Clinical characteristics.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Death usually occurs before age 50 years. The clinical course of PLOSL can be divided into four stages: (1) The latent stage is characterized by normal early development. (2) The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. (3) In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social issues. (4) The late neurologic stage is characterized by progressive dementia and loss of mobility.

Diagnosis/testing.

The diagnosis of PLOSL can be established in a proband with radiologically demonstrable polycystic osseous lesions, frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Identification of biallelic pathogenic variants in TYROBP or TREM2 confirms the diagnosis since radiographic and clinical features may be inconclusive.

Management.

Treatment of manifestations: Treatment is symptomatic. Standard orthopedic management of fractures; pain management; supportive orthopedic devices may be helpful; symptomatic medication may be applied for behavioral symptoms; psychological support and early education of family members and caregivers; anti-seizure medication can be used to prevent epileptic seizures and secondary worsening of the condition.

Surveillance: Clinical evaluation for evidence of fractures; neurologic and neuropsychiatric examination with frequency as needed; assess family/caregiver needs at each visit.

Genetic counseling.

PLOSL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TREM2 or TYROBP pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with PLOSL are not at risk of developing PLOSL. However, individuals heterozygous for a TYROBP pathogenic variant may have cyst-like bone lesions without presenile dementia, and population studies of individuals heterozygous for the TYROBP 5.2-kb deletion show an increased risk for developing Alzheimer disease. Once the PLOSL-related pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk family members, predictive testing for at-risk sibs, and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

PLOSL should be suspected in individuals with the following features:

• Radiologically demonstrable polycystic osseous lesions and fractures of the wrists and ankles after minor trauma at the mean age of 27 years (range: 18-33 years) [Paloneva et al 2001]. Cyst-like lesions and loss of bone trabeculae are most conspicuous in the fingers and in the carpal and tarsal bones (see Figure 1 and Figure 2) [Mäkelä et al 1982, Nwawka et al 2014]. See also Figures 2 and 3 in Nwawka et al [2014]. If an individual has multiple lytic or cyst-like lesions on radiographs primarily in the distal extremities, CT and MRI are useful in establishing a diagnosis [Nwawka et al 2014]. In some affected individuals, PLOSL can manifest without cyst-like bone lesions [Chouery et al 2008, Guerreiro et al 2013, Le Ber et al 2014, Samanci et al 2021, Barczak et al 2024].
• Frontal lobe syndrome in the fourth decade manifested by euphoria and loss of judgment and social inhibitions
• Progressive presenile dementia beginning in the fourth decade. Dementia is mild at the onset of neurologic symptoms. The disease culminates in severe dementia; affected individuals typically die before age 50 years.

Figure 1.

A radiograph of the hand of a person with PLOSL demonstrates multiple cyst-like lesions and loss of bone trabeculae.

Figure 2.

A radiograph shows a well-demarcated cyst-like lesion (arrow) in the talus of a person with PLOSL, age 28 years. Reprinted with permission from Paloneva et al [2001]

Neuroradiologic findings (See Figure 3, 4, and 5.)

Figure 3.

T₂-weighted brain MRI of an individual with PLOSL age 33 years shows very low signal intensity in the putamina. Signal intensities are higher in the central white matter (including internal capsules) than in the deep gray matter structures. The central (more...)

Figure 4.

T₂-weighted brain MRI of an individual age 32 years displays severely enlarged cerebral sulci and lateral ventricles. Note high periventricular signal intensity spreading toward periphery. The arcuate fibers are partly spared. Paloneva et al [2001]; reprinted (more...)

Figure 5.

