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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal recessive HP:0000007

BANDDOS segregates as an autosomal recessive trait; the parents of an affected individual are presumed heterozygous carriers and each sib has a 25% recurrence risk.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:22934315 SUPPORT Human Clinical

"If both parents are known to be heterozygous for a 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 CSF1R pathogenic variants."

GeneReviews states the recurrence risk that follows from autosomal recessive inheritance of biallelic CSF1R disease.

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Discussions and Knowledge Gaps

3

Why do humans with biallelic CSF1R loss of function develop severe congenital brain malformations while Csf1r knockout rats, which lack microglia just as completely, undergo essentially normal brain development?

HUMAN MODEL MISMATCH OPEN banddos_rodent_brain_development_mismatch

Attached to

pathophysiology#Disrupted Brain Development and Structural Malformation animal_models#Csf1r knockout rat (Csf1rko)

The rat Csf1rko removes the entire microglial population - the same cellular lesion documented at autopsy in BANDDOS - yet diffusion imaging and region-wise RNA-seq show only small fibre-tract reductions and no neuronal or regional transcriptomic change, and the authors conclude that most brain developmental processes occur normally without microglia. Human biallelic CSF1R brains instead show callosal agenesis, Dandy-Walker complex, heterotopia, and non-decussating pyramidal tracts. The same paper concludes that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy, which is directly at odds with the established human monoallelic CSF1R-ALSP disorder. Either microglia have human-specific developmental roles (the CUX1-positive upper-layer neuron route proposed from the zebrafish and human tissue work is one candidate), or the human phenotype depends on something other than microglial absence per se. Until this is resolved, rodent rescue data cannot be read as predicting that restoring myeloid cells will correct the malformation arm of BANDDOS.

Proposed experiments

Human cerebral organoid or xenotransplant model with biallelic CSF1R loss

exp_banddos_human_organoid_cux1_requirement

Compare corpus callosum-relevant projection neuron specification (CUX1-positive upper-layer neurons) in human iPSC-derived cortical systems with and without CSF1R-competent microglia, using patient-derived biallelic CSF1R lines, to test whether the developmental requirement is human-specific.

Developmental staging of the rodent versus human microglial requirement

exp_banddos_microglial_colonisation_timing

Determine whether the discrepancy reflects the timing of microglial colonisation relative to commissural axon guidance, by comparing microglial colonisation windows and callosal pathfinding in rat, zebrafish, and human fetal tissue.

Show evidence (4 references)

PMID:33450391 SUPPORT Model Organism

"We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy."

The rat conclusion that brain development proceeds normally without microglia is the model side of the mismatch.

PMID:37349768 SUPPORT Human Clinical

"Postmortem examination showed multiple brain anomalies, including an absence of corpus callosum, reduced volume of white matter, Dandy-Walker malformation, colpocephaly, numerous periventricular and brainstem calcifications, and heterotopia, abnormal gyration of hippocampi, and non-decussation..."

The human side of the mismatch: a microglia-deficient human brain shows severe congenital malformation that the rodent model does not reproduce.

PMID:34145972 SUPPORT Other

"Here we review the genetics, penetrance, and histopathological features of these diseases and discuss to what extent the animal models of Csf1r deficiency currently available provide systems in which to study the underlying mechanisms involved."

The dedicated review of Csf1r-deficiency models frames the adequacy of available animal systems as an open question, which is exactly what this mismatch records.

+ 1 more reference

Does hematopoietic stem cell transplantation modify the course of BANDDOS, and is there a therapeutic window before the degenerative phase begins?

KNOWLEDGE GAP OPEN banddos_hsct_efficacy_gap

Attached to

treatments#Allogeneic Hematopoietic Stem Cell Transplantation (investigational in BANDDOS)

HSCT is now offered in CSF1R-ALSP, and the review literature explicitly proposes translating it to BANDDOS on the basis of a shared pathomechanism. But no outcome data exist in genetically confirmed BANDDOS. Two features of BANDDOS complicate the extrapolation: the congenital malformations are already established at birth and cannot plausibly be reversed by any myeloid replacement, and in the Csf1rko rat the brain was the one organ where donor-derived cells did not transcriptionally match resident microglia. A meaningful trial would therefore have to specify which arm of the disease it expects to modify.

Proposed experiments

International BANDDOS natural history registry with prospective HSCT arm

exp_banddos_registry_hsct_arm

Pool the very small worldwide case population into a registry capturing genotype, residual CSF1R function, serial MRI, and neurodevelopmental outcome, and follow any transplanted patients prospectively against untransplanted controls, with the degenerative (not developmental) arm as the pre-specified endpoint.

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"This opens windows of opportunity for applying already available therapy in CSF1R-ALSP in BANDDOS."

The review proposes translating CSF1R-ALSP therapy to BANDDOS, framing the gap as an untested opportunity rather than established practice.

PMID:39869647 SUPPORT Model Organism

"The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia."

Identifies the specific reason CNS correction by marrow transfer may be incomplete, which is part of what makes the gap substantive.

Why does profound CSF1R deficiency spare peripheral immune function in BANDDOS patients?

KNOWLEDGE GAP OPEN banddos_spared_peripheral_immunity_gap

Attached to

pathophysiology#Biallelic CSF1R Loss of Function

CSF1R is the master regulator of the mononuclear phagocyte system, and the Csf1rko rat has a broad myeloid deficit with granulocytosis, B cell deficiency, and failure to thrive. Yet detailed immunological workup of a BANDDOS family found normal blood markers, monocytes, dendritic cell subsets, and T cell proliferation, and no clinical immunodeficiency has been reported. Whether this reflects the hypomorphic nature of human alleles, redundancy with CSF2/IL-34 signalling in the periphery, or simply incomplete phenotyping across the small case population is unresolved, and it matters for how aggressively transplant conditioning would be justified.

Proposed experiments

Systematic immunophenotyping across the BANDDOS case population

exp_banddos_systematic_immunophenotyping

Apply uniform deep immunophenotyping (tissue-resident macrophage compartments, monocyte subsets, circulating CSF1 concentration) across reported BANDDOS patients and their heterozygous relatives, correlated with allele-specific residual CSF1R signalling measured in vitro.

Show evidence (2 references)

PMID:38934054 SUPPORT Human Clinical

"Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent."

States the unexplained observation directly: myeloid-lineage receptor loss without clinical immunodeficiency.

PMID:38934054 SUPPORT Human Clinical

"Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal."

Provides the measured immunological workup showing normal peripheral immune parameters in BANDDOS patients.

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Pathophysiology

7

Biallelic CSF1R Loss of Function

CSF1R encodes a transmembrane receptor tyrosine kinase activated by two ligands, CSF1 and IL-34. In BANDDOS both alleles carry pathogenic variants - most often splice, nonsense, or deep-intronic changes that disrupt the tyrosine kinase domain or trigger nonsense-mediated decay, less often hypomorphic missense changes that leave the protein expressed but unable to autophosphorylate on ligand binding. Because complete CSF1R nullity is lethal or far more severe than what is observed clinically, at least one allele in each reported individual is thought to retain partial function, and the residual level of CSF1R signalling grades disease severity across the CSF1R-related disorder continuum.

cell surface receptor protein tyrosine kinase signaling pathway GO:0007169 ↓ DECREASED CSF1R autophosphorylation on ligand binding GO:0046777 ↓ DECREASED

macrophage colony-stimulating factor receptor activity GO:0005011 ↓ DECREASED

Downstream

Microglial Deficiency in the Developing Brain Microglia depend on CSF1R for their proliferation, differentiation, and survival, so loss of receptor signalling depletes the brain of its resident macrophage population.

Osteoclast Deficiency and Impaired Bone Resorption Osteoclasts arise from the same CSF1R-dependent monocyte/macrophage lineage, so the same receptor lesion compromises osteoclastogenesis.

Show evidence (3 references)

PMID:37349768 SUPPORT Human Clinical

"All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay."

Across all 11 BANDDOS-associated CSF1R variants reviewed, the molecular consequence converges on loss of tyrosine kinase function or loss of the transcript, establishing loss of function as the molecular lesion.

PMID:32464672 SUPPORT In Vitro

"Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele."

Functional assay of the p.T833M allele shows normal receptor abundance but impaired ligand-dependent autophosphorylation, directly demonstrating the signalling defect in a hypomorphic BANDDOS allele.

PMID:30982609 SUPPORT Human Clinical

"Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic."

Supports the dose-dependent model: complete nullity is not what is seen clinically, and residual CSF1R activity from a hypomorphic allele sets the severity.

Microglial Deficiency in the Developing Brain

Loss of CSF1R signalling prevents the establishment and expansion of the microglial population, so the fetal and postnatal brain develops with few or no microglia. Post-mortem examination of a homozygous splice-variant case showed almost complete absence of microglia, with only rare abnormal perivascular cells remaining. This is a primary microgliopathy: the initiating cellular lesion is loss of the brain's resident macrophage, not a primary defect of neurons or oligodendrocytes.

microglial cell CL:0000129 ↓ DECREASED central nervous system macrophage CL:0000878 ↓ DECREASED

microglial cell proliferation GO:0061518 ↓ DECREASED macrophage differentiation GO:0030225 ↓ DECREASED

Animal models

Csf1r knockout rat (Csf1rko) Rat recapitulates Csf1rko rats lose the entire microglial transcriptomic signature across every brain region examined.

csf1rDM zebrafish (csf1ra/csf1rb double mutant) Zebrafish recapitulates csf1rDM brains lack microglia, reproducing the defining cellular lesion.

Downstream

Disrupted Brain Development and Structural Malformation In the absence of microglia the developing brain fails to form normal commissural, ventricular, and posterior-fossa structures. One proposed intermediate is a reduction in CUX1-positive upper-layer neurons, many of which project callosal axons.

Progressive White Matter Degeneration with Axonal Spheroids The same microglial deficiency that disrupts development also leaves the white matter without its resident phagocyte, producing the progressive leukoencephalopathy that is neuropathologically indistinguishable from CSF1R-ALSP.

Show evidence (3 references)

PMID:30982608 SUPPORT Human Clinical

"Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the..."

Direct human neuropathological demonstration that a biallelic CSF1R brain is essentially devoid of microglia, and that development proceeded in their absence.

PMID:37349768 SUPPORT Human Clinical

"A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications."

Independent review confirms absence of microglia as the defining histological finding alongside the structural and degenerative changes.

PMID:30982608 SUPPORT Model Organism

"We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor."

A vertebrate model lacking Csf1r function reproduces the microglial deficiency, supporting conservation of the cellular mechanism.

Disrupted Brain Development and Structural Malformation

The developmental arm of BANDDOS. Some brain abnormality is present in every reported case; the individual congenital malformations vary in frequency and include agenesis or hypoplasia of the corpus callosum, ventriculomegaly and colpocephaly, Dandy-Walker complex and large cisterna magna, cortical malformations, heterotopia, abnormal hippocampal gyration, and non-decussation of pyramidal tracts. These congenital malformations are the feature that most cleanly separates BANDDOS from adult-onset CSF1R-ALSP, in which they are not seen.

CUX1-positive upper-layer cortical projection neuron CL:0000540 ↓ DECREASED

corpus callosum development GO:0022038 ↓ DECREASED

Animal models

Csf1r knockout rat (Csf1rko) Rat fails to recapitulate Unlike humans with biallelic CSF1R variants, Csf1rko rats do not develop the congenital brain malformations (callosal agenesis, Dandy-Walker complex, cortical malformation) that define BANDDOS; brain development is largely normal without microglia.

Downstream

Progressive Neurological Decline Congenital brain malformation underlies the developmental delay, early-onset epilepsy, and baseline neurological deficit on which later degeneration is superimposed.

Show evidence (3 references)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."

Quantifies the spectrum and frequency of congenital brain abnormalities across the reviewed BANDDOS cohort.

PMID:37349768 SUPPORT Human Clinical

"Compared to CSF1R-ALSP, cases with BANDDOS also displayed other congenital brain anomalies, including Dandy-Walker malformation, ventriculomegaly, and cortical abnormalities."

Establishes congenital brain malformation as the discriminating feature of BANDDOS relative to the adult-onset monoallelic disorder.

PMID:28383543 SUPPORT Human Clinical

"The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout..."

The first report of the recessive CSF1R phenotype names brain malformation and osteopetrosis as the novel biallelic presentation.

Progressive White Matter Degeneration with Axonal Spheroids

The degenerative arm of BANDDOS, superimposed on the developmental lesion. White matter changes are present in 100% of reported cases. Histology shows prominent white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications concentrated in periventricular white matter - the same picture as CSF1R-ALSP but more severe. On MRI the leukoencephalopathy is progressive and takes on the appearance of ALSP at the time of secondary neurological decline.

oligodendrocyte CL:0000128 astrocyte CL:0000127 ↑ INCREASED

myelination GO:0042552 ↓ DECREASED reactive gliosis GO:0048143 ↑ INCREASED

Downstream

Progressive Neurological Decline Progressive loss of white matter integrity produces the cognitive decline, pyramidal signs, dysarthria, and dysphagia that dominate the later disease course.

Show evidence (3 references)

PMID:37349768 SUPPORT Human Clinical

"Histological evaluation evidenced severe microglia deficiency with only rare spotting of abnormal microglia around the blood vessels, prominent white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications predominantly in the periventricular white matter"

The single published BANDDOS brain autopsy documents white matter atrophy, axonal spheroids, gliosis, and dystrophic calcification.

PMID:38934054 SUPPORT Human Clinical

"During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP."

Documents the progressive, ALSP-like radiological evolution of the white matter disease during secondary neurological decline.

PMID:37349768 SUPPORT Human Clinical

"Macroscopically both disorders shared extensive white matter degeneration, most prominent in the periventricular region, corpus callosum, and pyramidal tracts"

Establishes the anatomical distribution of the white matter degeneration shared with CSF1R-ALSP.

Osteoclast Deficiency and Impaired Bone Resorption

Osteoclasts differentiate from the CSF1R-dependent monocyte/macrophage lineage, and CSF1-CSF1R signalling is required for their generation and survival. Reduced CSF1R signalling therefore reduces osteoclastic bone resorption, so bone formed during modelling is not removed. The result is increased bone mineral density with failure of metaphyseal remodelling - the mechanistic basis of the sclerosing bone dysplasia. In the Csf1rko rat, transfer of wild-type bone marrow restores osteoclasts and eliminates the osteopetrosis, demonstrating that the bone phenotype is cell-autonomous to the marrow-derived lineage.

osteoclast CL:0000092 ↓ DECREASED monocyte CL:0000576

osteoclast differentiation GO:0030316 ↓ DECREASED bone resorption GO:0045453 ↓ DECREASED bone remodeling GO:0046849 ↓ DECREASED

Animal models

Csf1r knockout rat (Csf1rko) Rat recapitulates Csf1rko rats develop osteopetrosis that is reversed by wild-type bone marrow transfer, establishing the osteoclast-deficiency mechanism.

Csf1r-null mouse Mouse recapitulates Csf1r-null mice show the loss of osteoclasts and of bone remodelling that underlies the human skeletal phenotype.

Downstream

Sclerosing Skeletal Dysplasia of the Dysosteosclerosis-Pyle Spectrum Failure of osteoclastic resorption yields the increased bone density and abnormal metaphyseal modelling that define the skeletal phenotype.

Show evidence (2 references)

PMID:33749994 SUPPORT Human Clinical

"Colony stimulating factor 1 receptor (CSF1R, MIM# 164770) encodes a tyrosine-kinase receptor playing an important role in development of osteoclasts and microglia."

States the osteoclast-development role of CSF1R that makes osteoclast failure the expected consequence of biallelic loss of function.

PMID:34081701 SUPPORT Model Organism

"WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency."

Rescue experiment in the Csf1rko rat establishes that osteoclast deficiency is the proximate cause of the osteopetrotic bone phenotype and that it is intrinsic to bone-marrow-derived cells.

Sclerosing Skeletal Dysplasia of the Dysosteosclerosis-Pyle Spectrum

The skeletal component of BANDDOS spans a spectrum: at the sclerotic end, osteopetrosis and dysosteosclerosis with generalised increased bone density; at the modelling-defect end, Pyle-disease-like metaphyseal widening with Erlenmeyer flask deformity of the long bones. Skeletal involvement is present in most but not all cases, is variable even between siblings carrying the same genotype, and may be entirely absent in individuals with hypomorphic missense alleles ("incomplete BANDDOS").

ossification GO:0001503 ⚠ ABNORMAL

Show evidence (4 references)

PMID:37349768 SUPPORT Human Clinical

"Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum."

Quantifies the frequency of skeletal involvement and defines its radiological spectrum.

PMID:33749994 SUPPORT Human Clinical

"Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."

Establishes the variability of the skeletal phenotype, including its complete absence in some individuals.

PMID:34135456 SUPPORT Human Clinical

"In addition, some individuals with bi-allelic missense mutations of CSF1R have been found to present with incomplete BANDDOS where skeletal dysplasia is absent."

Documents the incomplete-BANDDOS presentation in which biallelic missense variants spare the skeleton.

+ 1 more reference

Progressive Neurological Decline

The clinical convergence point of the developmental and degenerative arms. Most patients present perinatally or in infancy with hypotonia, developmental delay, and seizures, then follow a course of cognitive regression, speech deterioration, spasticity and rigidity with pyramidal signs, and dysphagia. A minority with hypomorphic alleles are normal or near-normal through childhood and decline in the second or third decade, an ALSP-like trajectory. In the end stage, patients become bedridden with loss of speech and voluntary movement; several reported patients died in infancy or childhood.

Show evidence (3 references)

PMID:37349768 SUPPORT Human Clinical

"Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia..."

Enumerates the neurological manifestations and their frequencies across the reviewed BANDDOS cohort.

PMID:22934315 SUPPORT Human Clinical

"Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk."

GeneReviews describes the end-stage trajectory shared across the CSF1R-related disorder spectrum.

PMID:37349768 SUPPORT Human Clinical

"Three patients died in infancy, two in childhood, and one case at unspecified age."

Documents the mortality observed in the reviewed BANDDOS cohort.

✶

Histopathology

2

Absence of parenchymal microglia

The defining neuropathological finding, though so far documented in only a single published autopsy: immunostaining of a biallelic CSF1R brain showed almost complete absence of microglia, with only rare abnormal perivascular cells identifiable.

Show evidence (1 reference)

PMID:30982608 SUPPORT Human Clinical

"Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia."

Human post-mortem immunostaining establishes near-total microglial absence in a biallelic CSF1R brain.

White matter atrophy with axonal spheroids and gliosis

Prominent white matter atrophy containing axonal spheroids, with reactive gliosis and numerous dystrophic calcifications predominantly in periventricular white matter - the same constellation as CSF1R-ALSP but more severe.

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"prominent white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications predominantly in the periventricular white matter"

Describes the degenerative white matter histopathology observed in the single published BANDDOS autopsy.

