Keywords
congenital syphilis - leukemia - leukoerythroblastic anemia - maternal syphilis
A common misconception in modern medicine is the notion that congenital syphilis is
a disease of the past; that the terms “snuffles” and “Hutchinson's triad” are merely
words we read in textbooks. On the contrary, after years of steady decline in reported
cases, recent data from the United States have shown that the prevalence of this disease
is again on the rise.[1]
[2] The resurgence of congenital syphilis in the United States represents a failure
of our current health care practices to identify and manage untreated maternal syphilis
cases. Every new case of congenital syphilis represents a system failure that would
have otherwise been easily prevented. Infants with congenital syphilis may be asymptomatic
at birth or present with a variety of early or late manifestations that can prove
to be a diagnostic challenge to pediatricians. We report a case of a 5-week-old infant,
whose mother received routine prenatal care, who presented with unusual manifestations
of congenital syphilis.
Case Study
A 5-week-old male was brought by his parents to the emergency department (ED) with
a 1-day history of progressive “gasping for air.” He had been born at 37 weeks' gestation
after an uncomplicated pregnancy. Before presentation, the parents reported that the
infant had breastfed well and had normal urine and stool output. The mother also reported
that 2 weeks prior, the infant developed a red, patchy rash on his right foot that
spread centrally to cover his entire body eventually. The rash waxed and waned over
2 weeks and had lessened by the time he presented to our facility. Upon questioning,
the mother reported adequate prenatal care and denied complications or infections
during pregnancy or delivery.
In the ED, the infant had hypothermia (36.2°C), a respiratory rate of 33 breaths per
minute (though deep inspiration was noted), normal heart rate of 114 beats per minute,
and a normotensive blood pressure of 81/63 mm Hg. Birth weight was 3,300 g (between
25th and 50th percentile), height was 53 cm (90th percentile) while head circumference
was not documented. Upon admission, the weight had increased by 720 g to 4,020 g,
and the head circumference was 36 cm (10th percentile). Physical examination revealed
an inactive, frail-appearing infant with significant pallor and dry mucous membranes.
He had grunting with intermittent gasping. There were diffuse salmon-colored patches
that did not blanch and could be felt deep into the subcutaneous tissue. The lesions
were around his mouth and on his extremities and trunk. There was poor peripheral
perfusion but no cardiac murmurs appreciated. There was splenomegaly with minimal
hepatomegaly. The infant had a normal tone with no focal neurological deficits.
Initial laboratory workup revealed severe metabolic acidosis with profound anemia,
thrombocytopenia, leukemoid reaction, and electrolyte abnormalities ([Table 1]). A chest radiograph showed no acute cardiopulmonary disease. Abdominal ultrasound
demonstrated hepatosplenomegaly. Blood, sputum, and urine cultures were obtained while
a lumbar puncture was deferred until the second day of hospitalization due to thrombocytopenia
and coagulopathy.
Table 1
Initial laboratory test results
|
Test
|
Result
|
Normal range
|
|
Complete blood count
|
|
White blood cells
|
53.7 K/µL
|
5–19.5
|
|
Neutrophils, %
|
23
|
15–35
|
|
Lymphocytes, %
|
65
|
41–71
|
|
Monocytes, %
|
7
|
3–15
|
|
Band neutrophils, %
|
1
|
0–10
|
|
Blasts, %
|
1
|
0–0
|
|
Myelocytes, %
|
1 (each)
|
0–0
|
|
Promyelocytes, %
|
|
Metamyelocytes, %
|
|
Hemoglobin
|
1.9 g/dL
|
9–18
|
|
Hematocrit
|
6.7%
|
28–55
|
|
Platelet Count
|
7 K/µL
|
150–450
|
|
Coagulation studies
|
|
Protime
|
21.7 s
|
11.8–15
|
|
INR
|
1.9
|
|
|
Prothrombin time
|
34.9 s
|
22.9–37.8
|
|
Fibrinogen level
|
145 mg/dL
|
215–485
|
|
D-dimer quantitative
|
1.74 µg/mL
|
<0.5
|
|
Blood chemistry
|
|
Sodium
|
125 mEq/L
|
130–145
|
|
Potassium
|
2.9 mEq/L
|
3.4–6.6
|
|
