this time, it is generally accepted that the term BOS encompasses both collagenous- and elastic fiber-predominant nevi, with the caveat that a majority of cases seem to be of the elastic fiber type.

Expected results of diagnostic studies

Concordantly, there is a spectrum of findings on histologic analysis of skin lesions in BOS (Figure 3). This includes poorly demarcated areas of increased dermal collagen bundles, haphazardly arranged, with no apparent increase of fibroblasts in the collagenous type. The elastic fiber type shows a marked increase in the amount of elastic fibers, which may be present as broad, interfacing bands without any overt signs of degeneration. Many lesions have characteristics of both.

Figure 3.

Biopsy specimen from a patient with BOS. A. Fibroplasia in the dermis and edema between collagen bundles. Of note, the reticular dermis is nearly altogether replaced by large, thickened, and disorganized collagen fibers (H&E stain, 4x magnification). B. Detail: enlarged fibrocyte nuclei between collagen bundles along with slight increase in interstitial cellularity (H&E stain, 40x magnification). C. Very thick elastic fibers splayed between and appearing to envelop the collagen bundles (elastic-van Gieson stain, 40x magnification). D. Increase of interstitial mucin in the interfascicular spaces and the areas of the enlarged elastic fibers (Alcian blue stain, 40x magnification).

On physical examination the yellow to flesh-colored papules and/or plaques mentioned above are not associated with pruritus, or other complaints. A careful family history is essential in detecting BOS, and it is important to note that family members may have different manifestations of the disease. Males are more likely to be afflicted with the bony abnormalities of osteopoikilosis. X-rays of the upper and lower extremity and the pelvis should be obtained to evaluate for osteopoikilosis.

Biopsy of the skin should be stained with Verhoeff-van Gieson or orcein for elastic tissue. It is important to obtain a sample of the surrounding normal skin for comparison with tissue from suspected connective tissue nevi, as abnormalities of collagen and elastin may not be readily apparent otherwise. A thin elliptical excision with normal skin at one end and the affected skin at the other may be sectioned longitudinally.

Diagnosis confirmation

The differential diagnosis of BOS includes many other syndromes and conditions involving skin lesions with increased collagen or elastin. Early recognition of BOS can help the clinician and patient avoid an unnecessary, costly, and potentially painful workup for other more worrisome conditions. Since BOS has such a varied clinical presentation, combining a strong index of suspicion with a comprehensive family history is critical. To this end, alternative presentations may represent a forme fruste (an attenuated, abortive phenotype) of BOS with juvenile elastoma and papular elastorrhexis representing prime examples.

Many other genodermatoses that have similarly variable presentations are included in the differential diagnosis of BOS.

Other connective tissue nevi, such as naevus anelasticus or papular elastorrhexis, are important in the differential. Due to their similarity, some of these conditions have even been proposed as alternative forms of BOS, as noted previously. Naevus anelasticus appears as small, yellowish to pink perifollicular papules on the trunk, resulting in a “wrinkled” appearance while histologically representing the focal absence of elastic fibers.

Papular elastorrhexis presents as non-follicular, symmetric papules on the trunk and sometimes limbs, histologically showing a diminution and fragmentation of elastic fibers. Importantly, these papules have no potential to coalesce into plaques. When these nevi are involved in complex syndromes such as pseudoxanthoma elasticum (PXE) and familial cutaneous collagenoma, there is no bone involvement. In PXE, there is skin laxity of the neck, axilla, or groin, in conjunction with angioid streaks (nb, bands radiating from the optic disc), or associated cardiovascular symptoms (intermittent claudication, blood vessel calcification).

Similarly, familial cutaneous collagenoma may have associated cardiac findings with no bone findings. Familial cutaneous collagenoma is also associated with hormonal abnormalities. Many patients experience worsening of symptoms during pregnancy. Collagenomas have also been described alongside angiofibromas in multiple endocrine neoplasia (MEN) type 1.

As the Shagreen patch often found in tuberous sclerosis (TS) represents a type of connective tissue nevus, there is an important distinction to make. Although TS is an autosomal dominant disease, greater than 50% of the cases of TS have been attributed to novel mutations, so there may not be a family history to cinch the diagnosis. The occurrence of a Shagreen patch should prompt a thorough search for characteristic lesions of TS --- angiofibromas, most often located in the nasolabial folds, on the cheeks, and the chin; periungual fibromas (Koenen’s tumor); ash-leaf, hypopigmented macules; and dental pitting. One may also expect to find neurologic signs, with epilepsy resulting from tubers in the cortex and subcortex.

