PEDIATRICS Vol. 104 No. 1
July 1999,
p. e4
ELECTRONIC ARTICLE:
Pituitary Gland Gumma in Congenital Syphilis After Failed
Maternal Treatment: A Case Report
Arthur E. Benzick, MD*,
Darren P. Wirthwein, MD
,
Arthur Weinberg, MD,
George D. Wendel,
Jr, MD§,
Rajiha Alsaadi*,
N. Kristine Leos*,
Fiker Zeray, RN*, and
Pablo J. Sánchez, MD*
From the Departments of * Pediatrics, Pathology, and
§ Obstetrics and Gynecology, University of Texas Southwestern Medical
Center at Dallas, Dallas, Texas.
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ABSTRACT |
A preterm, very low birth weight infant was born to a
mother with early latent syphilis who was treated 10 days and 3 days before delivery with 2.4 mU of benzathine penicillin. The infant had
clinical, laboratory, and radiographic abnormalities consistent with
congenital syphilis, ie, a Venereal Disease Research Laboratory test titer that was fourfold greater than was the maternal titer, hepatosplenomegaly, abnormal liver function tests, pneumonitis, osteochondritis of the long bones, and cerebrospinal fluid (CSF) examination showing a reactive Venereal Disease Research Laboratory test, pleocytosis, and elevated protein content. The infant died on the
third day of life, and an autopsy revealed an evolving gumma of the
anterior pituitary. Immunoglobulin M immunoblotting of serum and CSF
was positive, and polymerase chain reaction detected Treponema
pallidum DNA in endotracheal aspirate and CSF. This case
highlights the pathologic abnormalities observed in congenital syphilis
and focuses on the rare finding of an evolving anterior pituitary
gumma. Furthermore, it documents the failure of maternal syphilis
treatment during the last 4 weeks of pregnancy to cure fetal infection
and supports the recommendation that all infants born to mothers with
syphilis treated during the last 4 weeks of pregnancy should receive
penicillin therapy.
Key words:
congenital syphilis,
gumma,
maternal syphilis,
congenital infection,
infant.
The elimination of congenital syphilis has remained an
elusive goal of public health policy. Worldwide, syphilis remains a significant cause of neonatal morbidity and mortality. Its occurrence during pregnancy, especially among racial and ethnic minority populations who underutilize the health care system is associated with
spontaneous abortion, stillbirth, nonimmune hydrops, preterm delivery,
and perinatal death.1 The continued occurrence of
congenital syphilis in both industrialized and developing nations highlights the need to better understand the extent of neonatal infection with Treponema pallidum and, in particular, its
effect on the central nervous system (CNS).2
Although the clinical and pathologic manifestations of congenital
syphilis in the CNS have been described, few reports discuss pituitary
abnormalities.3-7 We report a case of a preterm infant
with congenital syphilis who, at autopsy, had an evolving gumma in the
anterior pituitary gland. The failure of appropriate maternal
penicillin therapy during the last 4 weeks of pregnancy to treat
adequately the fetal infection emphasizes the need for evaluation and
treatment of these high-risk infants.
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CASE REPORT |
A 1236-g male infant was delivered vaginally at 26 weeks of
gestation (85% weight for gestational age) to a 26-year-old gravida V,
para V Latin American female. Prenatal serologic tests at 22 weeks of
gestation revealed an absence of antibodies to human immunodeficiency
virus, a negative hepatitis B surface antigen test, and immunity to
rubella but a Venereal Disease Research Laboratory (VDRL) test titer of
1:16 with a reactive microhemagglutination assay for T
pallidum antibody test. A rapid plasma reagin test that was
performed 12 months earlier was nonreactive. The mother was diagnosed
with early latent syphilis, and she received 2 doses of 2.4 mU of
benzathine penicillin G, 10 days and 3 days before delivery. One day
after her second dose of benzathine penicillin G, she developed preterm
labor, and subsequently, she presented to the labor suite 4 hours
before delivery. Ampicillin for group B streptococcal chemoprophylaxis
and dexamethasone for promotion of lung maturation were administered 2 hours before delivery. There was no history of illicit drug use.
Maternal VDRL titer at delivery was 1:16.
