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Congenital Syphilis and the Prozone Phenomenon: Case Report

Catueno, Samanta MD*; Tsou, Po-Yang MD, MPH*; Wang, Yu-Hsun MD, MPH*; Becker, Emily MD*,†; Fergie, Jaime MD*‡

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The Pediatric Infectious Disease Journal: June 2022 - Volume 41 - Issue 6 - p e268-e270
doi: 10.1097/INF.0000000000003522
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Syphilis is caused by the spirochete Treponema pallidum. Syphilis left untreated, or inadequately treated during pregnancy, can result in congenital syphilis.1 In the United States in 2018, the incidence of congenital syphilis was 33.1 cases per 100,000 live births, representing a 39.7% increase relative to 2017, and a 185.3% increase relative to 2014. This increase has paralleled increases in primary and secondary syphilis among all women and reproductive-age women during 2014 to 2018.2

Here, we report a 3-month infant with congenital syphilis presenting with recurrent exanthem and persistent rhinorrhea since birth. His diagnosis was delayed caused by the false negative result on prenatal screening secondary to prozone phenomenon and incorrect diagnoses in the initial encounters.


A 1-month-old male infant was seen by his pediatrician for persistent nasal congestion, intermittent emesis, fever, and exanthem with ulceration involving arms, face, and the scalp with scattered hair loss, and mouth ulcers.

He was the product of the first pregnancy of his 17-year-old mother. Her pregnancy was complicated by gestational diabetes and preeclampsia. Her human immunodeficiency virus (HIV), hepatitis B, rapid plasma reagin (RPR), and group B streptococcus were negative in her prenatal care. The boy was born via vaginal delivery after a prolonged labor of 18 hours, and there were no reported complications except for neonatal jaundice requiring phototherapy. Since records from the nursery were not available, this episode of neonatal jaundice could be assumed to be physiologic, although it could also be an early sign of syphilis.

Patient was diagnosed with an upper respiratory tract infection and amoxicillin was prescribed. The fever resolved but not the exanthem. A course of topical silver nitrate cream was further prescribed, which led to resolution of the exanthem. However, similar exanthem reoccurred when he was 2 months old. He was referred to Dermatology, where he was initially diagnosed with congenital syphilis based on clinical findings. This was confirmed by positive RPR test and skin biopsy demonstrating the presence of spirochetes. Patient was admitted to Driscoll Children’s Hospital, Corpus Christi, TX.

On admission, he was irritable but afebrile. On physical examination, he was microcephalic (head circumference 4th percentile) but with normal weight and height. He had a generalized maculopapular annular and erythematous exanthem on the chest, upper back, neck, palms, and soles (Fig. 1). He also had desquamation of the skin in the perioral area and scalp with hair loss, serous nasal discharge, white plaques in the buccal mucosa, hepatomegaly, and occipital as well as cervical adenopathy. His white blood cell count was 11.6 th/µL, Hgb 8 gr/dL, mean corpuscular volume 81.5 fL, platelets 608,000 th/µL, and C-reactive protein of 5.3 mg/dL. His RPR result was 1:128, which was confirmed by a reactive fluorescent treponemal antibody (FTA) IgG and IgM. In the spinal fluid, there were 5 white blood cells, 0 red blood cell, glucose 55 mg/dL, and protein 41 mg/dL, with a negative result on Venereal Disease Research Laboratory test. Blood culture, urine culture, cerebrospinal fluid culture, HIV testing, and cytomegalovirus urine polymerase chain reaction were negative for bacterial or viral infection during the hospitalization. His electrolytes, liver function, and renal function were unremarkable. Radiograph revealed bilateral tibial Wimberger’s sign. The brain magnetic resonance imaging was unremarkable. Upon admission, penicillin G IV was administered (50,000 U/kg every 6 hours for 10 days). After confirming the diagnosis of congenital syphilis his mother, who initially had a negative result on prenatal screening for syphilis, tested positive, with a Venereal Disease Research Laboratory titer of 1:16, and a reactive FTA IgG and IgM. An RPR was also done, which was initially negative. After requesting the laboratory to dilute the sample, RPR was positive. She was prescribed doxycycline for secondary syphilis.

FIG. 1.:
Generalized maculopapular annular and erythematous rash on admission (left), with almost complete resolution 4 days after discharge (right).

After the 10-day antimicrobial treatment, the exanthem had significantly improved, and he was discharged. On follow up 4 days after hospital discharge, he had near complete resolution of the rash and the rhinorrhea, with only minimal erythema at sites of previous involvement and no mucosal lesions (Fig. 1).


This case report describes the classical presentation of congenital syphilis, an important medical and public health problem, and highlights the problem of the increase in syphilis cases in the United States.

