Buschke–Ollendorff syndrome

Rare autosomal dominant connective tissue disorder with skin nevi and osteopoikilosis

Buschke–Ollendorff syndrome
Synonyms	Dermatofibrosis lenticularis disseminata, dermato-osteopoikilosis, familial cutaneous collagenoma, BOS
Pronounce	N/A
Specialty	Dermatology, Medical genetics, Orthopedics, Radiology
Symptoms	Connective tissue nevi, osteopoikilosis, firm skin papules or plaques, bone pain in some patients
Complications	Bone pain, joint pain, cosmetic concerns, diagnostic confusion with sclerotic bone metastases, rarely reported cardiac or hearing complications
Onset	Usually childhood or adolescence; may be recognized incidentally in adulthood
Duration	Lifelong
Types	N/A
Causes	Usually heterozygous loss-of-function pathogenic variants in LEMD3
Risks	Family history of autosomal dominant connective tissue disorder or osteopoikilosis
Diagnosis	Clinical examination, skin biopsy, radiography, bone scan, genetic testing
Differential diagnosis	Osteopoikilosis, melorheostosis, sclerotic bone metastasis, tuberous sclerosis, eruptive collagenoma, pseudoxanthoma elasticum
Prevention	N/A
Treatment	Usually reassurance and monitoring; symptomatic treatment for pain or complications
Medication	N/A
Prognosis	Usually good; most cases are benign
Frequency	Rare
Deaths	N/A

Buschke–Ollendorff syndrome is a rare inherited connective tissue disease characterized by connective tissue nevi of the skin and areas of increased bone density called osteopoikilosis. It is most often inherited in an autosomal dominant pattern and is usually caused by heterozygous loss-of-function variants in the LEMD3 gene, also called MAN1.Buschke-Ollendorff syndrome(link). MedlinePlus Genetics.Buschke-Ollendorff syndrome(link). UpToDate.

The syndrome is also known as dermatofibrosis lenticularis disseminata, dermato-osteopoikilosis, and familial cutaneous collagenoma. The disorder was named after Abraham Buschke and Helene Ollendorff Curth, who described the association of disseminated skin lesions and osteopoikilosis in 1928."Buschke-Ollendorff syndrome: a novel case series and systematic review".British Journal of Dermatology.2016;174(4)

723-729.doi:10.1111/bjd.14366.PMID:26708699.

Overview

Buschke–Ollendorff syndrome primarily affects the skin and bones. The skin findings are usually small, firm, non-tender papules, nodules, or plaques caused by abnormalities of dermal connective tissue. The bone findings are usually multiple small, round or ovoid sclerotic spots in the skeleton, known as osteopoikilosis. These bone lesions are often discovered incidentally on X-ray and may be mistaken for sclerotic bone metastasis if the diagnosis is not recognized.

Most affected people are otherwise healthy. Many cases are mild and do not require treatment. Diagnosis is important because recognition of osteopoikilosis can prevent unnecessary cancer workups, biopsies, or anxiety when multiple sclerotic bone lesions are seen on imaging.

Signs and symptoms

The clinical features vary. Some people have only skin findings, some have only radiographic bone findings, and others have both.

Skin findings

• Connective tissue nevus - A benign skin lesion caused by excess or abnormal dermal connective tissue.
• Dermatofibrosis lenticularis disseminata - Multiple firm papules or nodules caused by collagen-rich connective tissue nevi.
• Elastoma - A connective tissue nevus with increased or abnormal elastic fibers.
• Collagenoma - A connective tissue nevus with increased collagen.
• Papule - A small raised skin lesion.
• Nodule - A deeper or larger raised lesion that may be firm to touch.
• Plaque - A broader raised or thickened area of skin.
• Flesh-colored lesion - A common appearance of Buschke–Ollendorff skin lesions.
• Yellowish skin lesion - Some lesions appear yellow or yellow-white.
• Asymptomatic skin lesion - Most lesions are painless and not itchy.
• Childhood onset - Skin lesions often begin in childhood or adolescence.
• Cosmetic concern - Lesions may be noticed because of appearance rather than symptoms.

