DiagnosisClinical DiagnosisThe combination of the following features is diagnostic of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL): Radiologically demonstrable polycystic osseous lesions and fractures of the wrists or ankles after minor trauma. Cyst-like lesions and loss of bone trabeculae are most conspicuous in the fingers and in the carpal and tarsal bones [Mäkelä et al 1982] (see Figure 1 and Figure 2). 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. FigureFigure 1. A radiograph of the hand of a person with PLOSL demonstrates multiple cyst-like lesions and loss of bone trabeculae. FigureFigure 2. A radiograph shows a well-demarcated cyst-like lesion (arrow) in the talus of a 28-year old with PLOSL [Paloneva et al 2001; reprinted with permission from Neurology] TestingBone biopsy. 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. Neuroradiologic examination (see Figure 3 and Figure 4)FigureFigure 3. T₂-weighted MR image of a 33-year-old 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 white matter (more...)FigureFigure 4. T₂-weighted MR image of a 32-year-old 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...)Cerebral atrophy (dilated ventricles and prominent sulci) of varying degree is a constant finding on CT and MRI and is evident even before the appearance of neuropsychiatric symptoms. In addition to progressive cerebral atrophy, cerebellar atrophy may appear [Araki et al 1991, Hakola & Puranen 1993, Paloneva et al 2001]. Bilateral calcifications of the basal ganglia are a common finding on CT. Most often, they are situated in the putamina. Calcifications, atrophy of the basal ganglia, and progressively increasing and abnormally high bicaudate ratios may occur before CNS symptoms [Bird et al 1983, Araki et al 1991, Hakola & Puranen 1993, Paloneva et al 2001]. The basal ganglia, particularly the putamina, may show very low signal intensities on T₂-weighted MR images [Araki et al 1991, Paloneva et al 2001].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 lesions are usually centrally located, sparing most of the arcuate fibers. In some instances, they also extend to the cortex. However, the white matter may look normal in some individuals with CNS symptoms [Paloneva et al 2001]. SPECT findings are variable. Hypoperfusion of the cortical areas, thalamus, and basal ganglia have been reported [Klünemann et al 2005, Takeshita et al 2005]. Electroencephalogram. EEG 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 in the EEG [Bird et al 1983, Hakola & Partanen 1983, Motohashi et al 1995, Paloneva et al 2001]. Molecular Genetic TestingGenes. TREM2 and TYROBP (previously known as DAP12 or KARAP) are the only genes known to be associated with PLOSL. Mutations in either of the two genes are likely to account for all cases of PLOSL. Almost all individuals are homozygous for their disease-causing mutation. In individuals outside of Finland and Japan, mutations in TREM2 appear to be more frequent than those in TYROBP [Klünemann et al 2005]. Clinical testing TREM2Sequence analysis is likely to detect 100% of mutations in affected individuals in whom TREM2 is mutated. To date, all TREM2 mutations in affected individuals have been homozygous.TYROBP (DAP12)
Sequence analysis detects mutations in fewer than 100% of affected individuals in whom TYROBP is mutated because all Finnish individuals with PLOSL are homozygous for deletion of exons 1-4 (c.-2897_276+1334del). Deletions of exons 1-4 have also been found in affected individuals in other countries as well. Although sequence analysis cannot confirm the presence of this deletion, failure of amplification of these exons suggests deletion of the corresponding exons. Therefore, sequence analysis suggests the presence of mutations in 100% of affected individuals who have mutations in TYROBP.
