Bejel

1. Disease Information

Overview

Bejel, also known as endemic syphilis, is one of the three endemic treponematoses (along with yaws and pinta) and is caused by Treponema pallidum subspecies endemicum (TEN). Unlike venereal syphilis, bejel is not primarily sexually transmitted but spreads through direct contact with infectious lesions or contaminated fomites (e.g., shared drinking vessels) in communities with poor hygiene and overcrowding. The disease predominantly affects children in arid tropical and subtropical environments.

As established by Mitjà et al. (2013): "T. pallidum subsp. pallidum causes venereal syphilis, while T. pallidum subsp. pertenue, T. pallidum subsp. endemicum, and T. carateum are the agents of the endemic treponematoses yaws, bejel (or endemic syphilis), and pinta, respectively" (PMID: 24396138). Šmajs et al. (2014) further clarified: "T. pallidum subsp. endemicum (TEN) is the causative agent of bejel (also known as endemic syphilis). Clinical symptoms of syphilis and bejel are overlapping and the epidemiological context is important for correct diagnosis of both diseases" (PMID: 25375929).

Key Identifiers

Synonyms and Alternative Names

• Endemic syphilis
• Bejel
• Dichuchwa (Southern Africa)
• Njovera (Zimbabwe)
• Belesh (Saudi Arabia)
• Skerljevo (Balkans)
• Firjal (Iraq)
• Siti
• Non-venereal endemic syphilis

Information Sources

Information on bejel is derived primarily from aggregated disease-level resources (WHO reports, epidemiological surveys, case series, molecular epidemiology studies) rather than individual electronic health records (EHR). This is because bejel is a neglected tropical disease primarily affecting populations with limited access to healthcare infrastructure. Individual-level data from MSM populations in Japan and Cuba represent a newer, more granular data source.

2. Etiology

Disease Causal Factors

Bejel is an infectious disease caused by the spirochete bacterium Treponema pallidum subspecies endemicum (TEN). The organism is a Gram-negative spirochete, 6-15 micrometer long and 0.15 micrometer wide, with endoflagella enabling corkscrew motility. It is an obligate human pathogen that cannot be cultured on artificial media, making laboratory study extremely challenging.

The TEN Bosnia A reference genome is 1,137,653 bp in length (1.6-2.8 kbp shorter than other pathogenic treponeme genomes), with 513x average genome coverage achieved through pooled segment genome sequencing. Phylogenomic analyses show that TEN is most closely related to yaws-causing T. pallidum subsp. pertenue (TPE) strains but contains several sequences previously unique to syphilis treponemes (PMID: 25375929).

Risk Factors

Environmental and Socioeconomic Risk Factors (Classical Bejel)

Bejel foci are "typically confined to underprivileged communities living in remote rural areas, with little or no access to health services and removed from the mainstream of socioeconomic development" (PMID: 1281363). Specific risk factors include:

• Poverty and overcrowding: Dense living conditions facilitate person-to-person transmission
• Hot, dry climate: Arid regions of the Middle East, Sahel Africa, and Central Asia favor transmission
• Age: Children aged 2-15 years are most commonly affected; 75% of all endemic treponematosis cases are in children (PMID: 2682125)
• Shared utensils and communal living: Drinking vessels shared among family members facilitate oral-to-oral transmission
• Poor access to clean water and hygiene infrastructure
• Limited access to health services

Emerging Risk Factors (Sexually Transmitted TEN)

• Men who have sex with men (MSM): TEN has been identified in MSM populations in Japan, Cuba, and Europe (PMID: 31310214; PMID: 29454847)
• HIV co-infection: In Japan, 97.2% of MSM with TEN infection were people with HIV (PMID: 39415268)
• High-risk sexual behavior in urban populations

Genetic Risk Factors

No specific host genetic susceptibility loci have been identified for bejel. Susceptibility is driven entirely by exposure in the context of environmental and behavioral risk factors. Host immune factors (HLA type, innate immune polymorphisms) may influence susceptibility, but these are unstudied specifically for TEN.

