Buschke-Ollendorff syndrome

INTRODUCTION — 

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 [OPK]) in association with connective tissue nevi (CTN; elastomas and collagenomas) [1,2]. BOS results from heterozygous, loss-of-function mutations in the LEMD3 gene on the chromosome band 12q14 [1,3]. Most patients present with both CTN and bone lesions, but some have only skin or skeletal lesions.

TERMINOLOGY — 

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 (spotted bones), dermato-osteopoikilosis, dermato-osteopoikilosis with melorheostosis (a dripping wax appearance along the outer bone), osteopathia condensans disseminata, and connective tissue nevus syndrome.

EPIDEMIOLOGY — 

BOS is a rare condition, with an estimated incidence of 1 in 20,000 individuals [4]. The precise incidence and prevalence are unknown, as both the cutaneous lesions and bone lesions are usually asymptomatic and detected incidentally [2,5,6]. Males and females are equally affected. Both inherited and sporadic forms have been described [7].

GENETICS — 

BOS is an autosomal dominant disorder with high penetrance and variable expressivity caused by loss-of-function germline variants in the LEM domain-containing protein 3 (LEMD3) gene (also called MAN1) on chromosome 12q14 [8]. However, there are reports of BOS occurring in families without a LEMD3 pathogenic variant [7,9], suggesting that other genes may be involved in the pathogenesis of BOS and connective tissue nevi (CTN).

LEMD3 encodes an inner nuclear membrane protein that antagonizes the bone morphogenic proteins (BMPs) and transforming growth factor (TGF)-beta signaling pathways through interactions with specific SMAD transcriptor family proteins [10]. A localized loss of the ribonucleic acid (RNA) recognition motif (RRM) of the LEMD3 gene and not necessarily the loss of the entire LEMD3 protein can also cause the characteristic findings of BOS [11,12].

More than 125 pathogenic variants of the LEMD3 gene have been detected, the vast majority of which are point mutations [3,9,11-20].

PATHOGENESIS

●Connective tissue nevi – 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 [21,22].

●Osteopoikilosis – The exact pathogenesis of osteopoikilosis (OPK) is unknown. It is thought to be a multifactorial process that may involve [23]:

•An inherited, abnormal formation of trabeculae along lines of stress

•A focal defect of endochondral ossification

•Altered osteogenesis

•Specific LEMD3 mutations

●Melorheostosis – Abnormalities of endochondral and membranous ossification lead to ectopic bone forming on the periosteal and endosteal surfaces of the long bones [24,25]. Molecular studies have identified mutations in the MAP2K1 gene (responsible for the dripping candle wax form) and the SMAD3 gene (responsible for the endosteal form) [26].

When melorheostosis arises in BOS, it is believed to be due to a second hit, and postzygotic mosaicism of the KRAS mutation has been reported [1,27,28]. Germline LEMD3 variants have been identified in patients with BOS who present with both OPK and melorheostosis [29].

CLINICAL MANIFESTATIONS — 

BOS is characterized by the association of multiple connective tissue nevi (CTN) with osteopoikilosis (OPK; "spotted bones"). In a review of 164 published cases of BOS, 6 percent of the patients had neurologic deficits, and 5 percent had cognitive delays [2]. (See 'Associated conditions' below.)

Connective tissue nevi — Connective tissue nevi (CTN) are hamartomas that arise in the reticular dermis. They include elastomas (most common), collagenomas, and mixed lesions (see 'Skin lesions' below). CTN present as painless, scattered, flesh-colored or yellowish papules or nodules 2 to 10 mm in size (dermatofibrosis lenticularis disseminata) or as more localized, grouped nodules or plaques 3 to 10 cm in size that may only be appreciated by palpation (picture 1 and picture 2 and picture 3) [19].

CTN may be congenital and/or acquired, progressing with time to adolescence. The disseminated lesions are symmetrically distributed, primarily on the trunk and volar surfaces of the proximal extremities. Rarely, the neck, scalp, face, and hands can be involved (picture 4). Localized plaques are usually located on the trunk and limbs in a segmental or linear pattern.

