In 1873, the Norwegian doctor Gerhard Hansen’s disease made an important discovery in the history of medicine, and first identified Mycobacterium leprae as the pathogen causing leprosy. Therefore, leprosy is also known as “Hansen’s disease” (1).

Leprosy is a chronic infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis that primarily affects the skin and peripheral nerves. However, it can also involve mucous membranes, eyes, and bones, leading to a wide range of clinical presentations. The exact transmission mechanisms of M. leprae are not fully understood; however, evidence indicates that the disease primarily spreads through the upper respiratory tract. Prolonged close contact with an untreated patient with multibacillary leprosy, likely via infectious aerosols, is considered a key factor in transmission. Additionally, Mycobacterium leprae prefers to multiply in cooler areas, typically around a mean surface temperature of 27.4 °C. The decrease in intraoral temperature was mainly due to the bacilli initially invading the nasal passages, causing obstruction. This leads individuals to breathe through the mouth, allowing incoming air to lower oral temperature (2).

Data from the World Health Organization (WHO) in 2023 show that there are approximately 180,000 new cases globally, with an incidence rate of 22.7 per million, an increase of 5% compared to 2022. The Southeast Asian region had the highest proportion of new cases (71.9%), whereas the European region had the lowest (<1%). From 2014 to 2023, the number of new cases globally decreased by 14.6% overall. In China, 315 new cases were reported, with an incidence rate of 0.2 per million population. According to a survey by Sun Peiwen et al., by the end of 2020, there were 1,893 registered leprosy patients in China, a significant decrease compared with 6,032 cases in 2010 (3). Although substantial achievements have been made in the field of leprosy prevention and control, there are deep-rooted misunderstandings and prejudices against leprosy in society. As a result, patients and their families may still suffer from discrimination and exclusion in many aspects of life and find it difficult to integrate into society.

In view of this, it is of great significance to better understand the various clinical features of leprosy, especially the presentation of atypical cases, to improve the accuracy of clinical diagnosis, optimize treatment, and reduce social discrimination. This article reports a case of borderline lepromatous leprosy initially presenting with generalized swelling, aiming to provide guidance to improve diagnostic clarity as a reference basis for clinicians and to promote further development of leprosy prevention and control.

The patient, a 52-year-old female farmer, presented with a six-month history of generalized edema and erythema on the trunk and extremities, along with numbness in the hands and feet in the previous 3 months. Six months previously, without any obvious precipitating factors, the patient reported the development of edema of the face, trunk, and extremities. There was also mild numbness in the hands and feet, yet no pain was experienced; therefore, she did not seek medical advice at that time. Over the subsequent 3 months, erythema emerged in the lumbar region, accompanied by mild pruritus, but no stinging sensation. The number of skin lesions progressively increased and spread to the extremities, buttocks, abdomen, back, neck, and face. Moreover, numbness in the hands and feet was more pronounced. The patient visited a local rural hospital (the specific diagnostic and therapeutic measures were unclear). Following a comprehensive biochemical profile, complete blood count, and abdominal and cardiac B-mode ultrasonography, no remarkable abnormalities were observed. To pursue further diagnosis and treatment, the patient attended our department’s outpatient clinic in May 2023.

Throughout the course of the disease, the patient had good spirits. Her diet, sleep, urination, and defecation were normal with no significant weight changes. She had a history of hypertension, but irregularly took antihypertensive medication. She denied any history of infectious diseases, such as tuberculosis and hepatitis B, coronary heart disease, or diabetes. There was no family history of leprosy and the patient had no known drug allergies.

On specialized physical examination, the patient had scattered, variably sized, round, oval, irregular hypopigmented macules across the face, neck, trunk, and extremities. A large infiltrated plaque was noted in the lumbar area along with mild facial and earlobe swelling. The lesions had blurred borders and dry surfaces on some scales (Figures 1A–F). The skin in some lesional areas was slightly indurated, with reduced elasticity. The dorsal surfaces of the hands, lower legs, and ankles showed evident edema with mild pitting features. No thickened nerves were palpable in or around the lesions, and the warm and pain sensations were normal. The patient exhibited normal vision, complete eyelid closure, active blinking, and no conjunctival redness or swelling.