Protective Factors

• Improved sanitation and hygiene: The single most effective protective factor; access to clean water and personal hygiene reduces fomite transmission
• Socioeconomic development: Elimination of overcrowding and improved housing
• Prior treponemal infection: Partial cross-immunity between treponemal subspecies may confer some protection
• Mass treatment campaigns: Population-level penicillin administration (as conducted by WHO/UNICEF in the 1950s-60s, treating over 50 million individuals in 46 countries)
• Access to primary healthcare: Early detection and treatment interrupt transmission chains

Gene-Environment Interactions

Not applicable for bejel as a purely infectious disease. However, host immune status (particularly HIV co-infection) significantly modifies disease presentation and may facilitate the emergence of sexually transmitted TEN in immunocompromised populations.

3. Phenotypes

Primary Stage

Secondary Stage

Latent Stage

• Phenotype type: Laboratory abnormality
• Description: Asymptomatic period with positive serological tests but no clinical manifestations. May persist indefinitely.
• Progression: May remain latent or progress to tertiary disease

Tertiary Stage

Sexually Transmitted TEN Phenotypes (Emerging)

In MSM populations, TEN infection presents with clinical features indistinguishable from venereal syphilis: genital chancres, maculopapular rash, mucous patches, and lymphadenopathy. Nishiki et al. (2021) described: "Bejel, caused by Treponema pallidum subsp. Endemicum (TEN), is a locally transmitted disease among children and juveniles in hot and dry regions. The number of adult cases of TEN infection outside of endemic areas has recently increased" (PMID: 34836779).

Quality of Life Impact

• Primary/secondary bejel: Moderate impact -- painful oral and skin lesions may impair eating and social interaction
• Tertiary bejel: Severe impact -- disfiguring gummatous destruction causes significant disability, social stigma, and functional impairment (eating, breathing, speech)
• Cardiovascular and neurological involvement: Unlike venereal syphilis, classic bejel is generally considered NOT to cause cardiovascular syphilis or neurosyphilis, though data are limited and this distinction is debated

4. Genetic/Molecular Information

Pathogen Genomics

As bejel is an infectious disease, the relevant genetic/molecular information pertains to the pathogen genome rather than host genetics.

TEN Bosnia A Reference Genome (PMID: 25375929): - Size: 1,137,653 bp - GenBank accession: CP007548 - Key finding: Most closely related to TPE (yaws) but containing sequences previously unique to TPA (syphilis) - Genome similarity: >99.8% identical to TPA and TPE

Key Virulence Factors and Molecular Features

Genomic Diversity and Recombination

Whole-genome sequencing of TEN isolates from Cuba revealed non-clonal diversity with nucleotide variability of 0.2-10.3 substitutions per 100 kbp, affecting 27 genes. Recombination events were detected between tprC and tprI, in TP0488, and in the intergenic region TP0127-TP0129. Pospisilova et al. (2022) concluded: "the determined non-clonal character of the isolates suggests a persistent infection in the Cuban population rather than a single outbreak caused by imported case" (PMID: 35687593).

Phylogenomic analysis of 75 T. pallidum genomes identified 21 recombination events involving 12 genes, mostly intersubspecies transfers from TPE/TEN to TPA, with strong positive selection on recombinant genes. As Arora et al. (2021) reported: "we found strong evidence for recombination among the T. pallidum subspecies, involving 12 genes and 21 events. In most cases, only one recombination event per gene was detected and all but one event corresponded to intersubspecies transfers, from TPE/TEN to TPA" (PMID: 34791386).

Pre-Columbian Treponemal History

Recent paleogenomic work has recovered treponemal genomes from pre-Columbian remains in Brazil, redefining the history of treponemal diseases (PMID: 38267579). The tpr gene evolution analyses show higher variation between human subspecies than within them, supporting the three-subspecies classification, while the divergence patterns do not support a much older origin of yaws at the emergence of modern humans (PMID: 16926243).

5. Environmental Information

Environmental Factors

• Climate: Hot, arid environments favor transmission (drying of skin creates entry points; communal water use increases fomite transmission)
• Overcrowding and poor sanitation: Critical environmental determinants
• Rural isolation: Limits access to healthcare for early diagnosis and treatment
• No toxin, radiation, or occupational exposure involvement

Lifestyle Factors

• Communal drinking and eating: Shared utensils and cups facilitate oral-to-oral transmission among children
• Sleeping arrangements: Shared bedding in close quarters
• Sexual behavior (emerging): MSM sexual networks now identified as transmission routes for TEN