The so-called "juvenile elastomas" are almost exclusively found in BOS. Juvenile elastomas with OPK lacking the germline LEMD3 mutation are diagnosed as BOS all the same [7,9]. Isolated juvenile elastomas, in the absence of OPK, are thought to be an incomplete manifestation of BOS [30].

Skeletal lesions

Osteopoikilosis — Osteopoikilosis (OPK; also called osteopathia condensans disseminata, spotted bones, osteosclerosis disseminata, osteosclerosis familiaris disseminata, and osteosclerosis fragilis generalisata) is a sclerosing bone dysplasia consisting of focal deposits of dense lamellar bone in the spongiosa [24]. In BOS, OPK displays incomplete penetrance and variable phenotypic expression and, therefore, may not be detected in all patients or may be the sole manifestation of the disease [2].

●Clinical presentation – OPK can present at any age, but it is usually detected by late childhood or puberty and persists throughout life. It typically affects the small tubular bones of the hands and feet, meta-epiphyseal regions of the long bones, and the pelvic bones. The hands are involved in nearly all patients, followed by the feet, pelvis, and long bones [31]. The ribs, skull, and vertebrae are typically spared. Lesions are symmetric but randomly distributed [32].

OPK is usually asymptomatic and is typically an incidental finding on imaging studies for unrelated conditions. Up to 20 percent of patients may report articular pain or, rarely, joint effusions [2,5,33,34]. However, whether these symptoms are truly related to the underlying osteopoikilotic lesions remains to be established.

●Radiologic findings – On plain radiographs, osteopoikilotic lesions appear as round, oval, or linear, hyperdense opacities, ranging in size from 2 to 10 mm (picture 5). The number of lesions in a single bone range from a few to hundreds and tend to increase with age. The largest number of lesions is usually detected in the pelvic bones [31]. In children, lesions may increase or decrease in size over time and, in rare instances, may even disappear completely [5]. In adults, osteopoikilotic lesions are usually stable and persist throughout life [35].

Melorheostosis (Leri disease) — Melorheostosis is an exceedingly rare, sclerosing bone dysplasia characterized by a "flowing" hyperostosis of the cortex of tubular bones with a radiologic appearance of "dripping candle wax" [24,27,36-38]. It is most often an isolated disorder or a very uncommon manifestation of BOS [26,27,29,39-41], alone or in association with osteopoikilosis (OPK; mixed or overlap sclerosing bone dysplasia) or CTN.

●Clinical presentation – Melorheostosis usually affects the lower extremities in a limited unilateral segment and may involve a single bone (monostotic form) or multiple adjacent bones (polyostotic form) [26,37,40,42]. In many cases, lesions are asymptomatic and found incidentally on imaging studies. However, symptoms may become apparent during childhood or early adulthood and include [24,27,28,37,43-45]:

•Local pain at the site of bone lesions

•Limb deformity

•Leg length discrepancy

•Reduced range of motion

•Contractures

•Paresthesia

•Muscle weakness and myositis ossificans

In some patients, melorheostosis may be associated with overlying sclerodermoid changes with stretched, shiny, and erythematous skin with varices [14,41,46-49]. Histologically, these vascular lesions show thickened vascular wall and increased density of superficial vessels compared with skin from the contralateral extremity [48]. Hypertrichosis, hyperpigmentation, skin thickening due to dermal fibrosis, ipsilateral epidermal nevus, and sebaceous nevus have also been reported at the site of melorheostosis [40,47].

●Radiologic findings – The classic radiologic appearance of melorheostosis is the "dripping candle wax" due to dense cortical hyperostotic lesions. Other radiologic patterns include osteoma-like lesions, myositis ossificans-like lesions, osteopathia striata-like lesions, or a blend of these [50,51].