Lastly, neoplasms of nearly every organ have been described with TS, most often occurring in the heart, kidney, lungs, bones, and gastrointestinal (GI) system. In equivocal cases, genetic testing for TSC is available, with up to 80% of cases presenting with an identifiable mutation.

Elastosis perforans serpingosa also represents a defect in elastic tissue, occurring in both idiopathic and drug-induced forms (secondary to d-penicillamine) and with systemic conditions such as Down syndrome, Ehlers-Danlos syndrome, and Marfan syndrome. The pathophysiology of the condition is considerably distinct from BOS, with granulomatous inflammation leading to destruction of connective tissue and invasion of phagocytic histiocytes, ultimately resulting in fibrosis. Clinically, this results in arcuate, hyperkeratotic papules and plaques, and a careful history may also suggest this diagnosis.

Who is at Risk for Developing this Disease?

BOS remains a rare syndrome, with roughly 100 known cases reported in the literature and an estimated incidence of 1:20,000. As it is an autosomal dominant condition, one may expect to see similar findings in family members, but due to incomplete penetrance and/or different states of zygosity, the phenotypic changes may vary considerably. Thus, a history suggestive of bone or skin changes in an individual presenting with characteristic papules or plaques may guide the clinician to a diagnosis of BOS. While many of the findings, both in skin and bone, have been reported in adults, children can and have often been shown to manifest both types of lesions from an early age.

What is the Cause of the Disease?

BOS has been reported to be associated with a loss-of-function mutation in LEMD3 (also known as MAN1), coding for an inner nuclear membrane protein and located on chromosome 12. Mutations in this region have been associated with perturbations of the Bone Morphogenic Protein (BMP) and Transforming Growth Factor β (TGF β) pathways; namely, loss of antagonism in these pathways — which is consistent with the clinical findings. In vitro studies of cultured fibroblasts from individuals afflicted with BOS show markedly increased elastin production, correlated with an increase in elastin mRNA.

Analysis of fibroblasts from unaffected, non-lesional skin sites show differing results, with either no increase in elastin production or similarly high levels of elastin production as compared to fibroblasts from the skin lesions. This may reflect mosaicism in affected individuals, as discussed below.

One proposed mechanism for the varying manifestations of skin lesions in BOS is loss of heterogeneity. The milder form of the syndrome (in this case, symmetric papules) occurs as a nonmosaic genodermatosis. A loss of heterozygosity for the same allele would then result in a more severe manifestation (larger plaques in BOS), albeit in a more geographically localized region. Both types may co-exist in BOS, with areas of milder involvement, as well as more serious changes (ie, symmetric papules and large plaques).

An interesting finding from genetic analyses of BOS has shown that melorheostosis, an osseous limb abnormality characterized by mesenchymal dysplasia with widening of the bony cortex leading to pain and physical deformity, also localizes to the LEMD3 region. This explains why many individuals found to have osteopoikilosis also have family members with melorheostosis.

However, sporadic melorheostosis has been demonstrated to occur without any involvement of LEMD3. Combined with a recent report that BOS has been shown to exist in a family without any alterations in the LEMD3 region, this suggests further heterogeneity in the molecular mechanisms of BOS. Additional nvestigation is required to establish phenotype-genotype correlation in BOS more clearly.

From a pathophysiologic standpoint, the bone lesions in osteopoikilosis histologically represent thickened trabeculae of lamellar bone. The skin lesions may be predominantly collagenous or made up of elastic fibers. In the latter, elastic fibers have been shown to lack a microfibrillar component, such that only the electrolucent elastin is present.

Systemic Implications and Complications

Since the diagnosis of BOS necessitates skeletal bone findings consistent with osteopoikilosis, this should be the first consideration. It is emphasized again that osteopoikilosis is a benign condition with no symptoms or propensity for pathologic fractures, as encountered in other bony abnormalities. It is worth reiterating that selected patients in families with BOS may also have melorheostosis, presenting with bone pain, deformity, and limited range of motion. Unfortunately, melorheostosis is often progressive, initially controlled with analgesics, physical therapy, and regional anesthetics but intractable cases may eventuate in surgical amputation.

Treatment Options

As BOS is generally benign and asymptomatic, no treatment per se is required. Surgical excision of the dermal lesions may be performed for cosmesis or, rarely, if involvement limits mobility. The latter has been caused by lesions on the hands.

