Spondyloenchondrodysplasia

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

SPENCD segregates as an autosomal recessive trait. Affected individuals carry homozygous or compound heterozygous ACP5 alleles; heterozygous parents are clinically unaffected and retain roughly half-normal serum TRAP activity. Reported cohorts are markedly enriched for parental consanguinity, consistent with the low population frequency of pathogenic ACP5 alleles.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:21217755 SUPPORT Human Clinical

"All mutations segregated with the disease in the families investigated, and all parents tested were heterozygous for a relevant familial mutation."

Biallelic segregation with unaffected heterozygous parents establishes autosomal recessive inheritance.

PMID:21217752 SUPPORT Human Clinical

"We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals"

Homozygosity mapping in consanguineous pedigrees is the recessive-model design that localised and identified the gene.

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Mechanistic Hypotheses

1

Osteopontin-TLR9 Model of Interferon Activation

opn_tlr9_pdc EMERGING

Evidence balance 2 support

The leading account of how a lysosomal phosphatase deficiency becomes an interferonopathy. TRAP dephosphorylates osteopontin; in its absence, phosphorylated osteopontin persists in plasmacytoid dendritic cells and sustains TLR9 signalling, driving type I interferon production. The model originates in mouse work and is put forward as a suggestion rather than an established pathway - the 2025 review's own framing is that the immunopathology of SPENCD remains unclear despite decades of TRAP research.

Pathograph links

Loss of Tartrate-Resistant Acid Phosphatase Activity -> Osteopontin Hyperphosphorylation DIRECT Osteopontin is the best-characterised TRAP substrate; without TRAP its phosphoserines are not removed and phosphorylated osteopontin accumulates in patient fluids and cells.

Osteopontin Hyperphosphorylation -> Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells INDIRECT UNKNOWN INTERMEDIATES The proposed but not formally established link between the substrate defect and the interferon phenotype. Whether osteopontin is a physical component of the TLR9/MyD88 complex in human plasmacytoid dendritic cells, or whether TRAP acts on a different substrate entirely, is unresolved.

Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells -> Type I Interferon Overproduction DIRECT Unrestrained TLR9-driven IRF7 activation in plasmacytoid dendritic cells is the proposed cellular source of the systemic interferon signature.

Show evidence (2 references)

PMID:41049574 SUPPORT Other

"Subsequently, based on earlier work in mouse (12), it was suggested that the immunological features of SPENCD might relate to a failure of mutant TRAP to dephosphorylate osteopontin (OPN) in plasmacytoid dendritic cells (pDCs), leading to persistent Toll-like receptor 9 (TLR9) signalling (13)."

States the model and, in its hedged wording, its status as a proposal rather than a demonstrated mechanism.

PMID:41049574 SUPPORT Other

"the immunopathology of SPENCD remains unclear"

The review's explicit statement that the mechanism is unresolved, which is why this is recorded as an emerging hypothesis and not as settled pathophysiology.

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Discussions and Knowledge Gaps

3

Why does the Acp5-null mouse reproduce the skeletal dysplasia of SPENCD but not the autoimmunity or the neurological disease that dominate the human phenotype?

HUMAN MODEL MISMATCH OPEN spencd_mouse_immune_mismatch

Attached to

pathophysiology#Systemic Autoimmunity

The only viable in vivo model of TRAP deficiency is silent on the arm of the disorder that causes most of the morbidity and all of the recorded deaths. Evidence for the immune mechanism therefore rests on human patient material and on knockdown in a plasmacytoid dendritic cell line, not on an organism-level system in which the interferon-to-autoimmunity link can be tested. Whether this reflects a species difference in the osteopontin-TLR9 axis, a difference in laboratory pathogen exposure, or a genuinely different mechanism in humans is unknown, and it is the reason the causal status of the interferon signature remains open.

Proposed experiments

Interferon-sensitised or humanised Acp5-deficient model

exp_spencd_sensitised_acp5_null_model

Test whether Acp5-null mice develop autoimmunity when the type I interferon axis is sensitised — for example on a lupus-prone background, under TLR9 agonist challenge, or with the human osteopontin phosphorylation sites knocked in — and whether JAK inhibition prevents it.

Would support

pathophysiology#Systemic Autoimmunity

Would refute

pathophysiology#Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells

Supporting outcome

Emergence of autoantibodies and cytopenias in sensitised Acp5-null animals, abrogated by JAK inhibition, would place the interferon node causally upstream of autoimmunity in vivo.

Refuting outcome

Failure of TLR9 agonist challenge to elicit autoimmunity in Acp5-null animals despite an intact interferon response would argue that the osteopontin-TLR9 route is not the operative mechanism.

Show evidence (1 reference)

PMID:41049574 SUPPORT Model Organism

"Acp5-null mice have not been described to manifest overt autoimmunity, which is such a prominent feature of ACP5-related disease in humans."

States the mismatch between the model and the human phenotype directly.

Is hyperphosphorylated osteopontin actually the substrate defect that drives type I interferon overproduction, or is TRAP acting on some other substrate?

KNOWLEDGE GAP OPEN spencd_trap_substrate_identity

Attached to

pathophysiology#Osteopontin Hyperphosphorylation

The osteopontin-TLR9 model rests on a single 2017 study, and its authors could not directly assess osteopontin phosphorylation in the plasmacytoid dendritic cell line they used. Alternative routes are plausible and untested: TRAP is a lysosomal enzyme that could act in TLR7 or TLR9 trafficking directly, or in STING degradation, or through its role in removing mannose-6-phosphate from acid hydrolases — two of which, DNase II and ribonuclease T2, are themselves interferonopathy genes.

Proposed experiments

Substrate mapping in TRAP-deficient primary human plasmacytoid dendritic cells

exp_spencd_substrate_mapping_pdc

Phosphoproteomics on primary patient-derived plasmacytoid dendritic cells, combined with a test of whether mannose-6-phosphate retention on DNase II and ribonuclease T2 impairs their activity in TRAP-deficient cells.

Would support

pathophysiology#Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells

Would refute

pathophysiology#Osteopontin Hyperphosphorylation

Supporting outcome

Selective osteopontin hyperphosphorylation in patient plasmacytoid dendritic cells, with intact DNase II and ribonuclease T2 activity, would confirm the osteopontin route.

Refuting outcome

Normal osteopontin phosphorylation alongside impaired lysosomal nuclease activity would relocate the mechanism to mannose-6-phosphate-dependent hydrolase maturation.

Show evidence (1 reference)

PMID:41049574 SUPPORT Other

"it remains to be formally determined if OPN is a physical component of the TLR9/MyD88 complex in these cells and/or whether TRAP acts on a different substrate(s) in this or other pathway(s)"

The review states the substrate question as formally unresolved.

What is the natural history of SPENCD in adulthood, and does early JAK inhibition change it?

KNOWLEDGE GAP OPEN spencd_adult_natural_history

Attached to

pathophysiology#Type I Interferon Overproduction

Published cases are overwhelmingly paediatric — only three of 77 individuals with recorded data presented after age 15 — and the 2025 review highlights a paucity of information on the disease beyond childhood. Whether short stature continues to worsen, whether intracranial calcification progresses, and whether the autoimmune burden accumulates or burns out are all unknown, which makes the benefit-risk of lifelong JAK inhibition started in early childhood impossible to assess.

Proposed experiments

International longitudinal SPENCD registry

exp_spencd_longitudinal_registry

Prospective longitudinal follow-up of molecularly confirmed patients into adulthood with standardised skeletal, neurological, immunological, and interferon-score endpoints, stratified by JAK inhibitor exposure.

Would support

pathophysiology#Type I Interferon Overproduction

Would refute

pathophysiology#Type I Interferon Overproduction

Supporting outcome

Divergence in autoimmune event rates and interferon scores between JAK-inhibitor-exposed and unexposed cohorts would strengthen the causal role of the interferon node.

Refuting outcome

Accumulating autoimmune events despite sustained interferon-score normalisation would argue that the signature is a biomarker rather than the driver.

Show evidence (1 reference)

PMID:41049574 SUPPORT Human Clinical

"we highlight a relative paucity of information relating to the natural history of the disease beyond childhood, and thus the need for longitudinal clinical and laboratory follow-up studies into adulthood"

The review names the adult natural history as the outstanding clinical gap.

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Pathophysiology

9

Biallelic ACP5 Loss of Function

Homozygous or compound heterozygous ACP5 alleles — missense, nonsense, frameshift, or whole-gene deletion — remove functional tartrate-resistant acid phosphatase. Missense alleles are not partial: they are expressed but catalytically inactive, so the initiating lesion is the same across the allelic spectrum.

ACP5 hgnc:124

Downstream

Loss of Tartrate-Resistant Acid Phosphatase Activity Absent or catalytically dead TRAP protein abolishes the enzyme's acid phosphatase activity in serum and in the cells that normally express it.

Show evidence (1 reference)

PMID:21217755 SUPPORT Human Clinical

"The observation of biallelic null mutations in four of eight families indicated that the SPENCD phenotype results from a loss of TRAP activity."

Null alleles in half the founding families identify loss of TRAP activity, not a neomorphic effect, as the initiating lesion.

Loss of Tartrate-Resistant Acid Phosphatase Activity

TRAP is a di-iron purple acid phosphatase with a low pH optimum, expressed by osteoclasts, macrophages, and dendritic cells. Its activity is undetectable in patient serum and leukocyte homogenates and roughly halved in heterozygous parents. This node is the point at which the skeletal and immune arms of the disorder diverge.

Osteopontin-TLR9 Model of Interferon Activation

osteoclast CL:0000092 macrophage CL:0000235

acid phosphatase activity GO:0003993 ⇓ LOSS OF FUNCTION

Downstream

Osteopontin Hyperphosphorylation Osteopontin is the best-characterised TRAP substrate; without TRAP its phosphoserines are not removed and phosphorylated osteopontin accumulates in patient fluids and cells.

Susceptibility to Infection TRAP is expressed by macrophages and dendritic cells, and Acp5-null macrophages show an altered cytokine profile and reduced bacterial clearance. Infection susceptibility in patients is therefore plausibly intrinsic rather than purely a consequence of immunosuppressive treatment, though the two are hard to separate clinically.

Osteoclast and Growth-Plate Dysfunction TRAP is an osteoclast enzyme; its loss impairs bone resorption and disorders the growth plate, the arm of the disorder the Acp5-null mouse reproduces.

Show evidence (3 references)

PMID:41049574 SUPPORT Other

"Type-5 acid phosphatase, also known as tartrate-resistant acid phosphatase (TRAP), is a lysosomal hydrolase expressed in cells of monocytic lineage, with activity against a wide variety of substrates"

Establishes the enzyme's cellular distribution, which is what makes a bone enzyme deficiency an immune disease.

PMID:21217755 SUPPORT Human Clinical

"Compared to five age-matched controls, and an unaffected sibling to patients 2 and 3 who was homozygous for the wild-type allele on gene sequencing, levels of total TRAP protein were negligible, and TRAP 5a protein undetectable, indicating an almost complete lack of TRAP synthesis or secretion..."

Direct patient measurement establishing that the disease state is absence of TRAP protein.

PMID:21217755 SUPPORT Human Clinical

"levels of total TRAP protein were negligible, and TRAP 5a protein undetectable, indicating an almost complete lack of TRAP synthesis or secretion in the affected patients tested"

Protein-level measurement in patient plasma confirms near-complete absence of the enzyme.

Osteopontin Hyperphosphorylation

Osteopontin accumulates in its hyperphosphorylated form. Dephosphorylation of osteopontin by TRAP is required for osteoclast migration, and intracellular phosphorylated osteopontin has been proposed to couple the TLR9/MyD88 signalosome to interferon-alpha expression in plasmacytoid dendritic cells.

Osteopontin-TLR9 Model of Interferon Activation

protein dephosphorylation GO:0006470 ↓ DECREASED

Downstream

Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells The proposed but not formally established link between the substrate defect and the interferon phenotype. Whether osteopontin is a physical component of the TLR9/MyD88 complex in human plasmacytoid dendritic cells, or whether TRAP acts on a different substrate entirely, is unresolved.

Show evidence (1 reference)

PMID:40786056 SUPPORT Other

"These mutations result in the loss of regulation of TRAP activity on the function of osteopontin (OPN), leading to an excess of phosphorylated OPN."

States the substrate-accumulation step as the accepted proximate consequence of TRAP loss.

Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells

Knockdown of TRAP in a plasmacytoid dendritic cell line raises interferon-alpha protein, interferon-stimulated gene expression, and IRF7 nuclear translocation on CpG-A stimulation, the in vitro correlate of unrestrained TLR9 signalling.

Osteopontin-TLR9 Model of Interferon Activation

plasmacytoid dendritic cell CL:0000784

toll-like receptor 9 signaling pathway GO:0034162 ↑ INCREASED

Downstream

Type I Interferon Overproduction Unrestrained TLR9-driven IRF7 activation in plasmacytoid dendritic cells is the proposed cellular source of the systemic interferon signature.