Congenital syphilis usually results from lack of prenatal care and adequate treatment for syphilis before or during pregnancy.3 The transmission rates are highest in primary and secondary stages of maternal syphilis infection (40%–90%).4 Untreated intrauterine syphilis infections cause abortion, stillbirth, or preterm delivery in 30%–40% of the cases.3 Up to two-thirds of patients with congenital syphilis are asymptomatic after birth.3 When symptoms appear, the disease may manifest in 2 categories: early congenital syphilis and late congenital syphilis.1 Early congenital syphilis is usually identified by 3 months of age but could be as late as 2 years of age. Classic symptoms include organomegaly, jaundice, anemia, thrombocytopenia, mucocutaneous lesions, generalized edema, and orofacial abnormalities.1 Bone involvement is very frequent, with periostitis and cortical demineralization of long bones, and osteochondritis of knees, ankles, wrists, and elbows.5 Late congenital syphilis is diagnosed any time after 2 years of age and symptoms include syphilitic rhinitis, vasculitis, interstitial keratitis, and neurologic and skeletal abnormalities.1 Laboratory diagnosis is based on a two-stage process1: The screening test using nontreponemal studies (eg, RPR) and the confirmatory test using treponemal studies (eg, FTA-ABS).6 A 4-fold increase in the nontreponemal serologic titer in the infant, compared with the mother, is confirmatory of congenital syphilis.1 The recommended treatment regimen for congenital syphilis is intravenous aqueous crystalline Penicillin G, prescribed as 50,000 U/kg every 12 hours during the first week of life, and increased to every 8 hours after the first week of life for a 10-day course.6 For infants age 1 month and older, the recommended treatment is intravenous penicillin G 200,000 to 300,000 U/kg/day, administered as 50,000 U/kg every 4 to 6 hours for 10 days.6 After discharge, infants should have structured follow up that includes nontreponemal serologic testing every 3 months until the tests are nonreactive or the titers are <4-fold.1

RPR, one of the antenatal screenings for syphilis, could be falsely negative secondary to multiple factors such as drugs, malignancy, malaria, viral infections, tuberculosis, collagen vascular disease, pregnancy itself, and the prozone phenomenon.6 This phenomenon occurs when an excess of antibody prevents the formation of the antibody-antigen lattice network needed to visualize a positive flocculation reaction. This occurs in 2% of cases of primary or secondary syphilis.7 Serum dilution re-establishes the proper concentrations of antibody and antigen that allow lattice formation.7 The predictive value and cost benefit of screening pregnant women for syphilis depends on the prevalence of the disease in the population being tested. Because the cost of treating infants with congenital syphilis is so high, screening and treatment of almost all populations of infected women is cost beneficial.7 Besides the traditional diagnostic algorithm described earlier, in which a positive nontreponemal test is confirmed by a treponemal test to avoid a false positive test, a “reverse algorithm” was introduced in 2009, which starts with a treponemal test, and positive samples are retested with a quantitative RPR. If the test is nonreactive, samples are retested using another treponemal test such as T. pallidum particle agglutination assay (TP-PA), confirming the infection is positive. If negative, could reflect very early disease or a false positive on the initial treponemal test, and in areas of high prevalence would be advisable to assume disease.8 Rac et al8 proposed that the reverse method would be more cost-effective for high volume laboratories due to automation and objective interpretation of the results.

One of the advantages of the reverse method, in our opinion, is the avoidance of the prozone phenomenon when screening starts with a treponemal test. In the presented case, the patient’s mother underwent the traditional screening algorithm, with a negative RPR, which contributed to the missed diagnosis of syphilis.

The incidence of congenital syphilis has steadily increased throughout the United States,2,9 and the reasons are most likely multifactorial.8 The remarkable increase in the number of cases of primary and secondary syphilis among women of childbearing age is mirrored by increasing numbers of congenital syphilis cases and increasing infant mortality.10 Men who have sex with men, HIV coinfection, having multiple sex partners, practicing unsafe sex, and illicit drug use are identified as some of the contributing factors to the marked increase in the incidence of syphilis in the United States.9 There are marked racial disparities in pregnant patients with syphilis, with African American women as one of the most affected groups, and geographic differences in congenital syphilis rates, with the south of the United States as the most affected region,8 all of which could show the impact of socioeconomic conditions in this matter. Important barriers in the successful management of congenital syphilis include lack of access to prenatal care, screening during pregnancy, and lack of access to adequate treatment. One of the strategies proposed by the Centers for Disease Control and Prevention, the key to prevent congenital syphilis is routine testing at the first prenatal visit for all pregnant women, and in the second trimester and delivery for high-risk women and those living in high prevalence areas.1 To timely diagnose and treat congenital syphilis, pediatricians should be aware of the local prevalence of syphilis, varied clinical manifestations of congenital syphilis and the false negative caused by prozone phenomenon.


Congenital syphilis continues to be a major public health issue due to multiple factors. The varied clinical manifestations, surging syphilis rate, inadequate prenatal care, and false negative result due to prozone phenomenon may lead to delayed diagnosis of congenital syphilis in developed countries. This case report helps raise awareness of the difficulties of the diagnosis and review the clinical presentation as well as treatment for congenital syphilis.


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2. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2018. U.S. Department of Health and Human Services; 2019.
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Syphilis; congenital syphilis; prozone phenomenon

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