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Pathograph

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Phenotypes

22

Digestive 1

Dysphagia FREQUENT HP:0002015

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Dysphagia was common and reported in 75% of cases of BANDDOS"

Quantifies dysphagia at 75% of cases, mapping to the FREQUENT band.

Eye 1

Optic atrophy OCCASIONAL HP:0000648

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"In addition, a minority of BANDDOS cases presented infantile hypotonia (27%) and atrophy of the optic nerve (29%), which were not reported in CSF1R-ALSP."

Quantifies optic nerve atrophy at 29%, mapping to the OCCASIONAL band.

Head and Neck 1

Dysmorphic features FREQUENT Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Dysmorphic features were reported in 41% of cases of BANDDOS."

Quantifies dysmorphic features at 41% of cases, mapping to the FREQUENT band. The term is deliberately kept at the general 'abnormal facial shape' level because the 41% figure covers dysmorphism as a whole; no individual dysmorphic sign has a reported cohort frequency.

Limbs 1

Metaphyseal widening with Erlenmeyer flask deformity Erlenmeyer flask deformity of the femurs HP:0004975

Show evidence (1 reference)

PMID:33749994 SUPPORT Human Clinical

"Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."

Establishes the Pyle-disease-like metaphyseal modelling defect as one end of the BANDDOS skeletal spectrum. No cohort-level frequency is reported for this specific radiographic sign, so no frequency band is asserted.

Musculoskeletal 3

Spasticity and rigidity VERY_FREQUENT HP:0001257

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Pyramidal signs (spasticity, hyperactive tendon reflexes, and pathological reflexes) were present in up to 80% of BANDDOS cases"

Quantifies pyramidal signs at up to 80% of cases, mapping to the VERY_FREQUENT band.

Infantile hypotonia OCCASIONAL Generalized hypotonia HP:0001290

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"In addition, a minority of BANDDOS cases presented infantile hypotonia (27%) and atrophy of the optic nerve (29%), which were not reported in CSF1R-ALSP."

Quantifies infantile hypotonia at 27%, mapping to the OCCASIONAL band, and marks it as a BANDDOS-specific feature.

Osteopetrosis HP:0011002

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"Skeletal abnormalities were observed in 76% of cases of BANDDOS."

Quantifies skeletal involvement at 76% of BANDDOS cases. No frequency band is asserted for osteopetrosis specifically: the 76% figure covers the whole dysosteosclerosis-Pyle spectrum, of which frank osteosclerosis is only one pole, and the sclerotic subset is not separately counted.

PMID:38934054 SUPPORT Human Clinical

"Skeletal survey revealed osteosclerosis, most severe in sibling three."

Independent family report documenting osteosclerosis on skeletal survey, with intrafamilial variability in severity.

Nervous System 11

Global developmental delay FREQUENT HP:0001263

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia..."

Reports developmental delay in 7 of 14 assessable BANDDOS patients (50%), mapping to the FREQUENT band.

PMID:22934315 SUPPORT Human Clinical

"Early-onset disease is associated with hypotonia, delayed acquisition of developmental milestones, and non-neurologic manifestations (such as skeletal abnormalities); both early- and late-onset disease have similar neurodegenerative involvement."

GeneReviews identifies delayed milestones as characteristic of the early-onset (biallelic) form of CSF1R-related disorder.

Cognitive decline VERY_FREQUENT Mental deterioration HP:0001268

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Progressive cognitive dysfunction was present in 86% of BANDDOS cases"

Directly quantifies progressive cognitive decline at 86% of cases, mapping to the VERY_FREQUENT band.

Developmental regression HP:0002376

Show evidence (1 reference)

PMID:32464672 SUPPORT Human Clinical

"The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months."

Documents rapid regression with loss of all achieved milestones after an acute encephalopathic presentation in a biallelic CSF1R child.

Speech disturbance VERY_FREQUENT Abnormal speech pattern HP:0002167

Course: PROGRESSIVE

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"Speech disturbances were the most common neurological symptom in BANDDOS and were present in 87% of cases, with dysarthria reported in more than half of cases."

Quantifies speech disturbance as a whole at 87%, mapping to the VERY_FREQUENT band.

PMID:37349768 SUPPORT Human Clinical

"As all cases with BANDDOS with speech disturbances had accompanying cognitive decline or developmental delay, the multifaceted nature of speech dysfunction, as seen in CSF1R-ALSP, is most likely."

Supports the multifactorial (language plus motor speech) characterisation rather than attributing the deficit to dysarthria alone.

Dysarthria FREQUENT HP:0001260

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"with dysarthria reported in more than half of cases"

Dysarthria specifically is reported in more than half of cases, which maps to the FREQUENT band (30-79%) - not to the 87% VERY_FREQUENT figure, which is for speech disturbance as a whole.

Hyperreflexia FREQUENT HP:0001347

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"hyperactive tendon reflex (n = 11/14)"

Reports hyperactive tendon reflexes in 11 of 14 assessable cases (79%), mapping to the FREQUENT band.

Seizures FREQUENT HP:0001250

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"Seizures were noted in 56% of cases in BANDDOS, compared to up to 32% of CSF1R-ALSP"

Quantifies seizure frequency at 56%, mapping to the FREQUENT band, and contrasts it with the adult-onset form.

PMID:38934054 SUPPORT Human Clinical

"Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities."

Documents therapy-resistant epilepsy as a presenting feature in a three-sibling BANDDOS family.

Agenesis of the corpus callosum FREQUENT Agenesis of corpus callosum HP:0001274

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"callosal abnormalities (agenesis in 75% of BANDDOS vs. atrophy in 29% with CSF1R-ALSP cases)"

Quantifies callosal agenesis at 75%, mapping to the FREQUENT band, and distinguishes it from the atrophy pattern of CSF1R-ALSP.

Ventriculomegaly FREQUENT HP:0002119

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."

Reports ventriculomegaly in 13 of 19 BANDDOS patients (68%), mapping to the FREQUENT band.

Cerebellar atrophy VERY_FREQUENT HP:0001272

Show evidence (1 reference)

PMID:34145972 SUPPORT Human Clinical

"Brain structural abnormalities vary, with ventriculomegaly reported in nine out of ten cases, agenesis/hypogenesis of the corpus callosum in five out of ten, and cerebellar atrophy in seven out of eight patients examined"

Reports cerebellar atrophy in 7 of 8 assessed patients (88%), mapping to the VERY_FREQUENT band.

Leukoencephalopathy OBLIGATE HP:0002352

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities were present in all cases (n = 19) on neuroimaging, including white matter changes (n = 19/19)"

Establishes white matter abnormality as present in 100% (19/19) of reported BANDDOS cases, the one obligate feature of the disorder.

Other 4

Dandy-Walker complex FREQUENT Dandy-Walker malformation HP:0001305

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."

Reports Dandy-Walker complex in 7 of 19 BANDDOS patients (37%), mapping to the FREQUENT band.

Cortical malformation FREQUENT Abnormal cortical gyration HP:0002536

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."

Reports cortical abnormalities in 4 of 10 assessable cases (40%), mapping to the FREQUENT band.

Gray matter heterotopia HP:0002282

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"numerous periventricular and brainstem calcifications, and heterotopia, abnormal gyration of hippocampi, and non-decussation of small pyramidal tracts"

Autopsy documentation of heterotopia. Only one BANDDOS autopsy has been published, so no frequency band is asserted.

Intracranial calcification VERY_FREQUENT Cerebral calcification HP:0002514

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"calcifications (in 83% of BANDDOS vs. 75% with CSF1R-ALSP cases)"

Quantifies intracranial calcification at 83% of BANDDOS cases, mapping to the VERY_FREQUENT band.

PMID:32464672 SUPPORT Human Clinical

"Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles."

Describes the anatomical distribution of the calcifications in a biallelic CSF1R sibling pair.

🧬

Genetic Associations

1

CSF1R (Causative)

Gene: CSF1R hgnc:2433 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (7 references)

PMID:30982609 SUPPORT Human Clinical

"Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease."

The defining report establishing biallelic CSF1R variants as the cause of the combined brain malformation and skeletal dysplasia phenotype.

PMID:37349768 SUPPORT Human Clinical

"We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion."

Summarises the mutational spectrum reported in BANDDOS.

PMID:30982609 SUPPORT Human Clinical

"Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA."

Documents the deep-intronic splice-disrupting mechanism, which is important because such variants are missed by exome-only analysis.

+ 4 more references

💊

Medical Actions

5

Multidisciplinary Supportive and Rehabilitative Care

Action: Supportive Care NCIT:C15747

There is no disease-modifying therapy of proven benefit in BANDDOS. Care is multidisciplinary and symptom-directed, spanning neurology, neuropsychological rehabilitation, physical, occupational and speech-language therapy, nutritional and swallowing support, and family support with genetic counselling. GeneReviews additionally advises caution with sedatives, antipsychotics, and other agents that reduce alertness in individuals who have gait problems and cognitive decline, because of fall risk.

Show evidence (2 references)

PMID:22934315 SUPPORT Human Clinical

"Treatment of manifestations: Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling."

GeneReviews sets out the multidisciplinary supportive management standard for CSF1R-related disorder, which includes the early-onset biallelic form.

PMID:22934315 SUPPORT Human Clinical

"For individuals with gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously."

GeneReviews Agents/Circumstances to Avoid guidance, recorded here as a drug-safety caution attached to supportive management.

Allogeneic Hematopoietic Stem Cell Transplantation (investigational in BANDDOS)

Action: Hematopoietic Cell Transplantation NCIT:C15431

HSCT replaces the CSF1R-deficient myeloid compartment with donor-derived cells and has become a disease-modifying option in adult-onset CSF1R-ALSP. It has NOT been demonstrated to benefit BANDDOS: the rationale is extrapolation from the shared genetic and neuropathological basis of the two disorders. Preclinical support comes from the Csf1rko rat, where wild-type bone marrow transfer restores tissue macrophages, eliminates osteopetrosis, and permits normal growth and long-term survival - although in that model the brain was the one organ where donor-derived microglia-like cells did not fully match resident microglia, and congenital malformations already present at birth would not be expected to reverse.

Mechanism Target:

RESTORES Microglial Deficiency in the Developing Brain — Donor-derived myeloid cells engraft the CNS and are intended to reconstitute the missing CSF1R-competent brain macrophage population.

Show evidence (1 reference)

PMID:34081701 SUPPORT INDIRECT Model Organism

"Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility."

Model-organism evidence that marrow transfer repopulates brain microglia and reverses the mutant phenotype; classified INDIRECT because this is a rat rescue experiment, not evidence of benefit in human BANDDOS.

Show evidence (2 references)

PMID:37349768 SUPPORT INDIRECT Human Clinical

"Therefore, both disorders are on the same continuum, albeit they differ in the severity of CSF1R mutations' consequences and phenotypes. This opens windows of opportunity for applying already available therapy in CSF1R-ALSP in BANDDOS."

The review proposes translating CSF1R-ALSP therapy to BANDDOS on the basis of shared pathomechanism; this is an argument for a trial, not evidence of efficacy, hence INDIRECT.

PMID:39869647 SUPPORT Model Organism

"The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia."

Tempers the rescue rationale: donor-derived brain macrophages are not transcriptionally equivalent to resident microglia, so CNS correction may be incomplete.

iPSC-Derived Microglia Replacement (preclinical)

Action: cellular therapy Ontology label: Cellular Therapy NCIT:C70601

A research-stage strategy that goes further than HSCT: transplanting human iPSC-derived microglial progenitors directly, rather than relying on marrow-derived cells to engraft the CNS. In a xenotolerant Csf1r-FIRE-enhancer mouse that develops nearly all the hallmark ALSP pathologies, transplanted iPSC-derived microglia restored a homeostatic microglial signature and prevented axonal spheroids, white matter abnormality, reactive astrocytosis, and brain calcification; CRISPR-corrected patient-derived microglia even reversed pre-existing spheroid, astrogliosis, and calcification pathology. This is preclinical and was done in an ALSP model, not a BANDDOS model, and it addresses the degenerative arm only - the congenital malformations of BANDDOS are established before birth.

Mechanism Target:

INHIBITS Progressive White Matter Degeneration with Axonal Spheroids — Restoring a CSF1R-competent microglial population prevents, and in established disease partially reverses, the white-matter degeneration, spheroids, gliosis, and calcification.

Show evidence (1 reference)

PMID:38897209 SUPPORT Model Organism

"transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications"

Direct evidence that microglial replacement prevents the degenerative white-matter pathology; PARTIAL because the model is an ALSP (heterozygous-equivalent) mouse, not a biallelic BANDDOS system.

Show evidence (2 references)

PMID:38897209 SUPPORT Model Organism

"Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies."

Shows reversal of established pathology, which is what would be required in an already-symptomatic patient; still preclinical and in an ALSP model.

PMID:38897209 SUPPORT Model Organism

"our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders"

The authors themselves extend the claim only as far as "perhaps other microglia-associated neurological disorders"; no BANDDOS-specific claim is made or asserted here.

Antiseizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Seizures occur in roughly half of patients and may be therapy-resistant, requiring standard antiseizure medication chosen for the seizure type.

Show evidence (1 reference)

PMID:38934054 SUPPORT Human Clinical

"Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities."

Documents that epilepsy in BANDDOS is a clinical management problem and is frequently refractory; classified PARTIAL because it establishes the indication rather than the efficacy of any specific agent.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Because BANDDOS is autosomal recessive and most families are consanguineous, counselling covers the 25% sib recurrence risk, carrier testing of relatives, and the availability of prenatal and preimplantation genetic testing once the familial variants are known.

Show evidence (1 reference)

PMID:22934315 SUPPORT Human Clinical

"Once the CSF1R pathogenic variant(s) have been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible."

GeneReviews establishes the availability of predictive, prenatal, and preimplantation testing once the familial variants are known.

🔬

Diagnosis

4

Molecular Confirmation of Biallelic CSF1R Variants (Biallelic (homozygous or compound heterozygous) pathogenic CSF1R variants)

The diagnosis is established by identifying biallelic pathogenic CSF1R variants in a proband with suggestive clinical and radiological findings. Because two of the originally described BANDDOS alleles were deep intronic and acted by abnormal intron inclusion, an exome-only strategy can miss the second allele; genome sequencing or targeted intronic analysis should be considered when only one variant is found in a phenotypically convincing case. Parental segregation should be confirmed.

Show evidence (3 references)

PMID:22934315 SUPPORT Human Clinical

"The diagnosis of CSF1R-related disorder is established in a proband with suggestive findings and a heterozygous CSF1R pathogenic variant or biallelic CSF1R pathogenic variants identified by molecular genetic testing."

GeneReviews states the diagnostic criterion; the biallelic branch is the one that defines BANDDOS.

PMID:30982609 SUPPORT Human Clinical

"Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA."

Justifies the caveat that exome-only testing can miss a BANDDOS allele, since deep intronic variants are a recognised mechanism in this disorder.

PMID:37431483 SUPPORT Human Clinical

"Targeted gene sequencing was performed on the genomic DNA samples of the deceased patient and a fetus along with ten healthy members of his family to identify the disease-causing mutation."

Illustrates the targeted-sequencing-plus-family-segregation approach used to establish the diagnosis in practice, including prenatal testing.

Brain MRI (Abnormal in all reported cases)

Brain MRI defines the white-matter abnormality (universal in BANDDOS) and the congenital malformations - callosal agenesis or hypogenesis, ventriculomegaly and colpocephaly, Dandy-Walker complex, and cortical abnormalities. It is the study that most clearly separates BANDDOS from adult-onset CSF1R-ALSP, in which congenital malformation is absent.

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"Brain abnormalities were present in all cases (n = 19) on neuroimaging, including white matter changes (n = 19/19)"

Establishes neuroimaging as abnormal in 100% of reported cases, making it the highest-yield diagnostic study.

Non-contrast Head CT for Intracranial Calcification (Calcification detected in most patients)

CT is more sensitive than MRI for the dystrophic periventricular and brainstem calcifications, which are present in most patients, are already present at birth, and share the stepping-stone appearance described in CSF1R-ALSP.

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"calcifications (in 83% of BANDDOS vs. 75% with CSF1R-ALSP cases)"

Quantifies the diagnostic yield of looking for intracranial calcification in suspected BANDDOS.

Skeletal Survey (Abnormal in about three quarters of patients)

Radiographic skeletal survey identifies the sclerosing bone dysplasia - increased bone density, craniofacial and vertebral sclerosis, and metaphyseal modelling abnormalities spanning the dysosteosclerosis to Pyle disease spectrum. A normal survey does not exclude the diagnosis, since about a quarter of reported patients had no skeletal involvement.

Show evidence (2 references)

PMID:37349768 SUPPORT Human Clinical

"Skeletal abnormalities were observed in 76% of cases of BANDDOS."

Quantifies the diagnostic yield of skeletal survey and, by complement, the fraction of patients in whom it is normal.

PMID:33749994 SUPPORT Human Clinical

"Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."

Supports the caveat that a normal skeletal survey does not exclude BANDDOS.

🩻

Imaging Findings

3

Multifocal cerebral white matter signal abnormality

Bilateral, often multifocal T2/FLAIR hyperintensity of cerebral white matter, most prominent periventricularly and in the corpus callosum and pyramidal tracts; progressive, and taking on the appearance of ALSP during secondary neurological decline.

Mri Diagnostic

Leukoencephalopathy HP:0002352

Show evidence (1 reference)

PMID:38934054 SUPPORT Human Clinical

"Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three."

Documents the MRI appearance of multifocal white matter abnormality with calcification in BANDDOS.

Periventricular and brainstem calcifications

Dystrophic calcifications concentrated in periventricular white matter and brainstem, present from birth, with a stepping-stone appearance shared with CSF1R-ALSP.

Ct Diagnostic

Intracranial calcification HP:0430048

Show evidence (1 reference)

PMID:32464672 SUPPORT Human Clinical

"Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles."

Radiological description of the calcification pattern in biallelic CSF1R disease.

Generalised osteosclerosis on skeletal survey

Skeletal survey shows increased bone density, cranial and vertebral sclerosis, and abnormal metaphyseal modelling, spanning the dysosteosclerosis to Pyle disease spectrum.

Xray

Increased bone mineral density HP:0011001

Show evidence (1 reference)

PMID:38934054 SUPPORT Human Clinical

"Skeletal survey revealed osteosclerosis, most severe in sibling three."

Documents the radiographic skeletal finding and its intrafamilial variability.

📊

Prevalence

1

Worldwide (published cases)

Cases In Literature Ultra Rare

Nineteen patients had been reported worldwide as of the 2023 systematic review; further isolated families have been described since.

Show evidence (1 reference)

PMID:37349768 SUPPORT Human Clinical

"We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3)."

The largest systematic review to date enumerates the total number of published BANDDOS cases, establishing the disorder as ultra-rare.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis:

Dysosteosclerosis due to SLC29A3 or TNFRSF11A variants

Overlapping Features Dysosteosclerosis is genetically heterogeneous; biallelic SLC29A3 and TNFRSF11A variants cause radiologically similar sclerosing bone dysplasia without the CSF1R brain phenotype.