Chloride
|
95 mEq/L
|
98–110
|
|
Carbon dioxide
|
8 mEq/L
|
20–27
|
|
Glucose
|
57 mg/dL
|
45–100
|
|
Blood urea nitrogen
|
15 mg/dL
|
3–19
|
|
Creatinine
|
0.27 mg/dL
|
0.20–0.80
|
|
Total bilirubin
|
2.3 mg/dL
|
0.3–1.8
|
|
Protein
|
3.7 g/dL
|
4.4–6.8
|
|
Albumin
|
1.2 g/dL
|
2.7–4.7
|
|
Calcium
|
8.2 mg/dL
|
8.5–11.2
|
|
Magnesium
|
2.0 mg/dL
|
1.6–2.5
|
|
Phosphorus
|
2.1 mg/dL
|
3.7–7.0
|
|
Aspartate aminotransferase
|
72 IU/L
|
10–60
|
|
Alanine aminotransferase
|
26 IU/L
|
17–63
|
|
Alkaline phosphatase
|
348 IU/L
|
67–391
|
|
Lactate dehydrogenase
|
387 IU/L
|
150–300
|
|
Uric acid
|
4.3 mg/dL
|
2–8.1
|
|
Blood gases
|
|
Arterial pH
|
7.28
|
7.35–7.45
|
|
Arterial Pco
2
|
14.7 mm Hg
|
35–45
|
|
Arterial Po
2
|
165 mm Hg
|
80–110
|
|
Arterial HCO3
|
7.0 mmol/L
|
22–26
|
|
Arterial base excess
|
−18 mmol/L
|
−3 to 3
|
|
Lactic acid
|
16.6 mmol/L
|
0.5–2.2
|
The infant was admitted to the pediatric intensive care unit with a working diagnosis
of severe leucoerythroblastic anemia, suspicious of leukemia. He was emergently intubated
with the placement of arterial and central venous catheters. He was transfused with
packed red blood cells and platelets while correcting his electrolytes and acid/base
status. Empiric antibiotics were initiated. Flow cytometry, peripheral blood smear,
and bone marrow aspirates were all negative for malignancy. Also, autoimmune hemolytic
anemia was ruled out by a negative Coombs test. The pediatric infectious diseases
service became involved due to suspicion of congenital infection and concerns for
sepsis. A comprehensive review of maternal prenatal laboratories revealed a maternal
rapid plasma reagin (RPR) performed at the time of delivery that was reactive at a
titer of 1:128 (normal: nonreactive). The mother was not aware of this positive result,
nor had she been treated during pregnancy or after delivery. She also denied history
of syphilis and had a nonreactive RPR during her previous pregnancy 5 years earlier.
The infant was immediately started on intravenous (IV) aqueous penicillin G (50,000
units/kg every 4 hours). He was found to have a reactive RPR titer of 1:128 and a
positive IgM fluorescent treponemal antibody absorption test (normal: nonreactive).
Cerebrospinal fluid (CSF) findings were: VDRL positive (normal: negative), white blood
cells (WBC) 74/µL (normal: 0–30/µL), protein 570 mg/dL (normal: 12–60 mg/dL), and
glucose 59 mg/dL (normal: 45–75 mg/dL). An ophthalmologic examination, long bone radiographs,
and cranial ultrasonography were normal. Additional infectious workup was unrevealing
([Table 2]). The infant was weaned off sedation and extubated on the second hospital day. He
completed an uneventful 14-day course of IV penicillin. Upon discharge, his hemoglobin
was 9.6 g/dL, and his platelet count was 227 K/µL. In the infectious diseases clinic,
6 weeks after discharge, he was asymptomatic with a normal physical examination. He
had a WBC count of 9.31 K/μL, hemoglobin of 9.3 g/dL, platelet count of 276 K/µL,
reticulocyte count of 2.5%, alanine aminotransferase of 27 IU/L, and an RPR titer
of 1:64 (i.e., a twofold decrease from pretreatment titer). His long-term neurodevelopmental
outcome remains uncertain; however, follow-up at the age of 6 months revealed normal
growth and development. He had a normal CSF profile, including a negative CSF VDRL,
and a further drop of his RPR titer to 1:16 (an eightfold drop from pretreatment titer).
Future follow-up to repeat his RPR test is planned.
Table 2
Additional infectious workup
|
Test
|
Specimen
|
Result
|
|
Epstein–Barr virus PCR
|
Blood
|
Undetected
|
|
Human immunodeficiency virus
|
Blood
|
Undetected
|
|
Parvovirus B19 PCR
|
Blood
|
Undetected
|
|
Rubella serology
|
Serum
|
Negative
|
|
Cytomegalovirus PCR
|
Urine
|
Negative
|
|
Respiratory viral PCR panel for:
• Influenza A
• Influenza B
• Respiratory syncytial virus
• Adenovirus
• Parainfluenza viruses
• Human metapneumovirus
|
Nasopharyngeal aspirate
|
Negative
|
Abbreviation: PCR, polymerase chain reaction.