Thickening of the superficial nerves was not observed. Muscle atrophy or ataxia was not observed. The abdominal wall reflexes were normal. No deformities were observed in the extremities. The bilateral biceps brachial, triceps brachial, knee tendon, and Achilles tendon reflexes were normal. The bilateral Babinski, Gordon, and Oppenheim signs were all negative.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that parasitizes the cytoplasm of macrophages and Schwann cells. Its main pathological features include granuloma formation and neurotropism. It mainly affects the skin and the peripheral nerves. Primary skin lesions usually present as erythema or hypopigmented macules with sensory loss (4). Several leprosy classification methods have been proposed. Rabello was the first to propose a classification system for leprosy, defining the undefined type of leprosy as the early form and introducing the concept of disease polarity - untreated cases can progress to tuberculous or tumor-like types. In 1953, this classification was further expanded, incorporating the less stable ‘boundary type’ subcategory (5, 6). Based on this classification, Ridley-Jopling further refined it, considering the correlations between skin lesion types, bacterial quantities, and cellular immune levels. They expanded the polarity system into five levels, namely leprosy can be classified as tuberculoid leprosy, borderline tuberculoid leprosy with intermediate borderline features, borderline papular leprosy, and papular leprosy. This has become a modern recognized classic classification system (7, 8). In addition, the WHO has developed a simple classification system for field use. Based on the number of skin sores, leprosy is divided into paucibacillary (PB, five or fewer skin sores) and multibacillary (MB, more than five skin sores) (9, 10). Based on this classification method, the patient was diagnosed with multi-bacillary borderline lepromatous leprosy.

Leprosy presents with complex and diverse clinical manifestations and has historically been referred to as the “Great Imitator,” making it difficult to diagnose, especially when patients present with atypical symptoms.

First, When the clinical manifestations of the skin lesions are diverse, such as erythema, papules, nodules, or maculopapular lesions without numbness or sensory abnormalities, misdiagnosis is common. Literature has shown that leprosy may be mistaken for mycosis fungoides, hemophagocy lymphohistiocytosis, sarcoidosis, or systemic lupus erythematosus (11–14). For example, a 55-year-old male presented with copper-colored papular lesions (0.3–0.5 cm in diameter) on the soles and red papules on the lower and upper legs, but no other symptoms, a presentation resembling secondary syphilis, but later considered leprosy (15). Another rare case involved a 36-year-old pregnant woman at 29 weeks of gestation, who developed pruritic papules over her body and large nodular lesions on her lower limbs without itching, initially misdiagnosed as pruritic urticarial papules and plaques of pregnancy (PUPPP) (16).

Second, when skin lesions present as hypopigmented or mildly discolored patches without numbness or inflammation, they may be misdiagnosed as vitiligo, tinea versicolor, or other dermatoses. In one case, a Nigerian immigrant to Italy developed widespread, pruritic, and poorly demarcated hypopigmented patches that tended to coalesce. After immunological, hematological, and allergological tests, biopsy, and empirical antifungal treatment, no definitive diagnosis was made. Only when numbness and sensory loss developed in the legs, and another biopsy with microbiological tests was performed, was the diagnosis of borderline lepromatous multibacillary leprosy confirmed (17)^.

Third, patients may present without skin lesions, showing only isolated peripheral nerve involvement such as nerve thickening, numbness, or muscle weakness. When only one nerve is affected, it is easily misdiagnosed as peripheral neuritis, nerve compression syndrome, local trauma, or entrapment neuropathy. A neurologist in Italy reported a patient whose primary presentation was inflammatory myopathy, ultimately diagnosed with leprosy (18). A 38-year-old man presented with radiating pain in the right leg and a tender, swollen area below the fibular head with radiation to the lateral leg, no skin lesions, and mild sensory deficit, eventually diagnosed with leprosy (19). In another rare case described by Maurya et al., the patient had only sensory symptoms, such as numbness over the dorsum of the right foot, without detectable muscle weakness or skin lesions. Deep tendon reflexes were normal (20). Studies have shown that 45–60% of leprosy cases involve the muscles, often without obvious symptoms. Pathological changes may be neurogenic or myogenic in nature. Approximately 30% of cases present with myositis, yet only 25% show detectable M. leprae in muscle tissue (21–23).