Distinguishing Features

Absence of leukoencephalopathy and intracranial calcification
Absence of congenital brain malformation
Different causal gene (SLC29A3 or TNFRSF11A) on molecular testing

Show evidence (2 references)

PMID:33837634 SUPPORT Human Clinical

"It is a genetically heterogeneous disorder caused by biallelic mutations in the SLC29A3, TNFRSF11A, TCIRG1, and CSF1R genes."

States the genetic heterogeneity of dysosteosclerosis directly: CSF1R is only one of at least four causal genes, so the radiological diagnosis does not settle the molecular one.

PMID:33402699 SUPPORT Human Clinical

"TNFRSF11A has been known as the causal gene for osteopetrosis, autosomal recessive 7, and is recently reported to cause DOS in three cases, which show a complex genotype-phenotype relationship."

Documents TNFRSF11A as an established non-CSF1R cause of dysosteosclerosis, confirming it as a genuine molecular differential.

Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, TREM2/TYROBP)

Overlapping Features The most instructive mimic: another autosomal recessive microglial-signalling disorder that, like BANDDOS, combines a leukoencephalopathy with bone lesions. TREM2 and TYROBP (DAP12) act in the same microglial signalling network as CSF1R, which is why the two disorders converge phenotypically.

Distinguishing Features

Bone lesions are polycystic and lytic (with pathological fractures), not sclerosing
Onset of the osseous stage in the third decade and dementia in the fourth, versus perinatal or infantile onset in most BANDDOS
Frontal lobe syndrome dominates the neurological presentation
Congenital brain malformation is not a feature
Biallelic TREM2 or TYROBP variants rather than biallelic CSF1R

Show evidence (2 references)

PMID:20301376 SUPPORT Human Clinical

"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."

GeneReviews description establishing the lytic/polycystic bone phenotype and the fourth-decade dementia that distinguish PLOSL from BANDDOS.

PMID:20301376 SUPPORT Human Clinical

"Identification of biallelic pathogenic variants in TYROBP or TREM2 confirms the diagnosis since radiographic and clinical features may be inconclusive."

Confirms that molecular testing is what separates the two, and names the alternative causal genes.

🐁

Animal Models

3

Csf1r knockout rat (Csf1rko)

Homozygous Csf1r knockout rats lack essentially all tissue macrophage populations including microglia, develop osteopetrosis, and fail to thrive postnatally. The model reproduces the myeloid and skeletal arms of human biallelic CSF1R disease, and wild-type bone marrow transfer at weaning rescues the phenotype - but the brain phenotype is much milder than in humans, which is a substantive translational caveat.

Species

Rat

Genotype

Csf1r homozygous knockout

Publication

PMID:33450391

Pathograph links

Microglial Deficiency in the Developing Brain recapitulates fidelity: high Csf1rko rats lose the entire microglial transcriptomic signature across every brain region examined.

Limitations: The rat models the cellular deficiency faithfully but not its human developmental consequences (see the FAILS_TO_RECAPITULATE link below).

Readouts

Microglial marker gene expression across brain regions

Direction: DECREASED

Interpretation: Transcriptomic confirmation that the microglial population is absent throughout the Csf1rko brain.

Show evidence (1 reference)

PMID:33450391 SUPPORT Model Organism

"RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats."

Quantifies the depletion of the microglial signature in every brain region of the knockout.

Show evidence (1 reference)

PMID:33450391 SUPPORT Model Organism

"RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats."

Establishes the model as informative for the microglial-deficiency node.

Disrupted Brain Development and Structural Malformation fails to recapitulate fidelity: low Unlike humans with biallelic CSF1R variants, Csf1rko rats do not develop the congenital brain malformations (callosal agenesis, Dandy-Walker complex, cortical malformation) that define BANDDOS; brain development is largely normal without microglia.

Limitations: Species differences in the developmental role of microglia mean the rat cannot be used to model, or to test therapies against, the congenital malformation arm of BANDDOS. The authors go further and conclude that CSF1R haploinsufficiency alone is unlikely to cause leukoencephalopathy, which is at odds with the human monoallelic disorder.

Readouts

Region-specific neuronal and glial transcript clusters

Direction: UNCHANGED

Interpretation: Absence of microglia leaves neuronal, oligodendrocyte, and astrocyte expression programmes essentially intact in the rat.

Show evidence (1 reference)

PMID:33450391 SUPPORT Model Organism

"Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster."

A negative result: no detectable effect of microglial loss on neuronal or regional gene expression in the rat brain.

Show evidence (1 reference)

PMID:33450391 SUPPORT Model Organism

"We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy."

The authors' own conclusion that brain development proceeds normally without microglia in the rat, which directly contradicts the human BANDDOS malformation phenotype and substantiates the failure to recapitulate.

Osteoclast Deficiency and Impaired Bone Resorption recapitulates fidelity: high Csf1rko rats develop osteopetrosis that is reversed by wild-type bone marrow transfer, establishing the osteoclast-deficiency mechanism.

Limitations: The rat osteopetrosis is more severe than the dysosteosclerosis-Pyle spectrum seen in humans, consistent with the human alleles being hypomorphic rather than null.

Readouts

Osteoclast restoration and reversal of osteopetrosis after bone marrow transfer

Direction: RESTORED

Interpretation: Restoring CSF1R-competent marrow-derived cells restores osteoclasts and eliminates the sclerotic bone phenotype.

Show evidence (1 reference)

PMID:34081701 SUPPORT Model Organism

"WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency."

Rescue readout showing osteoclast restoration and resolution of osteopetrosis.

Show evidence (1 reference)

PMID:34081701 SUPPORT Model Organism

"Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities."

Establishes the rat Csf1rko as the cross-species model of homozygous CSF1R mutation, the same lesion as in BANDDOS.

Show evidence (1 reference)

PMID:39869647 SUPPORT Model Organism

"These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity."

The authors position the Csf1rko rat explicitly as a model for human CSF1R-mutation pathology and its treatment.

Csf1r-null mouse

The Csf1r-null mouse is the original and most extensively characterised CSF1R-deficiency system, and is the model the human BANDDOS phenotype was first compared against. It loses most tissue macrophages and osteoclasts and is osteopetrotic. Its central caveat for BANDDOS is severity and background dependence: the human phenotype is milder and more variable than the mouse null, which is the observation that led to the inference that at least one BANDDOS allele is always hypomorphic.

Species

Mouse

Genotype

Csf1r homozygous null (Csf1r-/-)

Publication

PMID:34145972

Pathograph links

Osteoclast Deficiency and Impaired Bone Resorption recapitulates fidelity: moderate Csf1r-null mice show the loss of osteoclasts and of bone remodelling that underlies the human skeletal phenotype.

Limitations: The complete null is more severe than any reported human genotype, and phenotypic differences between Csf1-null and Csf1r-null mice are only revealed on defined inbred backgrounds, so strain background is a confounder when reading severity across studies.

Show evidence (1 reference)

PMID:34145972 SUPPORT Model Organism

"Studies in homozygous Csf1r- and Csf1- null mice have shown that the CSF-1/CSF-1R pathway regulates the differentiation and maintenance of most tissue macrophages and osteoclasts, contributing to the development and remodeling of bones and soft tissues"

Establishes the mouse null as the system in which the macrophage and osteoclast requirement for CSF1R signalling was demonstrated.

Cited via the dedicated review of Csf1r-deficiency models rather than a single primary mouse paper, because the relevant claim (what the mouse null does and does not capture about human CSF1R disease) is a synthesis across that literature.

Show evidence (1 reference)

PMID:30982609 SUPPORT Human Clinical

"Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic."

The explicit human-versus-Csf1r-null comparison that both establishes the model's relevance and bounds its fidelity.

csf1rDM zebrafish (csf1ra/csf1rb double mutant)

Zebrafish lacking Csf1r function have brains devoid of microglia and reduced levels of the upper-layer neuronal transcription factor CUX1, paralleling the reduction of CUX1-positive neurons seen in human biallelic CSF1R brain tissue.

Species

Zebrafish

Genotype

csf1ra; csf1rb double mutant (csf1rDM)

Publication

PMID:30982608

Pathograph links

Microglial Deficiency in the Developing Brain recapitulates fidelity: moderate csf1rDM brains lack microglia, reproducing the defining cellular lesion.

Limitations: Zebrafish brain architecture lacks a corpus callosum and the mammalian six-layered cortex, so the model cannot address the specific human malformations; the shared readout is the CUX1 reduction, not the malformation itself.

Readouts

Brain CUX1 level

Direction: DECREASED

Interpretation: Reduced CUX1 in the microglia-less fish brain, matched by reduced CUX1-positive neurons in human biallelic CSF1R brain, identifies a conserved microglia-dependent neuronal readout.

Show evidence (1 reference)

PMID:30982608 SUPPORT Model Organism

"We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor."

Reports both the microglial absence and the CUX1 reduction in the zebrafish model.

Show evidence (1 reference)

PMID:30982608 SUPPORT Model Organism

"CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons."

The cross-species concordance of the CUX1 readout is what makes the fish informative for the human microglial-deficiency node.

{ }

Source YAML

click to show

name: Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
synonyms:
- BANDDOS
- Early-onset CSF1R-related disorder
- Biallelic CSF1R-related brain malformation and osteopetrosis
disease_term:
  preferred_term: Brain abnormalities, neurodegeneration, and dysosteosclerosis
  term:
    id: MONDO:0032772
    label: brain abnormalities, neurodegeneration, and dysosteosclerosis
parents:
  - CSF1R-related disorder
  - leukodystrophy
  - sclerosing bone dysplasia
description: >
  Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS,
  MIM 618476) is an exceedingly rare autosomal recessive disorder caused by
  biallelic loss-of-function variants in CSF1R, the gene encoding the
  colony-stimulating factor 1 receptor. CSF1R is the master regulator of the
  mononuclear phagocyte lineage, and the two CSF1R-dependent tissue-resident
  populations that fail in BANDDOS - brain microglia and bone osteoclasts -
  account for the two halves of the disease name. Severe reduction or loss of
  CSF1R signalling during fetal life leaves the developing brain deficient in
  microglia, producing congenital structural malformations (agenesis of the
  corpus callosum, Dandy-Walker complex, ventriculomegaly, cortical
  abnormalities) that are not seen in the adult-onset, monoallelic form of
  CSF1R disease. Brain abnormality of some kind is present in every reported
  case, though the individual malformations vary in frequency. Superimposed on
  this developmental lesion is a progressive
  leukoencephalopathy with white-matter degeneration, axonal spheroids,
  gliosis, and dystrophic intracranial calcification that is
  neuropathologically continuous with CSF1R-ALSP. In bone, deficient
  osteoclastic resorption produces a sclerosing bone dysplasia spanning the
  dysosteosclerosis - Pyle disease spectrum. Onset is usually perinatal or in
  infancy, with developmental delay, seizures, spasticity, dysarthria,
  dysphagia, and progressive cognitive decline - about half of reported
  patients first became symptomatic perinatally or in infancy; some with
  hypomorphic alleles present only in later childhood or adulthood, and
  skeletal involvement may be absent. BANDDOS and CSF1R-ALSP are now regarded
  as the early- and late-onset ends of a single CSF1R-related disorder
  continuum whose severity tracks residual CSF1R function.

references:
  - reference: PMID:22934315
    title: "CSF1R-Related Disorder."
    tags:
      - GeneReviews
  - reference: PMID:30982609
    title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
  - reference: PMID:30982608
    title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
  - reference: PMID:37349768
    title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
  - reference: PMID:33749994
    title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
  - reference: PMID:32464672
    title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
  - reference: PMID:38934054
    title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
  - reference: PMID:34135456
    title: "From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R."
  - reference: PMID:37839910
    title: "CSF1R-related disorder: State of the art, challenges, and proposition of a new terminology."
  - reference: PMID:28383543
    title: "Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation."
  - reference: PMID:33450391
    title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
  - reference: PMID:34081701
    title: "CSF1R-dependent macrophages control postnatal somatic growth and organ maturation."
  - reference: PMID:39869647
    title: "Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation."
  - reference: PMID:37431483
    title: "Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)."
  - reference: PMID:34145972
    title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
  - reference: PMID:38897209
    title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
  - reference: PMID:33837634
    title: "Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl."
  - reference: PMID:33402699
    title: "Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis."
  - reference: PMID:20301376
    title: "Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy."
    tags:
      - GeneReviews

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      BANDDOS is dominated by a congenital brain malformation plus progressive
      leukoencephalopathy and neurodegeneration.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      BANDDOS is a monogenic autosomal recessive disorder caused by biallelic
      CSF1R variants.
  isds_skeletal_category:
  - classification_value: osteopetrosis_and_related
    notes: >-
      The skeletal component falls within the dysosteosclerosis - Pyle disease
      spectrum of sclerosing bone dysplasias, grouped with osteopetrosis and
      related disorders in the ISDS nosology.

prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Nineteen patients had been reported worldwide as of the 2023 systematic
    review; further isolated families have been described since.
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3)."
    explanation: >
      The largest systematic review to date enumerates the total number of
      published BANDDOS cases, establishing the disorder as ultra-rare.

pathophysiology:
- name: Biallelic CSF1R Loss of Function
  biological_scale: MOLECULAR
  description: >
    CSF1R encodes a transmembrane receptor tyrosine kinase activated by two
    ligands, CSF1 and IL-34. In BANDDOS both alleles carry pathogenic variants -
    most often splice, nonsense, or deep-intronic changes that disrupt the
    tyrosine kinase domain or trigger nonsense-mediated decay, less often
    hypomorphic missense changes that leave the protein expressed but unable to
    autophosphorylate on ligand binding. Because complete CSF1R nullity is
    lethal or far more severe than what is observed clinically, at least one
    allele in each reported individual is thought to retain partial function,
    and the residual level of CSF1R signalling grades disease severity across
    the CSF1R-related disorder continuum.
  molecular_functions:
  - preferred_term: macrophage colony-stimulating factor receptor activity
    term:
      id: GO:0005011
      label: macrophage colony-stimulating factor receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: cell surface receptor protein tyrosine kinase signaling pathway
    term:
      id: GO:0007169
      label: cell surface receptor protein tyrosine kinase signaling pathway
    modifier: DECREASED
  - preferred_term: CSF1R autophosphorylation on ligand binding
    term:
      id: GO:0046777
      label: protein autophosphorylation
    modifier: DECREASED
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay."
    explanation: >
      Across all 11 BANDDOS-associated CSF1R variants reviewed, the molecular
      consequence converges on loss of tyrosine kinase function or loss of the
      transcript, establishing loss of function as the molecular lesion.
  - reference: PMID:32464672
    reference_title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Total CSF1R protein expression levels were normal as compared with wild-type allele, but CSF1 ligand dependent autophosphorylation was consistent with a hypomorphic allele."
    explanation: >
      Functional assay of the p.T833M allele shows normal receptor abundance
      but impaired ligand-dependent autophosphorylation, directly demonstrating
      the signalling defect in a hypomorphic BANDDOS allele.
  - reference: PMID:30982609
    reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic."
    explanation: >
      Supports the dose-dependent model: complete nullity is not what is seen
      clinically, and residual CSF1R activity from a hypomorphic allele sets
      the severity.
  downstream:
  - target: Microglial Deficiency in the Developing Brain
    causal_link_type: DIRECT
    description: >
      Microglia depend on CSF1R for their proliferation, differentiation, and
      survival, so loss of receptor signalling depletes the brain of its
      resident macrophage population.
    evidence:
    - reference: PMID:37349768
      reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both microglia of the central nervous system and osteoclasts stem from the monocyte phagocytic system, and their differentiation process depends on CSF1R."
      explanation: >
        States the dependence of microglial differentiation on CSF1R that makes
        this causal edge direct.
  - target: Osteoclast Deficiency and Impaired Bone Resorption
    causal_link_type: DIRECT
    description: >
      Osteoclasts arise from the same CSF1R-dependent monocyte/macrophage
      lineage, so the same receptor lesion compromises osteoclastogenesis.
    evidence:
    - reference: PMID:30982609
      reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts."
      explanation: >
        Establishes osteoclasts as a CSF1R-dependent lineage, grounding the
        causal edge from receptor loss of function to osteoclast failure.

- name: Microglial Deficiency in the Developing Brain
  biological_scale: CELLULAR
  description: >
    Loss of CSF1R signalling prevents the establishment and expansion of the
    microglial population, so the fetal and postnatal brain develops with few
    or no microglia. Post-mortem examination of a homozygous splice-variant
    case showed almost complete absence of microglia, with only rare abnormal
    perivascular cells remaining. This is a primary microgliopathy: the
    initiating cellular lesion is loss of the brain's resident macrophage,
    not a primary defect of neurons or oligodendrocytes.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
    modifier: DECREASED
  - preferred_term: central nervous system macrophage
    term:
      id: CL:0000878
      label: central nervous system macrophage
    modifier: DECREASED
  biological_processes:
  - preferred_term: microglial cell proliferation
    term:
      id: GO:0061518
      label: microglial cell proliferation
    modifier: DECREASED
  - preferred_term: macrophage differentiation
    term:
      id: GO:0030225
      label: macrophage differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:30982608
    reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia."
    explanation: >
      Direct human neuropathological demonstration that a biallelic CSF1R brain
      is essentially devoid of microglia, and that development proceeded in
      their absence.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications."
    explanation: >
      Independent review confirms absence of microglia as the defining
      histological finding alongside the structural and degenerative changes.
  - reference: PMID:30982608
    reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor."
    explanation: >
      A vertebrate model lacking Csf1r function reproduces the microglial
      deficiency, supporting conservation of the cellular mechanism.
  downstream:
  - target: Disrupted Brain Development and Structural Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      In the absence of microglia the developing brain fails to form normal
      commissural, ventricular, and posterior-fossa structures. One proposed
      intermediate is a reduction in CUX1-positive upper-layer neurons, many of
      which project callosal axons.
    evidence:
    - reference: PMID:30982608
      reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons."
      explanation: >
        The authors explicitly frame the microglia-to-callosal-agenesis link as
        a speculative mechanism via CUX1+ neuron loss, so the edge is supported
        only partially and its intermediates remain unproven.
    - reference: PMID:30982608
      reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that CSF1R is required for human brain development"
      explanation: >
        Supports the general claim that CSF1R (and hence microglia) is required
        for normal human brain development. The quote is deliberately trimmed
        to the human clause; the rest of the sentence concerns the zebrafish
        model and is cited separately as MODEL_ORGANISM evidence.
  - target: Progressive White Matter Degeneration with Axonal Spheroids
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The same microglial deficiency that disrupts development also leaves the
      white matter without its resident phagocyte, producing the progressive
      leukoencephalopathy that is neuropathologically indistinguishable from
      CSF1R-ALSP.
    evidence:
    - reference: PMID:37349768
      reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Likewise, histological evaluation evidenced a deficiency of microglia in the brain parenchyma, atrophic white matter with axonal spheroids, gliosis, and dystrophic calcifications in BANDDOS and CSF1R-ALSP"
      explanation: >
        Directly couples parenchymal microglial deficiency with the white
        matter degeneration, spheroids, gliosis, and calcification seen in both
        CSF1R disorders.