Infectious Agent

6. Mechanism / Pathophysiology

Causal Chain: Initial Trigger to Clinical Manifestation

TEN inoculation (oral mucosa or skin / genital mucosa in sexual transmission)
|
v
Local multiplication in epithelium
|
v
Primary lesion (mucous patch / chancre)  <-- Innate immune response
|                                      (neutrophils, macrophages)
v
Hematogenous/lymphatic dissemination (hours to days)
|
v
Secondary stage                          <-- Adaptive immune response
 - Mucocutaneous lesions                      (CD4+ and CD8+ T cells,
 - Periostitis                                 plasma cells, IFN-gamma, IL-17)
 - Condylomata lata
|
v
Partial immune control --> Latency
|
v
Tertiary stage (~10% untreated)          <-- Chronic granulomatous inflammation
 - Gummatous destruction                      (delayed-type hypersensitivity)
 - Bone/cartilage necrosis
 - Nasal/palatal destruction

Immune System Involvement

Cell-mediated immunity is critical for anti-treponemal host defense. Cruz et al. (2010) demonstrated that in HIV-negative individuals with secondary syphilitic lesions, the inflammatory infiltrate contained equal numbers of CD4+ and CD8+ T cells, "whereas in HIV+ patients, the majority of T cells belonged to the CD8 lineage and produced both IFN-gamma and IL-17". Furthermore, "Regulatory T cells and Langerhans cells were reduced in these patients compared with their HIV- counterparts" (PMID: 20889558).

Key immune pathways: - Macrophage activation: IFN-gamma enhances CD64-potentiated phagocytosis of T. pallidum (PMID: 29051759) - TLR2 signaling: Recombinant TprK activates M1 macrophage polarization and induces indoleamine 2,3-dioxygenase (IDO) production through the TLR2/JAK1/STAT1 pathway. "Inhibition of TLR2, JAK1, or STAT1 effectively reduces IDO expression and attenuates macrophage activation" (PMID: 40513619) - Interferon-stimulated genes: IFIT2 is upregulated in T. pallidum infection, modulating immune responses and infection outcomes (PMID: 41046825) - CRP as bacteremia marker: Elevated CRP (cut-off 0.5 mg/dL) was significantly associated with detectable spirochetes in blood (PMID: 39415268)

GO Terms for Biological Processes

• GO:0006955 -- Immune response
• GO:0006954 -- Inflammatory response
• GO:0042742 -- Defense response to bacterium
• GO:0050776 -- Regulation of immune response
• GO:0030593 -- Neutrophil chemotaxis
• GO:0007155 -- Cell adhesion
• GO:0044409 -- Entry into host
• GO:0009405 -- Pathogenesis

Cell Types Involved (CL Terms)

• CL:0000235 -- Macrophage
• CL:0000084 -- T cell
• CL:0000625 -- CD8-positive, alpha-beta T cell
• CL:0000624 -- CD4-positive, alpha-beta T cell
• CL:0000775 -- Neutrophil
• CL:0000786 -- Plasma cell
• CL:0000451 -- Dendritic cell (Langerhans cell)

Tissue Damage Mechanisms

Primary/Secondary stages: - Direct tissue invasion by spirochetes - Inflammatory infiltration (lymphocytes, plasma cells, macrophages, neutrophils) - Endothelial swelling and perivascular inflammation (endarteritis obliterans) - Periosteal invasion triggering inflammatory osteitis and new bone formation

Tertiary stage: - Granulomatous inflammation (gumma): central necrosis surrounded by epithelioid cells, giant cells, lymphocytes, and plasma cells - Immune-mediated tissue destruction (delayed-type hypersensitivity) - Fibrosis and scarring

Metabolic/Biochemical Features

• T. pallidum has extremely limited metabolic capacity (~5% of genome dedicated to biosynthesis)
• Cannot synthesize most amino acids, nucleotides, fatty acids, or enzyme cofactors
• Depends entirely on host for most metabolic precursors
• No known toxins produced; tissue damage results from host immune response

Molecular Profiling

Limited molecular profiling data exist for bejel specifically. No transcriptomic, proteomic, or metabolomic studies have been conducted on TEN-infected human tissues. Comparative genomics shows the TEN genome is most similar to TPE but with TPA-specific sequences in several loci (PMID: 25375929).

7. Anatomical Structures Affected

Organ Level

Body systems involved: Integumentary, skeletal, lymphatic/immune, upper respiratory tract

Notable absence: Unlike venereal syphilis, classic bejel does not typically involve the cardiovascular system (aortitis) or central nervous system (neurosyphilis), though the accuracy of this distinction remains debated due to limited data.