Bone findings

• Osteopoikilosis - Multiple small sclerotic bone islands, usually near joints and in the epiphyses or metaphyses.
• Bone island - A small focus of compact bone within cancellous bone.
• Sclerotic bone lesion - An area of increased bone density on imaging.
• Metaphysis - The growing region near the end of a long bone, often involved in osteopoikilosis.
• Epiphysis - The end region of a long bone, often near a joint.
• Pelvis - A common site where osteopoikilosis may be seen.
• Hands - Hand radiographs may show multiple small sclerotic foci.
• Feet - Foot radiographs may show osteopoikilosis.
• Long bones - Osteopoikilotic lesions may be present near the ends of long bones.
• Bone pain - Usually absent, but mild pain has been reported in some patients.
• Joint pain - May occur in some affected individuals, though most are asymptomatic.

Other reported findings

Most people have only cutaneous and skeletal findings, but other associations have been reported in some cases.

• Melorheostosis - A sclerosing bone dysplasia that can rarely overlap with LEMD3-related disease.
• Aortic stenosis - Reported rarely in association with the syndrome.
• Hearing loss - Reported rarely; evaluation depends on symptoms.
• Developmental normality - Intelligence and overall development are usually normal.
• Variable expressivity - Family members with the same LEMD3 variant may have different skin or bone findings.

Causes

Buschke–Ollendorff syndrome is usually caused by heterozygous pathogenic variants in LEMD3.

• LEMD3 - A gene that encodes an inner nuclear membrane protein also called MAN1.
• MAN1 - The protein encoded by LEMD3, involved in regulation of signaling pathways.
• Inner nuclear membrane - The membrane location where LEMD3/MAN1 functions.
• Loss-of-function mutation - A mutation that reduces or abolishes normal gene function.
• Haploinsufficiency - A mechanism in which one functional copy of a gene is not enough for normal function.
• Chromosome 12 - LEMD3 is located on chromosome 12q14.3.
• Pathogenic variant - A disease-causing genetic change.

LEMD3 normally helps regulate signaling by transforming growth factor beta and bone morphogenetic protein pathways. When LEMD3 function is reduced, altered signaling may contribute to abnormal skin connective tissue and sclerotic bone lesions."Laminopathies and the long strange trip from basic cell biology to therapy".Journal of Clinical Investigation.2009;119(7)

1825-1836.doi:10.1172/JCI37679.PMID:19587457.PMC:2701866.

Inheritance

Buschke–Ollendorff syndrome is usually inherited in an autosomal dominant pattern.

• Autosomal dominant inheritance - One altered copy of LEMD3 can be sufficient to cause the disorder.
• Familial disorder - Multiple family members may be affected across generations.
• Variable expressivity - Some relatives may have skin lesions, others may have osteopoikilosis, and some may have both.
• Reduced penetrance - Some people with a pathogenic variant may have subtle or unrecognized features.
• De novo mutation - A new pathogenic variant may occur in a person with no known family history.
• Genetic counseling - Recommended when a familial pathogenic variant is identified.

Each child of an affected individual has a 50 percent chance of inheriting the familial pathogenic variant, although the severity and type of findings cannot be predicted reliably.

Pathophysiology

Buschke–Ollendorff syndrome is sometimes discussed among laminopathies or nuclear-envelope related disorders because LEMD3/MAN1 is an inner nuclear membrane protein. However, its main clinical manifestations are in the skin and bone.

• Transforming growth factor beta - A signaling pathway regulated in part by LEMD3/MAN1.
• Bone morphogenetic protein - A signaling pathway important in bone formation and regulated in part by LEMD3/MAN1.
• SMAD protein - Intracellular signaling protein involved in TGF-beta and BMP pathways.
• Osteoblast - Bone-forming cell that may be affected by abnormal signaling.
• Dermis - Skin layer where connective tissue nevi arise.
• Collagen - Structural protein increased in collagenomas.
• Elastic fiber - Connective tissue component increased or altered in elastomas.
• Sclerotic bone - Dense bone visible on radiographs in osteopoikilosis.

Altered LEMD3 function may increase or dysregulate signaling involved in connective-tissue and bone formation. This helps explain the combination of skin nevi and sclerotic bone lesions.

Diagnosis

Diagnosis is based on clinical examination, imaging, histopathology, family history, and genetic testing.

Clinical examination

• Skin examination - Identifies firm papules, nodules, plaques, collagenomas, or elastomas.
• Musculoskeletal examination - Assesses bone pain, joint pain, deformity, or limited motion.
• Family history - Looks for relatives with similar skin lesions or osteopoikilosis.
• Dermatology evaluation - Helps identify connective tissue nevi and distinguish them from other skin lesions.
• Orthopedic evaluation - Useful when bone pain, deformity, or functional limitation is present.