- name: Disrupted Brain Development and Structural Malformation
  biological_scale: TISSUE
  description: >
    The developmental arm of BANDDOS. Some brain abnormality is present in
    every reported case; the individual congenital malformations vary in
    frequency and include agenesis or hypoplasia of the
    corpus callosum, ventriculomegaly and colpocephaly, Dandy-Walker complex
    and large cisterna magna, cortical malformations, heterotopia, abnormal
    hippocampal gyration, and non-decussation of pyramidal tracts. These
    congenital malformations are the feature that most cleanly separates
    BANDDOS from adult-onset CSF1R-ALSP, in which they are not seen.
  cell_types:
  - preferred_term: CUX1-positive upper-layer cortical projection neuron
    term:
      id: CL:0000540
      label: neuron
    modifier: DECREASED
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: DECREASED
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."
    explanation: >
      Quantifies the spectrum and frequency of congenital brain abnormalities
      across the reviewed BANDDOS cohort.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared to CSF1R-ALSP, cases with BANDDOS also displayed other congenital brain anomalies, including Dandy-Walker malformation, ventriculomegaly, and cortical abnormalities."
    explanation: >
      Establishes congenital brain malformation as the discriminating feature
      of BANDDOS relative to the adult-onset monoallelic disorder.
  - reference: PMID:28383543
    reference_title: "Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes."
    explanation: >
      The first report of the recessive CSF1R phenotype names brain
      malformation and osteopetrosis as the novel biallelic presentation.
  downstream:
  - target: Progressive Neurological Decline
    causal_link_type: DIRECT
    description: >
      Congenital brain malformation underlies the developmental delay,
      early-onset epilepsy, and baseline neurological deficit on which later
      degeneration is superimposed.
    evidence:
    - reference: PMID:38934054
      reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications."
      explanation: >
        Links the developmental brain anomalies to the developmental delay and
        epilepsy that constitute the initial clinical disease.

- name: Progressive White Matter Degeneration with Axonal Spheroids
  biological_scale: TISSUE
  description: >
    The degenerative arm of BANDDOS, superimposed on the developmental lesion.
    White matter changes are present in 100% of reported cases. Histology shows
    prominent white matter atrophy with axonal spheroids, gliosis, and numerous
    dystrophic calcifications concentrated in periventricular white matter -
    the same picture as CSF1R-ALSP but more severe. On MRI the leukoencephalopathy
    is progressive and takes on the appearance of ALSP at the time of secondary
    neurological decline.
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
    modifier: INCREASED
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  - preferred_term: reactive gliosis
    term:
      id: GO:0048143
      label: astrocyte activation
    modifier: INCREASED
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological evaluation evidenced severe microglia deficiency with only rare spotting of abnormal microglia around the blood vessels, prominent white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications predominantly in the periventricular white matter"
    explanation: >
      The single published BANDDOS brain autopsy documents white matter
      atrophy, axonal spheroids, gliosis, and dystrophic calcification.
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP."
    explanation: >
      Documents the progressive, ALSP-like radiological evolution of the white
      matter disease during secondary neurological decline.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Macroscopically both disorders shared extensive white matter degeneration, most prominent in the periventricular region, corpus callosum, and pyramidal tracts"
    explanation: >
      Establishes the anatomical distribution of the white matter degeneration
      shared with CSF1R-ALSP.
  downstream:
  - target: Progressive Neurological Decline
    causal_link_type: DIRECT
    description: >
      Progressive loss of white matter integrity produces the cognitive
      decline, pyramidal signs, dysarthria, and dysphagia that dominate the
      later disease course.
    evidence:
    - reference: PMID:38934054
      reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP."
      explanation: >
        Directly attributes the secondary neurological decline to the
        progressive leukoencephalopathy.

- name: Osteoclast Deficiency and Impaired Bone Resorption
  biological_scale: CELLULAR
  description: >
    Osteoclasts differentiate from the CSF1R-dependent monocyte/macrophage
    lineage, and CSF1-CSF1R signalling is required for their generation and
    survival. Reduced CSF1R signalling therefore reduces osteoclastic bone
    resorption, so bone formed during modelling is not removed. The result is
    increased bone mineral density with failure of metaphyseal remodelling -
    the mechanistic basis of the sclerosing bone dysplasia. In the Csf1rko rat,
    transfer of wild-type bone marrow restores osteoclasts and eliminates the
    osteopetrosis, demonstrating that the bone phenotype is cell-autonomous to
    the marrow-derived lineage.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
    modifier: DECREASED
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: DECREASED
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: DECREASED
  - preferred_term: bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: DECREASED
  evidence:
  - reference: PMID:33749994
    reference_title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Colony stimulating factor 1 receptor (CSF1R, MIM# 164770) encodes a tyrosine-kinase receptor playing an important role in development of osteoclasts and microglia."
    explanation: >
      States the osteoclast-development role of CSF1R that makes osteoclast
      failure the expected consequence of biallelic loss of function.
  - reference: PMID:34081701
    reference_title: "CSF1R-dependent macrophages control postnatal somatic growth and organ maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency."
    explanation: >
      Rescue experiment in the Csf1rko rat establishes that osteoclast
      deficiency is the proximate cause of the osteopetrotic bone phenotype and
      that it is intrinsic to bone-marrow-derived cells.
  downstream:
  - target: Sclerosing Skeletal Dysplasia of the Dysosteosclerosis-Pyle Spectrum
    causal_link_type: DIRECT
    description: >
      Failure of osteoclastic resorption yields the increased bone density and
      abnormal metaphyseal modelling that define the skeletal phenotype.
    evidence:
    - reference: PMID:30982609
      reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function."
      explanation: >
        Attributes the human skeletal phenotype directly to CSF1R deficiency
        and grades it by residual receptor function.

- name: Sclerosing Skeletal Dysplasia of the Dysosteosclerosis-Pyle Spectrum
  biological_scale: ORGANISM
  description: >
    The skeletal component of BANDDOS spans a spectrum: at the sclerotic end,
    osteopetrosis and dysosteosclerosis with generalised increased bone
    density; at the modelling-defect end, Pyle-disease-like metaphyseal
    widening with Erlenmeyer flask deformity of the long bones. Skeletal
    involvement is present in most but not all cases, is variable even between
    siblings carrying the same genotype, and may be entirely absent in
    individuals with hypomorphic missense alleles ("incomplete BANDDOS").
  biological_processes:
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum."
    explanation: >
      Quantifies the frequency of skeletal involvement and defines its
      radiological spectrum.
  - reference: PMID:33749994
    reference_title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."
    explanation: >
      Establishes the variability of the skeletal phenotype, including its
      complete absence in some individuals.
  - reference: PMID:34135456
    reference_title: "From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, some individuals with bi-allelic missense mutations of CSF1R have been found to present with incomplete BANDDOS where skeletal dysplasia is absent."
    explanation: >
      Documents the incomplete-BANDDOS presentation in which biallelic missense
      variants spare the skeleton.
  - reference: PMID:34145972
    reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal anomalies include osteosclerosis of the craniofacial bones and skull, optic canal narrowing, kyphosis, platyspondyly and abnormalities of the long bones, e.g. undermodeling, widened metaphyses, and constricted and sclerotic diaphysis"
    explanation: >
      Enumerates the specific radiographic elements of the BANDDOS skeletal
      phenotype, including the optic canal narrowing relevant to visual loss.

- name: Progressive Neurological Decline
  biological_scale: ORGANISM
  description: >
    The clinical convergence point of the developmental and degenerative arms.
    Most patients present perinatally or in infancy with hypotonia,
    developmental delay, and seizures, then follow a course of cognitive
    regression, speech deterioration, spasticity and rigidity with pyramidal
    signs, and dysphagia. A minority with hypomorphic alleles are normal or
    near-normal through childhood and decline in the second or third decade, an
    ALSP-like trajectory. In the end stage, patients become bedridden with loss
    of speech and voluntary movement; several reported patients died in infancy
    or childhood.
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7)."
    explanation: >
      Enumerates the neurological manifestations and their frequencies across
      the reviewed BANDDOS cohort.
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected individuals eventually become bedridden with spasticity, rigidity, and loss of the ability to walk."
    explanation: >
      GeneReviews describes the end-stage trajectory shared across the
      CSF1R-related disorder spectrum.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients died in infancy, two in childhood, and one case at unspecified age."
    explanation: >
      Documents the mortality observed in the reviewed BANDDOS cohort.

phenotypes:
- category: Neurologic
  name: Global developmental delay
  description: >
    Delayed acquisition of developmental milestones is a common early feature,
    reported in 7 of 14 assessable cases.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7)."
    explanation: >
      Reports developmental delay in 7 of 14 assessable BANDDOS patients (50%),
      mapping to the FREQUENT band.
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early-onset disease is associated with hypotonia, delayed acquisition of developmental milestones, and non-neurologic manifestations (such as skeletal abnormalities); both early- and late-onset disease have similar neurodegenerative involvement."
    explanation: >
      GeneReviews identifies delayed milestones as characteristic of the
      early-onset (biallelic) form of CSF1R-related disorder.

- category: Neurologic
  name: Cognitive decline
  description: >
    Progressive loss of previously acquired cognitive ability, present in 12 of
    14 assessable cases (86%) and typically the dominant clinical problem.
  phenotype_term:
    preferred_term: Mental deterioration
    term:
      id: HP:0001268
      label: Mental deterioration
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cognitive dysfunction was present in 86% of BANDDOS cases"
    explanation: >
      Directly quantifies progressive cognitive decline at 86% of cases,
      mapping to the VERY_FREQUENT band.

- category: Neurologic
  name: Developmental regression
  description: >
    Loss of previously achieved milestones following an initial period of
    normal or near-normal development is characteristic; in one reported
    sibling pair all achieved milestones were lost within 6-8 months of an
    acute encephalopathic presentation.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:32464672
    reference_title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The female child experienced acute encephalopathy at the age of 2 years, followed by spasticity and loss of all achieved milestones over 6 months."
    explanation: >
      Documents rapid regression with loss of all achieved milestones after an
      acute encephalopathic presentation in a biallelic CSF1R child.

- category: Neurologic
  name: Speech disturbance
  description: >
    Speech disturbance is the single most common neurological symptom in
    BANDDOS, reported in 87% of cases. As in CSF1R-ALSP the deficit is likely
    multifactorial, combining language disturbance with motor speech
    impairment, since every BANDDOS case with speech disturbance also had
    cognitive decline or developmental delay.
  phenotype_term:
    preferred_term: Speech disturbance
    term:
      id: HP:0002167
      label: Abnormal speech pattern
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech disturbances were the most common neurological symptom in BANDDOS and were present in 87% of cases, with dysarthria reported in more than half of cases."
    explanation: >
      Quantifies speech disturbance as a whole at 87%, mapping to the
      VERY_FREQUENT band.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As all cases with BANDDOS with speech disturbances had accompanying cognitive decline or developmental delay, the multifaceted nature of speech dysfunction, as seen in CSF1R-ALSP, is most likely."
    explanation: >
      Supports the multifactorial (language plus motor speech) characterisation
      rather than attributing the deficit to dysarthria alone.

- category: Neurologic
  name: Dysarthria
  description: >
    Motor speech impairment specifically, reported in more than half of BANDDOS
    cases - a subset of the broader 87% with speech disturbance.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with dysarthria reported in more than half of cases"
    explanation: >
      Dysarthria specifically is reported in more than half of cases, which
      maps to the FREQUENT band (30-79%) - not to the 87% VERY_FREQUENT figure,
      which is for speech disturbance as a whole.

- category: Neurologic
  name: Spasticity and rigidity
  description: >
    Pyramidal and extrapyramidal motor signs, present in 12 of 15 assessable
    cases; together with hyperreflexia and pathological reflexes, pyramidal
    signs occur in up to 80% of patients.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pyramidal signs (spasticity, hyperactive tendon reflexes, and pathological reflexes) were present in up to 80% of BANDDOS cases"
    explanation: >
      Quantifies pyramidal signs at up to 80% of cases, mapping to the
      VERY_FREQUENT band.

- category: Neurologic
  name: Hyperreflexia
  description: >
    Hyperactive tendon reflexes were documented in 11 of 14 assessable cases.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperactive tendon reflex (n = 11/14)"
    explanation: >
      Reports hyperactive tendon reflexes in 11 of 14 assessable cases (79%),
      mapping to the FREQUENT band.

- category: Neurologic
  name: Seizures
  description: >
    Seizures occur in about 56% of BANDDOS patients, a higher proportion than
    in adult-onset CSF1R-ALSP, and may be therapy-resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were noted in 56% of cases in BANDDOS, compared to up to 32% of CSF1R-ALSP"
    explanation: >
      Quantifies seizure frequency at 56%, mapping to the FREQUENT band, and
      contrasts it with the adult-onset form.
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities."
    explanation: >
      Documents therapy-resistant epilepsy as a presenting feature in a
      three-sibling BANDDOS family.

- category: Gastrointestinal
  name: Dysphagia
  description: >
    Swallowing difficulty is common (75% of BANDDOS cases, versus 18% in
    CSF1R-ALSP) and contributes to aspiration risk.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia was common and reported in 75% of cases of BANDDOS"
    explanation: >
      Quantifies dysphagia at 75% of cases, mapping to the FREQUENT band.

- category: Neurologic
  name: Infantile hypotonia
  description: >
    Generalised hypotonia in infancy was reported in about 27% of cases and is
    not a feature of adult-onset CSF1R-ALSP.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, a minority of BANDDOS cases presented infantile hypotonia (27%) and atrophy of the optic nerve (29%), which were not reported in CSF1R-ALSP."
    explanation: >
      Quantifies infantile hypotonia at 27%, mapping to the OCCASIONAL band,
      and marks it as a BANDDOS-specific feature.

- category: Ophthalmologic
  name: Optic atrophy
  description: >
    Optic nerve atrophy was reported in 2 of 7 assessable cases (29%). It is
    not a feature of adult-onset CSF1R-ALSP. Narrowing of the optic canal by
    craniofacial osteosclerosis is a recognised complication of the
    osteopetrosis spectrum and is a plausible contributor, but the mechanism
    has not been established in BANDDOS.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, a minority of BANDDOS cases presented infantile hypotonia (27%) and atrophy of the optic nerve (29%), which were not reported in CSF1R-ALSP."
    explanation: >
      Quantifies optic nerve atrophy at 29%, mapping to the OCCASIONAL band.

- category: Neurologic
  name: Agenesis of the corpus callosum
  description: >
    Callosal agenesis is a congenital, developmental feature of BANDDOS,
    present in 12 of 16 assessable cases (75%), and contrasts with the callosal
    atrophy seen in adult-onset CSF1R-ALSP. It is the single most useful
    radiological discriminator between the two disorders.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  frequency: FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "callosal abnormalities (agenesis in 75% of BANDDOS vs. atrophy in 29% with CSF1R-ALSP cases)"
    explanation: >
      Quantifies callosal agenesis at 75%, mapping to the FREQUENT band, and
      distinguishes it from the atrophy pattern of CSF1R-ALSP.

- category: Neurologic
  name: Ventriculomegaly
  description: >
    Enlargement of the lateral ventricles, often with colpocephaly, reported in
    13 of 19 cases.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."
    explanation: >
      Reports ventriculomegaly in 13 of 19 BANDDOS patients (68%), mapping to
      the FREQUENT band.

- category: Neurologic
  name: Dandy-Walker complex
  description: >
    Posterior fossa malformation ranging from a large cisterna magna to full
    Dandy-Walker malformation, reported in 7 of 19 cases.
  phenotype_term:
    preferred_term: Dandy-Walker malformation
    term:
      id: HP:0001305
      label: Dandy-Walker malformation
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."
    explanation: >
      Reports Dandy-Walker complex in 7 of 19 BANDDOS patients (37%), mapping
      to the FREQUENT band.

- category: Neurologic
  name: Cortical malformation
  description: >
    Cortical abnormalities including heterotopia and abnormal gyration were
    reported in 4 of 10 assessable cases.
  phenotype_term:
    preferred_term: Abnormal cortical gyration
    term:
      id: HP:0002536
      label: Abnormal cortical gyration
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10)."
    explanation: >
      Reports cortical abnormalities in 4 of 10 assessable cases (40%), mapping
      to the FREQUENT band.

- category: Neurologic
  name: Cerebellar atrophy
  description: >
    Cerebellar atrophy was reported in seven of eight BANDDOS patients in whom
    the cerebellum was assessed, making it one of the most consistent
    structural findings alongside ventriculomegaly. It is under-represented in
    the larger systematic review, which did not tabulate it separately.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34145972
    reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain structural abnormalities vary, with ventriculomegaly reported in nine out of ten cases, agenesis/hypogenesis of the corpus callosum in five out of ten, and cerebellar atrophy in seven out of eight patients examined"
    explanation: >
      Reports cerebellar atrophy in 7 of 8 assessed patients (88%), mapping to
      the VERY_FREQUENT band.

- category: Neurologic
  name: Gray matter heterotopia
  description: >
    Neuronal heterotopia was documented at autopsy alongside abnormal
    hippocampal gyration and non-decussation of the pyramidal tracts, part of
    the cortical-malformation component of the developmental arm.
  phenotype_term:
    preferred_term: Gray matter heterotopia
    term:
      id: HP:0002282
      label: Gray matter heterotopia
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "numerous periventricular and brainstem calcifications, and heterotopia, abnormal gyration of hippocampi, and non-decussation of small pyramidal tracts"
    explanation: >
      Autopsy documentation of heterotopia. Only one BANDDOS autopsy has been
      published, so no frequency band is asserted.

- category: Skeletal
  name: Osteopetrosis
  description: >
    Generalised increased bone density due to deficient osteoclastic
    resorption; the sclerotic end of the BANDDOS skeletal spectrum.
  phenotype_term:
    preferred_term: Osteopetrosis
    term:
      id: HP:0011002
      label: Osteopetrosis
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities were observed in 76% of cases of BANDDOS."
    explanation: >
      Quantifies skeletal involvement at 76% of BANDDOS cases. No frequency
      band is asserted for osteopetrosis specifically: the 76% figure covers
      the whole dysosteosclerosis-Pyle spectrum, of which frank osteosclerosis
      is only one pole, and the sclerotic subset is not separately counted.
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal survey revealed osteosclerosis, most severe in sibling three."
    explanation: >
      Independent family report documenting osteosclerosis on skeletal survey,
      with intrafamilial variability in severity.

- category: Skeletal
  name: Metaphyseal widening with Erlenmeyer flask deformity
  description: >
    The modelling-defect (Pyle-disease-like) end of the skeletal spectrum, with
    undertubulation and flaring of the long bone metaphyses.
  phenotype_term:
    preferred_term: Erlenmeyer flask deformity of the femurs
    term:
      id: HP:0004975
      label: Erlenmeyer flask deformity of the femurs
  evidence:
  - reference: PMID:33749994
    reference_title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."
    explanation: >
      Establishes the Pyle-disease-like metaphyseal modelling defect as one end
      of the BANDDOS skeletal spectrum. No cohort-level frequency is reported
      for this specific radiographic sign, so no frequency band is asserted.