Tissue and Cell Level

• Epithelial tissue: Initial site of infection and primary lesion formation
• Connective tissue: Periosteum, bone marrow (periostitis and osteitis)
• Mucosal tissue: Oral and nasal mucosa
• Vascular endothelium: Endarteritis obliterans

Subcellular Level

T. pallidum is an extracellular pathogen that primarily resides in the extracellular space but can traverse endothelial barriers and invade perivascular spaces. - GO:0005576 -- Extracellular region - GO:0005615 -- Extracellular space - GO:0031012 -- Extracellular matrix

Localization

• Primary lesion: Typically oral/oropharyngeal mucosa in classic bejel; genital in sexually transmitted cases
• Secondary lesions: Bilateral, symmetric; oral mucosa, intertriginous areas, long bone periosteum
• Tertiary lesions: Nasopharynx, tibial bones, skull, skin
• Lateralization: Generally bilateral and symmetric

8. Temporal Development

Onset

• Typical age of onset: 2-15 years (classic childhood bejel); young to middle-aged adults (sexually transmitted TEN)
• Onset pattern: Subacute to insidious; primary lesions are often painless and subclinical
• Incubation period: Approximately 2-6 weeks

Progression

• Progression rate: Slow; disease evolves over years to decades
• Disease course pattern: Relapsing-remitting in secondary stage; progressive in tertiary
• Disease duration: Chronic lifelong if untreated
• Self-limited features: Primary and secondary lesions may resolve spontaneously, but latent infection persists

Critical Periods

• Childhood (2-10 years): Primary window of vulnerability for classic bejel due to close communal living and shared utensils
• Early treatment window: Treatment in primary or secondary stage prevents progression to destructive tertiary disease

9. Inheritance and Population

Epidemiology

Global Burden: As described by Antal et al. (1989): "Today there are more than 2.5 million cases of these diseases, 75% of them in children. More than 100 million additional children are at risk for these disabling and disfiguring infections which destroy tissue and bone" (PMID: 2682125). These figures encompass all endemic treponematoses (yaws, bejel, pinta), with bejel representing a subset concentrated in arid regions.

Historical context: The WHO/UNICEF mass treatment campaigns of the 1950s-1960s treated over 50 million individuals in 46 countries with remarkable success. However, resurgence occurred after campaign discontinuation, particularly in West and Central Africa. WHO set yaws eradication goals (initially 2020, extended to 2030).

Precise prevalence and incidence for bejel alone remain poorly characterized due to serological indistinguishability from other treponemal infections and limited surveillance in affected regions.

Inheritance Pattern

Not applicable. Bejel is an infectious disease with no Mendelian or polygenic inheritance pattern. Familial clustering reflects shared environmental exposure rather than genetic susceptibility.

Geographic Distribution

Population Demographics

• Classic bejel: Primarily children in rural, impoverished communities; no sex predilection (M:F ~1:1)
• Sexually transmitted TEN: Predominantly adult MSM, often HIV-co-infected
• Age distribution: Bimodal -- childhood in endemic settings; young to middle-aged adults in sexually transmitted cases

10. Diagnostics

Serological Tests (Primary Diagnostic Method)

Serological tests for bejel are identical to those for venereal syphilis, as the antigens of TEN and TPA are indistinguishable:

Critical Diagnostic Limitation

Serological tests CANNOT distinguish between TEN, TPA, and TPE infections. This is the single most important diagnostic challenge. Grillova et al. (2018) demonstrated: "Molecular identification of Treponema pallidum subsp. endemicum, the agent of bejel, in Cuban patients diagnosed with venereal syphilis indicates the clear limitations of a diagnosis based exclusively on serology, geographical occurrence, clinical symptoms and anamnestic data" (PMID: 29454847).