Most affected individuals tested to date are homozygous for their disease-causing mutation; a single person with a compound heterozygous mutation has been reported [Kuroda et al 2007].Table 1. Summary of Molecular Genetic Testing Used in Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL)View in own windowGene Symbol% of PLOSL Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityTREM2UnknownSequence analysis Sequence variants 2, 3100%ClinicalTYROBPUnknownSequence analysis Deletion of exons 1-4 4See footnote 5Research onlySequence variants 2, 6UnknownClinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Most of the mutations found outside Finland and Japan are found in single families.3. Mutations reported in more than one family are p.Trp78X (found in 2 Swedish families) and p.Val126Gly (found in 1 Canadian family and 1 British family, both originating from Sri Lanka).4. c.-2897_276+1334del5. 100% of affected individuals from Finland, unknown percentage of affected individuals from Sweden and Norway6. Mutations reported in more than one family are p.Met48Trpfs*6 (found in an unknown portion of affected individuals of Japanese ethnicity); p.Met1Thr (found in two Japanese families)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandThe combination of radiologically demonstrable polycystic osseous lesions, frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade is diagnostic. Fractures of the wrists or ankles after minor trauma with typical polycystic osseous lesions identified on x-ray examination suggest the possibility of PLOSL. In uncertain cases or when molecular confirmation is required, molecular genetic testing helps to establish the diagnosis. In individuals outside of Finland and Japan, mutations in TREM2 appear to be more frequent than in TYROBP [Klünemann et al 2005]. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other disorders are known to be caused by mutations in either TYROBP or TREM2.A family with a homozygous mutation in TREM2 with neurologic symptoms typical of PLOSL but no osseous manifestations has been reported (see Differential Diagnosis) [Chouery et al 2008].}

Natural HistoryThe clinical course of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) can be divided into four stages: latent, osseous, early neurologic, and late neurologic [Hakola 1972, Hakola 1990a, Paloneva et al 2001, 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 [Mäkelä et al 1982, Paloneva et al 2001]. The first fractures usually occur shortly before age 30 years; however, affected individuals may have been experiencing 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 problems [Matsuo et al 1982, Paloneva et al 2001, Chouery et al 2008]. 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 [Hakola 1990b, Paloneva et al 2001]. 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. Progressive signs of upper motor neuron involvement (spasticity, extensor plantar reflexes) are noticed. With advancing disease, lack of initiative and activity conceal the aforementioned symptoms [Paloneva et al 2001].Memory disturbances begin at approximately the same age as the personality changes, and are best detectable by psychometric tests [Hakola 1998]. The memory disturbance is less severe than the personality change, and affected individuals are able to retain the most important personal data 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 [Hakola 1972, Minagawa et al 1985, Ishigooka et al 1993, 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 [Verloes et al 1997, Paloneva et al 2001]. It should be noted that a mutation in TREM2 has been reported to cause dementia and frontal lobe syndrome without osseous manifestations. Therefore, PLOSL should be considered in all cases of presenile dementia of unknown origin [Chouery et al 2008].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 [Nasu et al 1973, Akai et al 1977, Kitajima et al 1989]. See Figure 5.FigureFigure 5. 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, greyish, and tough. The basal ganglia, particularly the caudate nuclei, are variably reduced in size [Paloneva et al 2001]. All affected individuals show marked hydrocephalus e 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 [Amano et al 1987, Miyazu et al 1991, Kalimo et al 1994, Paloneva et al 2001]. Thalamic degeneration may occur [Tanaka 1980, Amano et al 1987, Miyazu et al 1991, 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 [Kalimo et al 1994, Paloneva et al 2001].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 CNS and the skeletal system have been insufficiently characterized.

Genotype-Phenotype CorrelationsIndividuals with homozygous mutations in TYROBP or TREM2 develop similar disease manifestations [Paloneva et al 2002, Klünemann et al 2005]. However, in a single family the deletion c.40+3delAGG in the 5’ consensus donor splice site in intron 1 of TREM2 has been reported to cause a dementia syndrome resembling PLOSL without evident osseous manifestations [Chouery et al 2008].