Show evidence (1 reference)

PMID:41049574 SUPPORT In Vitro

"CpG-A stimulation in a pDC line with stable knockdown of TRAP resulted in increased expression of IFN"

A TRAP-knockdown plasmacytoid dendritic cell line responds to TLR9 ligand with excess interferon, the cell-level basis for this node.

Type I Interferon Overproduction

Serum interferon-alpha activity is elevated and whole blood carries an interferon-stimulated gene signature in the great majority of patients tested, persisting across repeat measurements. This is the finding that classified SPENCD as a type I interferonopathy. Whether it drives the pathology or is a biomarker of it is not settled.

type I interferon production GO:0032606 ↑ INCREASED type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED

Downstream

Systemic Autoimmunity Sustained type I interferon exposure is the proposed route to the autoimmune phenotype, by analogy with lupus and the other interferonopathies; the intervening steps in SPENCD have not been mapped. The therapeutic response to JAK inhibition is the strongest evidence that the link is causal.

Interferon-Associated CNS Involvement Spasticity with intracranial calcification is the neurological signature shared with Aicardi-Goutieres syndrome and other type I interferonopathies, which is the basis for placing it downstream of interferon rather than of the skeletal arm. No mechanism has been established, and JAK inhibition has not clearly reversed the neurological features.

Show evidence (2 references)

PMID:21217755 SUPPORT Human Clinical

"All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature."

Establishes both the elevated interferon activity and the transcriptional signature in patients.

PMID:41049574 SUPPORT INDIRECT Human Clinical

"Type I IFN signalling is enhanced in the majority of patients tested, although whether this is a driver of pathology or simply represents a disease biomarker remains unclear."

Records that the causal status of the interferon signature is itself an open question, which is why downstream edges from this node are hedged.

Systemic Autoimmunity

At least one autoimmune diagnosis is recorded in the large majority of patients, and a third carry three or more. Immune thrombocytopenia, systemic lupus erythematosus, autoimmune haemolytic anaemia, and hypothyroidism are the commonest; antinuclear and anti-dsDNA antibodies are near-universal. The thrombocytopenia is characteristically treatment-refractory and has caused death and intracranial haemorrhage.

Animal models

Acp5-null mouse Mouse fails to recapitulate The defining extraskeletal feature of human SPENCD is absent in the null mouse, which is the central obstacle to studying the immune arm in vivo.

Downstream

Autoimmune Thrombocytopenia Immune thrombocytopenia is the commonest single autoimmune diagnosis and the one most often responsible for serious harm.

Systemic Lupus Erythematosus A third of patients meet ACR criteria for SLE, with near-universal antinuclear and frequent anti-dsDNA antibodies.

Autoimmune Hemolytic Anemia Coombs-positive haemolysis; co-occurring with the thrombocytopenia it yields a diagnosis of Evans syndrome.

Autoimmune Hypothyroidism Thyroid autoimmunity in around a fifth of patients.

Celiac Disease Coeliac disease is among the autoimmune diagnoses recorded in SPENCD cohorts and has been the presenting autoimmune feature in a reported case.

Sensorineural Hearing Loss Bilateral sensorineural hearing loss has been reported once, severe enough to require cochlear implantation. Autoimmune inner-ear disease is the proposed route, but the reporting authors could not establish whether the lesion is cochlear or central, and skeletal dysplasia itself independently raises the rate of hearing loss — so the edge is left with unknown intermediates.

Show evidence (3 references)

PMID:21217755 SUPPORT Human Clinical

"Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo."

Source for the breadth of the autoimmune spectrum described here.

PMID:41049574 SUPPORT Human Clinical

"at least one autoimmune diagnosis was recorded in 22 patients overall (85%), with 9 (34%) assigned 3 or more such diagnoses"

Quantifies the autoimmune burden in the best-characterised cohort.

PMID:42459138 SUPPORT Human Clinical

"Patients showed elevated inflammatory activity, with enrichment of the NF-κB, MAPK, and cell death pathways, as well as up-regulation of type I interferon (IFN) genes in monocytes."

The 2026 multicentre cohort adds transcriptomic confirmation of elevated inflammatory activity; the same sentence names NF-kappaB, MAPK, and cell-death pathway enrichment alongside the interferon signature.

Interferon-Associated CNS Involvement

Spasticity, sometimes evident in the first months of life, with calcification of the basal ganglia and other sites on computed tomography, and learning difficulty in a minority. Unlike Aicardi-Goutieres syndrome, significant cerebral white matter disease is unusual.

Downstream

Spasticity Spasticity is the commonest neurological sign and can be evident within the first months of life.

Intracranial Calcification Calcification of the basal ganglia and other sites, detectable in early infancy.

Global Developmental Delay Motor and cognitive delay accompanying the spasticity. Whether it follows from the calcification, the white-matter involvement, or interferon action on the developing brain more broadly is not established.

Learning Difficulty Learning difficulty occurs in a minority and its relationship to the calcification and spasticity is not established; marked global impairment and frank regression both occur.

Show evidence (2 references)

PMID:37010587 SUPPORT Human Clinical

"Such variable phenotypic presentations were masking the disease and led to the delay in diagnosis until exome sequencing was used revealing homozygous variants in the ACP5 gene as the cause of the patients' phenotype."

Documents the diagnostic delay caused by a neurology-dominant presentation.

PMID:41049574 SUPPORT Human Clinical

"observed spasticity in 11 patients (44%), and intracranial calcification on computed tomography imaging in 9 of 13 patients assessed, variably involving the basal ganglia, pons, cerebellar dentate nuclei, and white-grey matter junction"

Gives the frequency and anatomical distribution of the two neurological features.

Osteoclast and Growth-Plate Dysfunction

TRAP loss impairs osteoclast-mediated bone resorption and disorders the endochondral growth plate. In the Acp5-null mouse this produces mild osteopetrosis with disorganised growth plates and bones that are stronger, not weaker, than wild type — consistent with the absence of increased fracture risk in SPENCD.

osteoclast CL:0000092 chondrocyte CL:0000138

bone resorption GO:0045453 ↓ DECREASED endochondral ossification GO:0001958 ⚠ ABNORMAL

Animal models

Acp5-null mouse Mouse recapitulates Loss of Acp5 alone is sufficient to produce the growth-plate disorganisation and resorptive defect, establishing this node as a direct consequence of TRAP loss rather than of inflammation.

Downstream

Vertebral and Metaphyseal Dysplasia Failure of cartilage-to-bone transition at the growth plate produces the persisting islands of chondroid tissue and the vertebral flattening that named the disorder.

Show evidence (1 reference)

PMID:41049574 SUPPORT Model Organism

"Acp5-null mice are viable under laboratory conditions but suffer from developmental deformities of the limb and axial skeleton"

The null mouse establishes that loss of TRAP is sufficient for a skeletal dysplasia independent of any immune phenotype.

Vertebral and Metaphyseal Dysplasia

The radiographic core of the disorder: platyspondyly with irregular upper and lower vertebral end plates and posterior nodular lesions, together with radiolucent punched-out non-ossifying lesions running from the growth plate into the metaphysis and diaphysis, typically at the distal femur, proximal fibula, and distal radius and ulna.

Downstream

Platyspondyly The vertebral lesion of the dysplasia read on plain radiography as flattened bodies with irregular end plates.

Metaphyseal Enchondroma-like Lesions The metaphyseal lesion read as radiolucent punched-out non-ossifying areas running from the growth plate into the metaphysis and diaphysis.

Disproportionate Short Stature Combined spinal and long-bone dysplasia reduces stature, with the short-trunk or short-limb pattern depending on which compartment dominates.

Show evidence (1 reference)

PMID:41049574 SUPPORT Human Clinical

"The characteristic skeletal radiological features of SPENCD are (1) platyspondyly, with irregularity of both upper and lower end plates and nodular lesions particularly involving the posterior aspect of the vertebral bodies"

Defines the vertebral component of the radiographic phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Blood 2

Autoimmune Thrombocytopenia FREQUENT HP:0001973

Show evidence (2 references)

PMID:26951490 SUPPORT Human Clinical

"In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus."

Identifies autoimmune thrombocytopenia as one of the two most frequent autoimmune features.

PMID:41049574 SUPPORT Human Clinical

"In order of frequency, AITP, SLE, autoimmune hemolytic anemia (AIHA), and hypothyroidism were observed in 12 (46%), 9 (36%), 7 (27%), and 5 (19%) cases, respectively"

Gives the ranked frequencies of the four commonest autoimmune diagnoses, supporting this and the three phenotype records that follow.

Autoimmune Hemolytic Anemia OCCASIONAL HP:0001890

Show evidence (1 reference)

PMID:40786056 SUPPORT Human Clinical

"The clinical manifestations were autoimmune hemolytic anemia, immune thrombocytopenia, abnormal bone development, intracranial calcification, short stature, and growth retardation."

Documents Coombs-positive haemolytic anaemia in two molecularly confirmed patients.

Ear 1

Sensorineural Hearing Loss OCCASIONAL Sensorineural hearing impairment HP:0000407

Severity: SEVERE

Show evidence (2 references)

PMID:38219511 SUPPORT Human Clinical

"the patient underwent a bilateral cochlear implant for sensorineural hearing loss at the age of four, which went uneventfully"

Documents profound bilateral sensorineural loss managed by implantation in a patient with SPENCD.

PMID:38219511 SUPPORT INDIRECT Human Clinical

"Out of the wide spectrum of presentation in SPENCD, hearing loss is one of the least presented symptoms."

Establishes the rarity of the feature, which is why the frequency band is OCCASIONAL and the entry does not claim it as a core feature.

Endocrine 1

Autoimmune Hypothyroidism OCCASIONAL HP:0000821

Show evidence (2 references)

PMID:39853520 SUPPORT Human Clinical

"Common findings included autoimmune hemolytic anemia, hypothyroidism, and elevated transaminase levels."

Cohort evidence for hypothyroidism.

PMID:41049574 SUPPORT Human Clinical

"In order of frequency, AITP, SLE, autoimmune hemolytic anemia (AIHA), and hypothyroidism were observed in 12 (46%), 9 (36%), 7 (27%), and 5 (19%) cases, respectively"

Places hypothyroidism at 19 percent, the OCCASIONAL band.

Immune 1

Susceptibility to Infection OCCASIONAL Recurrent infections HP:0002719

Show evidence (3 references)

PMID:39853520 SUPPORT Human Clinical

"Recurrent bacterial and viral infections, including respiratory tract infections, were prevalent."

Cohort evidence for recurrent infection.

PMID:37010587 SUPPORT Human Clinical

"All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient)."

Documents the immunodeficiency underlying the infection susceptibility.

PMID:41049574 SUPPORT Human Clinical

"significant bacterial and viral infections were recorded in five patients (19%), including recurrent pneumonia, disseminated herpes zoster, skin, and dental abscesses"

Gives the frequency and the spectrum of infections.

Musculoskeletal 2

Platyspondyly VERY_FREQUENT HP:0000926

Show evidence (3 references)

PMID:41049574 SUPPORT Other

"In 1976, Schorr, Legum, and Oshchorn described two brothers with a skeletal dysplasia notable for the presence of flattened vertebrae (platyspondyly) and islands of chondroid tissue within bone (enchondroma), a combination leading them to coin the novel term spondyloenchondrodysplasia (SPENCD)"

The naming account, which records platyspondyly as one of the two defining radiographic findings.

PMID:41049574 SUPPORT Human Clinical

"The characteristic skeletal radiological features of SPENCD are (1) platyspondyly, with irregularity of both upper and lower end plates and nodular lesions particularly involving the posterior aspect of the vertebral bodies"

Names platyspondyly as a characteristic radiological feature.

PMID:40786056 SUPPORT Human Clinical

"X-Ray of spine showed platyspondyly and X-Ray of forearm and wrist showed metaphyseal dysplasia"

Documents platyspondyly on plain radiography in a molecularly confirmed patient.

Spasticity FREQUENT HP:0001257

Show evidence (2 references)

PMID:37010587 SUPPORT Human Clinical

"All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia."

Documents spasticity in all patients of the series.

PMID:41049574 SUPPORT Human Clinical

"observed spasticity in 11 patients (44%), and intracranial calcification on computed tomography imaging in 9 of 13 patients assessed"

Gives the 44 percent frequency behind the FREQUENT band.

Nervous System 2

Global Developmental Delay HP:0001263

Show evidence (1 reference)

PMID:37010587 SUPPORT Human Clinical

"Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures."

Names global developmental delay among the neurological features.

Learning Difficulty OCCASIONAL Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:41049574 SUPPORT Human Clinical

"also recorded learning difficulties in seven patients (28%)"

The 28 percent frequency places this in the OCCASIONAL band.

Growth 1

Disproportionate Short Stature FREQUENT HP:0004322

Show evidence (2 references)

PMID:39853520 SUPPORT Human Clinical

"All patients exhibited short stature and skeletal abnormalities."

Cohort frequency for short stature.