Direct Detection Methods

• Dark-field microscopy: Can visualize live spirochetes in lesion exudate; cannot distinguish subspecies
• Direct fluorescent antibody (DFA): Monoclonal antibody-based detection (PMID: 3897267)
• PCR: Can detect and amplify treponemal DNA from clinical specimens; subspecies determination requires additional targets

Molecular Typing (Essential for Subspecies Identification)

• Multi-locus sequence typing (MLST): Using TP0136, TP0548, TP0705 loci to differentiate TPA from TEN (PMID: 39415268)
• Multi-locus sequence analysis (MLSA): Definitive subspecies classification (PMID: 29454847)
• Whole-genome sequencing: Gold standard for subspecies identification; reveals genetically distinct TEN lineages in different geographic regions (PMID: 41987031)

Imaging

• X-ray of long bones: Periostitis, cortical thickening (sabre tibia), metaphyseal changes
• CT/MRI: Evaluation of nasopharyngeal destruction in tertiary disease

Differential Diagnosis

Screening

No routine population screening programs exist specifically for bejel. In endemic areas, treponemal rapid tests may be used for community surveys. Mass screening is integrated with WHO yaws/endemic treponematosis eradication programs.

11. Outcome / Prognosis

Survival and Mortality

• Mortality: Bejel is rarely directly fatal
• Life expectancy: Not significantly reduced with treatment; untreated tertiary disease causes significant morbidity but rarely death
• Disease-specific mortality: Deaths mainly from secondary infections of destructive lesions (historical)

Morbidity and Function

• Primary/secondary stages: Mild to moderate morbidity; mucous patches may be painful; periostitis causes bone pain
• Latent stage: No morbidity
• Tertiary stage: Severe morbidity including disfiguring facial destruction (gangosa), chronic bone pain and deformity, difficulty eating/breathing/speaking, and profound social isolation

Disease Course

• Complications: Secondary bacterial infection of ulcerative lesions; permanent scarring; nasopharyngeal stenosis
• Recovery potential: Excellent with early treatment; primary and secondary lesions resolve completely with penicillin. Tertiary destruction is irreversible.

Prognostic Factors

• Favorable: Early diagnosis and treatment; access to penicillin
• Unfavorable: Late presentation; tertiary disease; lack of healthcare access; macrolide resistance limiting alternative treatments
• No established prognostic biomarkers specific to bejel

12. Treatment

Pharmacotherapy

First-Line Treatment

Benzathine penicillin G (BPG) is the treatment of choice for all stages:

MAXO term: MAXO:0010357 (antibiotic treatment)

No documented penicillin resistance has ever been found in any T. pallidum subspecies.

Alternative Treatments

Azithromycin: NOT Recommended

Azithromycin should NOT be used for bejel treatment due to widespread macrolide resistance (A2058G mutation in 23S rDNA) found in circulating TEN strains. Most TEN strains from MSM in Japan carried this mutation (PMID: 34836779). The 2020 European syphilis guidelines exclude azithromycin as an alternative treatment at any stage (PMID: 33094521). This has significant implications for mass drug administration campaigns, as azithromycin is the WHO-recommended drug for yaws MDA.

Experimental Therapeutics

Linezolid has shown promise: in vitro bactericidal activity against T. pallidum at concentrations >=0.5 microg/mL, and in vivo efficacy similar to BPG in the rabbit model (hazard ratio 3.84; 95% CI 2.05-7.17; p < 0.0001 compared to untreated controls) (PMID: 33721817). Clinical trials are warranted.

Mass Treatment Campaigns

The WHO/UNICEF mass treatment campaigns of the 1950s-60s treated over 50 million individuals in 46 countries with remarkable success, dramatically reducing endemic treponematoses prevalence. Resurgence after discontinuation underscores the need for sustained surveillance and treatment (PMID: 2682125).

Surgical and Interventional

• Reconstructive surgery for tertiary gangosa (MAXO:0000004)
• Orthopedic intervention for severe bone deformities

Treatment Outcomes

• Response rate: >95% clinical cure with appropriate penicillin therapy
• Monitoring: Serial non-treponemal test titers (RPR/VDRL); fourfold decline expected within 6-12 months
• Side effects: Jarisch-Herxheimer reaction may occur after treatment initiation (febrile reaction from spirochete killing)

13. Prevention

Primary Prevention

• Improved hygiene and sanitation: Access to clean water, individual eating utensils, improved housing -- the most effective long-term strategy
• Socioeconomic development: Poverty reduction in endemic areas
• Health education: Community awareness of transmission routes (MAXO:0000015)
• Safe sexual practices: Relevant for emerging sexually transmitted TEN in MSM populations
• MAXO terms: MAXO:0000058 (preventive measure); MAXO:0000521 (hygiene intervention)

Secondary Prevention

• Mass drug administration (MDA): Community-wide treatment in endemic areas
• Active case finding: Surveillance in endemic communities and contact tracing
• Point-of-care testing: Rapid treponemal tests for field use
• Molecular surveillance: Essential for identifying TEN in non-endemic settings where it may be misdiagnosed as syphilis