Imaging

• X-ray - Often shows multiple small, round or ovoid sclerotic bone lesions.
• Skeletal survey - May show widespread osteopoikilosis.
• Bone scan - Usually normal or low-uptake in osteopoikilosis, helping distinguish it from metastases.
• Computed tomography - Can better characterize sclerotic bone lesions when needed.
• Magnetic resonance imaging - May be used for symptomatic bones or uncertain lesions.
• Ultrasound - May be used for selected soft-tissue or skin lesions, though radiography is more typical for bone findings.

Skin biopsy and histology

• Skin biopsy - May confirm connective tissue nevus when diagnosis is uncertain.
• Histopathology - Shows changes in dermal collagen or elastic tissue.
• Elastoma - Shows increased or abnormal elastic fibers.
• Collagenoma - Shows increased collagen bundles.
• Dermatofibrosis lenticularis disseminata - Refers to collagen-rich disseminated connective tissue nevi.
• Special stain - Elastic tissue stains or collagen stains may help characterize the lesion.

Genetic testing

• LEMD3 genetic testing - Can confirm the molecular diagnosis.
• Skeletal dysplasia gene panel - May include LEMD3 and related bone dysplasia genes.
• Exome sequencing - May be considered in atypical presentations.
• Deletion-duplication analysis - May be useful if sequencing is negative and suspicion remains high.
• Variant interpretation - Important because variants must be correlated with clinical and radiographic findings.
• Cascade testing - Testing relatives may identify mildly affected family members.

Differential diagnosis

The differential diagnosis includes other disorders causing connective tissue nevi, sclerotic bone lesions, or both.

• Osteopoikilosis - May occur without obvious skin lesions.
• Melorheostosis - Sclerosing bone dysplasia with flowing cortical hyperostosis.
• Sclerotic bone metastasis - Important radiographic mimic, especially in adults with cancer history.
• Osteoblastic metastasis - Metastatic bone lesion that can appear dense on imaging.
• Mastocytosis - May cause skin lesions and bone findings.
• Tuberous sclerosis - May include connective tissue nevi such as shagreen patches.
• Pseudoxanthoma elasticum - Disorder of elastic tissue with characteristic skin, eye, and vascular findings.
• Eruptive collagenoma - Multiple collagen-rich connective tissue nevi without osteopoikilosis.
• Familial cutaneous collagenoma - Inherited collagenoma disorder.
• Elastoma - Elastic tissue nevus that may be isolated or syndromic.
• Gardner syndrome - Can cause osteomas and skin findings but has different inheritance and cancer risk.
• Osteopathia striata - Linear striations in bone distinct from osteopoikilosis.
• Paget disease of bone - Bone remodeling disorder that may mimic other sclerotic disorders.

Management

Most patients do not need specific treatment. Management is based on symptoms, complications, and diagnostic reassurance.

General management

• Reassurance - Appropriate for asymptomatic patients with typical findings.
• Observation - Periodic follow-up may be sufficient for mild cases.
• Patient education - Helps patients understand the benign nature of typical osteopoikilosis.
• Family screening - May be useful when an autosomal dominant pattern is suspected.
• Genetic counseling - Helps explain inheritance and recurrence risk.
• Medical record documentation - Important so future imaging is not mistaken for metastatic disease.

Skin lesion management

• Dermatology follow-up - Useful for diagnosis or symptomatic skin lesions.
• Cosmetic treatment - Considered when lesions are bothersome in appearance.
• Surgical excision - May be used for isolated symptomatic or cosmetically concerning nodules.
• Biopsy - Used when the lesion is atypical or diagnosis is uncertain.
• Scar management - Considered after removal of lesions.

Bone and joint management

• Pain management - Used when bone pain or joint pain is present.
• Orthopedic referral - Appropriate for persistent pain, deformity, or functional limitation.
• Physical therapy - May help if joint symptoms or functional problems occur.
• Imaging follow-up - Considered when lesions are atypical, painful, changing, or clinically concerning.
• Avoidance of unnecessary biopsy - Typical osteopoikilosis should be recognized to prevent unnecessary invasive procedures.

Management of rare complications

• Aortic stenosis - Requires cardiology evaluation if a murmur, symptoms, or imaging abnormality is present.
• Hearing loss - Requires audiology and otolaryngology evaluation when present.
• Melorheostosis - Symptomatic cases may need orthopedic, pain, or rehabilitation care.
• Functional limitation - May require rehabilitation, orthotics, or specialist referral.