Brain MRI. High-intensity lesions in the bilateral periventricular white matter on an axial FLAIR image (TR: 8000 ms, TE: 120 ms) Kuroda et al [2007]; reprinted with permission from Elsevier

• Cerebral atrophy. Dilated ventricles, atrophy of the basal ganglia and thalamus, prominent sulci, or thin corpus callosum is a constant finding on CT and MRI and usually is evident before the appearance of neuropsychiatric symptoms. Cerebellar atrophy may also be present [Paloneva et al 2001, Klünemann et al 2005, Solje et al 2014, Samanci et al 2021].
• Bilateral calcifications of the basal ganglia are usually but not always found on CT and MRI. The basal ganglia and thalamus, particularly the putamina, may show very low signal intensities on T₂-weighted MRI [Klünemann et al 2005]. Calcifications may occur before central nervous system (CNS) clinical manifestations [Paloneva et al 2001, Solje et al 2014, Samanci et al 2021].
• Increased signal intensities of the cerebral white matter are usually found on T₂-weighted images after the appearance of clinical CNS symptoms. These white matter changes are diffuse and have no region of predilection, apart from the frontal lobes. The changes are usually centrally located (periventricular white matter, centrum semiovale, internal capsules). As the disease progresses, the high periventricular signal intensity spreads toward the periphery, sparing most of the arcuate fibers. In some instances, the white matter changes also extend to the cortex. However, the white matter may look normal in some individuals with CNS manifestations [Paloneva et al 2001, Guerreiro et al 2013, Samanci et al 2021].
• SPECT and PET findings are variable. Hypoperfusion of the cortical areas, thalamus, and basal ganglia have been reported [Klünemann et al 2005, Takeshita et al 2005].

Electroencephalogram is normal early in the disease. With advancing disease, individuals show accentuation of theta and delta activity. Initially, theta is typically rhythmic, 6-8 Hz, dominating in the centrotemporal areas; later, diffuse slowing becomes evident. In the late stage of the disease, irritative activity usually appears on EEG [Paloneva et al 2001].

Bone biopsy is not required to establish the diagnosis. The cyst-like bone lesions are filled with lipid material that microscopically consists of characteristic 1-2 µm thick lipid membranes and amorphous lipid substance.

Establishing the Diagnosis

Clinical Description

The clinical course of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) can be divided into four stages: latent, osseous, early neurologic, and late neurologic [Klünemann et al 2005].

Latent stage. Early development is normal.

Osseous stage (3rd decade of life). The first symptoms of PLOSL appear in early adulthood as pain and tenderness, mostly in the ankles and feet, usually following strain or a minor accident. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities [Paloneva et al 2001]. The first fractures usually occur shortly before age 30 years; however, affected individuals may have had pain and swelling of the ankles and wrists after strain for years. The fractures heal well. It is important to note that some individuals may present with neurologic symptoms without any preceding osseous manifestations [Paloneva et al 2001, Bock et al 2013, Guerreiro et al 2013].

Early neurologic stage (4th decade of life). Personality changes begin insidiously in the fourth decade. Affected individuals show progressive loss of judgment, leading to serious social consequences, including divorce, unemployment, and financial trouble [Paloneva et al 2001, Ilonen et al 2012, Samanci et al 2021]. Some individuals may attempt suicide. The full-blown picture of frontal lobe syndrome subsequently appears: loss of judgment; euphoria; lack of social inhibitions, including Witzelsucht; disturbance of concentration; and lack of insight, libido, and motor persistence. Parkinsonism is common [Samanci et al 2021].

Progressive signs of upper motor neuron involvement (spasticity, extensor plantar reflexes) are noticed. With advancing disease, lack of initiative and activity conceal the aforementioned neurologic manifestations [Paloneva et al 2001]. Protein and total tau concentrations may be increased in cerebrospinal fluid [Samanci et al 2021].

Memory disturbances begin at approximately the same age as the personality changes and are best detectable by neuropsychological tests [Vanhanen et al 2013]. The amnestic memory disturbance is less severe than the decline in frontal cognitive functions and personality change, and affected individuals retain basic personal information until the last stage of the disease.

Other disturbances of higher cortical function, such as motor aphasia, agraphia, acalculia, and apraxia, appear only at the last stage of the disease.

Affected individuals may develop postural dyspraxia: they walk or sit in peculiar skewed postures. Involuntary athetotic or choreatic movements or myoclonic twitches are common. Individuals who reach their mid-thirties frequently experience epileptic seizures. In some individuals, impotence or lack of libido and urinary incontinence are among the first symptoms [Paloneva et al 2001].