Syndromic Buschke-Ollendorff syndrome — Characteristic syndromic manifestations that are associated with the 12q14 microdeletion syndrome that encompasses LEMD3 include short stature and developmental delay, which have been reported in association with BOS [52]. A syndromic variant, characterized by late-onset generalized morphea, lichen sclerosus and atrophicus, and OPK, has been reported in a patient with an identified new mutation in LEMD3 [14].

Associated conditions — Although there is no definite link between BOS and other diseases, multiple associations have been described in the literature, most often in single case reports. They include ossifying fibroma [53], bilateral cutaneous syndactyly [54], otosclerosis and congenital spine stenosis [55], hypertrophic scarring [56], and PASH (pyoderma gangrenosum, acne, and suppurative hidradenitis) syndrome [57]. However, it is unclear if these are true associations or coincidental findings [52].

PATHOLOGY

Skin lesions — Connective tissue nevi (CTN) are hamartomas that arise in the reticular dermis. Since routine hematoxylin and eosin (H&E) stains cannot differentiate collagen and elastic fiber, special stains are required for the accurate histopathologic diagnosis of CTN. These include hematoxylin phloxine saffron stain (which stains collagen in yellow and elastic fibers in red), Masson's trichrome stain, orcein, Weigert, and Verhoeff-van Gieson [11,30,58-62].

CTN are characterized by the abnormal accumulation of components of the extracellular dermal matrix, specifically collagen, elastin, and proteoglycans [58]. They typically show a normal or papillomatous epidermis overlying an unaffected papillary dermis. Based on the predominance of collagen or elastic fibers in the reticular dermis, CTN have been divided into three histopathologic groups [19,63,64]:

●Pure collagenoma

●Pure elastoma

●Mixed CTN

However, the histopathologic findings can be very heterogeneous, with most lesions showing both collagen and elastin fiber abnormalities.

Pure collagenoma demonstrates accumulation of dense and coarse collagen fibers in the reticular dermis with either an irregular or regular distribution, sometimes associated with a relative reduction in the number of elastic fibers (picture 6) [63]. Pure elastomas show broad, ramified, interlaced, and sometimes clumped elastic fibers in the reticular dermis, whereas mixed-type CTN show both collagen and elastic fiber abnormalities without a specific pattern (picture 7) [59]. Mucin deposition may be present in elastomas [19,64].

Elastomas are the most common type of CTN found in patients with BOS. Collagenomas or CTN with mixed features of elastoma and collagenoma have been reported in approximately one-third of patients [2].

Bone lesions — Bone lesions of osteopoikilosis (OPK) are not routinely biopsied unless there is doubt about the underlying diagnosis. On histopathologic assessment, sclerotic bone samples demonstrate foci of thickened trabeculae of lamellar bone. These foci vary in thickness but are arranged in a regular pattern, similar to that of normal spongiosus bone. This histology is similar to that of bone islands. Osteoclasts and osteoblasts are present in the sections, although they do not show increased activity [65].

Similar to OPK, biopsy is rarely necessary in melorheostosis. Histopathologic features include variable degrees of cortical bone thickening and fibrotic changes within the bone marrow space. The bone structure is irregular, with mixed areas of lamellar and woven bone and increased vascularity. The associated soft tissue masses are composed of a mixture of osteocartilaginous, fibrovascular, and adipose tissue [65]. There have been rare cases of malignant transformation of melorheostosis with the development of malignant fibrous histiocytoma or osteosarcoma [40].

DIAGNOSIS — 

The diagnosis of BOS is based upon the finding of multiple cutaneous lesions with histopathologic features of connective tissue nevi (CTN) associated with osteopoikilosis (OPK) detected on plain radiographs.

When to suspect Buschke-Ollendorff syndrome — The diagnosis of BOS is suspected in a patient presenting with multiple cutaneous lesions with clinical and histopathologic features of CTN or in a patient with osteopoikilotic lesions found incidentally on radiologic studies for unrelated conditions. (See 'Osteopoikilosis' above.)

Diagnostic workup — The diagnostic workup of a patient with suspected BOS may involve a careful personal and family history, physical examination, skin biopsy, radiologic studies, and genetic testing.