PMID:41049574 SUPPORT Human Clinical

"skeletal disease, manifest as short stature and/or leg pain/bowing, was the reason for initial presentation in 12 patients (46%), with height varying between the normal range to 6.5 SD below the mean"

Supports the FREQUENT rather than VERY_FREQUENT band, since height can be normal.

Other 4

Metaphyseal Enchondroma-like Lesions VERY_FREQUENT Metaphyseal enchondromatosis HP:0005868

Show evidence (1 reference)

PMID:21217755 SUPPORT Human Clinical

"Radiological investigations in our patients revealed the characteristic metaphyseal and vertebral bone lesions described in SPENCD."

Confirms the metaphyseal lesions in the founding molecularly defined cohort.

Intracranial Calcification VERY_FREQUENT Basal ganglia calcification HP:0002135

Show evidence (2 references)

PMID:37010587 SUPPORT Human Clinical

"All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia."

Documents basal ganglia calcification in nearly all patients of the series.

PMID:41049574 SUPPORT Human Clinical

"intracranial calcification on computed tomography imaging in 9 of 13 patients assessed, variably involving the basal ganglia, pons, cerebellar dentate nuclei, and white-grey matter junction"

Nine of thirteen assessed patients supports the VERY_FREQUENT band among those imaged.

Systemic Lupus Erythematosus FREQUENT HP:0002725

Show evidence (3 references)

PMID:21217755 SUPPORT Human Clinical

"Four patients fulfilled American College of Rheumatology classification criteria for a diagnosis of SLE4. These included elevated anti-nuclear antibodies, anti-dsDNA antibodies, thrombocytopenia, and nephritis or non-erosive arthritis."

Documents formally classified SLE and its serological and organ features in the discovery cohort.

PMID:41049574 SUPPORT Human Clinical

"21 of the 22 (95%) patients tested in the cohort were positive for the presence of antinuclear antibodies, and 15 of 21 (71%) were anti-dsDNA antibody positive"

Serological data supporting the lupus phenotype across nearly the whole cohort.

PMID:21217755 SUPPORT Human Clinical

"These included elevated anti-nuclear antibodies, anti-dsDNA antibodies, thrombocytopenia, and nephritis or non-erosive arthritis."

Lists the ACR criteria met by the patients diagnosed with SLE in the founding cohort.

Celiac Disease OCCASIONAL HP:0002608

Show evidence (1 reference)

PMID:38883133 SUPPORT Human Clinical

"He was previously diagnosed with spastic diplegia, short stature, and celiac disease."

Documents coeliac disease in a molecularly confirmed patient, alongside the spasticity and short stature.

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Genetic Associations

1

Biallelic ACP5 Loss-of-Function Variants (Causative)

Gene: ACP5 hgnc:124 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:39853520 SUPPORT Human Clinical

"The NM_001611.5 (ACP5): c.772_790del p.(Ser258TrpfsTer39) frameshift variant was identified in all patients."

Source for the shared frameshift allele noted here.

PMID:41049574 SUPPORT Human Clinical

"We list 45 distinct mutations (28 missense substitutions; 8 STOP and 7 frameshift mutations; 2 large deletions) distributed throughout the gene"

Gives the allelic spectrum and its distribution across the gene.

PMID:41049574 SUPPORT In Vitro

"showing that while expressed, all mutants lacked enzymatic activity"

Recombinant characterisation of the eight founding missense substitutions shows they are catalytically null, which is why missense and truncating alleles converge on one phenotype.

+ 2 more references

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Medical Actions

4

JAK Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: ruxolitinib CHEBI:66919 tofacitinib CHEBI:71200 baricitinib CHEBI:95341

Oral JAK1/2 or JAK1/3 inhibitors — ruxolitinib, baricitinib, tofacitinib — block signalling downstream of the type I interferon receptor. In reported cases they have controlled autoimmune cytopenias refractory to glucocorticoids, sirolimus, rituximab, and mycophenolate, allowing steroid tapering. The evidence is case reports only; no trial exists, optimal dosing is undefined, and the effect on the skeletal and neurological arms is unknown.

Mechanism Target:

INHIBITS Type I Interferon Overproduction — JAK1/2 inhibition blocks IFNAR-proximal JAK-STAT signalling, so it acts on the consequences of excess interferon rather than on its production. The clinical benefit in autoimmune features is the main human evidence that this node is causal rather than a bystander biomarker.

Show evidence (1 reference)

PMID:41049574 SUPPORT INDIRECT Human Clinical

"The apparent efficacy of JAK1/2 /JAK1/3 inhibition in affected patients (Table S3), particularly relating to features of systemic autoimmunity"

Efficacy against systemic autoimmunity but not clearly against neurological involvement is why the supporting evidence is graded INDIRECT.

Show evidence (5 references)

PMID:41049574 SUPPORT Other

"Table S3 shows the data provided on patients recorded in Table S1 treated using JAK inhibition."

Establishes that a cohort of SPENCD patients has been treated with JAK inhibition and tabulated, which is the evidence base for this treatment.

PMID:40786056 SUPPORT Human Clinical

"On 16 August 2024, oral ruxolitinib (5 mg daily) combined with prednisone (7.5 mg daily) was started. Coombs test successfully turned negative after 1 month of treatment adjustment."

A documented remission of refractory Coombs-positive haemolysis on ruxolitinib after failure of prednisone and sirolimus.

PMID:40786056 SUPPORT Human Clinical

"was switched to oral Tofacitinib (5 mg twice daily) in April 2023, with regular follow-ups. Currently, her hemoglobin and platelet levels remain within the normal range."

Sustained haematological remission on tofacitinib in the second reported case.

+ 2 more references

Glucocorticoid and Conventional Immunosuppressive Therapy

Action: immunosuppressive therapy Ontology label: Immunosuppressive Therapy NCIT:C15261

Agent: prednisone CHEBI:8382

Glucocorticoids, intravenous immunoglobulin, rituximab, mycophenolate mofetil, and sirolimus are the conventional first-line treatments for the autoimmune cytopenias. Responses are frequently incomplete or transient — the thrombocytopenia of SPENCD is characteristically refractory — and prolonged corticosteroid exposure is itself a problem in a child with a skeletal dysplasia and short stature.

Show evidence (3 references)

PMID:26951490 SUPPORT Human Clinical

"the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia"

A single-patient observation, hedged by its authors, which is why this mechanism link is recorded as partially supported.

PMID:26951490 SUPPORT Human Clinical

"Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy."

Documents autoimmune disease controlled on immunosuppression in a molecularly confirmed patient.

PMID:40786056 SUPPORT INDIRECT Human Clinical

"Considering the long history of oral glucocorticoid treatment and the poor control effect of AIHA, oral sirolimus was added on 17 April 2023, but Coombs test did not recover to negative."

Documents the incomplete response to conventional immunosuppression that motivates escalation to JAK inhibition.

Supportive Skeletal and Developmental Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

No therapy modifies the skeletal dysplasia. Management is orthopaedic and developmental, directed at limb pain and bowing, stature, and learning support. The response of skeletal dysplasias to growth hormone is contested and no SPENCD-specific data exist.

Show evidence (2 references)

PMID:37010587 SUPPORT Human Clinical

"One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from -3.0 SD before GH therapy to -2.35 SD at presentation."

The single reported treated patient, in whom growth hormone deficiency was a comorbidity rather than a feature of the dysplasia.

PMID:40786056 SUPPORT INDIRECT Human Clinical

"The response to growth hormone therapy in patients with skeletal dysplasia remains contentious"

Supports recording growth hormone as unresolved rather than as a recommended intervention.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance carries a 25 percent recurrence risk, and reported families are heavily enriched for consanguinity, so counselling and — once the familial alleles are known — prenatal or preimplantation testing are central to family management.

Show evidence (1 reference)

PMID:21217752 SUPPORT Human Clinical

"We mapped a locus in five consanguineous families to chromosome 19p13"

Establishes the consanguineous, recessive family structure that makes recurrence-risk counselling the relevant action.

🔬

Biochemical Markers

2

Plasma tartrate-resistant acid phosphatase (Absent or negligible)

Context: Total TRAP protein is negligible and the TRAP 5a isoform undetectable in affected individuals, including those homozygous for missense alleles. The assay is therefore a direct functional readout of the genetic lesion.

Show evidence (1 reference)

PMID:21217755 SUPPORT Human Clinical

"levels of total TRAP protein were negligible, and TRAP 5a protein undetectable, indicating an almost complete lack of TRAP synthesis or secretion in the affected patients tested"

Direct measurement of the biochemical defect.

Interferon-stimulated gene expression score (Elevated)

Context: Whole-blood ISG expression is raised in most patients and is the practical biomarker of the interferonopathy. It is not universal, and immunosuppression appears able to normalise it.

Show evidence (1 reference)

PMID:26951490 SUPPORT Human Clinical

"In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP)."

Establishes the ISG score as elevated in most molecularly confirmed patients.

🔬

Diagnosis

3

Radiographic Recognition of the SPENCD Skeletal Pattern

Plain radiography of the spine and long bones showing platyspondyly with irregular end plates together with radiolucent metaphyseal lesions is the finding that raises the diagnosis and directs ACP5 testing. The radiographic features markedly increase the likelihood of finding biallelic ACP5 variants even when subtle, but some patients have minimal or no skeletal manifestations in early childhood, so normal radiographs do not exclude the diagnosis in a child presenting with autoimmunity.

X-ray imaging NCIT:C38101

Results: Platyspondyly with enchondroma-like radiolucent metaphyseal and vertebral lesions.

Show evidence (3 references)

PMID:37010587 SUPPORT Human Clinical

"SPENCD can be differentiated from other spondylometaphyseal dysplasias by the presence of bone enchondromas which are radiographic radiolucent spondylar and metaphyseal lesions caused by persistence of chondroid tissue within the ossified bones"

Establishes the radiographic discriminator on which diagnosis is raised.

PMID:41049574 SUPPORT Human Clinical

"while the presence of characteristic radiological features (even if subtle) significantly increases the likelihood of finding biallelic mutations in ACP5, some patients have minimal"

States both the diagnostic value of the radiographs and the limit on their sensitivity.

PMID:38883133 SUPPORT Human Clinical

"Our patient did not have skeletal dysplasia, despite having ACP gene mutations, suggesting that there is a wide range of phenotypic severity in spondyloenchondrodysplasia"

A molecularly confirmed patient reported specifically as lacking a skeletal dysplasia, which is the clearest statement that normal radiographs do not exclude the diagnosis.

ACP5 Sequencing

Biallelic ACP5 variants confirm the diagnosis. Because the disease appears genetically homogeneous, a classical phenotype without an ACP5 result should prompt review for a deletion allele rather than a search for a second locus.

genetic testing NCIT:C15709

Results: Biallelic ACP5 loss-of-function variants.

Show evidence (2 references)

PMID:37010587 SUPPORT Human Clinical

"Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg)."

Documents exome sequencing as the diagnostic route in a recent series.

PMID:41049574 SUPPORT Human Clinical

"We are unaware of any patients conforming to the classical SPENCD phenotype being negative for mutations in ACP5, suggesting that the disease is genetically homogeneous."

Genetic homogeneity is what makes single-gene testing the definitive confirmatory step.

Serum TRAP Activity and Type I Interferon Signature

Total and isoform 5b TRAP activity are undetectable in patient serum and leukocyte homogenates and roughly halved in heterozygous parents, providing a functional confirmation of a variant of uncertain significance. Serum interferon-alpha activity and a whole-blood interferon-stimulated gene score are elevated in most patients, but are neither specific to SPENCD nor invariably present, and can be suppressed by immunosuppressive treatment.

molecular diagnostic method NCIT:C18194

Results: Absent or negligible plasma TRAP, with upregulated interferon-stimulated gene expression in most patients.

Show evidence (1 reference)

PMID:21217755 SUPPORT Human Clinical

"All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature."

Establishes the interferon assays as consistently abnormal in molecularly confirmed patients.

📊

Prevalence

1

Worldwide

Cases In Literature 0.0 per 100,000 Ultra Rare

A 2025 review counted 90 molecularly proven cases across 27 published reports, four decades after the first clinical description in 1976. Reported families are heavily enriched for consanguinity. No population-based incidence or prevalence figure exists, and the review is explicit that its case-collection approach cannot yield one; rate_per_100000 is recorded as 0.0 only to mark that the true rate is far below the resolution of any published survey.

Show evidence (4 references)

PMID:26951490 SUPPORT Human Clinical

"We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations."

The size of the largest reported cohort, standing in for a population estimate that does not exist.

PMID:41049574 SUPPORT Human Clinical

"a review of the 90 molecularly proven cases of SPENCD that we have been able to identify in the literature"

Establishes the cases-in-literature scale of the disorder at roughly 90 molecularly confirmed individuals worldwide.

PMID:41049574 SUPPORT INDIRECT Human Clinical

"In the absence of a comprehensive prospective survey of affected patients within a defined geographical region, such an approach carries a risk of ascertainment bias and imperfect definition of both the frequency of individual disease features and the full spectrum of the clinical phenotype, as..."