Late neurologic stage. In the last stage of the disease, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp and mouth-opening reflexes, as well as the sucking reflex, may become noticeable. Affected individuals typically die before age 50 years [Paloneva et al 2001].

Bone pathology. The cyst-like bone lesions are filled with lipid material that microscopically consists of characteristic 1-2 µm thick lipid membranes and amorphous lipid substance [Kitajima et al 1989] (see Figure 6).

Figure 6.

Contents of a cyst-like bone lesion. Microscopically, the lesions contain (C) convoluted lipid membrane structures filled with amorphous lipid substance and (F) fat. (B) Bone trabeculae are partially preserved. Scale bar corresponds to 250 μm (more...)

Neuropathology. Generalized cerebral gyral atrophy with frontal accentuation is observed at autopsy. The corpus callosum is abnormally thin. The central white matter is severely reduced in amount, grayish, and tough. The basal ganglia, particularly the caudate nuclei, are variably reduced in size [Paloneva et al 2001]. All affected individuals show marked hydrocephalus ex vacuo.

Histologic examination reveals scattered neurons showing features of central chromatolysis. Intraneuronal or glial pathologic inclusions have not been observed [Paloneva et al 2001]. Neuronal loss as well as astrocytic proliferation and hypertrophy are observed in the caudate nuclei. In addition, scattered calcospherites are seen, particularly in the putamina and globi pallidi [Paloneva et al 2001]. Thalamic degeneration may occur [Kobayashi et al 2000]. Affected individuals show advanced loss of axons and myelin and a pronounced astrocytic reaction in the centrum semiovale, accentuated in the frontal and temporal lobes, with moderate involvement of the gyral white matter. In addition, widespread activation of microglia in the cerebral white matter is seen [Paloneva et al 2001]. Scattered small arterioles and capillaries in the deep frontal and temporal white matter show concentric thickening of the vascular wall with multiple thickened basement membranes and narrowing or obliteration of the lumen [Paloneva et al 2001]. The cerebral cortices are less severely affected [Aoki et al 2011].

Pathologic findings in other organs. Characteristic lipomembranous changes have been described in systemic adipose tissue [Nasu et al 1973]. Pathologic manifestations in organs other than the central nervous system (CNS) and the skeletal system have been insufficiently characterized.

Genotype-Phenotype Correlations

Individuals with homozygous pathogenic variants in TYROBP or TREM2 seem to develop similar CNS manifestations [Paloneva et al 2002, Klünemann et al 2005].

Some TREM2 pathogenic variants have been reported to cause a dementia syndrome resembling PLOSL without evident osseous manifestations [Chouery et al 2008, Guerreiro et al 2013, Le Ber et al 2014, Samanci et al 2021, Barczak et al 2024].

Nomenclature

The first affected individuals were described in the 1960s independently by Järvi and Hakola in Finland and Nasu in Japan.

In the early literature, PLOSL was also known as membranous lipodystrophy. This term is outdated and should not be used.

Prevalence

The prevalence of PLOSL is highest in Finland due to a TYROBP founder variant, deletion of exons 1-4 (c.-2897_277-1227del5265), with an estimated prevalence of 1-2:1,000,000 [Pekkarinen et al 1998]. The prevalence of PLOSL in other countries is lower; no detailed data are available. Most affected individuals have been diagnosed in Japan (>100 individuals) [Pekkarinen et al 1998].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PLOSL, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for PLOSL; only symptomatic treatment is available. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended. The interval of surveillance for bone lesions and neurologic and psychiatric manifestations must be determined individually.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Calcium substitution alone has been shown to be ineffective in preventing the development of the osseous manifestations. The effect of bisphosphonates has not been studied.

It has been speculated that nonsteroidal anti-inflammatory drugs could slow the progression of PLOSL; however, clinical trials have not been performed.

A single individual with PLOSL improved temporarily when taking donepezil [D Hemelsoet, personal observation]. Clinical trials in a series of individuals with PLOSL have not been reported.