Differential DiagnosisThe combination of frontal-type dementia beginning in the fourth decade and radiologically demonstrable polycystic osseous lesions makes it easy to clinically distinguish PLOSL from the established forms of familial and non-familial frontotemporal dementia (e.g., Pick's disease, nonspecific frontal lobe degeneration, and the various entities of frontotemporal dementia and parkinsonism linked to chromosome 17), in several of which mutations in MAPT, encoding the protein tau, have been reported. It should be noted that a mutation in TREM2 has been reported to cause dementia and frontal lobe syndrome without osseous manifestations. Therefore, PLOSL should be considered in all cases of presenile dementia of unknown origin [Chouery et al 2008].

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with PLOSL, the following evaluations are appropriate:Radiographs of the bones of wrists, hands, ankles, and feet to determine the extent of osseous manifestations of the disease Brain CT and/or MRI to determine the extent of CNS manifestations Neurologic and neuropsychological examination to establish the extent of neurologic impairment and cognitive disturbance Treatment of ManifestationsOnly symptomatic treatment is available.Orthopedic ankle surgery as well as supportive orthopedic devices may be of value in individual cases. The fractures have been reported to heal well [Paloneva et al 2001].Epileptic seizures may worsen the individual's condition. Consequently, adequate antiepileptic drugs (AEDs) are important. Prevention of Primary ManifestationsNo therapy to delay or halt the progression of the disease is known.Prevention of Secondary ComplicationsSocial problems (unemployment, divorce, financial troubles, and alcoholism) and suicidal tendency are often associated with the progression of the disease. Some of the social consequences may be avoided if family members are informed early about the nature of the disorder [Hakola 1990b].SurveillanceThe interval of surveillance for bone lesions and neurologic and psychiatric manifestations must be determined individually. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherCalcium 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 (NSAIDs) 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. PLOSL: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTYROBP19q13​.12TYRO protein tyrosine kinase-binding proteinFinnish Disease DatabaseTYROBPTREM26p21​.1Triggering receptor expressed on myeloid cells 2Finnish Disease DatabaseTREM2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for PLOSL (View All in OMIM) View in own window 221770POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY; PLOSL 604142TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; TYROBP 605086TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; TREM2TREM2 Normal allelic variants. TREM2 consists of five exons and codes for a 693-bp cDNA. No normal allelic variants have been reported. Pathologic allelic variants. Several homozygous mutations have been identified. Most individuals with TREM2 mutations have a previously unknown mutation [Paloneva et al 2002, Paloneva et al 2003, Soragna et al 2003, Klünemann et al 2005]. Only mutations found in more than one family are presented here. For a more comprehensive list of published mutations, see Klünemann et al [2005]. c.233G>A, a mutation in the extracellular domain of TREM2, results in premature termination of translation with no transmembrane and cytoplasmic domains after 77 amino acids. The mutation has been reported in two Swedish families with PLOSL [Paloneva et al 2003]. c.377T>G126Gly, a mutation in the extracellular domain of TREM2. The mutation was found in one Canadian and one British individual with PLOSL, both originating from Sri Lanka [Klünemann et al 2005]. Table 2. Selected TREM2 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.40+3delAGG--NM_018965​.2