The review states directly that no accurate incidence or prevalence figure can be derived, which is why this record is a case count rather than a rate.

+ 1 more reference

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Spondyloenchondrodysplasia:

Aicardi-Goutieres Syndrome

Overlapping Features Shares spasticity, intracranial calcification, and a type I interferon signature, and was the differential that prompted interferon assays in SPENCD. Significant cerebral white matter disease is usual in Aicardi-Goutieres and unusual in SPENCD, and the SPENCD skeletal dysplasia and the frank organ-specific autoimmunity are not features of Aicardi-Goutieres.

Show evidence (1 reference)

PMID:41049574 SUPPORT Human Clinical

"In contrast to Aicardi–Goutières syndrome (AGS), significant cerebral white matter disease is apparently unusual."

Names the neuroimaging feature that separates the two disorders.

Childhood-Onset Systemic Lupus Erythematosus

Overlapping Features SPENCD is one of the monogenic causes of lupus, and a third of patients meet ACR criteria. Very early onset, refractory cytopenias, intracranial calcification, short stature, or any vertebral or metaphyseal radiographic abnormality should prompt ACP5 testing rather than a diagnosis of idiopathic childhood lupus.

Show evidence (2 references)

PMID:41049574 SUPPORT Other

"Lausch and colleagues (9) made a molecular diagnosis of SPENCD in a 63-year-old male first reported in 1958 as a 10-year-old child with a skeletal dysplasia and systemic lupus erythematosus (SLE) (11)."

A concrete instance of the diagnostic confusion this differential describes.

PMID:21217755 SUPPORT Human Clinical

"TRAP deficiency now represents a third monogenic disorder associated with the development of lupus also showing an up-regulation of type I interferon activity"

Places SPENCD explicitly among the monogenic lupus disorders, which is why it belongs in this differential.

Other Spondylometaphyseal Dysplasias

Overlapping Features Within ISDS group 12, odontochondrodysplasia (TRIP11), SMD Sutcliffe or corner fracture type (FN1), SMD with cone-rod dystrophy (PCYT1A), SMD with corneal dystrophy (PLCB3), and chondrodysplasia-pseudohermaphroditism syndrome (HHAT) share the combined vertebral and metaphyseal radiographic pattern. None of them produces intracranial calcification with systemic autoimmunity, so the extraskeletal triad resolves the differential in practice.

🐁

Animal Models

1

Acp5-null mouse

The Acp5 knockout mouse, reported in 1996, is viable and reproduces the skeletal arm of SPENCD — disorganised growth plates and mild osteopetrosis from an osteoclast resorptive defect — while developing neither overt autoimmunity nor neurological disease. Its bones are stronger than wild type, matching the absence of increased fracture risk in patients.

Species

Mouse

Genotype

Acp5 knockout (homozygous null)

Publication

PMID:8898228

Pathograph links

Osteoclast and Growth-Plate Dysfunction recapitulates fidelity: high Loss of Acp5 alone is sufficient to produce the growth-plate disorganisation and resorptive defect, establishing this node as a direct consequence of TRAP loss rather than of inflammation.

Limitations: The mouse skeletal phenotype is described as mild osteopetrosis with limb and axial deformity; the enchondroma-like metaphyseal lucencies and platyspondyly of the human disorder are not asserted to be reproduced lesion for lesion.

Show evidence (3 references)

PMID:41049574 SUPPORT Model Organism

"Reminiscent of the skeletal features seen in patients with SPENCD, these defects include disorganized growth plates indicative of a role for TRAP in endochondral ossification, and mild osteopetrosis due to a resorptive defect of osteoclasts resulting in defective bone remodelling."

States both that the mouse skeletal phenotype resembles the human one and what the underlying cellular defects are.

+ 2 more references

Systemic Autoimmunity fails to recapitulate fidelity: low The defining extraskeletal feature of human SPENCD is absent in the null mouse, which is the central obstacle to studying the immune arm in vivo.

Limitations: Acp5-null mice show altered macrophage cytokine profiles, impaired bacterial clearance, and impaired Th1 responses, but no overt autoimmune disease and no neurological involvement. Any inference about the human autoimmune mechanism from this model is therefore indirect.

Show evidence (2 references)

PMID:41049574 REFUTE Model Organism

"Acp5-null mice have not been described to manifest overt autoimmunity, which is such a prominent feature of ACP5-related disease in humans."

Explicit negative result: the model does not reproduce the human autoimmune phenotype, which is what FAILS_TO_RECAPITULATE records.

