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Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL)

Synonym: Nasu-Hakola Disease

, MD, PhD, , MD, PhD, , MD, PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: March 12, 2015.

Summary

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. 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 problems. (4) The late neurologic stage is characterized by progressive dementia and loss of mobility. Death usually occurs before age 50 years.

Diagnosis/testing.

The 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, molecular genetic testing helps to establish the diagnosis. TYROBP (DAP12) and TREM2 are the only two genes in which pathogenic variants are known to cause PLOSL.

Management.

Treatment of manifestations: Treatment is symptomatic. Orthopedic surgery and/or devices may be of value in individual cases. Antiepileptic drugs can be used to prevent epileptic seizures and secondary worsening of the condition.

Prevention of secondary complications: Some of the social consequences of PLOSL may be avoided if family members are informed early about the nature of the disorder.

Surveillance: Intervals for follow up of bone lesions and neurologic and psychiatric manifestations must be determined individually.

Genetic counseling.

PLOSL is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

Diagnosis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) should be suspected in individuals with the combination of 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] (full text). If an individual has multiple lytic or cyst-like lesions on radiograph primarily in the distal extremities, CT and MRI are useful in making an accurate diagnosis [Nwawka et al 2014].
  • 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 1.

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

Figure 2.

Figure 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]

Figure 3. . T2-weighted MR image of a 33-year-old shows very low signal intensity in the putamina.

Figure 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 partially (more...)

Testing

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.

Neuroradiologic examination (Figure 3, Figure 4, Figure 5)

Figure 4. . T2-weighted MR image of a 32-year-old displays severely enlarged cerebral sulci and lateral ventricles.

Figure 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 with permission (more...)

Figure 5. . Brain MRI.

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 in addition with the atrophy of the basal ganglia and thalamus, prominent sulci or thin corpus callosum) 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, Klünemann et al 2005, Solje et al 2014].
  • 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 and thalamus, particularly the putamina, may show very low signal intensities on T2-weighted MR images [Araki et al 1991, Paloneva et al 2001, Klünemann et al 2005].
  • 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 symptoms [Paloneva et al 2001].
  • 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 [Bird et al 1983, Hakola & Partanen 1983, Motohashi et al 1995, Paloneva et al 2001].

Establishing the Diagnosis

The diagnosis of PLOSL is established in a proband with identification of biallelic pathogenic variants in either TREM2 or TYROBP (see Table 1).

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing:

  • Serial single-gene testing. The order of testing is based on the individual’s ethnicity. In individuals outside of Finland and Japan, pathogenic variants in TREM2 appear to be more frequent than in TYROBP [Klünemann et al 2005].
  • A multi-gene panel that includes TREM2 and TYROBP and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes the genes in listed in Table 1) fails to confirm a diagnosis in an individual with features of PLOSL. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For more information on comprehensive genome sequencing click here.

Table 1.

Summary of Molecular Genetic Testing Used in Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL)

Gene 1Proportion of PLOSL Attributed to Mutation of This GeneTest Method
TREM2UnknownSequence analysis 2, 3, 4
Deletion/duplication analysis 5
TYROBPUnknownSequence analysis 2, 6, 7, 8
Deletion/duplication analysis 5, 8, 9
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Pathogenic variants reported in more than one family are p.Trp78Ter (found in 2 Swedish families) and p.Val126Gly (found in one Canadian family and one British family, both originating from Sri Lanka).

4.

Most affected individuals tested to date are homozygous for their pathogenic variant [Paloneva et al 2000, Klünemann et al 2005].

5.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

Most affected individuals tested to date are homozygous for their pathogenic variant [Paloneva et al 2000, Klünemann et al 2005].

7.

Pathogenic variants reported in more than one family: p.Met48TrpfsTer6 (found in an unknown portion of affected individuals of Japanese ethnicity); p.Met1Thr (found in 2 Japanese families) [Paloneva et al 2000, Klünemann et al 2005]

8.

Variant detection frequency is 100% of affected individuals from Finland, unknown percentage of affected individuals from Sweden and Norway [Paloneva et al 2000, Klünemann et al 2005].

9.

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 [Paloneva et al 2000, Klünemann et al 2005].

Clinical Characteristics

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 [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 manifestations [Matsuo et al 1982, Paloneva et al 2001, Chouery et al 2008, Bock 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 [Hakola 1990b, Paloneva et al 2001, Ilonen et al 2012]. 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, Vanhanen et al 2013]. The memory disturbance is less severe than the 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 [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].

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 6.

Figure 6. . Contents of a cyst-like bone lesion.

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, 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]. 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 CNS and the skeletal system have been insufficiently characterized.

Genotype-Phenotype Correlations

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

However, osseous pathology is not always present or diagnosed.

Nomenclature

PLOSL or Nasu-Hakola disease is the recommended name.

Some authors have preferred the abbreviation "PLO-SL."

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, where it is estimated at 1:1,000,000 to 2:1,000,000 [Pekkarinen et al 1998]. The prevalence of PLOSL in other countries is lower; no detailed data on the prevalence elsewhere are available. Most affected individuals have been diagnosed in Japan (>100 cases) [Pekkarinen et al 1998]. Single families with PLOSL have been diagnosed worldwide [Klünemann et al 2005].

Differential Diagnosis

The 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 pathogenic variants in MAPT, encoding the protein tau, have been reported.