History and physical examination — Patients should be questioned for any personal or family history of skin lesions suggestive of CTN as well as of any bone lesions found on radiologic investigations suggestive of OPK. In a review of 164 published cases of BOS, a positive family history was noted in 92 percent of patients [2].

Any prior imaging studies from the patient and from any suspected affected family members should also be reviewed. Because of the highly variable expressivity of the disease, the extent of specific skin and skeletal findings is unpredictable within any affected family.

Total body skin examination should be performed to identify CTN or other skin lesions. Although CTN are the initial manifestation of BOS in most cases, they may go unnoticed if they are small and in limited number. Musculoskeletal examination is often noncontributory since OPK is usually asymptomatic. (See 'Clinical manifestations' above.)

Skin biopsy — A full-thickness punch biopsy of a cutaneous lesion that also includes perilesional normal skin for comparison will provide an optimal specimen for histopathologic assessment [58]. In addition to routine histologic stains, specific elastic and collagen fiber staining is required to determine the CTN type. (See 'Pathology' above.)

Skeletal lesions are not normally biopsied, as the diagnosis of OPK can usually be confirmed by means of radiographic imaging.

Radiologic imaging — Patients who present with multiple CTN should undergo radiologic investigation with plain radiographs to detect OPK lesions. These lesions typically appear as multiple rounded, dense opacities randomly and symmetrically distributed. (See 'Osteopoikilosis' above.)

The extent of imaging studies required in each patient should be determined on a case-by-case basis. Although a whole-body radiographic bone survey would be most informative, many authors recommend a conservative "high-yield" approach to decrease exposure to radiation, which includes plain anteroposterior radiographs of the hands, wrists, feet, ankles, knees, and pelvis [55,58]. Given the benign nature of BOS, even more limited radiographic examinations can be performed in young children [66].

If performed, computed tomography (CT) shows numerous areas of hyperdense, well-rounded, sclerotic foci [5,67]. Bone scintigraphy is not usually done unless there is a suspicion for intercurrent bone metastases. (See 'Differential diagnosis' below.)

Genetic testing — Genetic testing is not necessary for the diagnosis of BOS in patients with characteristic clinical and radiologic findings. However, if the diagnosis is uncertain, genetic analysis for germline variants in the LEMD3 gene may be helpful to confirm the diagnosis and differentiate BOS from other conditions associated with either CTN or sclerotic bone lesions. (See 'Differential diagnosis' below.)

DIFFERENTIAL DIAGNOSIS

Connective tissue nevi — Connective tissue nevi (CTN) and, in particular, collagenomas can be sporadic or associated with a number of inherited or congenital disorders other than BOS, including [58]:

●Eruptive collagenoma/papular elastorrhexis – Eruptive collagenoma is a rare, sporadic condition of unknown etiology characterized by acquired, numerous, discrete, firm, skin-colored papules and nodules on the trunk and upper extremities [68,69]. Eruptive collagenoma usually arises in children and young adults. On histology, lesions show thickened collagen bundles in the dermis along with decreased or degenerated elastic fibers. Indeed, "eruptive papular collageno-elastopathy" has been proposed as a new term to unify the two indistinguishable entities: eruptive collagenoma and papular elastorrhexis [70]. Fine, dense collagen is also characteristic in both, as well as in nevus anelasticus [71]. The absence of osteopoikilosis (OPK) on plain radiographs of the hands and pelvic bones and lack of a LEMD3 mutation help to differentiate eruptive collagenoma from BOS [61].

●Familial cutaneous collagenoma – Familial cutaneous collagenoma is a rare, autosomal dominant disorder characterized by the development during adolescence of multiple asymptomatic cutaneous nodules on the trunk and upper arms with histologic features of CTN [72,73]. There are no associated bone abnormalities. A splice-site mutation in the LEMD3 gene has been demonstrated in one kindred with familial cutaneous collagenoma [74]. This finding suggests that familial cutaneous collagenoma and BOS may be allelic disorders.