- category: Craniofacial
  name: Dysmorphic features
  description: >
    Facial and craniofacial dysmorphism was present in about 41% of cases and
    is variable: reported findings include a depressed nasal bridge,
    epicanthus, down-slanting palpebral fissures, coarse facies, high-arched
    palate, and bony prominences of the parietal skull.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features were reported in 41% of cases of BANDDOS."
    explanation: >
      Quantifies dysmorphic features at 41% of cases, mapping to the FREQUENT
      band. The term is deliberately kept at the general 'abnormal facial
      shape' level because the 41% figure covers dysmorphism as a whole; no
      individual dysmorphic sign has a reported cohort frequency.

- category: Neurologic
  name: Intracranial calcification
  description: >
    Dystrophic calcifications, predominantly periventricular and in the
    brainstem, are present in 15 of 18 assessable cases and are already present
    at birth, sharing the stepping-stone appearance seen in CSF1R-ALSP.
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "calcifications (in 83% of BANDDOS vs. 75% with CSF1R-ALSP cases)"
    explanation: >
      Quantifies intracranial calcification at 83% of BANDDOS cases, mapping to
      the VERY_FREQUENT band.
  - reference: PMID:32464672
    reference_title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles."
    explanation: >
      Describes the anatomical distribution of the calcifications in a
      biallelic CSF1R sibling pair.

- category: Neurologic
  name: Leukoencephalopathy
  description: >
    Cerebral white matter abnormality is the one universal finding in BANDDOS,
    present in every reported case on neuroimaging, and progresses over time to
    an ALSP-like appearance.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
    clinical_course: PROGRESSIVE
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities were present in all cases (n = 19) on neuroimaging, including white matter changes (n = 19/19)"
    explanation: >
      Establishes white matter abnormality as present in 100% (19/19) of
      reported BANDDOS cases, the one obligate feature of the disorder.

imaging_findings:
- name: Multifocal cerebral white matter signal abnormality
  modality: MRI
  description: >
    Bilateral, often multifocal T2/FLAIR hyperintensity of cerebral white
    matter, most prominent periventricularly and in the corpus callosum and
    pyramidal tracts; progressive, and taking on the appearance of ALSP during
    secondary neurological decline.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  diagnostic: true
  evidence:
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three."
    explanation: >
      Documents the MRI appearance of multifocal white matter abnormality with
      calcification in BANDDOS.

- name: Periventricular and brainstem calcifications
  modality: CT
  description: >
    Dystrophic calcifications concentrated in periventricular white matter and
    brainstem, present from birth, with a stepping-stone appearance shared with
    CSF1R-ALSP.
  phenotype_term:
    preferred_term: Intracranial calcification
    term:
      id: HP:0430048
      label: Intracranial calcification
  diagnostic: true
  evidence:
  - reference: PMID:32464672
    reference_title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain imaging in both children revealed multiple well-defined areas of calcification in the parietal and frontal regions and the occipital horns of both lateral ventricles."
    explanation: >
      Radiological description of the calcification pattern in biallelic CSF1R
      disease.

- name: Generalised osteosclerosis on skeletal survey
  modality: XRAY
  description: >
    Skeletal survey shows increased bone density, cranial and vertebral
    sclerosis, and abnormal metaphyseal modelling, spanning the
    dysosteosclerosis to Pyle disease spectrum.
  phenotype_term:
    preferred_term: Increased bone mineral density
    term:
      id: HP:0011001
      label: Increased bone mineral density
  evidence:
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal survey revealed osteosclerosis, most severe in sibling three."
    explanation: >
      Documents the radiographic skeletal finding and its intrafamilial
      variability.

histopathology:
- name: Absence of parenchymal microglia
  description: >
    The defining neuropathological finding, though so far documented in only a
    single published autopsy: immunostaining of a biallelic CSF1R brain showed
    almost complete absence of microglia, with only rare abnormal perivascular
    cells identifiable.
  diagnostic: true
  evidence:
  - reference: PMID:30982608
    reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia."
    explanation: >
      Human post-mortem immunostaining establishes near-total microglial
      absence in a biallelic CSF1R brain.

- name: White matter atrophy with axonal spheroids and gliosis
  description: >
    Prominent white matter atrophy containing axonal spheroids, with reactive
    gliosis and numerous dystrophic calcifications predominantly in
    periventricular white matter - the same constellation as CSF1R-ALSP but
    more severe.
  finding_term:
    preferred_term: gliosis
    term:
      id: NCIT:C26783
      label: Gliosis
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications predominantly in the periventricular white matter"
    explanation: >
      Describes the degenerative white matter histopathology observed in the
      single published BANDDOS autopsy.

genetic:
- name: CSF1R
  gene_term:
    preferred_term: CSF1R
    term:
      id: hgnc:2433
      label: CSF1R
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >
      BANDDOS is caused by biallelic CSF1R variants. Most reported patients are
      homozygous and born to consanguineous parents; heterozygous relatives are
      typically asymptomatic, at least until the age at which CSF1R-ALSP would
      declare itself.
    evidence:
    - reference: PMID:22934315
      reference_title: "CSF1R-Related Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early-onset CSF1R-related disorder is typically caused by biallelic pathogenic variants and inherited in an autosomal recessive manner"
      explanation: >
        GeneReviews states the autosomal recessive inheritance of the
        early-onset, biallelic form of CSF1R-related disorder.
    - reference: PMID:37349768
      reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Most cases (n = 17/19) were born of consanguineous parents and carried homozygous mutations (n = 17/19), whereas only two were compound heterozygotes born of unrelated parents."
      explanation: >
        Documents the homozygous/consanguineous genetic architecture of the
        reported BANDDOS cohort.
    - reference: PMID:32464672
      reference_title: "A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heterozygous family members, including both parents, were asymptomatic, with the eldest being 68 years of age."
      explanation: >
        Demonstrates that carriers of a single hypomorphic CSF1R allele can
        remain asymptomatic into old age, consistent with recessive
        inheritance for this phenotype.
  notes: >
    Reported BANDDOS variants cluster in or disrupt the tyrosine kinase domain
    (amino acids 582-910). Splice, nonsense, and deep-intronic variants
    predominate; two of the originally described alleles were deep intronic and
    caused abnormal inclusion of intron sequence in the mRNA. No variant has
    yet been reported to occur in both BANDDOS and CSF1R-ALSP.
  evidence:
  - reference: PMID:30982609
    reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease."
    explanation: >
      The defining report establishing biallelic CSF1R variants as the cause of
      the combined brain malformation and skeletal dysplasia phenotype.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion."
    explanation: >
      Summarises the mutational spectrum reported in BANDDOS.
  - reference: PMID:30982609
    reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA."
    explanation: >
      Documents the deep-intronic splice-disrupting mechanism, which is
      important because such variants are missed by exome-only analysis.
  - reference: PMID:33749994
    reference_title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this clinical report, we describe three siblings with variable skeletal findings along with neurological symptoms ranging from mild to severe in whom exome sequencing revealed a novel homozygous splice site variant in canonical splice donor site of intron 21 adjacent to an exon, which encoding part of kinase domain of CSF1R along with a review of the literature."
    explanation: >
      An independent family expanding the splice-variant spectrum and
      demonstrating intrafamilial phenotypic variability.
  - reference: PMID:37431483
    reference_title: "Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous variant was identified in the gene CSF1R, c.2498C>T; p.T833M in exon 19, in the index patient and the fetus."
    explanation: >
      An independent consanguineous family homozygous for the p.T833M kinase-domain
      variant, in which the variant was also detected prenatally in a fetus.
  - reference: PMID:37431483
    reference_title: "Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The variant is located within the functionally essential PTK domain of the receptor. However, no structural damage was introduced by this substitution."
    explanation: >
      In silico analysis places p.T833M in the protein tyrosine kinase domain
      without predicted structural disruption - consistent with the independent
      in vitro finding that the same allele is hypomorphic (normal protein
      level, impaired autophosphorylation) rather than null.
  - reference: PMID:34145972
    reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The extent of skeletal involvement may depend on CSF1R gene dosage with marked osteosclerosis reported in patients carrying two amorphic"
    explanation: >
      Supports the dose-dependent genotype-phenotype model in which residual
      CSF1R activity, not the variant class alone, grades skeletal severity.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    BANDDOS segregates as an autosomal recessive trait; the parents of an
    affected individual are presumed heterozygous carriers and each sib has a
    25% recurrence risk.
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a 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 CSF1R pathogenic variants."
    explanation: >
      GeneReviews states the recurrence risk that follows from autosomal
      recessive inheritance of biallelic CSF1R disease.

animal_models:
- name: Csf1r knockout rat (Csf1rko)
  species: Rat
  genotype: Csf1r homozygous knockout
  publication: PMID:33450391
  description: >
    Homozygous Csf1r knockout rats lack essentially all tissue macrophage
    populations including microglia, develop osteopetrosis, and fail to thrive
    postnatally. The model reproduces the myeloid and skeletal arms of human
    biallelic CSF1R disease, and wild-type bone marrow transfer at weaning
    rescues the phenotype - but the brain phenotype is much milder than in
    humans, which is a substantive translational caveat.
  modeled_mechanisms:
  - target: Microglial Deficiency in the Developing Brain
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Csf1rko rats lose the entire microglial transcriptomic signature across
      every brain region examined.
    limitations: >
      The rat models the cellular deficiency faithfully but not its human
      developmental consequences (see the FAILS_TO_RECAPITULATE link below).
    readouts:
    - name: Microglial marker gene expression across brain regions
      target: Microglial Deficiency in the Developing Brain
      direction: DECREASED
      interpretation: >
        Transcriptomic confirmation that the microglial population is absent
        throughout the Csf1rko brain.
      evidence:
      - reference: PMID:33450391
        reference_title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats."
        explanation: >
          Quantifies the depletion of the microglial signature in every brain
          region of the knockout.
    evidence:
    - reference: PMID:33450391
      reference_title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats."
      explanation: >
        Establishes the model as informative for the microglial-deficiency
        node.
  - target: Disrupted Brain Development and Structural Malformation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >
      Unlike humans with biallelic CSF1R variants, Csf1rko rats do not develop
      the congenital brain malformations (callosal agenesis, Dandy-Walker
      complex, cortical malformation) that define BANDDOS; brain development is
      largely normal without microglia.
    limitations: >
      Species differences in the developmental role of microglia mean the rat
      cannot be used to model, or to test therapies against, the congenital
      malformation arm of BANDDOS. The authors go further and conclude that
      CSF1R haploinsufficiency alone is unlikely to cause leukoencephalopathy,
      which is at odds with the human monoallelic disorder.
    readouts:
    - name: Region-specific neuronal and glial transcript clusters
      target: Disrupted Brain Development and Structural Malformation
      direction: UNCHANGED
      interpretation: >
        Absence of microglia leaves neuronal, oligodendrocyte, and astrocyte
        expression programmes essentially intact in the rat.
      evidence:
      - reference: PMID:33450391
        reference_title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster."
        explanation: >
          A negative result: no detectable effect of microglial loss on
          neuronal or regional gene expression in the rat brain.
    evidence:
    - reference: PMID:33450391
      reference_title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy."
      explanation: >
        The authors' own conclusion that brain development proceeds normally
        without microglia in the rat, which directly contradicts the human
        BANDDOS malformation phenotype and substantiates the failure to
        recapitulate.
  - target: Osteoclast Deficiency and Impaired Bone Resorption
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >
      Csf1rko rats develop osteopetrosis that is reversed by wild-type bone
      marrow transfer, establishing the osteoclast-deficiency mechanism.
    limitations: >
      The rat osteopetrosis is more severe than the dysosteosclerosis-Pyle
      spectrum seen in humans, consistent with the human alleles being
      hypomorphic rather than null.
    readouts:
    - name: Osteoclast restoration and reversal of osteopetrosis after bone marrow transfer
      target: Osteoclast Deficiency and Impaired Bone Resorption
      direction: RESTORED
      interpretation: >
        Restoring CSF1R-competent marrow-derived cells restores osteoclasts and
        eliminates the sclerotic bone phenotype.
      evidence:
      - reference: PMID:34081701
        reference_title: "CSF1R-dependent macrophages control postnatal somatic growth and organ maturation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "WT BM transfer restored osteoclasts, eliminated osteopetrosis, restored bone marrow cellularity and architecture and reversed granulocytosis and B cell deficiency."
        explanation: >
          Rescue readout showing osteoclast restoration and resolution of
          osteopetrosis.
    evidence:
    - reference: PMID:34081701
      reference_title: "CSF1R-dependent macrophages control postnatal somatic growth and organ maturation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Homozygous mutation of the Csf1r locus (Csf1rko) in mice, rats and humans leads to multiple postnatal developmental abnormalities."
      explanation: >
        Establishes the rat Csf1rko as the cross-species model of homozygous
        CSF1R mutation, the same lesion as in BANDDOS.
  evidence:
  - reference: PMID:39869647
    reference_title: "Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity."
    explanation: >
      The authors position the Csf1rko rat explicitly as a model for human
      CSF1R-mutation pathology and its treatment.

- name: Csf1r-null mouse
  species: Mouse
  genotype: Csf1r homozygous null (Csf1r-/-)
  publication: PMID:34145972
  description: >
    The Csf1r-null mouse is the original and most extensively characterised
    CSF1R-deficiency system, and is the model the human BANDDOS phenotype was
    first compared against. It loses most tissue macrophages and osteoclasts and
    is osteopetrotic. Its central caveat for BANDDOS is severity and background
    dependence: the human phenotype is milder and more variable than the mouse
    null, which is the observation that led to the inference that at least one
    BANDDOS allele is always hypomorphic.
  modeled_mechanisms:
  - target: Osteoclast Deficiency and Impaired Bone Resorption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      Csf1r-null mice show the loss of osteoclasts and of bone remodelling that
      underlies the human skeletal phenotype.
    limitations: >
      The complete null is more severe than any reported human genotype, and
      phenotypic differences between Csf1-null and Csf1r-null mice are only
      revealed on defined inbred backgrounds, so strain background is a
      confounder when reading severity across studies.
    evidence:
    - reference: PMID:34145972
      reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Studies in homozygous Csf1r- and Csf1- null mice have shown that the CSF-1/CSF-1R pathway regulates the differentiation and maintenance of most tissue macrophages and osteoclasts, contributing to the development and remodeling of bones and soft tissues"
      explanation: >
        Establishes the mouse null as the system in which the macrophage and
        osteoclast requirement for CSF1R signalling was demonstrated.
  evidence:
  - reference: PMID:30982609
    reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic."
    explanation: >
      The explicit human-versus-Csf1r-null comparison that both establishes the
      model's relevance and bounds its fidelity.
  notes: >
    Cited via the dedicated review of Csf1r-deficiency models rather than a
    single primary mouse paper, because the relevant claim (what the mouse null
    does and does not capture about human CSF1R disease) is a synthesis across
    that literature.

- name: csf1rDM zebrafish (csf1ra/csf1rb double mutant)
  species: Zebrafish
  genotype: csf1ra; csf1rb double mutant (csf1rDM)
  publication: PMID:30982608
  description: >
    Zebrafish lacking Csf1r function have brains devoid of microglia and
    reduced levels of the upper-layer neuronal transcription factor CUX1,
    paralleling the reduction of CUX1-positive neurons seen in human biallelic
    CSF1R brain tissue.
  modeled_mechanisms:
  - target: Microglial Deficiency in the Developing Brain
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >
      csf1rDM brains lack microglia, reproducing the defining cellular lesion.
    limitations: >
      Zebrafish brain architecture lacks a corpus callosum and the mammalian
      six-layered cortex, so the model cannot address the specific human
      malformations; the shared readout is the CUX1 reduction, not the
      malformation itself.
    readouts:
    - name: Brain CUX1 level
      target: Microglial Deficiency in the Developing Brain
      direction: DECREASED
      interpretation: >
        Reduced CUX1 in the microglia-less fish brain, matched by reduced
        CUX1-positive neurons in human biallelic CSF1R brain, identifies a
        conserved microglia-dependent neuronal readout.
      evidence:
      - reference: PMID:30982608
        reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We analyzed a zebrafish model (csf1rDM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor."
        explanation: >
          Reports both the microglial absence and the CUX1 reduction in the
          zebrafish model.
    evidence:
    - reference: PMID:30982608
      reference_title: "Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons."
      explanation: >
        The cross-species concordance of the CUX1 readout is what makes the
        fish informative for the human microglial-deficiency node.

treatments:
- name: Multidisciplinary Supportive and Rehabilitative Care
  description: >
    There is no disease-modifying therapy of proven benefit in BANDDOS. Care is
    multidisciplinary and symptom-directed, spanning neurology,
    neuropsychological rehabilitation, physical, occupational and
    speech-language therapy, nutritional and swallowing support, and family
    support with genetic counselling. GeneReviews additionally advises caution
    with sedatives, antipsychotics, and other agents that reduce alertness in
    individuals who have gait problems and cognitive decline, because of fall
    risk.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Multidisciplinary care by specialists in neurology, psychotherapy, neuropsychological rehabilitation, physical therapy, occupational therapy, speech-language therapy, social services for family support, and genetic counseling."
    explanation: >
      GeneReviews sets out the multidisciplinary supportive management standard
      for CSF1R-related disorder, which includes the early-onset biallelic
      form.
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For individuals with gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously."
    explanation: >
      GeneReviews Agents/Circumstances to Avoid guidance, recorded here as a
      drug-safety caution attached to supportive management.

- name: Allogeneic Hematopoietic Stem Cell Transplantation (investigational in BANDDOS)
  description: >
    HSCT replaces the CSF1R-deficient myeloid compartment with donor-derived
    cells and has become a disease-modifying option in adult-onset CSF1R-ALSP.
    It has NOT been demonstrated to benefit BANDDOS: the rationale is
    extrapolation from the shared genetic and neuropathological basis of the
    two disorders. Preclinical support comes from the Csf1rko rat, where
    wild-type bone marrow transfer restores tissue macrophages, eliminates
    osteopetrosis, and permits normal growth and long-term survival - although
    in that model the brain was the one organ where donor-derived
    microglia-like cells did not fully match resident microglia, and
    congenital malformations already present at birth would not be expected to
    reverse.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Microglial Deficiency in the Developing Brain
    treatment_effect: RESTORES
    description: >
      Donor-derived myeloid cells engraft the CNS and are intended to
      reconstitute the missing CSF1R-competent brain macrophage population.
    evidence:
    - reference: PMID:34081701
      reference_title: "CSF1R-dependent macrophages control postnatal somatic growth and organ maturation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Transfer of WT bone marrow (BM) cells at weaning without conditioning repopulated resident macrophages in all organs, including microglia in the brain, and reversed the mutant phenotypes enabling long term survival and fertility."
      explanation: >
        Model-organism evidence that marrow transfer repopulates brain
        microglia and reverses the mutant phenotype; classified INDIRECT because
        this is a rat rescue experiment, not evidence of benefit in human
        BANDDOS.
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, both disorders are on the same continuum, albeit they differ in the severity of CSF1R mutations' consequences and phenotypes. This opens windows of opportunity for applying already available therapy in CSF1R-ALSP in BANDDOS."
    explanation: >
      The review proposes translating CSF1R-ALSP therapy to BANDDOS on the
      basis of shared pathomechanism; this is an argument for a trial, not
      evidence of efficacy, hence INDIRECT.
  - reference: PMID:39869647
    reference_title: "Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia."
    explanation: >
      Tempers the rescue rationale: donor-derived brain macrophages are not
      transcriptionally equivalent to resident microglia, so CNS correction may
      be incomplete.
  notes: >
    No published series reports HSCT outcomes in genetically confirmed BANDDOS.
    Any use is investigational and should be undertaken in a research setting.