NP_061838​.1c.233G>Ap.Trp78Xc.377T>Gp.Val126GlySee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The protein encoded by TREM2 has 230 amino acids and is an activating cell-surface receptor that forms a complex with the transmembrane adaptor protein TYROBP (DAP12). TREM2 is expressed by a variety of cells of myeloid origin [Colonna 2003]. The natural ligand for TREM2 is unknown. The TREM2-TYROBP protein complex regulates the differentiation and function of osteoclasts, the bone-resorbing cells [Cella et al 2003, Paloneva et al 2003, Humphrey et al 2005]. In the CNS, TREM2 is expressed by microglial cells [Colonna 2003, Kiialainen et al 2005]. The function of TREM2 in the CNS is unknown. TREM2 also activates monocyte-derived dendritic cells and is expressed by macrophages [Bouchon et al 2001b, Colonna 2003, Thrash et al 2009].Abnormal gene product. Depending on the type of mutation: either the defective TREM2 protein is truncated, not translated, or not transported to the cell surface; or the consequences of the mutation cannot be predicted. The differentiation of osteoclasts is impaired in TREM2-deficient individuals, and the cells show a reduced bone resorption capability in vitro [Cella et al 2003, Paloneva et al 2003, Humphrey et al 2005].TYROBP Normal allelic variants. TYROBP consists of five exons and codes for a 342-bp cDNA. No normal allelic variants have been reported. Pathologic allelic variants. Several homozygous mutations have been identified. Three of them, c.-2897_276+1334del, p.Met1Thr, and p.Met48Trpfs*6, have been found in more than one family with PLOSL [Paloneva et al 2000, Kondo et al 2002]. Other mutations reported in TYROBP have been found in single families only [Baeta et al 2002, Paloneva et al 2002, Klünemann et al 2005]. A single patient with a compound heterozygous mutation in TYROBP has been reported [Kuroda et al 2007]. c.-2897_276+1334del. All Finnish individuals with PLOSL are homozygous for this deletion, which has also been found in Swedish and Norwegian families [Paloneva et al 2000, Tranebjaerg et al 2000]. The 5.3-kb deletion encompasses the first four exons of TYROBP. Because the exon 1-4 deletion is an Alu- mediated recombination event, the breakpoint is not known precisely; here it is shown at the repetitive sequence at the 5’ end of the breakpoint. No mRNA encoding TYROBP (DAP12) is produced. p.Met1Thr, a homozygous start methionine mutation, has been reported in two Japanese families with PLOSL [Kondo et al 2002]. This mutation results in conversion of the translation initiation methionine to threonine. No TYROBP (DAP12) polypeptide is produced. p.Met48Trpfs*6, another homozygous mutation, has been found in a number of Japanese individuals with PLOSL. This single-base deletion creates a frameshift in the open reading frame (ORF), resulting in a premature termination of the polypeptide chain after 52 amino acids, and changes a functionally critical aspartic acid residue in the transmembrane domain. The defective protein is not transported to the cell surface [Paloneva et al 2000, Kondo et al 2002]. Table 3. Selected TYROBP Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.-2897_276+1334del ^{2(deletion of ex 1-4)--NM_003332​.2
NP_003323​.1c.2T>Cp.Met1Thrc.141delGp.Met48Trpfs*6See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Because the exon 1-4 deletion is an Alu- mediated recombination event, the breakpoint is not known precisely; here it is shown at the repetitive sequence at the 5’ end of the breakpoint.Normal gene product. The protein contains 113 amino acids and is a transmembrane adaptor protein that mediates the activation of a wide variety of cells of myeloid and lymphoid origin [Lanier et al 1998b, Bakker et al 1999, Bouchon et al 2000, Bouchon et al 2001a]. 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 in addition to TREM2 have been reported [Lanier et al 1998a, Lanier et al 1998b, Bouchon et al 2000, Dietrich et al 2000, Diefenbach et al 2002, Gilfillan et al 2002, Lanier 2009]. The cytoplasmic domain of TYROBP contains an immunoreceptor tyrosine-based activation motif (ITAM) which, upon receptor engagement, becomes phosphorylated and binds the cytoplasmic protein tyrosine kinases SYK and ZAP70 [Lanier et al 1998b]. This interaction results in intracellular calcium mobilization and subsequent cellular activation [McVicar et al 1998]. The TYROBP-TREM2 protein complex regulates the differentiation and function of osteoclasts [Paloneva et al 2003, Humphrey et al 2004]. In the CNS, TYROBP is expressed by microglial cells; the exact function of the protein in these cells is unknown [Kiialainen et al 2005, Takahashi et al 2005, Thrash et al 2009]. Abnormal gene product. Depending on the type of mutation: either the defective TYROBP protein is truncated, not translated, or not transported to the cell surface; or the consequences of the mutation cannot be predicted. The differentiation of osteoclasts in TYROBP-deficient individuals is impaired, and the osteoclasts show a reduced bone resorption capability in vitro [Paloneva et al 2003, Humphrey et al 2004].}