The infant had Apgar scores of 5 and 6 at 1 and 5 minutes,
respectively. Respiratory distress developed shortly after birth, and
the infant required mechanical ventilation. Physical examination revealed a hypertonic infant with a head circumference in the 40th
percentile, a peeling skin rash over the extremities and trunk, a
protuberant abdomen with a liver palpable 4 cm below the right costal
margin in the midclavicular line, and a spleen palpable 2 cm below the
left costal margin. Laboratory studies showed a hemoglobin level of
14.3 g/L; a hematocrit level of 43%; a white blood cell count of
1.8 × 109/L with 33% segmented neutrophils, 5% band
forms, 3% metamyelocytes, 48% lymphocytes, and 6% monocytes; and a
platelet count of 143 × 109/L. VDRL titer performed
on umbilical cord blood was 1:128. Liver function tests showed an
aspartate aminotransferase of 108 U/L, an alanine aminotransferase of
14 U/L, alkaline phosphatase of 178 U/L, 
-glutamyltransferase of
2476 U/L, and total bilirubin of 6.6 mg/dL with a direct component of
2.4 mg/dL. The infant was treated initially with ampicillin (50 mg/kg
IV q 12 hours) and gentamicin (2.5 mg/kg IV q 24 hours). At 16 hours of
life, he had a lumbar puncture performed, and therapy with aqueous
penicillin G (50 000 U/kg IV q 12 hours) was initiated because of a
presumptive diagnosis of congenital syphilis. The cerebrospinal fluid
(CSF) examination showed a VDRL titer of 1:32, a white blood cell count of 65 (4% segmented neutrophils, 50% lymphocytes, 43% monocytes, 1%
eosinophils, 1% basophils, and 1% atypical lymphocytes), a red blood
cell count of 55, and glucose and protein concentrations of 34 mg/dL
and 767 mg/dL, respectively. Urine culture for cytomegalovirus was
sterile. Cytogenetic analysis revealed a normal male karyotype.
Chest radiograph (Fig 1) was consistent with
pneumonitis. Cranial ultrasound revealed moderate ventriculomegaly with a slightly enlarged fourth ventricle but no evidence of
intraventricular hemorrhage (Fig 2). Long
bone radiographs showed osteochondritis of both upper and lower
extremities, consistent with a diagnosis of congenital syphilis.
Because of the abnormal neurological examination, cerebral
abnormalities, and continued respiratory deterioration, the infant was
removed from life support, and subsequently, he died on the third day
of life.
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Fig. 1.
Chest radiograph of infant showing increased interstitial markings
consistent with pneumonitis. Note osteochondritis affecting the
iliac crest.
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Consent for an autopsy was granted by the parents. The findings were
consistent with the diagnosis of congenital syphilis. The placenta
weighed 618 g (>90th percentile). The triad of focal villitis
with mononuclear infiltration, vascular abnormalities consisting of
endothelial proliferation and perivascular fibrosis and inflammation,
and immature villi were characteristic of syphilis. In addition, there
was neutrophilic infiltration of the chorion and amnion with focal
microabscesses suggestive of acute chorioamnionitis.
The pancreas, spleen, thymus, lungs, kidneys, and testes demonstrated
lymphocytic infiltration with extensive fibrosis in the pancreas,
capsule of the spleen, and interstitium of the thymus. There was
prominent extramedullary hematopoiesis in the portal areas of the liver
with focal subcapsular fibrosis and giant cell transformation. The
tibiae and femurs displayed reactive periostitis of the metaphyses with
thickening of the cortex and irregularity of the growth zone. Steiner
staining of the liver, spleen, pancreas, tibia, and femur demonstrated
no spirochetes.
Macroscopic examination of the brain revealed yellow cloudy CSF and
enlarged lateral ventricles. Microscopically, there was lymphocytic
infiltration of the leptomeninges and of the walls of the cerebral
vessels. A friable yellow mass extended from the anterior pituitary
gland under the optic chiasm and into the anterior sella turcica (Fig
3). This mass was comprised of necrotic debris and degenerating neutrophils. Steiner stain of this lesion demonstrated numerous spirochetes; this was consistent with an evolving
gumma of the anterior pituitary gland (Fig
4). There also was lymphocytic and plasma
cell infiltration with fibrosis in the meninges overlying the pituitary
gland. In addition, the frontoparietal area of the brain as well as the
temporal lobes and basis pontis showed extensive neuronal and white
matter loss with intense gliosis, microcystic change, and infiltration
by macrophages. These changes were consistent with extensive
hypoxic/ischemic encephalopathy.
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Fig. 3.
Gross photograph of base of skull shows pituitary gland and evolving
syphilitic gumma. A indicates the anterior fossa; P indicates the
posterior fossa;  indicates the anterior pituitary;  indicates
the optic nerves; and the star indicates the evolving pituitary
gumma.
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Fig. 4.