- name: iPSC-Derived Microglia Replacement (preclinical)
  description: >
    A research-stage strategy that goes further than HSCT: transplanting human
    iPSC-derived microglial progenitors directly, rather than relying on
    marrow-derived cells to engraft the CNS. In a xenotolerant Csf1r-FIRE-enhancer
    mouse that develops nearly all the hallmark ALSP pathologies, transplanted
    iPSC-derived microglia restored a homeostatic microglial signature and
    prevented axonal spheroids, white matter abnormality, reactive astrocytosis,
    and brain calcification; CRISPR-corrected patient-derived microglia even
    reversed pre-existing spheroid, astrogliosis, and calcification pathology.
    This is preclinical and was done in an ALSP model, not a BANDDOS model, and
    it addresses the degenerative arm only - the congenital malformations of
    BANDDOS are established before birth.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: cellular therapy
    term:
      id: NCIT:C70601
      label: Cellular Therapy
  target_mechanisms:
  - target: Progressive White Matter Degeneration with Axonal Spheroids
    treatment_effect: INHIBITS
    description: >
      Restoring a CSF1R-competent microglial population prevents, and in
      established disease partially reverses, the white-matter degeneration,
      spheroids, gliosis, and calcification.
    evidence:
    - reference: PMID:38897209
      reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications"
      explanation: >
        Direct evidence that microglial replacement prevents the degenerative
        white-matter pathology; PARTIAL because the model is an ALSP
        (heterozygous-equivalent) mouse, not a biallelic BANDDOS system.
  evidence:
  - reference: PMID:38897209
    reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies."
    explanation: >
      Shows reversal of established pathology, which is what would be required
      in an already-symptomatic patient; still preclinical and in an ALSP model.
  - reference: PMID:38897209
    reference_title: "Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders"
    explanation: >
      The authors themselves extend the claim only as far as "perhaps other
      microglia-associated neurological disorders"; no BANDDOS-specific claim
      is made or asserted here.
  notes: >
    Preclinical only. No microglia-replacement trial exists in any CSF1R
    disorder, let alone in BANDDOS.

- name: Antiseizure Pharmacotherapy
  description: >
    Seizures occur in roughly half of patients and may be therapy-resistant,
    requiring standard antiseizure medication chosen for the seizure type.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities."
    explanation: >
      Documents that epilepsy in BANDDOS is a clinical management problem and
      is frequently refractory; classified PARTIAL because it establishes the
      indication rather than the efficacy of any specific agent.

- name: Genetic Counseling
  description: >
    Because BANDDOS is autosomal recessive and most families are consanguineous,
    counselling covers the 25% sib recurrence risk, carrier testing of
    relatives, and the availability of prenatal and preimplantation genetic
    testing once the familial variants are known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the CSF1R pathogenic variant(s) have been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for CSF1R-related disorder are possible."
    explanation: >
      GeneReviews establishes the availability of predictive, prenatal, and
      preimplantation testing once the familial variants are known.

diagnosis:
- name: Molecular Confirmation of Biallelic CSF1R Variants
  description: >
    The diagnosis is established by identifying biallelic pathogenic CSF1R
    variants in a proband with suggestive clinical and radiological findings.
    Because two of the originally described BANDDOS alleles were deep intronic
    and acted by abnormal intron inclusion, an exome-only strategy can miss the
    second allele; genome sequencing or targeted intronic analysis should be
    considered when only one variant is found in a phenotypically convincing
    case. Parental segregation should be confirmed.
  presence: Biallelic (homozygous or compound heterozygous) pathogenic CSF1R variants
  evidence:
  - reference: PMID:22934315
    reference_title: "CSF1R-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of CSF1R-related disorder is established in a proband with suggestive findings and a heterozygous CSF1R pathogenic variant or biallelic CSF1R pathogenic variants identified by molecular genetic testing."
    explanation: >
      GeneReviews states the diagnostic criterion; the biallelic branch is the
      one that defines BANDDOS.
  - reference: PMID:30982609
    reference_title: "Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA."
    explanation: >
      Justifies the caveat that exome-only testing can miss a BANDDOS allele,
      since deep intronic variants are a recognised mechanism in this disorder.
  - reference: PMID:37431483
    reference_title: "Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted gene sequencing was performed on the genomic DNA samples of the deceased patient and a fetus along with ten healthy members of his family to identify the disease-causing mutation."
    explanation: >
      Illustrates the targeted-sequencing-plus-family-segregation approach used
      to establish the diagnosis in practice, including prenatal testing.

- name: Brain MRI
  description: >
    Brain MRI defines the white-matter abnormality (universal in BANDDOS) and
    the congenital malformations - callosal agenesis or hypogenesis,
    ventriculomegaly and colpocephaly, Dandy-Walker complex, and cortical
    abnormalities. It is the study that most clearly separates BANDDOS from
    adult-onset CSF1R-ALSP, in which congenital malformation is absent.
  presence: Abnormal in all reported cases
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain abnormalities were present in all cases (n = 19) on neuroimaging, including white matter changes (n = 19/19)"
    explanation: >
      Establishes neuroimaging as abnormal in 100% of reported cases, making it
      the highest-yield diagnostic study.

- name: Non-contrast Head CT for Intracranial Calcification
  description: >
    CT is more sensitive than MRI for the dystrophic periventricular and
    brainstem calcifications, which are present in most patients, are already
    present at birth, and share the stepping-stone appearance described in
    CSF1R-ALSP.
  presence: Calcification detected in most patients
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "calcifications (in 83% of BANDDOS vs. 75% with CSF1R-ALSP cases)"
    explanation: >
      Quantifies the diagnostic yield of looking for intracranial calcification
      in suspected BANDDOS.

- name: Skeletal Survey
  description: >
    Radiographic skeletal survey identifies the sclerosing bone dysplasia -
    increased bone density, craniofacial and vertebral sclerosis, and
    metaphyseal modelling abnormalities spanning the dysosteosclerosis to Pyle
    disease spectrum. A normal survey does not exclude the diagnosis, since
    about a quarter of reported patients had no skeletal involvement.
  presence: Abnormal in about three quarters of patients
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities were observed in 76% of cases of BANDDOS."
    explanation: >
      Quantifies the diagnostic yield of skeletal survey and, by complement,
      the fraction of patients in whom it is normal.
  - reference: PMID:33749994
    reference_title: "Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS."
    explanation: >
      Supports the caveat that a normal skeletal survey does not exclude
      BANDDOS.

differential_diagnoses:
- name: CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP)
  description: >
    The monoallelic, autosomal dominant CSF1R disorder. It shares the
    leukoencephalopathy, calcifications, axonal spheroids, gliosis, and
    microglial deficiency, but presents in the fourth to sixth decade and lacks
    congenital brain malformation, skeletal dysplasia, and dysmorphic features.
  distinguishing_features:
  - Age at onset - adult (4th-6th decade) in CSF1R-ALSP versus perinatal or infantile in BANDDOS
  - Congenital brain malformations (callosal agenesis, Dandy-Walker complex, cortical malformation) occur in BANDDOS only
  - Sclerosing skeletal dysplasia and dysmorphic features occur in BANDDOS only
  - Biallelic CSF1R genotype in BANDDOS versus heterozygous in CSF1R-ALSP
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal deformities and dysmorphic features have not been reported in CSF1R-ALSP."
    explanation: >
      Names the skeletal and dysmorphic features as the discriminators absent
      from the adult-onset monoallelic disorder.
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP."
    explanation: >
      Emphasises that the degenerative phase of BANDDOS is radiologically and
      clinically ALSP-like, which is precisely why the two must be
      distinguished genetically.

- name: Dysosteosclerosis due to SLC29A3 or TNFRSF11A variants
  description: >
    Dysosteosclerosis is genetically heterogeneous; biallelic SLC29A3 and
    TNFRSF11A variants cause radiologically similar sclerosing bone dysplasia
    without the CSF1R brain phenotype.
  distinguishing_features:
  - Absence of leukoencephalopathy and intracranial calcification
  - Absence of congenital brain malformation
  - Different causal gene (SLC29A3 or TNFRSF11A) on molecular testing
  evidence:
  - reference: PMID:33837634
    reference_title: "Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a genetically heterogeneous disorder caused by biallelic mutations in the SLC29A3, TNFRSF11A, TCIRG1, and CSF1R genes."
    explanation: >
      States the genetic heterogeneity of dysosteosclerosis directly: CSF1R is
      only one of at least four causal genes, so the radiological diagnosis
      does not settle the molecular one.
  - reference: PMID:33402699
    reference_title: "Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TNFRSF11A has been known as the causal gene for osteopetrosis, autosomal recessive 7, and is recently reported to cause DOS in three cases, which show a complex genotype-phenotype relationship."
    explanation: >
      Documents TNFRSF11A as an established non-CSF1R cause of
      dysosteosclerosis, confirming it as a genuine molecular differential.

- name: Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, TREM2/TYROBP)
  description: >
    The most instructive mimic: another autosomal recessive microglial-signalling
    disorder that, like BANDDOS, combines a leukoencephalopathy with bone
    lesions. TREM2 and TYROBP (DAP12) act in the same microglial signalling
    network as CSF1R, which is why the two disorders converge phenotypically.
  distinguishing_features:
  - Bone lesions are polycystic and lytic (with pathological fractures), not sclerosing
  - Onset of the osseous stage in the third decade and dementia in the fourth, versus perinatal or infantile onset in most BANDDOS
  - Frontal lobe syndrome dominates the neurological presentation
  - Congenital brain malformation is not a feature
  - Biallelic TREM2 or TYROBP variants rather than biallelic CSF1R
  evidence:
  - reference: PMID:20301376
    reference_title: "Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      GeneReviews description establishing the lytic/polycystic bone phenotype
      and the fourth-decade dementia that distinguish PLOSL from BANDDOS.
  - reference: PMID:20301376
    reference_title: "Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in TYROBP or TREM2 confirms the diagnosis since radiographic and clinical features may be inconclusive."
    explanation: >
      Confirms that molecular testing is what separates the two, and names the
      alternative causal genes.

discussions:
- discussion_id: banddos_rodent_brain_development_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Disrupted Brain Development and Structural Malformation
  - animal_models#Csf1r knockout rat (Csf1rko)
  prompt: >
    Why do humans with biallelic CSF1R loss of function develop severe
    congenital brain malformations while Csf1r knockout rats, which lack
    microglia just as completely, undergo essentially normal brain development?
  rationale: >
    The rat Csf1rko removes the entire microglial population - the same
    cellular lesion documented at autopsy in BANDDOS - yet diffusion imaging
    and region-wise RNA-seq show only small fibre-tract reductions and no
    neuronal or regional transcriptomic change, and the authors conclude that
    most brain developmental processes occur normally without microglia. Human
    biallelic CSF1R brains instead show callosal agenesis, Dandy-Walker
    complex, heterotopia, and non-decussating pyramidal tracts. The same paper
    concludes that CSF1R haploinsufficiency is unlikely to cause
    leukoencephalopathy, which is directly at odds with the established human
    monoallelic CSF1R-ALSP disorder. Either microglia have human-specific
    developmental roles (the CUX1-positive upper-layer neuron route proposed
    from the zebrafish and human tissue work is one candidate), or the human
    phenotype depends on something other than microglial absence per se. Until
    this is resolved, rodent rescue data cannot be read as predicting that
    restoring myeloid cells will correct the malformation arm of BANDDOS.
  evidence:
  - reference: PMID:33450391
    reference_title: "Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy."
    explanation: >
      The rat conclusion that brain development proceeds normally without
      microglia is the model side of the mismatch.
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postmortem examination showed multiple brain anomalies, including an absence of corpus callosum, reduced volume of white matter, Dandy-Walker malformation, colpocephaly, numerous periventricular and brainstem calcifications, and heterotopia, abnormal gyration of hippocampi, and non-decussation of small pyramidal tracts"
    explanation: >
      The human side of the mismatch: a microglia-deficient human brain shows
      severe congenital malformation that the rodent model does not reproduce.
  - reference: PMID:34145972
    reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Here we review the genetics, penetrance, and histopathological features of these diseases and discuss to what extent the animal models of Csf1r deficiency currently available provide systems in which to study the underlying mechanisms involved."
    explanation: >
      The dedicated review of Csf1r-deficiency models frames the adequacy of
      available animal systems as an open question, which is exactly what this
      mismatch records.
  - reference: PMID:34145972
    reference_title: "Modeling CSF-1 receptor deficiency diseases - how close are we?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain developmental deficits, e.g. callosal agenesis/hypogenesis, seem to follow a similar pattern, being present in all individuals carrying amorphic mutations and absent in those carrying bi-allelic hypomorphic mutations."
    explanation: >
      Offers a competing, allele-dose explanation for the discrepancy: the
      developmental malformations track residual CSF1R activity rather than
      microglial absence alone, which the rodent null cannot test.
  proposed_experiments:
  - experiment_id: exp_banddos_human_organoid_cux1_requirement
    name: Human cerebral organoid or xenotransplant model with biallelic CSF1R loss
    description: >
      Compare corpus callosum-relevant projection neuron specification
      (CUX1-positive upper-layer neurons) in human iPSC-derived cortical
      systems with and without CSF1R-competent microglia, using patient-derived
      biallelic CSF1R lines, to test whether the developmental requirement is
      human-specific.
  - experiment_id: exp_banddos_microglial_colonisation_timing
    name: Developmental staging of the rodent versus human microglial requirement
    description: >
      Determine whether the discrepancy reflects the timing of microglial
      colonisation relative to commissural axon guidance, by comparing
      microglial colonisation windows and callosal pathfinding in rat, zebrafish,
      and human fetal tissue.

- discussion_id: banddos_hsct_efficacy_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Allogeneic Hematopoietic Stem Cell Transplantation (investigational in BANDDOS)
  prompt: >
    Does hematopoietic stem cell transplantation modify the course of BANDDOS,
    and is there a therapeutic window before the degenerative phase begins?
  rationale: >
    HSCT is now offered in CSF1R-ALSP, and the review literature explicitly
    proposes translating it to BANDDOS on the basis of a shared pathomechanism.
    But no outcome data exist in genetically confirmed BANDDOS. Two features of
    BANDDOS complicate the extrapolation: the congenital malformations are
    already established at birth and cannot plausibly be reversed by any
    myeloid replacement, and in the Csf1rko rat the brain was the one organ
    where donor-derived cells did not transcriptionally match resident
    microglia. A meaningful trial would therefore have to specify which arm of
    the disease it expects to modify.
  evidence:
  - reference: PMID:37349768
    reference_title: "Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This opens windows of opportunity for applying already available therapy in CSF1R-ALSP in BANDDOS."
    explanation: >
      The review proposes translating CSF1R-ALSP therapy to BANDDOS, framing
      the gap as an untested opportunity rather than established practice.
  - reference: PMID:39869647
    reference_title: "Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia."
    explanation: >
      Identifies the specific reason CNS correction by marrow transfer may be
      incomplete, which is part of what makes the gap substantive.
  proposed_experiments:
  - experiment_id: exp_banddos_registry_hsct_arm
    name: International BANDDOS natural history registry with prospective HSCT arm
    description: >
      Pool the very small worldwide case population into a registry capturing
      genotype, residual CSF1R function, serial MRI, and neurodevelopmental
      outcome, and follow any transplanted patients prospectively against
      untransplanted controls, with the degenerative (not developmental) arm as
      the pre-specified endpoint.

- discussion_id: banddos_spared_peripheral_immunity_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic CSF1R Loss of Function
  prompt: >
    Why does profound CSF1R deficiency spare peripheral immune function in
    BANDDOS patients?
  rationale: >
    CSF1R is the master regulator of the mononuclear phagocyte system, and the
    Csf1rko rat has a broad myeloid deficit with granulocytosis, B cell
    deficiency, and failure to thrive. Yet detailed immunological workup of a
    BANDDOS family found normal blood markers, monocytes, dendritic cell
    subsets, and T cell proliferation, and no clinical immunodeficiency has
    been reported. Whether this reflects the hypomorphic nature of human
    alleles, redundancy with CSF2/IL-34 signalling in the periphery, or simply
    incomplete phenotyping across the small case population is unresolved, and
    it matters for how aggressively transplant conditioning would be justified.
  evidence:
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent."
    explanation: >
      States the unexplained observation directly: myeloid-lineage receptor
      loss without clinical immunodeficiency.
  - reference: PMID:38934054
    reference_title: "Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal."
    explanation: >
      Provides the measured immunological workup showing normal peripheral
      immune parameters in BANDDOS patients.
  proposed_experiments:
  - experiment_id: exp_banddos_systematic_immunophenotyping
    name: Systematic immunophenotyping across the BANDDOS case population
    description: >
      Apply uniform deep immunophenotyping (tissue-resident macrophage
      compartments, monocyte subsets, circulating CSF1 concentration) across
      reported BANDDOS patients and their heterozygous relatives, correlated
      with allele-specific residual CSF1R signalling measured in vitro.

notes: >
  BANDDOS is best understood as the severe, early-onset end of a single
  CSF1R-related disorder continuum rather than as a separate disease: the 2024
  terminology proposal recommends replacing the ALSP/BANDDOS split with
  early-onset (<18 years) and late-onset (>=18 years) CSF1R-related disorder,
  precisely because compound heterozygous patients can present with an
  ALSP-like clinical picture on a BANDDOS-like genotype. This entry is curated
  under the BANDDOS label because MONDO:0032772 and MIM 618476 are still
  defined that way, but curators should expect the nosology to move. Note also
  that despite the central role of CSF1R in myeloid development, clinical
  immunodeficiency has not been observed in BANDDOS.

📚

References & Deep Research

References

19

PMID:22934315

CSF1R-Related Disorder.

No top-level findings curated for this source.

PMID:30982609

Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.

No top-level findings curated for this source.

PMID:30982608

Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.

No top-level findings curated for this source.

PMID:37349768

Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP.

No top-level findings curated for this source.

PMID:33749994

Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features.

No top-level findings curated for this source.

