Unusual presentation of secondary syphilis: membranoproliferative glomerulonephritis andmuco-cutaneous lesions

Case report

A 30-year-old man presented with a three-week history of a generalized erythematous macular rash associated with a few papular elements and intense diffuse scaling (Figure 1(a)) along with multiple erosions and ulcers of the orolabial and anal mucosae (Figure 1(b)). Superficial lymph nodes were palpable in the cervical, axillary, and inguinal regions. He also reported low-grade evening fevers, headache and general malaise during the previous month. Clinical history was otherwise unremarkable. Blood analysis revealed leukocytosis, increased erythrocyte sedimentation rate (95 mm/h; normal range <15 mm/h for men <20 years) and C-reactive protein (20 mg/dL; normal range 0–10 mg/L), reduced albumin (3.1 g/dL; normal range 3.5–5.5 g/dL), creatinine of 1.7 mg/dL and BUN of 31 mg/dL (normal range 0.6–1.2 mg/dL and 7–20 mg/dL, respectively). Urine testing showed hematuria (100 erythrocytes/µL), bilirubinuria, and a protein level exceeding 300 mg/dL; a 24-h urine collection revealed 2.5 g/24 h of protein with 1.2 g/L urinary albumin. Systolic and diastolic hypertension was also present. Kidney ultrasound showed no significant alterations. Normal levels of serum C3 with slightly reduced C4 (7 mg/dL), increased serum IgG and IgM (2560 mg/dL and 570 mg/dL, respectively). Autoimmune study was negative for antinuclear, anti-dsDNA, antineutrophil cytoplasmic antibodies and rheumatoid factor, with normal levels of IgA. Testing for HBV, HCV, HIV, parvovirus B19, HSV1-2, EBV, CMV and anti-streptolysin-O titer was negative. Serologic testing for syphilis revealed positive TPHA and VDRL at a titer of 1:256. Based on these results, the patient was again interviewed, and he reported episodes of unprotected sex in the previous eight months. A kidney biopsy specimen of 15 glomeruli was obtained for histopathologic, immunohistochemical and ultrastructural studies. Immunofluorescence showed C3 and IgG subendothelial deposits. The findings were consistent with the diagnosis of post-infective membranoproliferative glomerulonephritis (MPGN) (Figure 2) eliciting a nephritic syndrome. The patient received benzathine penicillin G, 2.4 × 10⁶ U intramuscularly. Mucosal erosions healed within three weeks; complete renal function was restored within one month, along with blood pressure and urinalysis. VDRL titer was 1:64 after four months and 1:16 after eight months. No relapse and/or re-infection was observed at 12-month follow-up, thus confirming an MPGN caused by Treponema pallidum.

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Figure 1.

Maculo-papular exathema with diffuse scaling (a) and mucous patches of the upper and lower orolabial mucosa (b).

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Figure 2.

Histopathologic studies of renal glomeruli show increased cellularity and lobular appearance of the glomerular tuft on hematoxylin and eosin stain (a) (original magnification (OM) 200×), along with thickened glomerular membranes and endocapillary proliferation on Jone’s Methenamine Silver Stain (b) (OM 400×). Immunohistochemical staining demonstrates that the glomerular hypercellularity is mainly due to the monocyte-macrophage component CD68+ (OM 400×) (c). Electron micrograph shows a segment of a glomerular capillary with discrete subendothelial electron-dense deposits (asterisks) and the double contour of the basement membrane (UAR-SEM, Uranyl Acetate Replacement Stain Electron Microscopy, ×15,000).

Discussion

The worldwide re-emergence of secondary syphilis, which has happened in the last decade, has led to an increase in primary and secondary syphilis cases, along with the presentation of atypical forms. Classical secondary syphilis signs such as condylomata lata (i.e., soft pinkish vegetative lesions of the anogenital area) or Biett’s collarette of papular syphiloderma were absent in our patient.

Although the exact prevalence of syphilitic nephropathy has yet to be assessed, case reports are nowadays increasing, compared with previous years.^1–6 Renal involvement in adults with secondary syphilis is usually characterized by proteinuria and/or nephrotic syndrome and rapid response to penicillin, while nephritic syndrome is rarely reported.^1–6 Based on histopathological studies, we know that membranous glomerulonephritis (MGN) is the most commonly described form,^1–4 followed by diffuse endocapillary GN (with or without the formation of crescents), minimal change GN and rapidly progressive GN.^1–5 Post-infectious MPGN in the adult population is usually elicited by hepatitis C and B, followed by Staphylococcus aureus and less commonly by other viral (HIV and parvovirus B19) or protozoal (malaria, schistosomiasis, leishmaniasis, filariasis, and toxoplasmosis) infections. ⁶ On the contrary, syphilis-induced MPGN has been described in infants with congenital syphilis and nephritic syndrome.^7,8 The exact pathogenetic mechanism is still unclear: both a direct glomerular injury occurring during the spirochetaemic phase and chronic exposure to T. pallidum causing formation and deposition of immune-complexes in renal glomeruli have been suggested.^7–9 In our patient, the intense antigenemia occurring at the beginning of secondary syphilis is likely to have induced an acute immune-complex formation and deposition, generating glomerular damage.

Accurate clinical history taking, thorough examination and focused laboratory investigations should be carried out in order to exclude other possible differential diagnoses. Indeed, the association of general malaise, macular scaling skin rash, oral and anal ulcers, asthenia, and nephritis can be observed in other diseases such as systemic lupus erythematosus (SLE), erythema multiforme (EM), and pemphigus vulgaris (PV) or drug-induced pemphigus.^10–13 Patients with SLE may present with malaise, headache, erythematous macular skin rash, oral ulcers, and, in about 50% of cases, nephritis.^10,11 However, oral ulcers of SLE are usually palatal and painless and the rash is generally more pronounced, with confluent and persistent lesions. Besides, the patient’s clinical history and the absence of lupus serology can exclude SLE; moreover, a full house pattern was absent in renal biopsy. In EM, the macular rash rapidly develops following a drug intake (after 24–48 h) and lesions spread to both cutaneous and mucous areas, with a peculiar targetoid appearance. ¹¹ Although papular syphiloderma can also be targetoid in shape, they usually localize on palms and soles, and occasionally on the face. PV and drug-induced pemphigus can be ruled out in the absence of primary bullous lesions of the oral cavity and a clinical history negative for drug intake; furthermore, the renal involvement is represented by an IgA interstitial nephritis related to the drug reaction. ¹⁰ HIV infection should be always suspected and excluded in the presence of fever, lymphoadenopathy, malaise and skin rash. Finally, a Mycoplasma pneumoniae infection can manifest with headache, malaise, oral ulcers, and an acute post-infectious glomerulonephritis. However, fever develops rapidly in the majority of cases, either moderate or high.

In conclusion, an unrecognized syphilitic infection should be suspected in sexually active patients presenting with nephritic syndrome of sudden onset that is otherwise unexplained, associated with generalised symptoms and atypical muco-cutaneous lesions. To confirm this, adequate interpretation of clinical signs and/or symptoms, syphilis testing serology and renal studies, along with therapy response monitoring and follow-up should be carried out.