Prognosis

The prognosis is usually excellent. Most affected people have benign skin and bone findings and a normal life expectancy.

• Benign course - Most cases do not progress to serious disease.
• Normal life expectancy - Expected for most affected individuals.
• Stable bone lesions - Osteopoikilotic lesions are often stable over time.
• Persistent skin lesions - Connective tissue nevi may persist or slowly increase.
• Variable symptoms - Some patients have pain or cosmetic concerns, while others are asymptomatic.
• Diagnostic importance - Correct diagnosis prevents confusion with metastatic bone disease.

Epidemiology

Buschke–Ollendorff syndrome is rare. Published estimates often cite a frequency of approximately 1 in 20,000 people, although the true frequency is uncertain because mild cases may be undiagnosed. The disorder affects both males and females.

Osteopoikilosis may be discovered incidentally on imaging performed for unrelated reasons. Skin findings may be subtle and overlooked, especially when small or asymptomatic.

History

The syndrome is named after Abraham Buschke and Helene Ollendorff Curth, who described the association of disseminated connective tissue skin lesions and osteopathia condensans disseminata in 1928.

• Abraham Buschke - German dermatologist associated with the original description.
• Helene Ollendorff Curth - Dermatologist associated with the original description.
• Dermatofibrosis lenticularis disseminata - Historical name for the skin findings.
• Osteopathia condensans disseminata - Historical term related to osteopoikilosis.
• LEMD3 - Gene later identified as the major molecular cause.

Patient education

Patients should understand that Buschke–Ollendorff syndrome is usually benign but inherited.

• Autosomal dominant inheritance - The condition can be passed from parent to child.
• Connective tissue nevus - Skin lesions are benign but may be cosmetically noticeable.
• Osteopoikilosis - Bone spots are usually benign and often need no treatment.
• Cancer mimic - Patients should tell clinicians about the diagnosis before future imaging.
• Genetic counseling - Helps families understand inheritance and testing.
• Pain symptoms - New or persistent bone pain should still be evaluated.
• Hearing evaluation - Appropriate if hearing symptoms occur.
• Cardiology evaluation - Appropriate if a heart murmur, chest symptoms, or suspected aortic stenosis occurs.

When to seek medical care

Medical evaluation is appropriate when symptoms are new, progressive, or atypical.

• New bone pain - Persistent or focal bone pain should be assessed.
• Changing skin lesion - Rapidly growing, painful, ulcerated, or unusual lesions should be evaluated.
• Joint limitation - Reduced movement or functional limitation may need orthopedic care.
• History of cancer - Sclerotic bone lesions in a person with cancer history require careful interpretation.
• Hearing loss - Hearing change should prompt audiology evaluation.
• Heart murmur - Possible aortic stenosis should be evaluated by a clinician.
• Family history - Relatives with similar skin or bone findings may benefit from genetic counseling.
• Uncertain imaging - A radiologist or specialist should review unclear sclerotic bone lesions.

See also

• Osteopoikilosis
• Connective tissue nevus
• Melorheostosis
• LEMD3
• MAN1
• Laminopathy
• Bone island
• Sclerotic bone lesion
• Dermatology
• Medical genetics
• Orthopedics
• Radiology
• List of cutaneous conditions
• Autosomal dominant disorder

Further reading

• "Buschke-Ollendorff syndrome: a novel case series and systematic review".British Journal of Dermatology.2016;174(4)

723-729.doi:10.1111/bjd.14366.PMID:26708699.

• "Clinical and Histopathological Characteristics of Buschke-Ollendorff Syndrome with LEMD3 Germline Stopgain Mutation p.R678* Presenting as Multiple Subcutaneous Nodules with Mucin Deposition".Acta Dermato-Venereologica.2025;Full text.
• "Buschke-Ollendorff syndrome presenting with asymptomatic connective tissue nevi".JAAD Case Reports.2022;Full text.

External links

• MedlinePlus Genetics - Buschke-Ollendorff syndrome
• DermNet - Buschke-Ollendorff syndrome
• Orphanet - Buschke-Ollendorff syndrome
• NCBI MedGen - Dermatofibrosis lenticularis disseminata
• NCBI MedGen - Osteopoikilosis
• PubMed - Buschke-Ollendorff syndrome systematic review

1. Buschke-Ollendorff syndrome