+ 1 more reference

{ }

Source YAML

click to show

name: Spondyloenchondrodysplasia
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Spondyloenchondrodysplasia with immune dysregulation (SPENCD/SPENCDI; OMIM
  #607944) is an ultra-rare autosomal recessive immuno-osseous dysplasia caused
  by biallelic loss-of-function variants in ACP5, which encodes tartrate-resistant
  acid phosphatase (TRAP), a lysosomal metallophosphoesterase of the mononuclear
  phagocyte lineage and of osteoclasts. Three organ systems are involved in
  varying combination: a skeletal dysplasia with platyspondyly and radiolucent
  enchondroma-like metaphyseal lesions; neurological disease with spasticity,
  intracranial calcification, and learning difficulty; and a striking
  predisposition to systemic autoimmunity — immune thrombocytopenia, systemic
  lupus erythematosus, autoimmune haemolytic anaemia, and hypothyroidism being
  the commonest diagnoses. Loss of TRAP phosphatase activity leaves osteopontin
  hyperphosphorylated, which is the proposed route to persistent TLR9 signalling
  in plasmacytoid dendritic cells and the elevated type I interferon activity that
  places SPENCD among the type I interferonopathies. The skeletal arm is
  separately explained by the osteoclast and growth-plate roles of TRAP, which the
  Acp5-null mouse reproduces without any autoimmune phenotype. That split — a
  mouse that models the bone but not the immunity — is the central unresolved
  question of the disorder.
disease_term:
  preferred_term: spondyloenchondrodysplasia with immune dysregulation
  term:
    id: MONDO:0011939
    label: Spondyloenchondrodysplasia with immune dysregulation
synonyms:
- SPENCD
- SPENCDI
- Spondyloenchondrodysplasia
- Spondyloenchondromatosis
- Roifman-Melamed syndrome
- Immuno-osseous dysplasia with spondyloenchondrodysplasia
- TRAP deficiency
- ACP5-related spondyloenchondrodysplasia
parents:
- hereditary disease
classifications:
  isds_skeletal_category:
  - classification_value: spondylometaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), Table 1 group 12 "Spondylometaphyseal dysplasias (SMD)",
      entry NOS 12-0010, listed as "Spondyloenchondrodysplasia with immune
      dysregulation (SPENCD), ACP5-related" (AR, ACP5, MIM 607944). Group 12 is
      the combined vertebral-plus-metaphyseal group; SPENCD earns its place on
      the platyspondyly and metaphyseal lesions, not on the autoimmunity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  rate_per_100000: 0.0
  notes: >-
    A 2025 review counted 90 molecularly proven cases across 27 published
    reports, four decades after the first clinical description in 1976. Reported
    families are heavily enriched for consanguinity. No population-based
    incidence or prevalence figure exists, and the review is explicit that its
    case-collection approach cannot yield one; rate_per_100000 is recorded as 0.0
    only to mark that the true rate is far below the resolution of any published
    survey.
  evidence:
  - reference: PMID:26951490
    reference_title: >-
      Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations.
    explanation: >-
      The size of the largest reported cohort, standing in for a population estimate that does
      not exist.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a review of the 90 molecularly proven cases of SPENCD that we have been able
      to identify in the literature
    explanation: >-
      Establishes the cases-in-literature scale of the disorder at roughly 90
      molecularly confirmed individuals worldwide.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the absence of a comprehensive prospective survey of affected patients
      within a defined geographical region, such an approach carries a risk of
      ascertainment bias and imperfect definition of both the frequency of
      individual disease features and the full spectrum of the clinical phenotype,
      as well as precluding the derivation of accurate figures on incidence and
      prevalence.
    explanation: >-
      The review states directly that no accurate incidence or prevalence figure
      can be derived, which is why this record is a case count rather than a rate.
  - reference: PMID:42459138
    reference_title: A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 17 patients with ACP5 deficiency from Egypt and China,
      discovering five novel pathogenic variants
    explanation: >-
      A 2026 multicentre cohort adds 17 further molecularly confirmed patients on top
      of the 90 tallied in the 2025 review, so the published caseload is now over a
      hundred and still rising.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    SPENCD segregates as an autosomal recessive trait. Affected individuals carry
    homozygous or compound heterozygous ACP5 alleles; heterozygous parents are
    clinically unaffected and retain roughly half-normal serum TRAP activity.
    Reported cohorts are markedly enriched for parental consanguinity, consistent
    with the low population frequency of pathogenic ACP5 alleles.
  evidence:
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations segregated with the disease in the families investigated, and
      all parents tested were heterozygous for a relevant familial mutation.
    explanation: >-
      Biallelic segregation with unaffected heterozygous parents establishes
      autosomal recessive inheritance.
  - reference: PMID:21217752
    reference_title: "Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped a locus in five consanguineous families to chromosome 19p13 and
      identified mutations in ACP5, which encodes tartrate-resistant phosphatase
      (TRAP), in 14 affected individuals
    explanation: >-
      Homozygosity mapping in consanguineous pedigrees is the recessive-model
      design that localised and identified the gene.
genetic:
- name: Biallelic ACP5 Loss-of-Function Variants
  gene_term:
    preferred_term: ACP5
    term:
      id: hgnc:124
      label: ACP5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    ACP5 (NM_001611.5) lies at 19p13.2 and comprises five exons encoding the
    325-amino-acid TRAP protein. Reported pathogenic alleles span missense,
    nonsense, frameshift, and whole-gene deletion classes and are distributed
    throughout the gene, with no genotype-phenotype correlation recognised. The
    missense alleles behave as functional nulls: expressed but catalytically dead,
    not proteolytically processed to the 5b isoform, and in most cases not
    secreted.
  evidence:
  - reference: PMID:39853520
    reference_title: >-
      Clinical, laboratory, and molecular characteristics of patients with
      spondyloenchondrodysplasia: a case series study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The NM_001611.5 (ACP5): c.772_790del p.(Ser258TrpfsTer39) frameshift variant was identified in all patients.
    explanation: >-
      Source for the shared frameshift allele noted here.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We list 45 distinct mutations (28 missense substitutions; 8 STOP and 7
      frameshift mutations; 2 large deletions) distributed throughout the gene
    explanation: Gives the allelic spectrum and its distribution across the gene.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      showing that while expressed, all mutants lacked enzymatic activity
    explanation: >-
      Recombinant characterisation of the eight founding missense substitutions
      shows they are catalytically null, which is why missense and truncating
      alleles converge on one phenotype.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We are unaware of any patients conforming to the classical SPENCD phenotype
      being negative for mutations in ACP5, suggesting that the disease is
      genetically homogeneous.
    explanation: >-
      Supports treating SPENCD as a single-gene disorder rather than a
      locus-heterogeneous radiographic category.
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified
      biallelic mutations in each of the cases studied, and in vivo testing
      confirmed a loss of expressed protein.
    explanation: >-
      The founding report establishes both the gene and that the mechanism is loss
      of expressed protein.
mechanistic_hypotheses:
- hypothesis_group_id: opn_tlr9_pdc
  hypothesis_label: Osteopontin-TLR9 Model of Interferon Activation
  status: EMERGING
  description: >-
    The leading account of how a lysosomal phosphatase deficiency becomes an
    interferonopathy. TRAP dephosphorylates osteopontin; in its absence,
    phosphorylated osteopontin persists in plasmacytoid dendritic cells and
    sustains TLR9 signalling, driving type I interferon production. The model
    originates in mouse work and is put forward as a suggestion rather than an
    established pathway - the 2025 review's own framing is that the
    immunopathology of SPENCD remains unclear despite decades of TRAP research.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subsequently, based on earlier work in mouse (12), it was suggested that the immunological features of SPENCD might relate to a failure of mutant TRAP to dephosphorylate osteopontin (OPN) in plasmacytoid dendritic cells (pDCs), leading to persistent Toll-like receptor 9 (TLR9) signalling (13).
    explanation: >-
      States the model and, in its hedged wording, its status as a proposal
      rather than a demonstrated mechanism.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the immunopathology of SPENCD remains unclear
    explanation: >-
      The review's explicit statement that the mechanism is unresolved, which is
      why this is recorded as an emerging hypothesis and not as settled
      pathophysiology.
pathophysiology:
- name: Biallelic ACP5 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous ACP5 alleles — missense, nonsense,
    frameshift, or whole-gene deletion — remove functional tartrate-resistant acid
    phosphatase. Missense alleles are not partial: they are expressed but
    catalytically inactive, so the initiating lesion is the same across the
    allelic spectrum.
  genes:
  - preferred_term: ACP5
    term:
      id: hgnc:124
      label: ACP5
  evidence:
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observation of biallelic null mutations in four of eight families
      indicated that the SPENCD phenotype results from a loss of TRAP activity.
    explanation: >-
      Null alleles in half the founding families identify loss of TRAP activity,
      not a neomorphic effect, as the initiating lesion.
  downstream:
  - target: Loss of Tartrate-Resistant Acid Phosphatase Activity
    causal_link_type: DIRECT
    description: >-
      Absent or catalytically dead TRAP protein abolishes the enzyme's acid
      phosphatase activity in serum and in the cells that normally express it.
    evidence:
    - reference: PMID:21217752
      reference_title: "Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        showed that these mutations abolish enzyme function in the serum and cells
        of affected individuals
      explanation: >-
        Direct enzymatic measurement in patient material links the genotype to
        abolished activity.
- name: Loss of Tartrate-Resistant Acid Phosphatase Activity
  biological_scale: MOLECULAR
  description: >-
    TRAP is a di-iron purple acid phosphatase with a low pH optimum, expressed by
    osteoclasts, macrophages, and dendritic cells. Its activity is undetectable in
    patient serum and leukocyte homogenates and roughly halved in heterozygous
    parents. This node is the point at which the skeletal and immune arms of the
    disorder diverge.
  molecular_functions:
  - preferred_term: acid phosphatase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003993
      label: acid phosphatase activity
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:41049574
    reference_title: >-
      Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Type-5 acid phosphatase, also known as tartrate-resistant acid phosphatase (TRAP), is a lysosomal hydrolase expressed in cells of monocytic lineage, with activity against a wide variety of substrates
    explanation: >-
      Establishes the enzyme's cellular distribution, which is what makes a bone enzyme
      deficiency an immune disease.
  - reference: PMID:21217755
    reference_title: >-
      Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity
      and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to five age-matched controls, and an unaffected sibling to patients 2 and 3 who was homozygous for the wild-type allele on gene sequencing, levels of total TRAP protein were negligible, and TRAP 5a protein undetectable, indicating an almost complete lack of TRAP synthesis or secretion in the affected patients tested
    explanation: >-
      Direct patient measurement establishing that the disease state is absence of TRAP protein.
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      levels of total TRAP protein were negligible, and TRAP 5a protein
      undetectable, indicating an almost complete lack of TRAP synthesis or
      secretion in the affected patients tested
    explanation: >-
      Protein-level measurement in patient plasma confirms near-complete absence of
      the enzyme.
  downstream:
  - target: Osteopontin Hyperphosphorylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - opn_tlr9_pdc
    description: >-
      Osteopontin is the best-characterised TRAP substrate; without TRAP its
      phosphoserines are not removed and phosphorylated osteopontin accumulates in
      patient fluids and cells.
    evidence:
    - reference: PMID:21217752
      reference_title: "Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Phosphorylated osteopontin, a protein involved in bone reabsorption and in
        immune regulation, accumulates in serum, urine and cells cultured from
        TRAP-deficient individuals.
      explanation: >-
        Demonstrates substrate accumulation in patient material, establishing the
        edge in humans rather than only in model systems.
  - target: Susceptibility to Infection
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      TRAP is expressed by macrophages and dendritic cells, and Acp5-null macrophages
      show an altered cytokine profile and reduced bacterial clearance. Infection
      susceptibility in patients is therefore plausibly intrinsic rather than purely
      a consequence of immunosuppressive treatment, though the two are hard to
      separate clinically.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TRAP-deficient macrophages from Acp5-null mice demonstrate an altered cytokine
        profile and a decreased ability to clear bacteria after infection
      explanation: >-
        Model-organism evidence for an intrinsic innate-immune defect downstream of
        TRAP loss, which is the proposed basis of the clinical infection
        susceptibility.
  - target: Osteoclast and Growth-Plate Dysfunction
    causal_link_type: DIRECT
    description: >-
      TRAP is an osteoclast enzyme; its loss impairs bone resorption and disorders
      the growth plate, the arm of the disorder the Acp5-null mouse reproduces.
    evidence:
    - reference: PMID:41049574
      reference_title: >-
        Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        TRAP was identified in human serum and cells >70 years ago, becoming recognized as an important, albeit nonspecific, marker of both bone disease and macrophage activation
      explanation: >-
        Establishes TRAP's standing as a bone-turnover enzyme, the basis for linking its loss to
        the skeletal lesion.
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        these defects include disorganized growth plates indicative of a role for
        TRAP in endochondral ossification, and mild osteopetrosis due to a
        resorptive defect of osteoclasts resulting in defective bone remodelling
      explanation: >-
        The Acp5-null mouse places both the resorptive defect and the growth-plate
        disorganisation immediately downstream of lost TRAP activity.
- name: Osteopontin Hyperphosphorylation
  biological_scale: MOLECULAR
  description: >-
    Osteopontin accumulates in its hyperphosphorylated form. Dephosphorylation of
    osteopontin by TRAP is required for osteoclast migration, and intracellular
    phosphorylated osteopontin has been proposed to couple the TLR9/MyD88
    signalosome to interferon-alpha expression in plasmacytoid dendritic cells.
  biological_processes:
  - preferred_term: protein dephosphorylation
    modifier: DECREASED
    term:
      id: GO:0006470
      label: protein dephosphorylation
  evidence:
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These mutations result in the loss of regulation of TRAP activity on the
      function of osteopontin (OPN), leading to an excess of phosphorylated OPN.
    explanation: >-
      States the substrate-accumulation step as the accepted proximate consequence
      of TRAP loss.
  downstream:
  - target: Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - opn_tlr9_pdc
    description: >-
      The proposed but not formally established link between the substrate defect
      and the interferon phenotype. Whether osteopontin is a physical component of
      the TLR9/MyD88 complex in human plasmacytoid dendritic cells, or whether TRAP
      acts on a different substrate entirely, is unresolved.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        suggested that the autoimmune features of SPENCD might relate to a failure
        of mutant TRAP to dephosphorylate OPN in pDCs in humans, leading to
        persistent TLR9 signalling
      explanation: >-
        The review presents this as a suggestion rather than a demonstrated
        mechanism, which is why the edge is graded INDIRECT with unknown
        intermediates.
- name: Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells
  biological_scale: CELLULAR
  description: >-
    Knockdown of TRAP in a plasmacytoid dendritic cell line raises
    interferon-alpha protein, interferon-stimulated gene expression, and IRF7
    nuclear translocation on CpG-A stimulation, the in vitro correlate of
    unrestrained TLR9 signalling.
  cell_types:
  - preferred_term: plasmacytoid dendritic cell
    term:
      id: CL:0000784
      label: plasmacytoid dendritic cell
  biological_processes:
  - preferred_term: toll-like receptor 9 signaling pathway
    modifier: INCREASED
    term:
      id: GO:0034162
      label: toll-like receptor 9 signaling pathway
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CpG-A stimulation in a pDC line with stable knockdown of TRAP resulted in