Tertiary Prevention

• Early treatment: Prevents progression to destructive tertiary disease
• Reconstructive surgery for gangosa and other tertiary disfigurements
• Rehabilitation and psychological support

Immunization

No vaccine exists for bejel or any treponemal disease. Outer membrane proteins (TprK, TprC, TprD, BamA, FadL) are being investigated as candidate vaccine antigens (PMID: 35422800; PMID: 40802283). Cross-protection between subspecies suggests a universal treponemal vaccine might protect against all human treponematoses.

Public Health Interventions

• WHO eradication strategy: Mass treatment campaigns targeting endemic treponematoses elimination by 2030
• Integration with primary healthcare: Essential for sustained control (PMID: 1281363)
• Molecular epidemiological surveillance: MLST/WGS for tracking transmission and resistance
• Monitoring for macrolide resistance: Critical for MDA program design
• Doxycycline post-exposure prophylaxis (doxyPEP): Being explored for STI prevention in MSM populations; may have relevance for sexually transmitted TEN

14. Other Species / Natural Disease

Natural Treponemal Infection in Non-Human Primates

Treponematosis has been documented in non-human primates, particularly baboons in Africa. Knauf et al. (2015) found that 90% (18/20) of clinically healthy Guinea baboons (Papio papio) in Senegal tested positive for anti-T. pallidum antibodies, despite having no clinical symptoms. They noted that "the West African simian strain has been shown to cause sustainable yaws infection when inoculated into humans" and that "Guinea baboons in West Africa serve as a natural reservoir for human infection" (PMID: 26588087).

Treponematosis has also been documented in critically endangered Western chimpanzees (Pan troglodytes verus), caused by strains closely related to TPE (PMID: 39010964).

Comparative Biology

• Tpr gene evolution studies show higher variation between human subspecies than within them, supporting the three-subspecies classification (PMID: 16926243)
• All simian strains characterized to date are closely related to human yaws-causing TPE strains
• High prevalence and genetic diversity of T. paraluiscuniculi in wild European rabbits (>98% genome identity with human T. pallidum) (PMID: 38095473)

Zoonotic Potential

While direct zoonotic transmission of TEN has not been documented, the close genetic relationship between simian and human treponemes suggests non-human primates may serve as a reservoir complicating eradication efforts. This is a major concern for the WHO yaws eradication campaign.

15. Model Organisms

Hamster Model

The most relevant animal model for bejel is the LSH hamster model. Wicher et al. (1993) demonstrated that female hamsters infected with TEN before or during early pregnancy transmitted infection to the fetus: "Female LSH hamsters infected with Treponema pallidum subsp. endemicum before pregnancy or during early pregnancy transmit a form of syphilis to the fetus that is similar to human congenital syphilis. The offspring develops rhinitis, skin rash, failure to thrive, and hepatosplenomegaly" (PMID: 8335390). T. pallidum was detectable in livers, spleens, and nasal secretions, and IgM antibodies were detected in offspring serum.

Phenotype recapitulation: Good recapitulation of human congenital syphilis features Limitations: Not widely used; hamster immune reagents limited

Rabbit Model

The rabbit (Oryctolagus cuniculus) is the standard model for all T. pallidum subspecies. Applications include: - Drug efficacy testing: Linezolid showed comparable efficacy to BPG in the rabbit model (PMID: 33721817) - Pathogenesis studies: Understanding tissue invasion and immune evasion - Propagation: T. pallidum is propagated by intratesticular rabbit inoculation

In Vitro Systems

• Short-term co-culture systems (1-3 weeks) in rabbit epithelial cells
• Used for in vitro drug susceptibility testing
• Limitations: T. pallidum cannot be continuously cultured on artificial media

Mechanistic Model / Interpretation

The Dual Epidemiology of Bejel

The evidence reveals a striking duality in bejel's epidemiology that has fundamental implications for public health:

Classic Pathway (Childhood Non-Venereal Transmission): Environmental poverty and poor hygiene --> shared utensils/close contact --> oral mucosal inoculation in children --> progressive treponemal disease in endemic communities

Emerging Pathway (Adult Sexual Transmission): MSM sexual networks (often HIV+) --> genital mucosal inoculation --> clinical presentation indistinguishable from syphilis --> misdiagnosed by serology alone --> silent spread of TEN in non-endemic populations

The convergence of these pathways creates a critical diagnostic and surveillance gap: sexually transmitted TEN masquerades as syphilis, escaping detection by standard diagnostic algorithms. The non-clonal diversity of TEN strains in Cuba (PMID: 35687593) suggests that this is not a single-outbreak phenomenon but rather a persistent, circulating reservoir of misidentified infection.

