Hemophagocytic Lymphohistiocytosis Masquerading as Child
Abuse:
Presentation of Three Cases and Review of Central Nervous System
Findings in Hemophagocytic Lymphohistiocytosis
Laura Rooms, MD*; Nancy Fitzgerald, MD‡; and Kenneth L. McClain, MD, PhD*
ABSTRACT. Hemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting
from abnormal proliferation of histiocytes in tissues and organs. Although the
disease generally presents with systemic symptoms such as pancytopenia,
coagulopathy, and organomegaly, HLH may also present with central nervous system
(CNS) manifestations. CNS events can range from irritability to encephalopathy
and coma. Retinal and intracranial hemorrhages are among the neuropathologic
findings in these children. Patients who present with CNS findings may have
symptoms that mimic those of inflicted injury. These children are at risk,
therefore, for misdiagnosis as victims of child abuse. Such an error causes not
only unnecessary additional trauma to the family but also, more important, a
delay in initiating effective therapy. We present 3 cases of children with HLH
who initially came to medical attention with neurologic findings, all suspected
to be victims of child abuse. Subsequent laboratory evaluations, however, were
consistent with the diagnosis of HLH. No additional evidence of child abuse was
obtained, and the charges eventually were dropped. Two of
the 3 children died from their disease shortly after presentation; the third is
surviving with no evidence of HLH several months after allogeneic bone marrow
transplantation. Although the diagnosis of child abuse certainly is all too
common, clinicians need to be diligent and informed to avoid assigning this
label erroneously. Several laboratory findings of HLH may alert physicians to
the
possibility of this diagnosis. The timely diagnosis of and institution of
therapy for HLH may reduce ultimate morbidity and mortality. Pediatrics
2003;111:e636–e640. URL:
http://www.pediatrics.org/cgi/content/full/111/5/e636;
child abuse, hemophagocytic lymphohistiocytosis.
ABBREVIATIONS. HLH, hemophagocytic lymphohistiocytosis; CNS, central nervous
system; ED, emergency department; PT, prothrombin time; PTT, partial
thromboplastin time; CT, computed tomography.
Hemophagocytic lymphohistiocytosis (HLH), a rare disorder primarily of
childhood, typically presents with fever, hepatosplenomegaly, lymphadenopathy,
and sometimes vague or dramatic central nervous system (CNS) dysfunction.
Supporting laboratory evidence includes cytopenias, elevated liver enzymes and
hyperbilirubinemia, coagulopathy, hypertriglyceridemia, hyperferritinemia, and
hypofibrinogenemia.1 When untreated, the disease is uniformly fatal. Optimal
therapy consists of cytotoxic and immunosuppressive chemotherapy with the HLH-94
protocol.2 Abone marrow transplant, given a suitable donor, provides the
greatest chance for a cure in very young children or in those with the familial
form of HLH. Although some cases are thought to be associated with virus
infection, others manifest a familial inheritance pattern, and a large
percentage of cases have no definable cause. Because of the relative rarity of
the disorder as well as unfamiliarity on the part of physicians, the diagnosis
can be elusive even with a classic presentation.
We report 3 cases of patients who received a diagnosis of HLH
after an atypical presentation involving CNS events initially suspected to be
evidence of child abuse. It is hoped that an increased awareness of HLH by
primary care and emergency department (ED) physicians will lead to prompt
initiation of proper therapy and avoidance of inappropriate accusations of child
abuse.
CASE REPORTS
Case 1
A Vietnamese boy was born at 35 weeks’ gestation to a 23-yearold Gravida 2 Para 1
mother by cesarean section performed because of preterm labor. The pregnancy was
otherwise uncomplicated, and the child’s birth weight was 2926 g (6 lb 7 oz)
with Apgar scores of 9/9. After a brief hospitalization to rule out sepsis
(maternal group B streptococcus status unknown), the patient was discharged in
good condition with the mother. The family history was remarkable for
consanguinity of the maternal great-grandparents, a maternal uncle who died at 3
years of age in Vietnam of unexplained “internal bleeding,” and retinitis
pigmentosa in the mother. The patient’s older sibling is healthy. On the 11th
day of life, the infant began to refuse feedings and cry inconsolably. After
several hours, the mother noticed that the infant was cold and blue, so he was
rushed to a local hospital ED where he was found to have profound hypothermia
and acidosis. In the ED, the patient had a temperature of 89°F (32°C) and pH of
6.9. His weight had decreased to 2200 g. Laboratory test abnormalities, aside
from acidosis, included a shortened prothrombin time (PT), prolonged partial
thromboplastin time (PTT), and slightly elevated alanine aminotransferase (Table
1). He received appropriate resuscitation and was transferred to the neonatal
intensive care unit. The patient developed seizure activity that was controlled
with Phenobarbital and a sepsis evaluation was negative. Acomputed tomography
(CT) scan of his head revealed moderate left-sided subdural hemorrhage with
cerebral edema and mass shift (Fig 1). An electroencephalogram was likewise
abnormal, consistent with diffuse encephalopathy. Ophthalmic From the Baylor
College of Medicine, Department of Pediatrics, *Texas Children’s Cancer Center
and Hematology Service and ‡Edward B. Singleton Diagnostic Imaging Department,
Houston, Texas. Received for publication Aug 19, 2002; accepted Dec 23, 2002.