Photomicrograph of histologic section from pituitary gland shows
neutrophils and necrotic anterior pituitary cells (hematoxylin-eosin,
original magnification 200 ×). Inset: Spirochetes
visualized by Steiner stain of gummatous lesion in anterior pituitary
gland. (original magnification 100 ×).
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The infant's serum and CSF were tested for immunoglobulin M (IgM)
antibodies against specific T pallidum antigens by
immunoblotting as previously described.2 IgM antibody
directed against the 47-kd antigen of T pallidum was
detected in both serum and CSF. The infant's endotracheal aspirate,
blood, and CSF, which was obtained from the lumbar puncture as well as
at autopsy, were tested by polymerase chain reaction (PCR) for specific
T pallidum DNA as previously described.2 Rabbit
infectivity testing (RIT) of the infant's blood and lumbar CSF was
performed as previously described.2 Both PCR and RIT of
the clinical specimens were performed after the infant had received 2 doses of ampicillin; PCR of CSF obtained at autopsy was performed after
3 days of penicillin therapy. PCR of blood and lumbar CSF was negative,
although PCR of endotracheal aspirate and CSF from autopsy was
positive. RIT of blood and CSF failed to detect spirochetes.
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DISCUSSION |
This case of congenital syphilis highlights the clinical
manifestations and extensive organ destruction that can accompany treponemal infection. In addition, it describes the unusual finding of
an evolving gumma of the pituitary gland in a newborn. Involvement of
the pituitary gland in congenital syphilis typically consists of
interstitial inflammation and fibrosis of the anterior lobe and, less
commonly, miliary gummas, whereas the neurohypophysis usually remains
intact.3,4 In a review of gummas of the hypophysis and
hypothalamus, Fink4 cited Simmonds who, in 1914, found
pituitary changes at autopsy in 5 of 12 (42%) infants with congenital
syphilis. In 1971, Oppenheimer and Hardy3 reported
hypophyseal abnormalities in 5 (38%) of 13 cases of congenital syphilis, with the anterior lobe showing typical interstitial inflammation and fibrosis but no gummas. In a subsequent review of 432 autopsies of infants and fetuses with congenital syphilis, Oppenheimer
and Dahms8 described "abscess-like necrosis" in
various organs including the adenohypophysis. The incidence of
hypophyseal disease was not noted. They considered these lesions to be
similar to the suppurative inflammation that occurs within dilated
thymic Hassle's corpuscles in some patients with congenital syphilis
known as Dubois' abscesses. However, the comparison of the destructive
extrathymic lesions seen in the current case to intracorpuscular
Dubois' abscesses seems tenuous. Although it is true that gummas in
adult tertiary syphilis contain only rare treponemes and lack
suppuration, the evolution of lesions in congenital syphilis does not
mimic exactly the evolution of syphilitic disease in adults. It is more
likely that large areas of suppurative necrosis with peripheral
fibrosis and the numerous spirochetes found in congenital syphilis
represent an evolving form of gumma unique to congenital
disease.9
In contrast to the pituitary gland, syphilitic abnormalities involving
the brain or meninges are uncommon in autopsy cases,3 although CNS invasion by T pallidum occurs in the majority
of infants who have clinical, laboratory, and/or radiographic
abnormalities of congenital syphilis.2 Because hypophyseal
involvement occurs more commonly in autopsy cases, it may be that the
majority of infants with CNS invasion survive their infection, whereas hypophyseal invasion represents a more significant disease resulting in
death.
In 1993, Daaboul et al7 described 2 infants who had
reactive serum and CSF VDRL tests and who presented with hypoglycemia and were later diagnosed with hypopituitarism. Of the 2 infants, 1 died
at ~2 months of age secondary to necrotizing enterocolitis and was
found to have almost total effacement of the anterior pituitary lobe by
fibrosis. Pituitary function was not evaluated in our patient; however,
he never experienced alterations in glucose homeostasis. It is likely
that if he had survived, the extensive destruction of the anterior
pituitary gland that was present at autopsy would have resulted in
pituitary dysfunction. Therefore, evaluation of pituitary function is
recommended in infants with congenital syphilis who manifest persistent
hypoglycemia and/or abnormal growth.
This case also addresses important issues concerning the treatment of
mothers with syphilis during pregnancy and the risk of fetal infection.