PMID:32464672

A Novel Hypomorphic CSF1R Gene Mutation in the Biallelic State Leading to Fatal Childhood Neurodegeneration.

No top-level findings curated for this source.

PMID:38934054

Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings.

No top-level findings curated for this source.

PMID:34135456

From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R.

No top-level findings curated for this source.

PMID:37839910

CSF1R-related disorder: State of the art, challenges, and proposition of a new terminology.

No top-level findings curated for this source.

PMID:28383543

Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.

No top-level findings curated for this source.

PMID:33450391

Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations.

No top-level findings curated for this source.

PMID:34081701

CSF1R-dependent macrophages control postnatal somatic growth and organ maturation.

No top-level findings curated for this source.

PMID:39869647

Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation.

No top-level findings curated for this source.

PMID:37431483

Homozygous mutation in CSF1R causes brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS).

No top-level findings curated for this source.

PMID:34145972

Modeling CSF-1 receptor deficiency diseases - how close are we?

No top-level findings curated for this source.

PMID:38897209

Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy.

No top-level findings curated for this source.

PMID:33837634

Resolution of sclerotic lesions of dysosteosclerosis due to biallelic SLC29A3 variant in a Turkish girl.

No top-level findings curated for this source.

PMID:33402699

Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis.

No top-level findings curated for this source.

PMID:20301376

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS): Disease-Characteristics Report

Edison Scientific Literature 20 citations 2026-08-19T21:08:15.215738

Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS): Disease-Characteristics Report

Executive summary

BANDDOS is an exceptionally rare, usually congenital or childhood-onset autosomal-recessive microgliopathy and skeletal dysplasia caused by biallelic loss-of-function variants in CSF1R. It combines developmental brain malformations, progressive white-matter degeneration, cerebral calcification, severe neurologic disability, and osteosclerotic skeletal abnormalities. The largest disease-specific analysis, published in June 2023, aggregated only 19 patients, so every frequency estimate remains vulnerable to ascertainment bias and incomplete reporting. Seventeen patients were homozygous and two compound heterozygous; most arose in consanguineous families. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)

The central causal model is failure of CSF1R signaling in mononuclear-phagocyte lineages: deficient microglial development compromises brain development and white-matter homeostasis, while deficient osteoclast differentiation/resorption causes dysosteosclerosis. There is no approved BANDDOS-specific disease-modifying treatment. Hematopoietic stem-cell transplantation (HSCT) and microglial replacement are biologically plausible but remain extrapolations from dominant CSF1R-related leukoencephalopathy and preclinical models, not established BANDDOS therapies. (chadarevian2024therapeuticpotentialof pages 23-24, dulski2023brainabnormalitiesneurodegeneration pages 7-9, dulski2023brainabnormalitiesneurodegeneration pages 2-5)

Domain	Finding / statistic	Ontology suggestions	Evidence type / source
Disease identity	Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS); OMIM 618476; Open Targets disease entity also indexed as EFO_0010268	MONDO: not confirmed from available sources; EFO_0010268; MeSH/Orphanet: not confirmed from available sources	Aggregated disease-level resources and literature synthesis (chitu2022modelingcsf‐1receptor pages 1-2, OpenTargets Search: brain abnormalities, neurodegeneration, and dysosteosclerosis-CSF1R, dulski2023brainabnormalitiesneurodegeneration pages 1-2)
Synonyms / disease framing	Pediatric-onset CSF1R-related disorder; autosomal-recessive CSF1R disorder; part of the CSF1R-related disorder continuum, distinct from dominant CSF1R-ALSP	NCIT: disease concept not confirmed; related concept suggestion: leukodystrophy / osteosclerosis terms as applicable	Review and systematic review (chitu2022modelingcsf‐1receptor pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 1-2)
Causal gene / inheritance	Biallelic CSF1R pathogenic variants; autosomal recessive inheritance; 17/19 homozygous and 2/19 compound heterozygous reported cases	HGNC gene: CSF1R; GO-linked process suggestions: microglia development, osteoclast differentiation	Human clinical genetics/systematic review (dulski2023brainabnormalitiesneurodegeneration pages 2-5, dulski2023brainabnormalitiesneurodegeneration pages 1-2)
Variant spectrum	11 distinct CSF1R variants in 19 patients: splice (n=3), missense (n=3), nonsense (n=2), intronic (n=2), in-frame deletion (n=1); all disrupted the tyrosine kinase domain or led to nonsense-mediated decay	Sequence ontology suggestions: missense_variant, splice_donor/acceptor_variant, stop_gained, intron_variant, inframe_deletion	Systematic review of reported patients (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 9-11)
Onset / course	First symptoms: perinatal n=5, infancy n=2, childhood n=5, adulthood n=1; severe, usually progressive neurodevelopmental/neurodegenerative course	HPO: HP:0003577 Congenital onset; HP:0003593 Infantile onset; HP:0012758 Neurodevelopmental abnormality; HP:0002063 Rigidity	Systematic review/natural history synthesis (dulski2023brainabnormalitiesneurodegeneration pages 1-2, chitu2022modelingcsf‐1receptor pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 5-6)
Neurologic phenotype frequency	Speech disturbance 13/15; cognitive decline 12/14; spasticity/rigidity 12/15; hyperreflexia 11/14; pathologic reflexes 8/11; seizures 9/16; dysphagia 9/12; developmental delay 7/14; infantile hypotonia 3/11; optic nerve atrophy 2/7	HPO suggestions: HP:0002463 Language developmental delay / speech disturbance; HP:0001263 Global developmental delay; HP:0001250 Seizure; HP:0001257 Spasticity; HP:0001347 Hyperreflexia; HP:0002015 Dysphagia; HP:0001252 Hypotonia; HP:0000648 Optic atrophy	Human case aggregation (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5, dulski2023brainabnormalitiesneurodegeneration pages 7-9)
Skeletal phenotype frequency	Skeletal deformities in 13/17; phenotype described within the dysosteosclerosis–Pyle disease spectrum	HPO suggestions: HP:0000925 Abnormality of the vertebral column; HP:0000938 Osteosclerosis; HP:0010669 Metaphyseal widening; UBERON: skeleton	Human case aggregation/review (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)
Neuroimaging frequency	White-matter changes 19/19; calcifications 15/18; agenesis/abnormality of corpus callosum 12/16; ventriculomegaly 13/19; Dandy-Walker complex 7/19; cortical abnormalities 4/10	HPO suggestions: HP:0007256 Agenesis of corpus callosum; HP:0002119 Ventriculomegaly; HP:0001272 Cerebral calcification; HP:0002500 Abnormal cerebral white matter morphology; UBERON: corpus callosum, cerebral white matter, cerebellum	Human imaging synthesis (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5, dulski2023brainabnormalitiesneurodegeneration pages 5-6)
Pathology	Single autopsy showed absence of corpus callosum, absence of microglia, severe white-matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications	CL suggestion: microglial cell; GO/CC: myelin sheath, axon; HPO: HP:0002500 Abnormal cerebral white matter morphology	Human neuropathology (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 9-11)
Mortality / prognosis	At least 6 reported deaths among 19 compiled cases: 3 in infancy, 2 in childhood, 1 at unspecified age; prognosis generally poor with high early-life morbidity and mortality	HPO suggestion: HP:0003819 Childhood death / mortality-related annotation as local schema permits	Human case aggregation (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)
Core mechanism	Loss of CSF1R signaling impairs mononuclear-phagocyte lineage development, especially microglia and osteoclasts, linking congenital brain malformation/white-matter degeneration with dysosteosclerosis	GO suggestions: microglia development, osteoclast differentiation, receptor tyrosine kinase signaling, myeloid cell differentiation; CL: microglial cell, osteoclast	Human + model-organism convergence (dulski2023brainabnormalitiesneurodegeneration pages 7-9, chitu2022modelingcsf‐1receptor pages 1-2, chadarevian2024therapeuticpotentialof pages 23-24)
Cellular / tissue mechanism	Upstream: CSF1R kinase-domain dysfunction or NMD; intermediate: deficient microglia and osteoclast development/function; downstream: white-matter degeneration, calcifications, ventriculomegaly/brain malformations, osteosclerosis	GO suggestions: colony-stimulating factor receptor signaling pathway, CNS development, bone resorption; UBERON: brain, cerebral white matter, bone	Mechanistic interpretation from human pathology and models (daghagh2022homozygousmutationin pages 6-7, dulski2023brainabnormalitiesneurodegeneration pages 7-9, chitu2022modelingcsf‐1receptor pages 1-2)
Diagnosis	Diagnosis relies on clinical phenotype plus neuroimaging and confirmation of biallelic CSF1R variants by sequencing; reported methods include targeted NGS/panel testing and prenatal CVS-based family testing in one family	HPO panel terms above; LOINC/SNOMED not confirmed from available sources	Human case report and review (daghagh2022homozygousmutationin pages 2-4, daghagh2022homozygousmutationin pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 1-2)
Differential diagnosis	Should be distinguished from dominant CSF1R-ALSP and from other genetic dysosteosclerosis/osteopetrosis entities such as SLC29A3-related dysosteosclerosis and TNFRSF11A-related osteoclast-poor dysosteosclerosis	Suggested disease neighbors for curation: CSF1R-related leukoencephalopathy, dysosteosclerosis, osteopetrosis	Expert review/systematic review (dulski2023brainabnormalitiesneurodegeneration pages 1-2, chitu2022modelingcsf‐1receptor pages 1-2)
Recent developments (2023–2024)	2023 systematic review expanded the cohort to 19 patients and formalized overlap with CSF1R-ALSP; 2024 translational work in CSF1R disorders advanced microglia disease modeling and microglia-replacement concepts, but not BANDDOS-specific therapy	GO/CL suggestions as above	Recent review and translational studies (dulski2023brainabnormalitiesneurodegeneration pages 1-2, chadarevian2024therapeuticpotentialof pages 23-24)
Treatment status	No BANDDOS-specific approved disease-modifying therapy identified. Management is supportive. Authors propose a potential “window of opportunity” to adapt therapies used in CSF1R-ALSP, especially HSCT, but direct BANDDOS efficacy data are lacking; no relevant BANDDOS interventional trial was identified in the retrieved evidence	NCIT suggestions: Supportive care; Hematopoietic Stem Cell Transplantation (as extrapolative/experimental concept)	Expert opinion/systematic review plus related-disease treatment literature (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)
Evidence base caveat	Evidence is derived from individual case reports/series aggregated into disease-level review; denominators vary by phenotype because not all features were reported in every patient	Evidence code suggestion: human clinical case report, systematic review, model organism	Methodological note from systematic review (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)

Table: This table condenses the most actionable disease-characteristic evidence for BANDDOS, emphasizing reported denominators, mechanistic interpretation, and current treatment limitations. It is useful as a compact knowledge-base population aid anchored to the available human and translational evidence.

1. Disease information

Definition. BANDDOS—brain abnormalities, neurodegeneration, and dysosteosclerosis—is a syndromic CSF1R deficiency disorder characterized by congenital brain abnormalities, pediatric leukoencephalopathy/neurodegeneration, and a dysosteosclerosis–Pyle disease skeletal phenotype. It belongs to the CSF1R-related disorder continuum but is genetically and clinically distinguished from usually adult-onset, autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP). (dulski2023brainabnormalitiesneurodegeneration pages 7-9, dulski2023brainabnormalitiesneurodegeneration pages 1-2)

Identifiers and terminology. Confirmed identifiers are OMIM/MIM 618476 and EFO:0010268. Open Targets associates EFO:0010268 specifically with CSF1R (Ensembl ENSG00000182578), supported by five evidence records and foundational PubMed records including PMID 30982609 and PMID 30982608. A disease-specific MONDO, Orphanet, MeSH, ICD-10, or ICD-11 code was not established in the retrieved evidence; generic osteopetrosis or leukodystrophy codes should not be treated as exact BANDDOS identifiers. (chitu2022modelingcsf‐1receptor pages 1-2, OpenTargets Search: brain abnormalities, neurodegeneration, and dysosteosclerosis-CSF1R)

Synonyms/alternative framing: BANDDOS; autosomal-recessive CSF1R disorder; biallelic CSF1R-related pediatric leukoencephalopathy; pediatric-onset CSF1R-related disorder; CSF1R-related dysosteosclerosis with neurodegeneration.

Evidence provenance. Available knowledge originates from individual pedigrees, case reports, imaging and one autopsy, subsequently aggregated at disease level. It is not derived from population-scale EHR cohorts. The 2023 review combined 16 previously published patients with three new patients. (dulski2023brainabnormalitiesneurodegeneration pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

The established cause is biallelic germline pathogenic or likely pathogenic variation in CSF1R, encoding colony-stimulating factor-1 receptor, a transmembrane receptor tyrosine kinase activated by CSF1 and IL-34. Pathogenic alleles disrupt the intracellular tyrosine-kinase domain or cause transcript degradation through nonsense-mediated decay. (dulski2023brainabnormalitiesneurodegeneration pages 7-9, dulski2023brainabnormalitiesneurodegeneration pages 1-2)

Risk factors

Genetic: two pathogenic CSF1R alleles; parental consanguinity increases the probability of homozygosity. Family history compatible with autosomal-recessive inheritance is important.
Variant severity: truncation/NMD and profound kinase-domain disruption appear associated with early severe disease, although the cohort is too small for a validated genotype–phenotype model. (dulski2023brainabnormalitiesneurodegeneration pages 9-11)
Environmental, infectious, lifestyle, age, or sex risks: none established. The observed 19-patient sex distribution—10 female, seven male, two unknown—does not establish sex-specific susceptibility. (dulski2023brainabnormalitiesneurodegeneration pages 2-5)

No validated protective variant, modifier gene, protective exposure, or gene–environment interaction has been reported. Apparent phenotypic variability may reflect residual kinase activity, background genetic modifiers, and ascertainment, but these remain hypotheses. Heterozygous relatives in one family carrying c.2498C>T (p.Thr833Met) were clinically unaffected, supporting recessive inheritance rather than a protective effect. (daghagh2022homozygousmutationin pages 1-2, daghagh2022homozygousmutationin pages 2-4)

3. Phenotypes

Reported frequencies use only patients with sufficient documentation; they are not population prevalence estimates.

Speech disturbance: 13/15 (87%), often dysarthria; progressive and functionally disabling. Suggested HPO: speech abnormality, dysarthria.
Cognitive decline/impairment: 12/14 (86%); developmental impairment may precede regression. HPO: cognitive impairment, developmental regression.
Spasticity or rigidity: 12/15 (80%); hyperreflexia 11/14; pathologic reflexes 8/11. HPO: HP:0001257 Spasticity; HP:0001347 Hyperreflexia; pyramidal sign.
Seizures: 9/16 (56%), generally childhood onset and potentially recurrent. HPO: HP:0001250 Seizure.
Dysphagia: 9/12 (75%), with aspiration and nutritional implications. HPO: HP:0002015 Dysphagia.
Developmental delay: 7/14 (50%); infantile hypotonia: 3/11; optic atrophy: 2/7. Suggested HPO: HP:0001263 Global developmental delay; HP:0001252 Hypotonia; HP:0000648 Optic atrophy.
Dysmorphism: 7/17 (41%).
Skeletal deformity/dysplasia: 13/17 (76%), spanning dysosteosclerosis and Pyle-like metaphyseal abnormalities; findings may include osteosclerosis, long-bone modeling defects, kyphosis, and optic-canal narrowing. Suggested HPO: HP:0000938 Osteosclerosis, metaphyseal widening, abnormal long-bone morphology, kyphosis. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 7-9, chitu2022modelingcsf‐1receptor pages 1-2)

Imaging phenotypes: white-matter abnormalities 19/19; intracranial calcifications 15/18; corpus-callosum agenesis/abnormality 12/16; ventriculomegaly 13/19; Dandy–Walker complex 7/19; cortical abnormalities 4/10. Calcifications can be congenital and have a characteristic “stepping-stone” distribution. Suggested HPO: abnormal cerebral white-matter morphology, HP:0001272 cerebral calcification, HP:0007256 agenesis of corpus callosum, HP:0002119 ventriculomegaly, Dandy–Walker malformation. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 5-6)

Quality of life. No BANDDOS-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study exists. Severe motor impairment, cognitive and speech loss, seizures, dysphagia, visual impairment, skeletal deformity, and respiratory aspiration collectively imply profound dependence and caregiver burden. This is clinical inference rather than instrument-derived evidence. (dulski2023brainabnormalitiesneurodegeneration pages 7-9)

4. Genetic and molecular information

Causal gene: CSF1R; approved name colony stimulating factor 1 receptor; Ensembl ENSG00000182578. The protein has 972 amino acids and includes extracellular immunoglobulin-like domains, a transmembrane segment, juxtamembrane regulatory region, and intracellular split tyrosine-kinase domain. (dulski2023brainabnormalitiesneurodegeneration pages 7-9, OpenTargets Search: brain abnormalities, neurodegeneration, and dysosteosclerosis-CSF1R)

In the 19-patient 2023 series, 11 distinct variants comprised three splice variants, three missense variants, two nonsense variants, two intronic variants, and one in-frame deletion. Nine of 11 affected the kinase domain; the remainder caused or were predicted to cause NMD. Classifications ranged from likely pathogenic to pathogenic under ACMG/AMP interpretation. All are germline; no somatic BANDDOS mechanism is known. (dulski2023brainabnormalitiesneurodegeneration pages 9-11, dulski2023brainabnormalitiesneurodegeneration pages 1-2)

Examples include:

c.2498C>T (p.Thr833Met), homozygous, exon 19/kinase domain. It was predicted damaging, highly conserved, and segregated with disease, but lacked direct in-vitro functional validation; consequently, computational evidence should not be overstated. (daghagh2022homozygousmutationin pages 2-4, daghagh2022homozygousmutationin pages 4-6)
c.1754G>T (p.Gly585Val), homozygous in three Brazilian siblings and predicted pathogenic. (dulski2023brainabnormalitiesneurodegeneration pages 2-5)

Population allele frequencies were not reliably reported in the retrieved evidence. These causal alleles are expected to be very rare, but a numerical gnomAD frequency should be added only after transcript- and genome-build-specific database verification. No established modifier genes, epigenetic signature, recurrent chromosomal abnormality, or structural-variant mechanism is known.