Optimal Therapeutic Approach for this Disease

Upon presentation, a comprehensive review of systems and family history is essential. There should be no systemic complaints attributable to a separate pathophysiologic process. Most patients with BOS will report family members with skin lesions and/or bone lesions. BOS has been postulated to be under-reported due to its benign nature and limited penetrance.

X-rays of the upper and lower extremity, along with the pelvis, should be performed to identify characteristic hyperintense foci representing areas of ectopic calcification. Most cases do not require further imaging studies unless there are concerns about other conditions such as Paget’s disease of bone. Radionucleide scans may be performed to show the absence of uptake in BOS.

Histologic analysis of tissue specimens often suggests a diagnosis of BOS, especially in cases with a negative family history.

Patient Management

Long term care is centered on reassurance, with follow-up scrutiny for skin and bone findings. It is valuable to identify skin conditions that may be erroneously attributed by the patient to be part of their syndrome.

Unusual Clinical Scenarios to Consider in Patient Management

Generally, Buschke-Ollendorff Syndrome is a benign process with no effect on life span and no medical implications. Because there is a great deal of heterogeneity in the presentation of BOS, both the characteristics and location of the lesions vary. For example, only one case report of BOS describes an individual with pruritic skin lesions on the scalp.

While the skin and bone findings are usually the sole manifestations of BOS, there have been numerous case reports describing putative associations with histiocytomas, otosclerosis, ocular abnormalities, pigmented lesions, short stature, microcephaly, and learning disabilities. Similarly, osteopoikilosis has also been described in conjunction with a wide variety of dermatologic conditions, including oral cavity fibromas, keloids, systemic sclerosis, and palmoplantar keratodermas. These may be random events or representations of differing mutations, but in any case, the clinician should be alerted to the possibility of coexisting conditions with BOS.

What is the Evidence?

Buschke, A, Ollendorff, H. "Ein Fall von Dermatofibrosis lenticularis disseminata and osteopathia condensans disseminata". Derm Wschr. vol. 86. 1928. pp. 257-62.

(The initial case report by Dr Abraham Buschke and Dr Helene Ollendorff Curth, where they commented on the presentation of dermatofibrosis lenticularis disseminata and osteopoikilosis in a 41-year-old woman.)

Morrison, JGL, Jones, EW, Macdonald, DM. "Juvenile elastoma and osteopoikilosis (the Buschke-Ollendorff syndrome)". Br J Dermatol. vol. 97. 1977. pp. 417-22.

(This large study encompassing 16 patients from seven different families with BOS establishes patterns of involvement in BOS and characteristic features of the syndrome.)

Giro, MG, Duvic, M, Smith, LT, Kennedy, R, Rapini, R, Arnett, FC. "Buschke–Ollendorff syndrome associated with elevated elastin production by affected skin fibroblasts in culture". J Invest Dermatol. vol. 99. 1992. pp. 129-37.

(In this study, fibroblasts were cultured from patients with BOS and differing levels of elastin production were found in lesional and non-lesional skin amongst two individuals, underscoring the genetic heterogeneity seen in BOS.)

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 Derm. vol. 49. 2003. pp. 1163-6.

(A very intriguing discussion about the inheritance of BOS with specific reference to segmental manifestations of an autosomal dominant cutaneous trait and mechanisms behind the varied clinical presentations of BOS.)

Hellemans, J, Preobrazhenska, O, Willaert, A, Debeer, P, Verdonk, PC, Costa, T. "Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke–Ollendorff syndrome and melorheostosis". Nat Genet. vol. 36. 2004. pp. 1213-8.

(This important study established a mutated region postulated to cause BOS. Multiple articles have since found similar mutations in this region causing BOS, thus closely linking this mutation and the disease. This publication further explains possible mechanisms of disease that arise from the mutation; specifically with regard to TGF-β and BMP pathways.)

Yadegari, M, Whyte, MP, Mumm, S, Phelps, RG, Shanske, A, Totty, WG. "Buschke-Ollendorff syndrome: Absence of LEMD3 mutation in an affected family". Arch Derm. vol. 146. 2010. pp. 63-68.

(While many major textbooks have definitively stated that the genetic basis for BOS has been determined, this article presents a familial presentation of BOS that exhibits no mutations in the LEMD3 region, suggesting that perhaps further clarification is needed as to the specific genetic and molecular pathways of BOS.)

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