It should be noted that some pathogenic variants in TREM2 have been reported to cause dementia and frontal lobe syndrome typical of PLOSL without osseous manifestations [Chouery et al 2008, Bock et al 2013, Guerreiro et al 2013a, Guerreiro et al 2013c, Le Ber et al 2014]. Therefore, PLOSL should be considered in all cases of early-onset dementia of unknown origin.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Clinical genetics consultation

Treatment of Manifestations

Only symptomatic treatment is available.

Relief of pain after curettage and iliac bone grafting of painful lesions in the talus has been reported [Arıkan et al 2014]. 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 Manifestations

No therapy to delay or halt the progression of the disease is known.

Prevention of Secondary Complications

Social problems (unemployment, divorce, financial troubles, and alcoholism) and suicidal tendency are often associated with the progression of the disease [Ilonen et al 2012]. Some of the social consequences may be avoided if family members are informed early about the nature of the disorder [Hakola 1990b].

Surveillance

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 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 (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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 obligate heterozygotes (i.e., carriers of one TREM2 or TYROBP pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    Note: The sibs of an affected individual who are under age 40 years are at risk for PLOSL. Polycystic osseous lesions in radiographs of the hands and feet of an at-risk adult suggest the diagnosis.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a TREM2 or TYROBP pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an affected person are obligate heterozygotes for a TREM2 or TYROBP pathogenic variant. Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is very low except in genetic isolates.

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

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TREM2 or TYROBP pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and clarification of carrier status, and discussion of the availability of prenatal 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 carriers, or are at risk of being affected or carriers.

Testing of at-risk asymptomatic adult relatives of individuals with PLOSL is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of PLOSL regardless of age.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TREM2 or TYROBP pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for PLOSL are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) (View All in OMIM)

221770POLYCYSTIC LIPOMEMBRANOUS OSTEODYSPLASIA WITH SCLEROSING LEUKOENCEPHALOPATHY; PLOSL
604142TYRO PROTEIN TYROSINE KINASE-BINDING PROTEIN; TYROBP
605086TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; TREM2

TREM2

Gene structure. TREM2 consists of five exons and codes for a 693-bp cDNA. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. No normal variants have been reported.

Pathogenic variants. Several homozygous pathogenic variants have been identified. Most individuals with TREM2 pathogenic variants have a previously unknown pathogenic variant [Paloneva et al 2002, Paloneva et al 2003, Soragna et al 2003, Klünemann et al 2005]. Only pathogenic variants found in more than one family are presented here. For a more comprehensive list of published pathogenic variants, see Klünemann et al [2005].

  • c.233G>A, a pathogenic variant in the region encoding the extracellular domain of TREM2, results in premature termination of translation with no transmembrane and cytoplasmic domains after 77 amino acids. The pathogenic variant has been reported in two Swedish families with PLOSL [Paloneva et al 2003].
  • c.377T>G, a pathogenic variant in the region encoding the extracellular domain of TREM2, was found in one Canadian and one British individual with PLOSL, both originating from Sri Lanka [Klünemann et al 2005].

Table 2.

Selected TREM2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.40+3delAGG--NM_018965​.2
NP_061838​.1
c.113A>Gp.Tyr38Cys
c.197C>Tp.Thr66Met
c.233G>Ap.Trp78Ter
c.377T>Gp.Val126Gly
c.97C>T 1p.Gln33Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

This variant has been reported to cause a PLOSL with typical bone pathology on radiologic examination but also a frontotemporal dementia-like syndrome without bone pathology on radiographs.

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 pathogenic variant: either the defective TREM2 protein is truncated, not translated, or not transported to the cell surface; or the consequences of the pathogenic variant cannot be predicted.

The differentiation of osteoclasts is impaired in TREM2-deficient individuals, and the cells show reduced bone resorption capability in vitro [Cella et al 2003, Paloneva et al 2003, Humphrey et al 2005].

TYROBP (previously known as DAP12)

Gene structure. TYROBP consists of five exons and codes for a 342-bp cDNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several homozygous pathogenic variants have been identified. Three of them, c.-2897_276+1334del, p.Met1Thr, and p.Met48TrpfsTer6, have been found in more than one family with PLOSL [Paloneva et al 2000, Kondo et al 2002]. Other pathogenic variants 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 pathogenic variant 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 pathogenic variant, has been reported in two Japanese families with PLOSL [Kondo et al 2002]. This pathogenic variant results in conversion of the translation initiation methionine to threonine. No TYROBP (DAP12) polypeptide is produced.
  • p.Met48TrpfsTer6, another homozygous pathogenic variant, has been found in a number of Japanese individuals with PLOSL. This single-base deletion creates a frameshift in the open reading frame, 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 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.-2897_276+1334del 1
(5.3 kb deletion; deletion of ex 1-4)
--NM_003332​.2
NP_003323​.1
c.2T>Cp.Met1Thr
c.141delGp.Met48TrpfsTer6

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

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 on 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 pathogenic variant: either the defective TYROBP protein is truncated, not translated, or not transported to the cell surface; or the consequences of the pathogenic variant 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].

References

Published Guidelines/Consensus Statements

  1. 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 2-14-17. [PubMed: 23428972]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 2-14-17.

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Chapter Notes

Revision History

  • 12 March 2015 (me) Comprehensive update posted live
  • 26 August 2010 (me) Comprehensive update posted live
  • 16 April 2009 (jp) Revision: sequence analysis available on a clinical basis for TYROBP and TREM2
  • 1 May 2006 (me) Comprehensive update posted to live Web site
  • 15 March 2004 (me) Comprehensive update posted to live Web site
  • 24 January 2002 (me) Review posted to live Web site
  • 31 October 2001 (jp) Original submission
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