The patient's mother and father both received treatment for syphilis with adequate
clinical and laboratory response.
Discussion
The prevalence of congenital syphilis is again on the rise after years of decline,
despite well-established preventative techniques, such as maternal screening, and
treatment. In 2014, the national rate of congenital syphilis in the United States
was 11.6 per 100,000 live births. This had increased from 8.4 in 2012, where it had
fallen from 107 in 1991.This dramatic 38% increase from 2012 to 2014, not surprisingly,
coincided with a 22% increase in rates of syphilis in women during the same time period.[2] The Centers for Disease Control and Prevention (CDC) recommends that all pregnant
women should be screened for several sexually transmitted infections (STI), including
syphilis, at least once during pregnancy, specifically at their very first prenatal
visit.[3] Screening for syphilis should be repeated at the time of delivery and at 28 weeks
of gestation in high-risk settings (e.g., a history of STI [particularly human immunodeficiency
virus], IV drug use, and homelessness and having multiple partners).
As our case demonstrates, there is significant variation, and unusual ways in which
congenital syphilis may present. In fact, syphilis has often been deemed “the great
imitator” because of the many possible ways it presents. Of particular importance
is differentiating congenital syphilis from leukemias that may affect infants (e.g.,
congenital leukemia, juvenile myelomonocytic leukemia, or congenital acute lymphoblastic
leukemia). Both entities can present with pallor, lethargy, skin manifestations (syphilitic
rash vs. leukemia cutis), hepatosplenomegaly, and a leukemoid reaction. Complete blood
count (CBC) findings in congenital syphilis often mirror findings of leukemia (e.g.,
leukocytosis, anemia, and thrombocytopenia). Several cases of congenital syphilis
reported in the literature presented with a CBC picture mimicking malignant disease
(e.g., leucoerythroblastic response, or lymphocytosis).[4]
[5] Thus, it is not surprising that congenital syphilis is often misdiagnosed as congenital
leukemia at first. Fortunately, unlike infants diagnosed with congenital leukemia,
congenital syphilis is easily and inexpensively treated.
Congenital syphilis may result in fetal death in up to 40% of cases, and the case
fatality ratio in the United States between 1992 and 1998 was 6.5%.[6] Fetal infection may occur as early as 9 weeks of gestation with the risk increasing
with gestational age. Infection may also occur upon contact with an infectious maternal
lesion at the time of birth. Pregnant women newly infected with syphilis may not be
aware of symptoms, particularly if their ulcers are painless and on the internal genital
tract. Screening of pregnant women remains an essential tool for prevention of congenital
syphilis. However, incomplete or absent serologic screening in pregnant women is not
uncommon. Close follow-up, and serologic monitoring of mother and fetus are indicated
after maternal treatment. However, despite receiving a single-dose penicillin regimen,
as many as 14% of women with secondary syphilis in late pregnancy will still have
a fetal death or deliver an infant with congenital syphilis.[7] All infants born to women with syphilis should be evaluated for congenital infection
based on interpretation of paired mother–infant serologic tests and in the context
of maternal history (i.e., stage of syphilis, treatment details, and serologic response).
Every new case of congenital syphilis is a demonstration of the Swiss Cheese Model
of system failure, in which many mistakes are usually made and missed, resulting in
a devastating result for the newborn. In the case of congenital syphilis, the first
opportunity for prevention of this outcome occurs with primary prevention of syphilis
infection in men and women. The second opportunity occurs with treatment of syphilis
upon diagnosis to prevent its morbidity and spread. The third opportunity occurs upon
screening for maternal infection during pregnancy. While the fourth opportunity occurs
with treatment of said maternal infection during pregnancy to reduce the chance of
transmission to the fetus or newborn. A final, yet crucial, opportunity is detection
and treatment of congenitally infected newborns by the pediatrician, preferably before
discharge from the nursery. Unfortunately for our patient, all these opportunities
were missed due to a combination of avoidable human and system errors.
Conclusion
Congenital syphilis is by no means an extinct entity of the past. It is imperative
for pediatricians attending to newborns in the normal nursery to formally confirm
the status of maternal syphilis screening before discharge. Also, primary care providers
should maintain a high index of clinical suspicion and a broad list of differential
diagnoses that include congenital syphilis when caring for infants who present with
severe anemia or leukocytosis suggestive of leukemia. Our case illustrates the need
to increase the efforts to raise public and provider awareness of this ancient, yet
ever-present, disease. It also emphasizes the role of vigilant providers in preventing
system errors and improving outcomes.