Evolutionary Context

The intersubspecies recombination between TEN/TPE and TPA (PMID: 34791386) suggests that the boundaries between treponemal subspecies are more porous than previously appreciated. This has implications for: 1. Understanding the historical origins of syphilis (the "Columbian vs. pre-Columbian" debate) 2. Predicting whether TEN may acquire additional virulence factors from TPA (e.g., neurotropism) 3. Vaccine development -- a universal approach may be both feasible and necessary

Evidence Base: Key Literature

Limitations and Knowledge Gaps

1. Diagnostic ambiguity: The inability of serological tests to distinguish TEN from TPA means the true burden of bejel is unknown in both endemic and non-endemic settings. Many cases may be permanently misclassified as syphilis.

2. Limited molecular surveillance: Whole-genome sequencing and MLST are required for definitive subspecies identification but are not routinely performed in most clinical settings, especially in resource-limited endemic areas.

3. Incomplete clinical characterization of sexually transmitted TEN: Whether TEN can cause neurosyphilis, cardiovascular disease, or congenital disease in humans remains uncertain. The hamster model suggests congenital transmission is possible (PMID: 8335390), but human data are absent.

4. Macrolide resistance threat: The presence of A2058G mutations in TEN strains raises concerns about azithromycin-based mass drug administration campaigns in regions where bejel and yaws may co-circulate.

5. Zoonotic reservoir uncertainty: While non-human primates harbor closely related treponemes, the role of animal reservoirs in maintaining TEN transmission is unknown.

6. Historical bias: Most clinical descriptions of bejel date from the pre-molecular era (1950s-1970s), and some features attributed to bejel may have been misclassified.

7. Absence of molecular profiling: No transcriptomic, proteomic, or metabolomic studies have been conducted specifically on bejel patients. Immune response data are extrapolated from syphilis studies.

8. No vaccine: No vaccine candidates have been tested specifically against TEN, though cross-reactive immunity between subspecies suggests a universal treponemal vaccine might protect against all human treponematoses.

Proposed Follow-up Experiments / Actions

1. Implement molecular typing in STI clinics: Integrate MLST or targeted PCR-based subspecies identification into routine syphilis diagnostic workflows, particularly in MSM clinics and in regions with endemic treponematoses. This would quantify the true burden of sexually transmitted TEN.

2. Prospective cohort study of sexually transmitted TEN: Recruit MSM diagnosed with TEN to characterize clinical outcomes longitudinally, including potential neurological and cardiovascular complications, and determine whether disease course differs from venereal syphilis.

3. Surveillance for macrolide resistance in endemic areas: Screen TEN and TPE isolates from Sahel Africa and the Middle East for 23S rDNA A2058G and A2059G mutations before implementing azithromycin-based MDA campaigns.

4. Investigate congenital TEN in humans: Conduct retrospective molecular analysis of archived samples from congenital syphilis cases in endemic bejel regions to determine whether congenital bejel occurs in humans.

5. Non-human primate reservoir assessment: Characterize simian treponemes in West and Central Africa molecularly to determine whether TEN (as distinct from TPE) circulates in animal reservoirs.

6. Comparative transcriptomics: Perform RNA-seq on skin/mucosal biopsies from bejel and syphilis patients to identify subspecies-specific host response signatures that might inform differential diagnosis.

7. Universal treponemal vaccine development: Leverage advances in structural characterization of outer membrane proteins (TprK, TprC, TprD, BamA, FadL) to develop vaccine candidates with cross-subspecies protection.

8. Point-of-care molecular diagnostics: Develop a rapid, field-deployable PCR or LAMP-based assay that can distinguish TEN from TPA and TPE to support eradication campaigns in endemic regions.

Report generated: 2026-05-05. Based on analysis of 69 peer-reviewed publications spanning molecular epidemiology, genomics, immunology, clinical medicine, and public health. This report is intended to populate a comprehensive disease knowledge base entry for Bejel (MONDO:0001714).