5. Environmental information

BANDDOS is a monogenic developmental disorder. No toxin, radiation, pollution, occupational exposure, diet, smoking, alcohol use, exercise pattern, or infectious agent has been shown to cause or modify it. Infectious and aspiration complications may worsen clinical outcome but are downstream complications, not etiology. Consequently, CHEBI annotations are not appropriate for a causal exposure at present.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic lesion: biallelic kinase-domain disruption, abnormal splicing, truncation, or NMD reduces functional CSF1R.
Signaling failure: inadequate CSF1/IL-34-induced receptor autophosphorylation impairs survival, proliferation, differentiation, and function of mononuclear-phagocyte lineages.
Microglial deficiency: failed embryonic/postnatal microglial development removes critical support for CNS morphogenesis, myelin/axon homeostasis, phagocytosis, and tissue repair.
CNS consequences: congenital malformations, ventriculomegaly, callosal agenesis and Dandy–Walker complex are followed or accompanied by white-matter atrophy, axonal spheroids, gliosis, calcification, spasticity, seizures, cognitive decline, and dysphagia.
Osteoclast deficiency/dysfunction: impaired differentiation and survival of bone-resorbing osteoclasts causes defective remodeling, osteosclerosis, abnormal metaphyseal modeling, skeletal deformity, and possible foraminal narrowing. (daghagh2022homozygousmutationin pages 6-7, dulski2023brainabnormalitiesneurodegeneration pages 7-9, chitu2022modelingcsf‐1receptor pages 1-2)

A single human autopsy showed near-complete/complete absence of microglia, absent corpus callosum, severe white-matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications—direct human tissue support for the microglial-deficiency model. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 9-11)

Suggested annotations include GO: receptor tyrosine-kinase signaling, macrophage differentiation, microglial-cell development, osteoclast differentiation, bone resorption, CNS development, phagocytosis, myelination, and axon maintenance; CL: microglial cell, osteoclast, monocyte/macrophage progenitor, astrocyte, oligodendrocyte; GO cellular components: plasma membrane, receptor complex, cytoplasmic kinase domain, axon, and myelin sheath.

No BANDDOS-specific human transcriptomic, proteomic, metabolomic, lipidomic, spatial-transcriptomic, single-cell, or epigenomic signature has been established. Work in broader CSF1R disease suggests altered microglial and compensatory astrocytic states, but this should not be represented as directly measured BANDDOS molecular profiling. (chadarevian2024therapeuticpotentialof pages 23-24)

7. Anatomical structures affected

Primary systems: CNS and skeleton. CNS sites include bilateral cerebral/periventricular white matter, corpus callosum, corticospinal/pyramidal tracts, cerebral cortex, basal ganglia, cerebellum and posterior fossa, ventricles, and optic nerves. Skeletal involvement includes long bones, metaphyses, vertebral column, ribs/chest, skull, and optic canals. Involvement is generally bilateral/systemic rather than unilateral. (daghagh2022homozygousmutationin pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 7-9)

Suggested UBERON concepts: brain, cerebral white matter, corpus callosum, cerebral cortex, basal ganglion, cerebellum, ventricular system of brain, optic nerve, bone tissue, long bone, metaphysis, vertebral column, skull. At tissue/cell level, nervous tissue, white matter, myelinated axon, microglia, astrocytes, oligodendrocytes, bone, and osteoclasts are most relevant.

8. Temporal development

Onset was perinatal in five patients, infancy in two, childhood in five, and adulthood in one among those with adequate data. Early disease may present with congenital hydrocephalus/ventriculomegaly, hypotonia, seizures, or developmental delay; later-onset cases can first develop normally and then lose language, cognition, and motor function. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, chitu2022modelingcsf‐1receptor pages 1-2)

The usual course is chronic, progressive, lifelong, and often severe. A representative p.Thr833Met patient had visual problems at one month, progressive cognitive decline, gait disturbance and seizures after age two, and died at nine years. No spontaneous remission is documented. Because microglia participate in prenatal brain development, the prenatal/perinatal period is likely a critical mechanistic window; whether intervention after congenital malformation can reverse deficits is unknown. (daghagh2022homozygousmutationin pages 1-2)

9. Inheritance and population

Inheritance is autosomal recessive. In the 2023 compilation, 17/19 patients were homozygous and 2/19 compound heterozygous. Consanguinity was common. Reported ancestries/geographies included Chaldean, Brazilian, Arab, Turkish, Indian, Japanese, and Native American families, indicating worldwide occurrence rather than a single endemic population. No validated founder allele, carrier frequency, prevalence per 100,000, annual incidence, penetrance estimate, anticipation, or germline-mosaicism rate is available. (dulski2023brainabnormalitiesneurodegeneration pages 2-5)

Observed sex counts—10 female, seven male, two unknown—are compatible with autosomal inheritance and do not demonstrate sex bias. For two carrier parents, the conventional per-pregnancy risks are 25% affected, 50% heterozygous carrier, and 25% unaffected/non-carrier, assuming both parental alleles are pathogenic and no unusual reproductive mechanism.

10. Diagnostics

Recommended approach

Recognize the combination of early developmental regression/leukoencephalopathy, calcification or congenital brain malformation, and osteosclerotic/modeling abnormalities.
Obtain brain MRI, including T1/T2/FLAIR and diffusion sequences, to define white-matter loss, callosal abnormalities, ventriculomegaly, posterior-fossa and cortical malformations.
Obtain noncontrast head CT, which is more sensitive for calcification.
Perform a skeletal survey or targeted radiographs/CT where clinically indicated.
Confirm biallelic CSF1R variants by sequencing and parental segregation. WES/WGS is appropriate when phenotype is atypical; a leukodystrophy, cerebral-calcification, osteopetrosis, or skeletal-dysplasia panel should include CSF1R.
Assess swallowing/aspiration, EEG for seizures, vision/optic nerves, developmental status, mobility, nutrition, respiratory status, and orthopedic complications. (daghagh2022homozygousmutationin pages 1-2, daghagh2022homozygousmutationin pages 2-4)

Targeted NGS identified p.Thr833Met, and chorionic-villus sampling enabled prenatal family testing. CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not first-line tests for a classic sequence-level BANDDOS presentation, although WGS can detect copy-number or noncoding alleles missed by routine panels. No validated blood, CSF, proteomic, metabolomic, or liquid-biopsy biomarker exists.

Differential diagnosis: dominant CSF1R-ALSP; Aicardi–Goutières/interferonopathy and congenital-infection mimics of intracranial calcification; osteopetrosis due to TCIRG1, CLCN7, OSTM1, TNFSF11, or TNFRSF11A; SLC29A3-related dysosteosclerosis; Pyle disease; Nasu–Hakola disease (TREM2/TYROBP); and other genetic leukodystrophies. Importantly, “dysosteosclerosis” is genetically heterogeneous and is not synonymous with BANDDOS. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, chitu2022modelingcsf‐1receptor pages 1-2)

11. Outcome and prognosis

At least six deaths were documented among the 19 compiled patients: three in infancy, two in childhood, and one at an unspecified age. This incomplete, heavily censored case series cannot support formal survival curves, life expectancy, or 5-/10-year survival estimates. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)

Morbidity is often profound: developmental and cognitive disability, progressive speech and motor loss, spasticity, seizures, dysphagia/aspiration, impaired vision, skeletal deformity, and dependence in activities of daily living. Established individual prognostic biomarkers do not exist. Earlier onset, severe congenital malformations, profound microglial deficiency, truncating/NMD alleles, dysphagia, and respiratory complications are plausible adverse indicators, but none has been validated in a sufficiently large cohort.

12. Treatment and current applications

There is no approved or evidence-based BANDDOS-specific pharmacotherapy, gene therapy, RNA therapy, cell therapy, or surgical cure. Clinical care is multidisciplinary and supportive:

antiseizure medication individualized to seizure type;
speech/communication, physical and occupational therapy;
tone management and orthopedic surveillance;
formal swallowing evaluation, texture modification, aspiration precautions, and enteral feeding when needed;
respiratory care, vaccination, and prompt infection treatment;
visual, dental, hearing, nutritional, and developmental support;
mobility aids, pain control, and palliative-care involvement in severe disease.

Suggested NCIT concepts include Supportive Care, Physical Therapy, Occupational Therapy, Speech Therapy, Anticonvulsant Therapy, Enteral Nutrition, Gastrostomy, and Hematopoietic Stem Cell Transplantation; HSCT must be flagged experimental/extrapolative for BANDDOS.

The 2023 expert review concluded that BANDDOS and CSF1R-ALSP form a continuum and proposed a possible therapeutic window for adapting ALSP-directed therapy. However, evidence that allogeneic HSCT can stabilize dominant CSF1R-ALSP does not demonstrate efficacy in children with congenital microglial absence and established malformations. Risks include conditioning toxicity, infection, graft-versus-host disease, and uncertain donor-cell entry/repopulation of the developing brain. No relevant BANDDOS-specific interventional trial was identified. (dulski2023brainabnormalitiesneurodegeneration pages 1-2, dulski2023brainabnormalitiesneurodegeneration pages 2-5)

A major 2024 translational development was human microglia transplantation in a chimeric CSF1R-related leukoencephalopathy model. This supports cell replacement as a research direction, not current clinical care for BANDDOS. (chadarevian2024therapeuticpotentialof pages 23-24)

13. Prevention

There is no lifestyle, vaccine, medication, or environmental intervention that prevents the molecular disease. Primary reproductive prevention consists of genetic counseling, carrier testing of relatives, partner testing where appropriate, preimplantation genetic testing for monogenic disease, and prenatal diagnosis once familial variants are known. One family underwent chorionic-villus testing of a fetus. (daghagh2022homozygousmutationin pages 2-4)

Secondary prevention means early molecular diagnosis and surveillance for seizures, aspiration, visual compromise, respiratory disease, and skeletal complications. Population newborn screening is not established. Tertiary prevention includes aspiration precautions, nutrition support, contracture prevention, rehabilitation, fracture/orthopedic management, and infection prevention. Cascade testing is appropriate for adult relatives, with careful counseling that heterozygous CSF1R variant interpretation may depend on the specific allele and its known dominant versus recessive effect.

14. Other species and natural disease

No naturally occurring veterinary disease precisely equivalent to human BANDDOS was established in the retrieved literature, and there is no zoonotic or cross-species transmission. CSF1R function is evolutionarily conserved in mammals and fish. Mouse (NCBI Taxon 10090), rat (10116), and zebrafish (7955) ortholog studies reproduce central elements of CSF1R deficiency—microglial/macrophage depletion, osteoclast defects, osteopetrosis, growth/developmental abnormalities, and brain pathology. Species differ in viability, paralog structure, genetic-background sensitivity, and degree of skeletal/CNS disease, limiting direct phenotypic equivalence. (chadarevian2024therapeuticpotentialof pages 23-24, chitu2022modelingcsf‐1receptor pages 1-2)

15. Model organisms and advanced research platforms

Mouse and rat: Csf1r null, kinase-dead, hypomorphic, and regulatory-element mutant models demonstrate dependence of tissue macrophages, microglia, and osteoclasts on CSF1R. Phenotypic severity is strongly background-dependent, an important limitation and a potential clue to human modifiers. (chitu2022modelingcsf‐1receptor pages 1-2)

Zebrafish: csf1r-deficient models permit live developmental analysis. They show arrested macrophage development, systemic macrophage/microglial depletion, and altered astrocytic responses. Zebrafish possess duplicated receptor genes, so dosage and paralog compensation complicate translation to humans. (chadarevian2024therapeuticpotentialof pages 23-24)

Human cellular systems: iPSC-derived microglia, CRISPR-edited isogenic lines, cerebral organoids, and microglia–organoid coculture are relevant for testing kinase activity, survival, migration, phagocytosis, inflammatory signaling, myelin handling, and cell-replacement strategies. As of 2024, advanced iPSC work principally modeled dominant ALSP rather than biallelic BANDDOS; a dedicated patient-derived BANDDOS isogenic model remains a major unmet need.

Recent authoritative synthesis and evidence limitations

The pivotal recent source is Dulski et al., Orphanet Journal of Rare Diseases, published June 2023, DOI: 10.1186/s13023-023-02772-9. Its abstract states: “We identified 19 patients with BANDDOS” and concludes that the disorder has “a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features.” (dulski2023brainabnormalitiesneurodegeneration pages 1-2)

The 2022 case report by Daghagh et al., DOI: 10.34172/bi.2022.23528, reported a novel homozygous p.Thr833Met allele; its abstract explicitly notes that heterozygous relatives had no disease manifestations and that the allele lies in the functionally essential protein-tyrosine-kinase domain. (daghagh2022homozygousmutationin pages 1-2)

The 2024 transplantation study, DOI: 10.1016/j.neuron.2024.05.023, provides high-quality preclinical support for human microglial replacement in CSF1R-related disease, but not clinical BANDDOS efficacy. (chadarevian2024therapeuticpotentialof pages 23-24)

Overall certainty is high for the gene–disease relationship, recessive inheritance, microglial/osteoclast mechanism, and core imaging phenotype; moderate to low for individual phenotype frequencies and genotype–phenotype associations; and very low/absent for epidemiology, quality-of-life metrics, validated biomarkers, natural-history staging, and treatment efficacy. These gaps should be represented explicitly in a disease knowledge base rather than filled by extrapolation.

References

(dulski2023brainabnormalitiesneurodegeneration pages 1-2): Jarosław Dulski, Josiane Souza, Mara Lúcia Santos, and Zbigniew K. Wszolek. Brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos): new cases, systematic literature review, and associations with csf1r-alsp. Orphanet Journal of Rare Diseases, Jun 2023. URL: https://doi.org/10.1186/s13023-023-02772-9, doi:10.1186/s13023-023-02772-9. This article has 26 citations and is from a peer-reviewed journal.
(dulski2023brainabnormalitiesneurodegeneration pages 2-5): Jarosław Dulski, Josiane Souza, Mara Lúcia Santos, and Zbigniew K. Wszolek. Brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos): new cases, systematic literature review, and associations with csf1r-alsp. Orphanet Journal of Rare Diseases, Jun 2023. URL: https://doi.org/10.1186/s13023-023-02772-9, doi:10.1186/s13023-023-02772-9. This article has 26 citations and is from a peer-reviewed journal.
(chadarevian2024therapeuticpotentialof pages 23-24): Jean Paul Chadarevian, Jonathan Hasselmann, Alina Lahian, Joia K. Capocchi, Adrian Escobar, Tau En Lim, Lauren Le, Christina Tu, Jasmine Nguyen, Sepideh Kiani Shabestari, William Carlen-Jones, Sunil Gandhi, Guojun Bu, David A. Hume, Clare Pridans, Zbigniew K. Wszolek, Robert C. Spitale, Hayk Davtyan, and Mathew Blurton-Jones. Therapeutic potential of human microglia transplantation in a chimeric model of csf1r-related leukoencephalopathy. Aug 2024. URL: https://doi.org/10.1016/j.neuron.2024.05.023, doi:10.1016/j.neuron.2024.05.023. This article has 85 citations and is from a highest quality peer-reviewed journal.
(dulski2023brainabnormalitiesneurodegeneration pages 7-9): Jarosław Dulski, Josiane Souza, Mara Lúcia Santos, and Zbigniew K. Wszolek. Brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos): new cases, systematic literature review, and associations with csf1r-alsp. Orphanet Journal of Rare Diseases, Jun 2023. URL: https://doi.org/10.1186/s13023-023-02772-9, doi:10.1186/s13023-023-02772-9. This article has 26 citations and is from a peer-reviewed journal.
(chitu2022modelingcsf‐1receptor pages 1-2): Violeta Chitu, Şölen Gökhan, and E. Richard Stanley. Modeling csf‐1 receptor deficiency diseases – how close are we? Jul 2022. URL: https://doi.org/10.1111/febs.16085, doi:10.1111/febs.16085. This article has 55 citations.
(OpenTargets Search: brain abnormalities, neurodegeneration, and dysosteosclerosis-CSF1R): Open Targets Query (brain abnormalities, neurodegeneration, and dysosteosclerosis-CSF1R, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(dulski2023brainabnormalitiesneurodegeneration pages 9-11): Jarosław Dulski, Josiane Souza, Mara Lúcia Santos, and Zbigniew K. Wszolek. Brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos): new cases, systematic literature review, and associations with csf1r-alsp. Orphanet Journal of Rare Diseases, Jun 2023. URL: https://doi.org/10.1186/s13023-023-02772-9, doi:10.1186/s13023-023-02772-9. This article has 26 citations and is from a peer-reviewed journal.
(dulski2023brainabnormalitiesneurodegeneration pages 5-6): Jarosław Dulski, Josiane Souza, Mara Lúcia Santos, and Zbigniew K. Wszolek. Brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos): new cases, systematic literature review, and associations with csf1r-alsp. Orphanet Journal of Rare Diseases, Jun 2023. URL: https://doi.org/10.1186/s13023-023-02772-9, doi:10.1186/s13023-023-02772-9. This article has 26 citations and is from a peer-reviewed journal.
(daghagh2022homozygousmutationin pages 6-7): Hossein Daghagh, Haniyeh Rahbar Kafshboran, Yousef Daneshmandpour, Maryam Nasiri Aghdam, Shahrzad Talebian, Jafar Nouri Nojadeh, Hamid Hamzeiy, Saskia Biskup, and Ebrahim Sakhinia. Homozygous mutation in csf1r causes brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos). BioImpacts : BI, 13:183-190, Nov 2022. URL: https://doi.org/10.34172/bi.2022.23528, doi:10.34172/bi.2022.23528. This article has 7 citations.
(daghagh2022homozygousmutationin pages 2-4): Hossein Daghagh, Haniyeh Rahbar Kafshboran, Yousef Daneshmandpour, Maryam Nasiri Aghdam, Shahrzad Talebian, Jafar Nouri Nojadeh, Hamid Hamzeiy, Saskia Biskup, and Ebrahim Sakhinia. Homozygous mutation in csf1r causes brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos). BioImpacts : BI, 13:183-190, Nov 2022. URL: https://doi.org/10.34172/bi.2022.23528, doi:10.34172/bi.2022.23528. This article has 7 citations.
(daghagh2022homozygousmutationin pages 1-2): Hossein Daghagh, Haniyeh Rahbar Kafshboran, Yousef Daneshmandpour, Maryam Nasiri Aghdam, Shahrzad Talebian, Jafar Nouri Nojadeh, Hamid Hamzeiy, Saskia Biskup, and Ebrahim Sakhinia. Homozygous mutation in csf1r causes brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos). BioImpacts : BI, 13:183-190, Nov 2022. URL: https://doi.org/10.34172/bi.2022.23528, doi:10.34172/bi.2022.23528. This article has 7 citations.
(daghagh2022homozygousmutationin pages 4-6): Hossein Daghagh, Haniyeh Rahbar Kafshboran, Yousef Daneshmandpour, Maryam Nasiri Aghdam, Shahrzad Talebian, Jafar Nouri Nojadeh, Hamid Hamzeiy, Saskia Biskup, and Ebrahim Sakhinia. Homozygous mutation in csf1r causes brain abnormalities, neurodegeneration, and dysosteosclerosis (banddos). BioImpacts : BI, 13:183-190, Nov 2022. URL: https://doi.org/10.34172/bi.2022.23528, doi:10.34172/bi.2022.23528. This article has 7 citations.

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References weighed for topical relevance	6
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Pathophysiology

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Phenotypes

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Diagnosis

Imaging Findings

Prevalence

Differential Diagnoses

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Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS): Disease-Characteristics Report

Executive summary

1. Disease information

2. Etiology, risk, and protective factors

Causal factor

Risk factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

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7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

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11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

14. Other species and natural disease

15. Model organisms and advanced research platforms

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