      increased expression of IFN
    explanation: >-
      A TRAP-knockdown plasmacytoid dendritic cell line responds to TLR9 ligand
      with excess interferon, the cell-level basis for this node.
  downstream:
  - target: Type I Interferon Overproduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - opn_tlr9_pdc
    description: >-
      Unrestrained TLR9-driven IRF7 activation in plasmacytoid dendritic cells is
      the proposed cellular source of the systemic interferon signature.
    evidence:
    - reference: PMID:21217755
      reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We did not find evidence of a circulating inducer of interferon activity in
        patient sera (Supplementary Table 4), possibly suggesting an up-regulation
        of type I interferon via a cell-intrinsic mechanism.
      explanation: >-
        The absence of a circulating inducer argues for a cell-intrinsic source,
        consistent with but not proof of the plasmacytoid dendritic cell origin.
- name: Type I Interferon Overproduction
  biological_scale: ORGANISM
  description: >-
    Serum interferon-alpha activity is elevated and whole blood carries an
    interferon-stimulated gene signature in the great majority of patients tested,
    persisting across repeat measurements. This is the finding that classified
    SPENCD as a type I interferonopathy. Whether it drives the pathology or is a
    biomarker of it is not settled.
  biological_processes:
  - preferred_term: type I interferon production
    modifier: INCREASED
    term:
      id: GO:0032606
      label: type I interferon production
  - preferred_term: type I interferon-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  evidence:
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight cases assayed showed elevated serum interferon alpha activity, and
      gene expression profiling in whole blood defined a type I interferon
      signature.
    explanation: >-
      Establishes both the elevated interferon activity and the transcriptional
      signature in patients.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Type I IFN signalling is enhanced in the majority of patients tested,
      although whether this is a driver of pathology or simply represents a disease
      biomarker remains unclear.
    explanation: >-
      Records that the causal status of the interferon signature is itself an open
      question, which is why downstream edges from this node are hedged.
  downstream:
  - target: Systemic Autoimmunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sustained type I interferon exposure is the proposed route to the autoimmune
      phenotype, by analogy with lupus and the other interferonopathies; the
      intervening steps in SPENCD have not been mapped. The therapeutic response to
      JAK inhibition is the strongest evidence that the link is causal.
    evidence:
    - reference: PMID:21217755
      reference_title: >-
        Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity
        and a type I interferon expression signature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.
      explanation: >-
        The discovery paper's own statement of the interferon-to-autoimmunity link.
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The apparent efficacy of JAK1/2 /JAK1/3 inhibition in affected patients
        (Table S3), particularly relating to features of systemic autoimmunity
      explanation: >-
        Blocking signalling downstream of the interferon receptor improves the
        autoimmune features, which supports but does not prove the causal edge.
  - target: Interferon-Associated CNS Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Spasticity with intracranial calcification is the neurological signature
      shared with Aicardi-Goutieres syndrome and other type I interferonopathies,
      which is the basis for placing it downstream of interferon rather than of the
      skeletal arm. No mechanism has been established, and JAK inhibition has not
      clearly reversed the neurological features.
    evidence:
    - reference: PMID:39853520
      reference_title: >-
        Clinical, laboratory, and molecular characteristics of patients with
        spondyloenchondrodysplasia: a case series study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        SPENCD exhibits similarities with other type I interferonopathies, including increased levels of type I interferon and specific neurological symptoms
      explanation: >-
        Links the neurological phenotype to the shared interferonopathy mechanism.
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        with the spasticity and intracranial calcification seen in SPENCD typical
        of a subset of type I interferonopathies
      explanation: >-
        Places the neurological features in the interferonopathy pattern, which is
        a phenotypic analogy rather than a demonstrated mechanism.
- name: Systemic Autoimmunity
  biological_scale: ORGANISM
  description: >-
    At least one autoimmune diagnosis is recorded in the large majority of
    patients, and a third carry three or more. Immune thrombocytopenia, systemic
    lupus erythematosus, autoimmune haemolytic anaemia, and hypothyroidism are the
    commonest; antinuclear and anti-dsDNA antibodies are near-universal. The
    thrombocytopenia is characteristically treatment-refractory and has caused
    death and intracranial haemorrhage.
  evidence:
  - reference: PMID:21217755
    reference_title: >-
      Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity
      and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo.
    explanation: >-
      Source for the breadth of the autoimmune spectrum described here.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at least one autoimmune diagnosis was recorded in 22 patients overall (85%),
      with 9 (34%) assigned 3 or more such diagnoses
    explanation: Quantifies the autoimmune burden in the best-characterised cohort.
  - reference: PMID:42459138
    reference_title: A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients showed elevated inflammatory activity, with enrichment of the NF-κB,
      MAPK, and cell death pathways, as well as up-regulation of type I interferon
      (IFN) genes in monocytes.
    explanation: >-
      The 2026 multicentre cohort adds transcriptomic confirmation of elevated
      inflammatory activity; the same sentence names NF-kappaB, MAPK, and cell-death
      pathway enrichment alongside the interferon signature.
  downstream:
  - target: Autoimmune Thrombocytopenia
    causal_link_type: DIRECT
    description: >-
      Immune thrombocytopenia is the commonest single autoimmune diagnosis and the
      one most often responsible for serious harm.
  - target: Systemic Lupus Erythematosus
    causal_link_type: DIRECT
    description: >-
      A third of patients meet ACR criteria for SLE, with near-universal antinuclear
      and frequent anti-dsDNA antibodies.
  - target: Autoimmune Hemolytic Anemia
    causal_link_type: DIRECT
    description: >-
      Coombs-positive haemolysis; co-occurring with the thrombocytopenia it yields a
      diagnosis of Evans syndrome.
  - target: Autoimmune Hypothyroidism
    causal_link_type: DIRECT
    description: Thyroid autoimmunity in around a fifth of patients.
  - target: Celiac Disease
    causal_link_type: DIRECT
    description: >-
      Coeliac disease is among the autoimmune diagnoses recorded in SPENCD cohorts
      and has been the presenting autoimmune feature in a reported case.
  - target: Sensorineural Hearing Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Bilateral sensorineural hearing loss has been reported once, severe enough to
      require cochlear implantation. Autoimmune inner-ear disease is the proposed
      route, but the reporting authors could not establish whether the lesion is
      cochlear or central, and skeletal dysplasia itself independently raises the
      rate of hearing loss — so the edge is left with unknown intermediates.
    evidence:
    - reference: PMID:38219511
      reference_title: "Bilateral cochlear implants in a case of spondyloenchondrodysplasia with sensorineural hearing loss: Case report."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Uncontrolled immune system response in autoimmune diseases commonly causes
        bilateral SNHL. However, the exact defect, in this case, is still unknown if
        it is cochlear or central.
      explanation: >-
        The authors propose the autoimmune route while stating the anatomical level
        is unresolved, which is exactly the uncertainty this edge encodes.
- name: Interferon-Associated CNS Involvement
  biological_scale: ORGANISM
  description: >-
    Spasticity, sometimes evident in the first months of life, with calcification
    of the basal ganglia and other sites on computed tomography, and learning
    difficulty in a minority. Unlike Aicardi-Goutieres syndrome, significant
    cerebral white matter disease is unusual.
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Such variable phenotypic presentations were masking the disease and led to the delay in diagnosis until exome sequencing was used revealing homozygous variants in the ACP5 gene as the cause of the patients' phenotype.
    explanation: >-
      Documents the diagnostic delay caused by a neurology-dominant presentation.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      observed spasticity in 11 patients (44%), and intracranial calcification on
      computed tomography imaging in 9 of 13 patients assessed, variably involving
      the basal ganglia, pons, cerebellar dentate nuclei, and white-grey matter
      junction
    explanation: >-
      Gives the frequency and anatomical distribution of the two neurological
      features.
  downstream:
  - target: Spasticity
    causal_link_type: DIRECT
    description: >-
      Spasticity is the commonest neurological sign and can be evident within the
      first months of life.
  - target: Intracranial Calcification
    causal_link_type: DIRECT
    description: >-
      Calcification of the basal ganglia and other sites, detectable in early
      infancy.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Motor and cognitive delay accompanying the spasticity. Whether it follows
      from the calcification, the white-matter involvement, or interferon action
      on the developing brain more broadly is not established.
  - target: Learning Difficulty
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Learning difficulty occurs in a minority and its relationship to the
      calcification and spasticity is not established; marked global impairment and
      frank regression both occur.
- name: Osteoclast and Growth-Plate Dysfunction
  biological_scale: CELLULAR
  description: >-
    TRAP loss impairs osteoclast-mediated bone resorption and disorders the
    endochondral growth plate. In the Acp5-null mouse this produces mild
    osteopetrosis with disorganised growth plates and bones that are stronger, not
    weaker, than wild type — consistent with the absence of increased fracture risk
    in SPENCD.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: bone resorption
    modifier: DECREASED
    term:
      id: GO:0045453
      label: bone resorption
  - preferred_term: endochondral ossification
    modifier: ABNORMAL
    term:
      id: GO:0001958
      label: endochondral ossification
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Acp5-null mice are viable under laboratory conditions but suffer from
      developmental deformities of the limb and axial skeleton
    explanation: >-
      The null mouse establishes that loss of TRAP is sufficient for a skeletal
      dysplasia independent of any immune phenotype.
  downstream:
  - target: Vertebral and Metaphyseal Dysplasia
    causal_link_type: DIRECT
    description: >-
      Failure of cartilage-to-bone transition at the growth plate produces the
      persisting islands of chondroid tissue and the vertebral flattening that
      named the disorder.
    evidence:
    - reference: PMID:37010587
      reference_title: >-
        Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
        variants with variable neurological presentations.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Spondyloenchondrodysplasia (SPENCD, OMIM# 271550) is a very rare autosomal recessive spondylometaphyseal dysplasia characterized by variable degrees of metaphyseal changes, enchondromas, platyspondyly and short stature.
      explanation: >-
        Names the components of the expressed skeletal phenotype.
    - reference: PMID:40786056
      reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with SPENCDI often exhibit areas where cartilage cannot transition
        into bone, as well as non-cancerous growths of cartilage.
      explanation: >-
        Names the failed cartilage-to-bone transition as the tissue-level basis of
        the enchondroma-like lesions.
- name: Vertebral and Metaphyseal Dysplasia
  biological_scale: TISSUE
  description: >-
    The radiographic core of the disorder: platyspondyly with irregular upper and
    lower vertebral end plates and posterior nodular lesions, together with
    radiolucent punched-out non-ossifying lesions running from the growth plate
    into the metaphysis and diaphysis, typically at the distal femur, proximal
    fibula, and distal radius and ulna.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic skeletal radiological features of SPENCD are (1)
      platyspondyly, with irregularity of both upper and lower end plates and
      nodular lesions particularly involving the posterior aspect of the vertebral
      bodies
    explanation: Defines the vertebral component of the radiographic phenotype.
  downstream:
  - target: Platyspondyly
    causal_link_type: DIRECT
    description: >-
      The vertebral lesion of the dysplasia read on plain radiography as flattened
      bodies with irregular end plates.
  - target: Metaphyseal Enchondroma-like Lesions
    causal_link_type: DIRECT
    description: >-
      The metaphyseal lesion read as radiolucent punched-out non-ossifying areas
      running from the growth plate into the metaphysis and diaphysis.
  - target: Disproportionate Short Stature
    causal_link_type: DIRECT
    description: >-
      Combined spinal and long-bone dysplasia reduces stature, with the short-trunk
      or short-limb pattern depending on which compartment dominates.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Individuals with SPENCD may be of reduced stature, due to short trunk
        and/or limbs depending on the relative degree of spinal and long bone
        dysplasia.
      explanation: >-
        Attributes the short stature directly to the spinal and long-bone dysplasia
        rather than to a separate growth-axis defect.
phenotypes:
- category: Skeletal
  name: Platyspondyly
  frequency: VERY_FREQUENT
  description: >-
    Flattened vertebral bodies with irregular upper and lower end plates and
    nodular lesions on the posterior aspect. Present from infancy and one of the
    two radiographic features that define the disorder.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:41049574
    reference_title: >-
      Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 1976, Schorr, Legum, and Oshchorn described two brothers with a skeletal dysplasia notable for the presence of flattened vertebrae (platyspondyly) and islands of chondroid tissue within bone (enchondroma), a combination leading them to coin the novel term spondyloenchondrodysplasia (SPENCD)
    explanation: >-
      The naming account, which records platyspondyly as one of the two defining radiographic
      findings.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The characteristic skeletal radiological features of SPENCD are (1)
      platyspondyly, with irregularity of both upper and lower end plates and
      nodular lesions particularly involving the posterior aspect of the vertebral
      bodies
    explanation: Names platyspondyly as a characteristic radiological feature.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-Ray of spine showed platyspondyly and X-Ray of forearm and wrist showed
      metaphyseal dysplasia
    explanation: Documents platyspondyly on plain radiography in a molecularly confirmed patient.
- category: Skeletal
  name: Metaphyseal Enchondroma-like Lesions
  frequency: VERY_FREQUENT
  description: >-
    Radiolucent, punched-out non-ossifying lesions extending from the growth plate
    into the metaphysis and diaphysis, representing islands of chondroid tissue
    that failed to ossify. The combination with platyspondyly gave the disorder its
    name in 1976.
  phenotype_term:
    preferred_term: Metaphyseal enchondromatosis
    term:
      id: HP:0005868
      label: Metaphyseal enchondromatosis
  evidence:
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiological investigations in our patients revealed the characteristic
      metaphyseal and vertebral bone lesions described in SPENCD.
    explanation: >-
      Confirms the metaphyseal lesions in the founding molecularly defined cohort.
- category: Growth
  name: Disproportionate Short Stature
  frequency: FREQUENT
  description: >-
    Short stature is common but not obligate; height spans the normal range to 6.5
    standard deviations below the mean, and some patients have minimal or no
    skeletal manifestations in early childhood.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:39853520
    reference_title: >-
      Clinical, laboratory, and molecular characteristics of patients with
      spondyloenchondrodysplasia: a case series study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients exhibited short stature and skeletal abnormalities.
    explanation: >-
      Cohort frequency for short stature.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal disease, manifest as short stature and/or leg pain/bowing, was the
      reason for initial presentation in 12 patients (46%), with height varying
      between the normal range to 6.5 SD below the mean
    explanation: >-
      Supports the FREQUENT rather than VERY_FREQUENT band, since height can be
      normal.
- category: Neurologic
  name: Spasticity
  frequency: FREQUENT
  description: >-
    Increased tone, sometimes clinically evident within the first months of life,
    recorded in 44 percent of one genetically defined cohort.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia.
    explanation: >-
      Documents spasticity in all patients of the series.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      observed spasticity in 11 patients (44%), and intracranial calcification on