●Tuberous sclerosis complex – Tuberous sclerosis complex is an inherited, neurocutaneous disorder characterized by pleomorphic features involving many organ systems, including multiple benign hamartomas of the brain, eyes, heart, lung, liver, kidney, and skin. Among the characteristic skin lesions, collagenoma and the so-called "shagreen patches" are firm, skin-colored to yellow-pink nodules or plaques with a dimpled surface that demonstrate histopathologic features of CTN (picture 8). (See "Tuberous sclerosis complex: Clinical features".)

●Multiple endocrine neoplasia type 1 – Multiple endocrine neoplasia type 1 is an autosomal dominant disorder characterized by a predisposition to tumors of the parathyroid glands, anterior pituitary, and pancreatic islet cells and a predisposition to nonendocrine tumors including lipomas, facial angiofibromas, collagenomas, and melanomas [75]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

●Proteus syndrome – Proteus syndrome is an extremely rare disorder comprising of malformations and overgrowth of multiple tissues. When present, a cerebriform plantar collagenoma (picture 9) is almost pathognomonic for Proteus syndrome. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Proteus-like syndrome'.)

●Fibroblastic connective tissue nevus – Fibroblastic connective tissue nevus is a benign, cutaneous, mesenchymal lesion of fibroblastic/myofibroblastic lineage [76]. This type of CTN, formerly called a cellular CTN [63], is not found in BOS. Fibroblastic connective tissue nevus usually presents as a solitary, congenital, slow-growing, large plaque or subcutaneous mass that is often erythematous. It has no malignant potential [77,78]. Biopsy shows involvement of the deep reticular dermis and extension into the subcutis by irregular bundles of bland fibroblasts that may or may not stain with CD34 or smooth muscle actin (SMA) and entrap skin appendages [77,78].

●Eosinophilic fasciitis – Eosinophilic fasciitis (Schulman syndrome) is characterized by inflammation and sclerosis of the fascia and the subcutaneous tissue of the limbs associated with peripheral eosinophilia. The onset is acute, with painful edema of the extremities, followed by progressive induration that symmetrically involves the extremities (particularly the lower limbs (picture 10)). The skin develops an irregular, "peau d'orange" appearance. A full-thickness skin biopsy deep to the fascia confirms the diagnosis. (See "Eosinophilic fasciitis".)

●Morphea – CTN may be misdiagnosed as morphea (localized scleroderma) [79], an inflammatory disease characterized by the development of indurated, fibrotic skin lesions that commonly affect the limbs (picture 11A-B). Early lesions typically have a lilac ring with a porcelain white center, which is absent in CTN. With time, the induration improves and leaves a hyperpigmented patch.

A skin biopsy of an early inflammatory lesion of morphea shows an intense inflammatory infiltrate with lymphocytes, plasma cells, macrophages, eosinophils, and mast cells. As sclerosis progresses, lesions demonstrate homogenization of the papillary dermis and thickened collagen bundles extending into the reticular dermis. In contrast, CTN is characterized by grossly thickened collagen fibers, normal vascular structures and skin adnexa, and absence of significant perivascular and perineural inflammatory infiltrate [79]. (See "Juvenile localized scleroderma" and "Morphea (localized scleroderma) in adults: Pathogenesis, clinical manifestations, and diagnosis".)

Osteopoikilosis — The differential diagnosis of osteopoikilosis (OPK) includes:

●Osteoblastic bone metastases – Osteoblastic bone metastases are the most important differential diagnosis of OPK (see "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults"). Cancers associated with predominantly osteoblastic bone metastasis include:

•Prostate cancer

•Small cell lung cancer

•Breast cancer

•Carcinoid

•Hodgkin lymphoma

•Medulloblastoma

Osteoblastic metastatic lesions are commonly located in the axial skeleton and proximal femur, are more asymmetric than OPK, and are often associated with pain. Skeletal scintigraphy with technetium-99m is the initial and most widely used method to detect osteoblastic bone metastases, which characteristically produce "hot spots" on bone scans due to increased radioisotope uptake [23,67,80]. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Detection and diagnosis'.)

