Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

Summary

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly (MONDO:0009092) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Finland) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.15	Finland	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000727	Frontal lobe dementia	Very frequent (80-99%)
HP:0000734	Disinhibition	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0000751	Personality changes	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002354	Memory impairment	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002652	Skeletal dysplasia	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0009124	Abnormal adipose tissue morphology	Very frequent (80-99%)
HP:0012062	Bone cyst	Very frequent (80-99%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0002072	Chorea	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0010524	Agnosia	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0002488	Acute leukemia	Occasional (5-29%)
HP:0012719	Functional abnormality of the gastrointestinal tract	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly
Mondo ID	MONDO:0009092
OMIM	221770
Orphanet	2770
DOID	DOID:0090112
SNOMED CT	702347001
UMLS	C1857316
MedGen	387795
GARD	0009921
Is cancer (heuristic)	no

Also known as: Nasu-Hakola disease · NHD · PLO-SL · PLOSL · polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy · polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

Data availability: 1 ClinVar variant · 2 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (2): polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1, polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5219	NM_018965.4(TREM2):c.97C>T (p.Gln33Ter)	TREM2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TREM2	Strong	Autosomal recessive	polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2	6
TYROBP	Strong	Autosomal recessive	polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TREM2	Orphanet:100069	Semantic dementia
TREM2	Orphanet:100070	Progressive non-fluent aphasia
TREM2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
TREM2	Orphanet:275864	Behavioral variant of frontotemporal dementia
TREM2	Orphanet:2770	Nasu-Hakola disease
TREM2	Orphanet:803	Amyotrophic lateral sclerosis
TYROBP	Orphanet:2770	Nasu-Hakola disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TREM2	HGNC:17761	ENSG00000095970	Q9NZC2	Triggering receptor expressed on myeloid cells 2	gencc,clinvar
TYROBP	HGNC:12449	ENSG00000011600	O43914	TYRO protein tyrosine kinase-binding protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TREM2	Triggering receptor expressed on myeloid cells 2	Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding.
TYROBP	TYRO protein tyrosine kinase-binding protein	Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TREM2	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Ig-like_dom_sf
TYROBP	Other/Unknown	no		Tyrobp

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
amniotic fluid	1
spinal cord	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TREM2	186	broad	marker	C1 segment of cervical spinal cord, spinal cord, amniotic fluid
TYROBP	271	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TYROBP	2,723
TREM2	2,354

Intra-cohort edges

A	B	Sources
TREM2	TYROBP	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TREM2	Q9NZC2	15
TYROBP	O43914	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Other semaphorin interactions	2	601.0×	1e-05	TREM2, TYROBP
DAP12 interactions	2	475.8×	1e-05	TREM2, TYROBP
DAP12 signaling	2	368.4×	1e-05	TREM2, TYROBP
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	87.2×	2e-04	TREM2, TYROBP
Signal regulatory protein family interactions	1	335.9×	0.004	TYROBP
Neutrophil degranulation	1	11.5×	0.085	TYROBP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microglial cell activation involved in immune response	2	3370.4×	5e-06	TREM2, TYROBP
positive regulation of macrophage fusion	2	3370.4×	5e-06	TREM2, TYROBP
T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	2	2106.5×	8e-06	TREM2, TYROBP
amyloid-beta clearance	2	936.2×	3e-05	TREM2, TYROBP
apoptotic cell clearance	2	887.0×	3e-05	TREM2, TYROBP
response to axon injury	2	510.7×	8e-05	TREM2, TYROBP
cellular response to amyloid-beta	2	391.9×	1e-04	TREM2, TYROBP
osteoclast differentiation	2	343.9×	1e-04	TREM2, TYROBP
myeloid leukocyte activation	1	8426.0×	7e-04	TYROBP
detection of peptidoglycan	1	8426.0×	7e-04	TREM2
regulation of toll-like receptor 6 signaling pathway	1	8426.0×	7e-04	TREM2
positive regulation of complement activation, classical pathway	1	8426.0×	7e-04	TREM2
detection of lipoteichoic acid	1	8426.0×	7e-04	TREM2
regulation of macrophage inflammatory protein 1 alpha production	1	8426.0×	7e-04	TREM2
import into cell	1	8426.0×	7e-04	TREM2
regulation of hippocampal neuron apoptotic process	1	8426.0×	7e-04	TREM2
regulation of plasma membrane bounded cell projection organization	1	8426.0×	7e-04	TREM2
positive regulation of C-C chemokine receptor CCR7 signaling pathway	1	8426.0×	7e-04	TREM2
excitatory synapse pruning	1	8426.0×	7e-04	TREM2
positive regulation of synapse pruning	1	8426.0×	7e-04	TREM2
positive regulation of CD40 signaling pathway	1	8426.0×	7e-04	TREM2
stimulatory killer cell immunoglobulin-like receptor signaling pathway	1	4213.0×	0.001	TYROBP
positive regulation of antigen processing and presentation of peptide antigen via MHC class II	1	4213.0×	0.001	TREM2
negative regulation of cell activation	1	4213.0×	0.001	TREM2
positive regulation of engulfment of apoptotic cell	1	4213.0×	0.001	TREM2
natural killer cell mediated immunity	1	2808.7×	0.001	TYROBP
negative regulation of triglyceride storage	1	2808.7×	0.001	TREM2
positive regulation of high-density lipoprotein particle clearance	1	2808.7×	0.001	TREM2
negative regulation of astrocyte activation	1	2808.7×	0.001	TREM2
negative regulation of macrophage colony-stimulating factor signaling pathway	1	2808.7×	0.001	TREM2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TREM2	0	0
TYROBP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TREM2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TREM2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TYROBP

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TREM2	1	—
TYROBP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.