Mode of Inheritance

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a TREM2 or TYROBP pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a TREM2 or TYROBP pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband with PLOSL are not at risk of developing PLOSL. However, individuals heterozygous for a TYROBP pathogenic variant may have cyst-like bone lesions without presenile dementia [Shboul et al 2019, Martiskainen et al 2025], and population studies of individuals heterozygous for the TYROBP 5.2-kb deletion show an increased risk for developing Alzheimer disease [Martiskainen et al 2025].

Sibs of a proband

• If both parents are known to be heterozygous for a PLOSL-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• All individuals reported to date with biallelic TREM2 or TYROBP pathogenic variants have had manifestations of PLOSL by age 40 years.
• The heterozygous sibs of a proband with PLOSL are not at risk of developing PLOSL. However, individuals heterozygous for a TYROBP pathogenic variant may have cyst-like bone lesions without presenile dementia [Shboul et al 2019, Martiskainen et al 2025], and population studies of individuals heterozygous for the TYROBP 5.2-kb deletion show an increased risk for developing Alzheimer disease [Martiskainen et al 2025].

Offspring of a proband. Unless an affected individual's reproductive partner also has PLOSL or is heterozygous for a PLOSL-related pathogenic variant, offspring will be obligate heterozygotes for a TREM2 or TYROBP pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a TREM2 or TYROBP pathogenic variant.

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the PLOSL-related pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being affected or heterozygous.
• Carrier testing should be considered for the reproductive partners of known heterozygotes and for the reproductive partners of individuals affected with PLOSL, particularly if both partners are of the same ancestry (see Prevalence). A founder variant has been identified in the Finnish population (see Table 6).

Predictive testing (i.e., testing of asymptomatic at-risk sibs of a proband)

• Predictive testing for at-risk sibs is possible once the PLOSL-related pathogenic variants have been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years) for typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of PLOSL, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the PLOSL-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for PLOSL are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TYROBP encodes TYRO protein tyrosine kinase-binding protein (TYROBP), which is a transmembrane adaptor protein that mediates the activation of a wide variety of cells of myeloid and lymphoid origin. On the cell plasma membrane, TYROBP is expressed as a disulfide-bonded homodimer linked to the associated cell surface receptors. Numerous TYROBP-associated cell surface receptors have been reported [Lanier 2009]. The cytoplasmic domain of TYROBP contains an immunoreceptor tyrosine-based activation motif that, on receptor engagement, becomes phosphorylated and binds the cytoplasmic protein tyrosine kinases SYK and ZAP70.

Triggering receptor expressed on myeloid cells 2 (TREM2), the protein encoded by TREM2, is an activating cell surface receptor that forms a complex with the transmembrane adaptor protein TYROBP. The TREM2-TYROBP protein complex regulates the differentiation and function of osteoclasts, the bone-resorbing cells. The differentiation of osteoclasts in TYROBP-deficient individuals is impaired, and the osteoclasts show a reduced bone resorption capability in vitro [Cella et al 2003, Paloneva et al 2003].

TREM2 is expressed by a variety of cells of myeloid origin. TREM2 also activates monocyte-derived dendritic cells and is expressed by macrophages [Thrash et al 2009]. In the central nervous system (CNS), TREM2 and TYROBP are expressed by microglial cells. The exact function of TREM2 in the CNS is unknown [Painter et al 2015]. TREM2/DAP12-mediated signaling has been postulated to promote proliferation, phagocytosis, and migration of microglia by induction and maintenance of microglial activation in the CNS [Konishi & Kiyama 2018].

The intracellular responses underlying the pathogenic mechanisms of PLOSL are poorly understood.

Mechanism of disease causation. Loss of function

Author History

Taina Autti, MD, PhD (2001-present)
Panu Hakola, MD, PhD; University of Kuopio (2001-2026)
Matti J Haltia, MD, PhD (2001-present)
Juha Paloneva, MD, PhD (2001-present)
Eino Solje, MD, PhD (2026-present)

Revision History

• 7 April 2026 (sw) Comprehensive update posted live
• 10 December 2020 (sw) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 26 August 2010 (me) Comprehensive update posted live
• 1 May 2006 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 24 January 2002 (me) Review posted live
• 31 October 2001 (jp) Original submission

Published Guidelines / Consensus Statements

• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 12-30-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2017. Accessed 12-30-22.

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