      computed tomography imaging in 9 of 13 patients assessed
    explanation: Gives the 44 percent frequency behind the FREQUENT band.
- category: Neurologic
  name: Intracranial Calcification
  frequency: VERY_FREQUENT
  description: >-
    Calcification on computed tomography, variably involving the basal ganglia,
    pons, cerebellar dentate nuclei, and the grey-white matter junction; present in
    9 of 13 assessed patients and detectable in early infancy.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia.
    explanation: >-
      Documents basal ganglia calcification in nearly all patients of the series.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intracranial calcification on computed tomography imaging in 9 of 13 patients
      assessed, variably involving the basal ganglia, pons, cerebellar dentate
      nuclei, and white-grey matter junction
    explanation: >-
      Nine of thirteen assessed patients supports the VERY_FREQUENT band among
      those imaged.
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Motor and cognitive delay accompanies the spasticity in many patients, and
    intellectual disability and autism-spectrum behaviours have been described as
    features that distinguish SPENCD from other interferonopathies.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5 variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures.
    explanation: >-
      Names global developmental delay among the neurological features.
- category: Neurologic
  name: Learning Difficulty
  frequency: OCCASIONAL
  description: >-
    Typically mild to moderate learning difficulty in around a quarter of patients,
    though marked global impairment and frank neurological regression have both
    been reported.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      also recorded learning difficulties in seven patients (28%)
    explanation: The 28 percent frequency places this in the OCCASIONAL band.
- category: Immunologic
  name: Autoimmune Thrombocytopenia
  frequency: FREQUENT
  description: >-
    The commonest single autoimmune diagnosis, recorded in 46 percent of one
    cohort, characteristically refractory to treatment, and responsible for death
    in infancy in one patient and cerebral haemorrhage in two others.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:26951490
    reference_title: >-
      Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus.
    explanation: >-
      Identifies autoimmune thrombocytopenia as one of the two most frequent autoimmune
      features.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order of frequency, AITP, SLE, autoimmune hemolytic anemia (AIHA), and
      hypothyroidism were observed in 12 (46%), 9 (36%), 7 (27%), and 5 (19%)
      cases, respectively
    explanation: >-
      Gives the ranked frequencies of the four commonest autoimmune diagnoses,
      supporting this and the three phenotype records that follow.
- category: Immunologic
  name: Systemic Lupus Erythematosus
  frequency: FREQUENT
  description: >-
    A third of patients meet American College of Rheumatology criteria for SLE, and
    antinuclear antibodies are present in 95 percent of those tested with anti-dsDNA
    in 71 percent. SPENCD is one of the monogenic causes of lupus.
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  evidence:
  - reference: PMID:21217755
    reference_title: >-
      Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity
      and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients fulfilled American College of Rheumatology classification criteria for a diagnosis of SLE4. These included elevated anti-nuclear antibodies, anti-dsDNA antibodies, thrombocytopenia, and nephritis or non-erosive arthritis.
    explanation: >-
      Documents formally classified SLE and its serological and organ features in the discovery
      cohort.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      21 of the 22 (95%) patients tested in the cohort were positive for the
      presence of antinuclear antibodies, and 15 of 21 (71%) were anti-dsDNA
      antibody positive
    explanation: >-
      Serological data supporting the lupus phenotype across nearly the whole
      cohort.
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These included elevated anti-nuclear antibodies, anti-dsDNA antibodies,
      thrombocytopenia, and nephritis or non-erosive arthritis.
    explanation: >-
      Lists the ACR criteria met by the patients diagnosed with SLE in the founding
      cohort.
- category: Immunologic
  name: Autoimmune Hemolytic Anemia
  frequency: OCCASIONAL
  description: >-
    Coombs-positive haemolysis in around a quarter of patients. Co-occurrence with
    autoimmune thrombocytopenia leads to a diagnosis of Evans syndrome in a
    significant minority.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations were autoimmune hemolytic anemia, immune
      thrombocytopenia, abnormal bone development, intracranial calcification,
      short stature, and growth retardation.
    explanation: >-
      Documents Coombs-positive haemolytic anaemia in two molecularly confirmed
      patients.
- category: Immunologic
  name: Autoimmune Hypothyroidism
  frequency: OCCASIONAL
  description: >-
    Hypothyroidism, typically with positive thyroid autoantibodies, in around a
    fifth of patients.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:39853520
    reference_title: >-
      Clinical, laboratory, and molecular characteristics of patients with
      spondyloenchondrodysplasia: a case series study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common findings included autoimmune hemolytic anemia, hypothyroidism, and elevated transaminase levels.
    explanation: >-
      Cohort evidence for hypothyroidism.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order of frequency, AITP, SLE, autoimmune hemolytic anemia (AIHA), and
      hypothyroidism were observed in 12 (46%), 9 (36%), 7 (27%), and 5 (19%)
      cases, respectively
    explanation: Places hypothyroidism at 19 percent, the OCCASIONAL band.
- category: Immunologic
  name: Susceptibility to Infection
  frequency: OCCASIONAL
  description: >-
    Significant bacterial and viral infection — recurrent pneumonia, disseminated
    herpes zoster, skin and dental abscesses — in around a fifth of patients.
    Lymphopenia and hypogammaglobulinaemia have been recorded in patients not on
    immunosuppression, so the susceptibility is not purely iatrogenic.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:39853520
    reference_title: >-
      Clinical, laboratory, and molecular characteristics of patients with
      spondyloenchondrodysplasia: a case series study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent bacterial and viral infections, including respiratory tract infections, were prevalent.
    explanation: >-
      Cohort evidence for recurrent infection.
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient).
    explanation: >-
      Documents the immunodeficiency underlying the infection susceptibility.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significant bacterial and viral infections were recorded in five patients
      (19%), including recurrent pneumonia, disseminated herpes zoster, skin, and
      dental abscesses
    explanation: Gives the frequency and the spectrum of infections.
- category: Immunologic
  name: Celiac Disease
  frequency: OCCASIONAL
  description: >-
    Coeliac disease is among the autoimmune diagnoses recorded across SPENCD
    cohorts, and has preceded the SPENCD diagnosis in a reported child who was
    already carrying diagnoses of spastic diplegia and short stature.
  phenotype_term:
    preferred_term: Celiac disease
    term:
      id: HP:0002608
      label: Celiac disease
  evidence:
  - reference: PMID:38883133
    reference_title: "Spondyloenchondrodysplasia With Immune Dysregulation, but Without Skeletal Dysplasia, in a Six-Year-Old Boy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was previously diagnosed with spastic diplegia, short stature, and celiac
      disease.
    explanation: >-
      Documents coeliac disease in a molecularly confirmed patient, alongside the
      spasticity and short stature.
- category: Otologic
  name: Sensorineural Hearing Loss
  frequency: OCCASIONAL
  description: >-
    Profound bilateral sensorineural hearing loss requiring cochlear implantation
    has been reported once, presenting at two years as hearing concern with delayed
    speech. Hearing loss is among the least reported features of SPENCD, and
    children with skeletal dysplasia in general have elevated rates of both
    conductive and sensorineural loss, so its specificity to SPENCD is unsettled.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    severity: SEVERE
  evidence:
  - reference: PMID:38219511
    reference_title: "Bilateral cochlear implants in a case of spondyloenchondrodysplasia with sensorineural hearing loss: Case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the patient underwent a bilateral cochlear implant for sensorineural hearing
      loss at the age of four, which went uneventfully
    explanation: >-
      Documents profound bilateral sensorineural loss managed by implantation in a
      patient with SPENCD.
  - reference: PMID:38219511
    reference_title: "Bilateral cochlear implants in a case of spondyloenchondrodysplasia with sensorineural hearing loss: Case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Out of the wide spectrum of presentation in SPENCD, hearing loss is one of the
      least presented symptoms.
    explanation: >-
      Establishes the rarity of the feature, which is why the frequency band is
      OCCASIONAL and the entry does not claim it as a core feature.
biochemical:
- name: Plasma tartrate-resistant acid phosphatase
  presence: Absent or negligible
  context: >-
    Total TRAP protein is negligible and the TRAP 5a isoform undetectable in
    affected individuals, including those homozygous for missense alleles. The
    assay is therefore a direct functional readout of the genetic lesion.
  evidence:
  - reference: PMID:21217755
    reference_title: >-
      Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      levels of total TRAP protein were negligible, and TRAP 5a protein undetectable, indicating an almost complete lack of TRAP synthesis or secretion in the affected patients tested
    explanation: >-
      Direct measurement of the biochemical defect.
- name: Interferon-stimulated gene expression score
  presence: Elevated
  context: >-
    Whole-blood ISG expression is raised in most patients and is the practical
    biomarker of the interferonopathy. It is not universal, and immunosuppression
    appears able to normalise it.
  evidence:
  - reference: PMID:26951490
    reference_title: "Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP).
    explanation: >-
      Establishes the ISG score as elevated in most molecularly confirmed
      patients.
diagnosis:
- name: Radiographic Recognition of the SPENCD Skeletal Pattern
  results: >-
    Platyspondyly with enchondroma-like radiolucent metaphyseal and vertebral
    lesions.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  description: >-
    Plain radiography of the spine and long bones showing platyspondyly with
    irregular end plates together with radiolucent metaphyseal lesions is the
    finding that raises the diagnosis and directs ACP5 testing. The radiographic
    features markedly increase the likelihood of finding biallelic ACP5 variants
    even when subtle, but some patients have minimal or no skeletal manifestations
    in early childhood, so normal radiographs do not exclude the diagnosis in a
    child presenting with autoimmunity.
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPENCD can be differentiated from other spondylometaphyseal dysplasias by the presence of bone enchondromas which are radiographic radiolucent spondylar and metaphyseal lesions caused by persistence of chondroid tissue within the ossified bones
    explanation: >-
      Establishes the radiographic discriminator on which diagnosis is raised.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      while the presence of characteristic radiological features (even if subtle)
      significantly increases the likelihood of finding biallelic mutations in
      ACP5, some patients have minimal
    explanation: >-
      States both the diagnostic value of the radiographs and the limit on their
      sensitivity.
  - reference: PMID:38883133
    reference_title: "Spondyloenchondrodysplasia With Immune Dysregulation, but Without Skeletal Dysplasia, in a Six-Year-Old Boy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient did not have skeletal dysplasia, despite having ACP gene mutations,
      suggesting that there is a wide range of phenotypic severity in
      spondyloenchondrodysplasia
    explanation: >-
      A molecularly confirmed patient reported specifically as lacking a skeletal
      dysplasia, which is the clearest statement that normal radiographs do not
      exclude the diagnosis.
- name: ACP5 Sequencing
  results: Biallelic ACP5 loss-of-function variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Biallelic ACP5 variants confirm the diagnosis. Because the disease appears
    genetically homogeneous, a classical phenotype without an ACP5 result should
    prompt review for a deletion allele rather than a search for a second locus.
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg).
    explanation: >-
      Documents exome sequencing as the diagnostic route in a recent series.
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We are unaware of any patients conforming to the classical SPENCD phenotype
      being negative for mutations in ACP5, suggesting that the disease is
      genetically homogeneous.
    explanation: >-
      Genetic homogeneity is what makes single-gene testing the definitive
      confirmatory step.
- name: Serum TRAP Activity and Type I Interferon Signature
  results: >-
    Absent or negligible plasma TRAP, with upregulated interferon-stimulated
    gene expression in most patients.
  diagnosis_term:
    preferred_term: molecular diagnostic method
    term:
      id: NCIT:C18194
      label: Molecular Diagnostic Method
  description: >-
    Total and isoform 5b TRAP activity are undetectable in patient serum and
    leukocyte homogenates and roughly halved in heterozygous parents, providing a
    functional confirmation of a variant of uncertain significance. Serum
    interferon-alpha activity and a whole-blood interferon-stimulated gene score
    are elevated in most patients, but are neither specific to SPENCD nor invariably
    present, and can be suppressed by immunosuppressive treatment.
  evidence:
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All eight cases assayed showed elevated serum interferon alpha activity, and
      gene expression profiling in whole blood defined a type I interferon
      signature.
    explanation: >-
      Establishes the interferon assays as consistently abnormal in molecularly
      confirmed patients.
differential_diagnoses:
- name: Aicardi-Goutieres Syndrome
  description: >-
    Shares spasticity, intracranial calcification, and a type I interferon
    signature, and was the differential that prompted interferon assays in SPENCD.
    Significant cerebral white matter disease is usual in Aicardi-Goutieres and
    unusual in SPENCD, and the SPENCD skeletal dysplasia and the frank organ-specific
    autoimmunity are not features of Aicardi-Goutieres.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to Aicardi–Goutières syndrome (AGS), significant cerebral white
      matter disease is apparently unusual.
    explanation: Names the neuroimaging feature that separates the two disorders.
- name: Childhood-Onset Systemic Lupus Erythematosus
  description: >-
    SPENCD is one of the monogenic causes of lupus, and a third of patients meet
    ACR criteria. Very early onset, refractory cytopenias, intracranial
    calcification, short stature, or any vertebral or metaphyseal radiographic
    abnormality should prompt ACP5 testing rather than a diagnosis of idiopathic
    childhood lupus.
  evidence:
  - reference: PMID:41049574
    reference_title: >-
      Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lausch and colleagues (9) made a molecular diagnosis of SPENCD in a 63-year-old male first reported in 1958 as a 10-year-old child with a skeletal dysplasia and systemic lupus erythematosus (SLE) (11).
    explanation: >-
      A concrete instance of the diagnostic confusion this differential describes.
  - reference: PMID:21217755
    reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TRAP deficiency now represents a third monogenic disorder associated with the
      development of lupus also showing an up-regulation of type I interferon
      activity
    explanation: >-
      Places SPENCD explicitly among the monogenic lupus disorders, which is why it
      belongs in this differential.
- name: Other Spondylometaphyseal Dysplasias
  description: >-
    Within ISDS group 12, odontochondrodysplasia (TRIP11), SMD Sutcliffe or corner
    fracture type (FN1), SMD with cone-rod dystrophy (PCYT1A), SMD with corneal
    dystrophy (PLCB3), and chondrodysplasia-pseudohermaphroditism syndrome (HHAT)
    share the combined vertebral and metaphyseal radiographic pattern. None of them
    produces intracranial calcification with systemic autoimmunity, so the
    extraskeletal triad resolves the differential in practice.
  notes: >-
    Recorded without an evidence item because it is a statement about the ISDS
    group-12 membership list, whose per-disorder placements are not quotable from
    the nosology abstract; the group assignment and its provenance are recorded in
    the classifications block.
treatments:
- name: JAK Inhibition
  description: >-
    Oral JAK1/2 or JAK1/3 inhibitors — ruxolitinib, baricitinib, tofacitinib —
    block signalling downstream of the type I interferon receptor. In reported
    cases they have controlled autoimmune cytopenias refractory to glucocorticoids,
    sirolimus, rituximab, and mycophenolate, allowing steroid tapering. The
    evidence is case reports only; no trial exists, optimal dosing is undefined,
    and the effect on the skeletal and neurological arms is unknown.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
    - preferred_term: tofacitinib
      term:
        id: CHEBI:71200
        label: tofacitinib
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Type I Interferon Overproduction