●Benign focal osteosclerotic lesions – Osteoid osteoma is a benign, bone-forming tumor, most commonly located in the long bones (eg, femur, tibia) and spine. It presents during the second decade of life in most cases and is typically associated with pain. Radiographs show a small, round lucency (nidus) with a sclerotic margin. (See "Nonmalignant bone lesions in children and adolescents".)

Enostosis (bone island) is a compact focus of cortical bone within the spongiosa or cancellous bone. Enostosis presents as oval, <1 cm, unilateral lesions that mainly involve the axial skeleton or long bones [81]. Enostosis is asymptomatic and typically an incidental finding on radiographs.

Focal osteosclerotic lesions may also occur in adults with systemic mastocytosis, but in contrast with OPK, they are predominantly located in the axial skeleton [82,83]. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

Sclerotic bone lesions are a common finding associated with tuberous sclerosis complex [84,85], varying in size from 0.2 mm to 3 cm in the cranial bones, vertebrae, ribs, and pelvis. (See "Tuberous sclerosis complex: Clinical features".)

●Other hereditary sclerosing bone dysplasias – OPK may be confused with other rare, hereditary sclerosing bone dysplasias, including osteopetrosis, pyknodysostosis, osteopathia striata, and multiple diaphyseal sclerosis (ribbing disease) [24,86,87]. (See "Skeletal dysplasias: Specific disorders", section on 'High bone density' and "Skeletal dysplasias: Approach to evaluation".)

●Other – Skeletal fluorosis and renal osteodystrophy may also present with areas of osteocondensation that favor the axial skeleton [88]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

MANAGEMENT — 

BOS is a benign disorder that does not require treatment. A correct diagnosis is therefore essential to spare patients from unnecessary investigations and interventions [60]. However, some patients may desire surgical excision of connective tissue nevi (CTN) because of cosmetic concerns.

Analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) may be indicated for pain relief in patients with osteopoikilosis (OPK) who are symptomatic [23].

For patients with melorheostosis associated with severe pain and limitation of function, there are anecdotal reports of benefit with systemic bisphosphonates [89-91]. Physical therapy with stretching is important in melorheostosis to keep good range of motion and minimize contractures [26].

PROGNOSIS AND FOLLOW-UP — 

BOS is a benign condition and generally carries an excellent prognosis. Patients, parents, and/or caregivers should be reassured that they can live an active life and expect a normal lifespan.

There is no specific follow-up required for most patients with BOS, especially if they are asymptomatic. Baseline documentation of skin and bone lesions when discovered is important in order to prevent any misdiagnoses in the future.

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Buschke-Ollendorff syndrome (BOS) is a rare, inherited, 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 and characterized by the presence of sclerotic bone lesions (osteopoikilosis [OPK]) and, less commonly, melorheostosis in association with connective tissue nevi (CTN). (See 'Introduction' above and 'Genetics' above.)

●Clinical presentation – CTN present as disseminated, flesh-colored or yellowish papules or as more localized, grouped nodules or plaques (picture 2). OPK is a sclerosing bone dysplasia that typically affects the small tubular bones of the hands and feet, epiphyseal region of the long bones, and the pelvic bones. OPK is usually asymptomatic and an incidental finding on imaging studies for unrelated conditions, but some patients may report articular pain. Melorheostosis is a rare, sclerosing dysplasia of the bone with a radiologic appearance of "dripping candle wax." It is typically unilateral with a predilection for the lower limbs and is asymptomatic in most cases. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of BOS is based upon the finding of multiple cutaneous lesions with histopathologic features of CTN associated with OPK detected on plain radiographs. Genetic analysis for germline mutations in the LEMD3 gene can confirm the diagnosis in uncertain cases. (See 'Diagnosis' above.)

●Management – BOS is a benign disorder that does not require treatment. Surgical excision of CTN may rarely be performed in some patients for cosmetic reasons. Analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) may be indicated in patients with OPK who are symptomatic. (See 'Management' above.)