Fourth, when patients present with other atypical symptoms such as joint pain or synovitis, they may be misdiagnosed with rheumatoid arthritis. Ocular manifestations, such as iritis or keratitis, can be the initial symptoms leading to misdiagnosis. Lymphadenopathy may be mistaken for tuberculous lymphadenitis or lymphomas. In some cases, multisystem involvement occurs, with fever, weight loss, anemia, and skin rashes, making the diagnosis more difficult. One case involved a 43-year-old woman with recurrent fever, superficial lymphadenopathy, and multiple facial and body rashes, without pain, itching, or burning. She also had sensory deficits in the eyes, hands, and feet, although there was no motor dysfunction. The patient was eventually diagnosed (24). Another patient presented with unexplained fever, anemia, wasting syndrome, and neuropathy and was ultimately diagnosed with leprosy (25). These cases suggest that bone marrow involvement should be considered when cytopenia and a positive epidemiological history are observed.

The immune response of the borderline type of leprosy with granulomas lies between the tuberculous type and the tumor type. Previous reported cases have shown the diversity of their clinical manifestations, particularly in terms of edema-related and other atypical symptoms (see Table 1 and Supplementary Table S1 for details) (26–45). The clinical manifestations are somewhat unstable and can transform into either the tuberculous type or the tumor type. In the reported cases of this study, the patients presented with generalized edema as the initial symptom, followed by skin lesions and numbness in the hands and feet as the disease progressed. There have been cases with generalized edema reported in the past, but they were not the initial symptoms. For instance, the case reported by Sujoy Ghosh et al. (32) occurred during the course of the disease. There are also reports of cases where edema appeared in the hands, feet, and limbs as the initial symptom, such as those by Barman KD, Moulick A, and Guerra MG (37, 42, 44). However, no studies have reported cases with generalized edema as the initial symptom. Some of the above reports and this case indicate that edema is one of the clinical symptoms that occur in leprosy patients, especially in the form of swelling in the hands and feet, and generalized edema can also occur in leprosy patients.

This may result from early immune responses involving a Th17/Treg imbalance, which leads to the release of inflammatory mediators. These mediators cause local vasodilation and increased vascular permeability, resulting in fluid leakage into interstitial tissues and subsequent swelling. Studies suggest that leprosy patients have reduced suppressive activity of regulatory T cells (Tregs) and increased activity of T helper 17 (Th17) cells. Th17 cells secrete cytokines like IL-17, IL-21, and IL-22, which promote neutrophil infiltration and inflammatory swelling (46–48). In addition, immune complex deposition in vessels contributes to further inflammation and secondary vasculitis, damaging vessel walls, impeding venous return, and preventing metabolic waste removal, thus worsening edema (49–51). These mechanisms may explain the facial, trunk, and limb edema observed in the present case, which may be misdiagnosed as cardiac or renal causes of edema.

Beyond edema, borderline lepromatous leprosy can present with various other atypical symptoms, such as skin ulcers, nerve thickening, ocular involvement, testicular pain, nasal congestion, and nipple abnormalities, which are summarized in Supplementary Table S1 for comprehensive reference.

Although leprosy is curable and preventable, its historical stigma persists, fueling public misunderstandings and discrimination. This psychological burden often delays or deters patients from seeking care. To mitigate these challenges, a multi-faceted strategy is essential.

These cases demonstrate the diversity and complexity of the clinical manifestations of leprosy. Although the prevalence of leprosy worldwide is currently low, with ease of international travel, it is still possible for leprosy cases to occur anywhere. This requires clinicians to enhance their understanding of the various presentations of leprosy and to be well prepared for diagnosis.