    treatment_effect: INHIBITS
    description: >-
      JAK1/2 inhibition blocks IFNAR-proximal JAK-STAT signalling, so it acts on
      the consequences of excess interferon rather than on its production. The
      clinical benefit in autoimmune features is the main human evidence that this
      node is causal rather than a bystander biomarker.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The apparent efficacy of JAK1/2 /JAK1/3 inhibition in affected patients
        (Table S3), particularly relating to features of systemic autoimmunity
      explanation: >-
        Efficacy against systemic autoimmunity but not clearly against neurological
        involvement is why the supporting evidence is graded INDIRECT.
  evidence:
  - reference: PMID:41049574
    reference_title: >-
      Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Table S3 shows the data provided on patients recorded in Table S1 treated using JAK inhibition.
    explanation: >-
      Establishes that a cohort of SPENCD patients has been treated with JAK inhibition and
      tabulated, which is the evidence base for this treatment.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On 16 August 2024, oral ruxolitinib (5 mg daily) combined with prednisone
      (7.5 mg daily) was started. Coombs test successfully turned negative after 1
      month of treatment adjustment.
    explanation: >-
      A documented remission of refractory Coombs-positive haemolysis on ruxolitinib
      after failure of prednisone and sirolimus.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was switched to oral Tofacitinib (5 mg twice daily) in April 2023, with
      regular follow-ups. Currently, her hemoglobin and platelet levels remain
      within the normal range.
    explanation: Sustained haematological remission on tofacitinib in the second reported case.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the use of JAK inhibitors (Ruxolitinib and Tofacitinib) in our cases
      showed promising results, further studies are needed to determine the optimal
      treatment protocols.
    explanation: >-
      The authors' own caveat that the evidence base is anecdotal and the protocol
      undefined.
  - reference: PMID:42459138
    reference_title: A Multicenter Integrative Cohort Characterizing the Genetic, Clinical, and Transcriptomic Features of ACP5 Deficiency.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therapeutically, prednisolone and azathioprine were the most common effective
      drugs, whereas patients treated with the JAK inhibitors ruxolitinib and
      upadacitinib achieved a partial response.
    explanation: >-
      The largest systematic treatment series to date is more equivocal than the
      individual case reports: JAK inhibition gave partial responses while
      conventional immunosuppression was the most commonly effective option. This
      tempers the case-report enthusiasm rather than contradicting it, since the
      reported JAK-inhibitor successes were in patients refractory to exactly those
      conventional drugs.
- name: Glucocorticoid and Conventional Immunosuppressive Therapy
  description: >-
    Glucocorticoids, intravenous immunoglobulin, rituximab, mycophenolate mofetil,
    and sirolimus are the conventional first-line treatments for the autoimmune
    cytopenias. Responses are frequently incomplete or transient — the
    thrombocytopenia of SPENCD is characteristically refractory — and prolonged
    corticosteroid exposure is itself a problem in a child with a skeletal
    dysplasia and short stature.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:26951490
    reference_title: >-
      Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia
    explanation: >-
      A single-patient observation, hedged by its authors, which is why this mechanism link is
      recorded as partially supported.
  - reference: PMID:26951490
    reference_title: >-
      Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy.
    explanation: >-
      Documents autoimmune disease controlled on immunosuppression in a molecularly confirmed
      patient.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Considering the long history of oral glucocorticoid treatment and the poor
      control effect of AIHA, oral sirolimus was added on 17 April 2023, but Coombs
      test did not recover to negative.
    explanation: >-
      Documents the incomplete response to conventional immunosuppression that
      motivates escalation to JAK inhibition.
- name: Supportive Skeletal and Developmental Management
  description: >-
    No therapy modifies the skeletal dysplasia. Management is orthopaedic and
    developmental, directed at limb pain and bowing, stature, and learning support.
    The response of skeletal dysplasias to growth hormone is contested and no
    SPENCD-specific data exist.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:37010587
    reference_title: >-
      Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5
      variants with variable neurological presentations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from -3.0 SD before GH therapy to -2.35 SD at presentation.
    explanation: >-
      The single reported treated patient, in whom growth hormone deficiency was a comorbidity
      rather than a feature of the dysplasia.
  - reference: PMID:40786056
    reference_title: "Case Report: Successful treatment of spondyloenchondrodysplasia with immune dysregulation using tofacitinib and ruxolitinib: a report of two pediatric cases."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The response to growth hormone therapy in patients with skeletal dysplasia
      remains contentious
    explanation: >-
      Supports recording growth hormone as unresolved rather than as a
      recommended intervention.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance carries a 25 percent recurrence risk, and
    reported families are heavily enriched for consanguinity, so counselling and —
    once the familial alleles are known — prenatal or preimplantation testing are
    central to family management.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:21217752
    reference_title: "Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped a locus in five consanguineous families to chromosome 19p13
    explanation: >-
      Establishes the consanguineous, recessive family structure that makes
      recurrence-risk counselling the relevant action.
animal_models:
- name: Acp5-null mouse
  species: Mouse
  genotype: Acp5 knockout (homozygous null)
  publication: PMID:8898228
  description: >-
    The Acp5 knockout mouse, reported in 1996, is viable and reproduces the
    skeletal arm of SPENCD — disorganised growth plates and mild osteopetrosis from
    an osteoclast resorptive defect — while developing neither overt autoimmunity
    nor neurological disease. Its bones are stronger than wild type, matching the
    absence of increased fracture risk in patients.
  modeled_mechanisms:
  - target: Osteoclast and Growth-Plate Dysfunction
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Loss of Acp5 alone is sufficient to produce the growth-plate disorganisation
      and resorptive defect, establishing this node as a direct consequence of TRAP
      loss rather than of inflammation.
    limitations: >-
      The mouse skeletal phenotype is described as mild osteopetrosis with limb and
      axial deformity; the enchondroma-like metaphyseal lucencies and platyspondyly
      of the human disorder are not asserted to be reproduced lesion for lesion.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reminiscent of the skeletal features seen in patients with SPENCD, these
        defects include disorganized growth plates indicative of a role for TRAP in
        endochondral ossification, and mild osteopetrosis due to a resorptive defect
        of osteoclasts resulting in defective bone remodelling.
      explanation: >-
        States both that the mouse skeletal phenotype resembles the human one and
        what the underlying cellular defects are.
    - reference: PMID:8898228
      reference_title: "Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Histomorphometry and mineralization density analysis of backscattered
        electron imaging revealed widened and disorganized epiphyseal growth plates
        with delayed mineralization of cartilage in 6- to 8-week-old mutant mice.
      explanation: >-
        The primary description of the model, measuring the growth-plate lesion
        directly rather than relying on the later review's summary of it.
    - reference: PMID:8898228
      reference_title: "Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus the findings reflect a mild osteopetrosis due to an intrinsic defect of
        osteoclastic modelling activity that was confirmed in the resorption pit
        assay in vitro.
      explanation: >-
        Establishes the resorptive defect as intrinsic to the osteoclast, confirmed
        by a functional assay rather than inferred from bone density alone.
  - target: Systemic Autoimmunity
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The defining extraskeletal feature of human SPENCD is absent in the null
      mouse, which is the central obstacle to studying the immune arm in vivo.
    limitations: >-
      Acp5-null mice show altered macrophage cytokine profiles, impaired bacterial
      clearance, and impaired Th1 responses, but no overt autoimmune disease and no
      neurological involvement. Any inference about the human autoimmune mechanism
      from this model is therefore indirect.
    evidence:
    - reference: PMID:41049574
      reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Acp5-null mice have not been described to manifest overt autoimmunity, which
        is such a prominent feature of ACP5-related disease in humans.
      explanation: >-
        Explicit negative result: the model does not reproduce the human autoimmune
        phenotype, which is what FAILS_TO_RECAPITULATE records.
    - reference: PMID:21217755
      reference_title: Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        they do not develop an overt autoimmune phenotype
      explanation: >-
        The founding report makes the same negative observation independently.
discussions:
- discussion_id: spencd_mouse_immune_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Systemic Autoimmunity
  prompt: >-
    Why does the Acp5-null mouse reproduce the skeletal dysplasia of SPENCD but
    not the autoimmunity or the neurological disease that dominate the human
    phenotype?
  rationale: >-
    The only viable in vivo model of TRAP deficiency is silent on the arm of the
    disorder that causes most of the morbidity and all of the recorded deaths.
    Evidence for the immune mechanism therefore rests on human patient material and
    on knockdown in a plasmacytoid dendritic cell line, not on an organism-level
    system in which the interferon-to-autoimmunity link can be tested. Whether this
    reflects a species difference in the osteopontin-TLR9 axis, a difference in
    laboratory pathogen exposure, or a genuinely different mechanism in humans is
    unknown, and it is the reason the causal status of the interferon signature
    remains open.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Acp5-null mice have not been described to manifest overt autoimmunity, which
      is such a prominent feature of ACP5-related disease in humans.
    explanation: States the mismatch between the model and the human phenotype directly.
  proposed_experiments:
  - experiment_id: exp_spencd_sensitised_acp5_null_model
    name: Interferon-sensitised or humanised Acp5-deficient model
    description: >-
      Test whether Acp5-null mice develop autoimmunity when the type I interferon
      axis is sensitised — for example on a lupus-prone background, under TLR9
      agonist challenge, or with the human osteopontin phosphorylation sites
      knocked in — and whether JAK inhibition prevents it.
    would_support:
    - pathophysiology#Systemic Autoimmunity
    supporting_outcome:
    - >-
      Emergence of autoantibodies and cytopenias in sensitised Acp5-null animals,
      abrogated by JAK inhibition, would place the interferon node causally upstream
      of autoimmunity in vivo.
    would_refute:
    - pathophysiology#Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells
    refuting_outcome:
    - >-
      Failure of TLR9 agonist challenge to elicit autoimmunity in Acp5-null animals
      despite an intact interferon response would argue that the osteopontin-TLR9
      route is not the operative mechanism.
- discussion_id: spencd_trap_substrate_identity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Osteopontin Hyperphosphorylation
  prompt: >-
    Is hyperphosphorylated osteopontin actually the substrate defect that drives
    type I interferon overproduction, or is TRAP acting on some other substrate?
  rationale: >-
    The osteopontin-TLR9 model rests on a single 2017 study, and its authors could
    not directly assess osteopontin phosphorylation in the plasmacytoid dendritic
    cell line they used. Alternative routes are plausible and untested: TRAP is a
    lysosomal enzyme that could act in TLR7 or TLR9 trafficking directly, or in
    STING degradation, or through its role in removing mannose-6-phosphate from
    acid hydrolases — two of which, DNase II and ribonuclease T2, are themselves
    interferonopathy genes.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it remains to be formally determined if OPN is a physical component of the
      TLR9/MyD88 complex in these cells and/or whether TRAP acts on a different
      substrate(s) in this or other pathway(s)
    explanation: The review states the substrate question as formally unresolved.
  proposed_experiments:
  - experiment_id: exp_spencd_substrate_mapping_pdc
    name: Substrate mapping in TRAP-deficient primary human plasmacytoid dendritic cells
    description: >-
      Phosphoproteomics on primary patient-derived plasmacytoid dendritic cells,
      combined with a test of whether mannose-6-phosphate retention on DNase II and
      ribonuclease T2 impairs their activity in TRAP-deficient cells.
    would_support:
    - pathophysiology#Persistent TLR9 Signaling in Plasmacytoid Dendritic Cells
    supporting_outcome:
    - >-
      Selective osteopontin hyperphosphorylation in patient plasmacytoid dendritic
      cells, with intact DNase II and ribonuclease T2 activity, would confirm the
      osteopontin route.
    would_refute:
    - pathophysiology#Osteopontin Hyperphosphorylation
    refuting_outcome:
    - >-
      Normal osteopontin phosphorylation alongside impaired lysosomal nuclease
      activity would relocate the mechanism to mannose-6-phosphate-dependent
      hydrolase maturation.
- discussion_id: spencd_adult_natural_history
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Type I Interferon Overproduction
  prompt: >-
    What is the natural history of SPENCD in adulthood, and does early JAK
    inhibition change it?
  rationale: >-
    Published cases are overwhelmingly paediatric — only three of 77 individuals
    with recorded data presented after age 15 — and the 2025 review highlights a
    paucity of information on the disease beyond childhood. Whether short stature
    continues to worsen, whether intracranial calcification progresses, and whether
    the autoimmune burden accumulates or burns out are all unknown, which makes the
    benefit-risk of lifelong JAK inhibition started in early childhood impossible to
    assess.
  evidence:
  - reference: PMID:41049574
    reference_title: "Spondyloenchondrodysplasia: An enigmatic immuno-osseus type I interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we highlight a relative paucity of information relating to the natural history
      of the disease beyond childhood, and thus the need for longitudinal clinical
      and laboratory follow-up studies into adulthood
    explanation: The review names the adult natural history as the outstanding clinical gap.
  proposed_experiments:
  - experiment_id: exp_spencd_longitudinal_registry
    name: International longitudinal SPENCD registry
    description: >-
      Prospective longitudinal follow-up of molecularly confirmed patients into
      adulthood with standardised skeletal, neurological, immunological, and
      interferon-score endpoints, stratified by JAK inhibitor exposure.
    would_support:
    - pathophysiology#Type I Interferon Overproduction
    supporting_outcome:
    - >-
      Divergence in autoimmune event rates and interferon scores between
      JAK-inhibitor-exposed and unexposed cohorts would strengthen the causal role
      of the interferon node.
    would_refute:
    - pathophysiology#Type I Interferon Overproduction
    refuting_outcome:
    - >-
      Accumulating autoimmune events despite sustained interferon-score
      normalisation would argue that the signature is a biomarker rather than the
      driver.
progression: []
clinical_trials: []
datasets: []
notes: >-
  Curated as part of filling ISDS Nosology group 12 (Spondylometaphyseal
  dysplasias), which was unpopulated when this work began. SPENCD is NOS 12-0010 in the 2023
  revision. It earns its place in the combined vertebral-plus-metaphyseal group
  on the platyspondyly and the enchondroma-like metaphyseal lesions, not on the
  autoimmunity, which is what makes it unusual among the group: it is
  simultaneously a skeletal dysplasia and a type I interferonopathy, and the
  route from the lysosomal phosphatase defect to the interferon signature is
  recorded here as an emerging hypothesis rather than as settled
  pathophysiology.

  This entry is the merge of two independently curated entries for
  MONDO:0011939 that reached the repository at the same time - one on main under
  this filename, and one on the ISDS group-12 branch as
  Spondyloenchondrodysplasia_with_Immune_Dysregulation.yaml. The surviving file
  keeps main's name and filename and takes the branch entry's content, which was
  the fuller of the two, together with main's osteopontin-TLR9 mechanistic
  hypothesis group (now carried by the three causal edges it covers) and its two
  biochemical markers. The superseded history records were moved into this slug
  directory with target.superseded_by blocks.
references:
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []

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PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

Spondyloenchondrodysplasia

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