Maternal penicillin treatment during pregnancy is considered adequate
fetal therapy in the majority of cases. However, as many as 14% of
pregnant women who are adequately treated with penicillin will have
fetal demise or deliver infants with clinical evidence of congenital
syphilis.1 The majority of these women were treated for
secondary syphilis, and this stage is associated with a high degree of
spirochetemia leading to placental and fetal infection.10
A second dose of benzathine penicillin G administered 1 week after the
initial dose has been recommended by some authorities for treatment of
early syphilis during pregnancy to minimize the risk of fetal treatment
failure. The mother of our patient received 2 weekly injections of
benzathine penicillin G before delivery, and at autopsy there were no
spirochetes detected in placental tissue or non-CNS organs. However, it
was not sufficient to treat effectively an established fetal infection
of the CNS, and it has been suggested that the CNS may represent a
sequestered site for persistence of treponemal infection despite the
administration of systemic penicillin therapy.11
Concern has been raised as to the adequacy of maternal treatment for
syphilis during the final 4 weeks of pregnancy to prevent or treat
fetal infection.12 The majority of fetal treatment failures have occurred when maternal treatment was provided late in
gestation. It may be that the increases in renal clearance and plasma
volume that occur as pregnancy progresses result in lower serum and CSF
penicillin concentrations in both the mother and fetus.13
Moreover, when maternal treatment occurs late in gestation (ie, during
the last 4 weeks of pregnancy), there may not be sufficient time for
the fetus to be treated adequately. However, it is also clear that the
clinical, laboratory, and radiographic abnormalities seen in infants
with congenital syphilis take several months to resolve and that their
presence may not be indicative of active infection in the newborn. The
visualization of spirochetes in the pituitary gland in our patient
along with a positive PCR performed on CSF obtained at autopsy support
ongoing infection. This is also supported by the infant's umbilical
cord VDRL titer, which was fourfold greater than was the maternal titer
at delivery. We also detected IgM antibody directed against specific
T pallidum antigens in this patient's serum and CSF, and
these findings support the diagnosis of congenital syphilis, because
IgM antibody is unable to cross the placenta.2 We were
unable to detect either the organism or T pallidum DNA in
blood and CSF. This was most likely attributable to the fact that both
the mother and infant received antimicrobial therapy before the
clinical specimens were obtained. These results support our previous
findings that a positive IgM immunoblot may be the only marker of fetal
infection with T pallidum.
Pneumonia alba, a focal obliterative fibrotic lesion consisting of
interstitial scarring and thickening of the alveolar walls with loss of
alveolar spaces, is the classic pulmonary lesion seen at autopsy in the
lungs of infants with congenital syphilis. It typically has a
roentgenographic appearance of complete opacification of the lung
fields. In our patient, chest radiograph showed bilateral haziness of
the lung fields and increased interstitial markings. The clinical
course was suggestive of pneumonia and T pallidum DNA was
detected in the endotracheal aspirate by PCR, supporting the role of
T pallidum in causing the roentgenographic abnormalities. This was also confirmed at autopsy by the finding of an interstitial lymphocytic infiltrate in the lungs that was consistent with pneumonia.
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CONCLUSION |
In summary, this case highlights some of the major clinical and
pathologic findings seen in early congenital syphilis, while focusing
on the rare autopsy finding of an evolving gumma in the pituitary gland
of a newborn. Furthermore, it documents the failure of maternal
syphilis treatment during the last 4 weeks of pregnancy to cure fetal
infection. This failure was demonstrated by the abnormal physical
examination of the infant at birth, an infant VDRL titer that was
fourfold greater than was the maternal titer, the finding of
spirochetes in the anterior pituitary gland, a positive PCR of CSF
obtained at autopsy, and a positive serum IgM immunoblot. This case
supports the recommendation from the Centers for Disease Control and
Prevention and the American Academy of Pediatrics that all infants born
to mothers with syphilis treated during the last 4 weeks of pregnancy
should receive penicillin therapy.14,15
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ACKNOWLEDGMENTS |
This work was supported by US Public Health Service Grant 1R29
AI 34932-01 from the National Institute of Allergy and Infectious Diseases and Centers for Disease Control and Prevention Contract C1000689.
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FOOTNOTES |
Received for publication Sep 15, 1998; accepted Mar 1, 1999.
Reprint requests to (P.J.S.) UT Southwestern Medical Center,
5323 Harry Hines Blvd, Dallas, TX 75235-9063. E-mail:
psanch{at}mednet.swmed.edu
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ABBREVIATIONS |
CNS, central nervous system;
VDRL, Venereal Disease
Research Laboratory;
CSF, cerebrospinal fluid;
PCR, polymerase chain
reaction;
RIT, rabbit infectivity testing.
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Abstract
Discussion