Address correspondence to Kenneth L. McClain, MD, PhD, Texas Children’s
Hospital, 6621 Fannin St, CC1510.00, Houston, TX 77030. E-mail:
kmcclain@txccc.org
PEDIATRICS (ISSN 0031 4005). Copyright © 2003 by the American Academy
of Pediatrics.
e636 PEDIATRICS Vol. 111 No. 5 May 2003 http://www.pediatrics.org/cgi/content/full/111/5/e636
examination revealed bilateral predominately peripheral perivascular retinal
hemorrhages with peripheral retinal necrosis compatible with an infectious cause
versus shaken infant syndrome. The composite findings of subdural hemorrhage,
failure to thrive, and retinal hemorrhages resulted in the diagnosis of shaken
infant syndrome. The patient and his older sibling were placed under child
protective custody. Approximately 2 months after a prolonged hospitalization for
malabsorption, the patient became febrile and was placed on antibiotics.
Cultures of the blood and cerebrospinal fluid were negative. During the next 7
days the patient developed massive hepatosplenomegaly resulting in respiratory
compromise. He also had a coagulopathy (PT 22.9 seconds/PTT 146.5 seconds) and
pancytopenia with an absolute neutrophil nadir of 250/ L, platelet count 27 000/
l, and hemoglobin of 9 g/dL (90 g/L). Liver function studies were abnormal with
mild unconjugated hyperbilirubinemia and ferritin of 19 923 ng/mL. Abone marrow
biopsy and aspirate revealed hemophagocytosis confirming diagnosis of HLH. The
patient was treated on the HLH-94 protocol with dexamethasone, VP-16, and
cyclosporine and improved dramatically over the next several weeks.
Approximately 6 months after diagnosis, he underwent a bone marrow transplant
and is cured of the HLH. Because of the diagnosis of HLH with its CNS
manifestations, the diagnosis of shaken infant syndrome was removed. The patient
and sibling were returned to parental custody after a social services
investigation failed to find other evidence of child abuse.
Case 2
A 4-month-old white boy had a 2-day history of fussiness, difficulty sleeping, a
small amount of bleeding from his nares, and an ecchymoses on his chest
(possibly from mild trauma by a sibling). On the evening before his death, the
child fed poorly, had a fever of 100.6°F, and had a high-pitched cry. He was
found pale, yellow, and cold by his mother and taken to a community hospital
with apparent seizures. Ahead CT showed a subdural and intraparenchymal bleeding
with no skull fracture and a unilateral enlarged pupil. Radiologic examinations
of the abdomen and skeleton revealed no intra-abdominal trauma or fractures. He
was transferred to a tertiary medical center, where bilateral retinal
hemorrhages and the chest ecchymoses were noted. Throughout the medical records
were comments that the brain and eye findings were the result of inflicted
injury. He had no lymphadenopathy or enlargement of the liver or spleen. In the
tertiary medical center, laboratory evaluations showed anemia hemoglobin of 8.8
g/dL (80 g/L), normal white blood cell count (9000/ L), and platelet count (544
000/ L), but elevated liver function tests alanine aminotransferase 363
U/L (6.1 kat/L), aspartate aminotransferase 414 U/L (6.9 kat/L), lactate
dehydrogenase 1305 U/L (21.7 kat/L), PT (20 seconds), PTT (46 seconds), and
elevated triglycerides of 194 mg/dL (2.2 mmol/L). He had a craniotomy to
evacuate the subdural bleed and vigorous support with transfused red cells,
platelets, fresh-frozen plasma, and ventilatory assistance. Despite these
interventions, he died 36 hours after presenting to the community hospital. An
autopsy showed focal hemophagocytic histiocytic infiltrate consistent with HLH
in the leptomeninges and the subdural hemorrhage (Fig 2A). Within the bilateral
retinal hemorrhages and perioptic sclera were hemophagocytic histiocytes (Fig
2B). The bone marrow, lymph nodes, and spleen did not have lymphohistiocytic
infiltrates. There was no family history of consanguinity or possible HLH. Fig
1. CT of brain without contrast. Extra-axial hemorrhage of the left temporal,
frontal, occipital, and parietal regions. Diffuse subarachnoid hemorrhage in the
basilar cisterns and along the tentorium on the left and posterior
interhemispheric falx, as well as focal hemorrhages in the cortex and subcortex
of the left occipital
parietal lobe. Diffuse brain edema is also present. TABLE 1. Summary of Clinical
and Laboratory Findings
Laboratory Data
(Normal Values)
Case 1
Initial
Case 1
HLH Diagnosis
(3 Months Later)
Case 2 Case 3
Seizure X X X
Retinal hemorrhages X X
Intracranial hemorrhage X X
Brain edema X X
Hepatosplenomegaly X X
Abnormal skeletal findings X
Hemophagocytosis X X X
WBC (5–19.5 103/ L) 16.1 5.21 16.6 6.19
ANC (1–8.5 103/ L) 9.36 0.250 10.9 2.17
Platelets (150–450 103/ L) 246 27 544 51
Hemoglobin (9.5–14.1 gm/dL) 11.6 9 7.3 12.5
Ferritin (20–236 ng/mL) ND 19 923 ND 20 286
Triglycerides (20–150 mg/dL) 105 136 194 66
PT/PTT (10.5–14.5/21–34 s) 9.3/39.8 22.9/146 22/46 16/81
AST (20–60 U/L) ND 363 363 719
ALT (6–50 U/L) 54 377 414 161
Bilirubin (mg/dL; unconjugated/
conjugated; 0.35/ 1.0)
0/9.4 1.6/0 0.6/1.3
WBC indicates white blood cells; ANC, absolute neutrophil count; AST, aspartate
aminotransferase;
ALT, alanine aminotransferase; ND, not done.
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Case 3
A7-week-old male Nigerian infant was found unresponsive and asystolic in his
child care center. The emergency medical service resuscitated him but noted that
the pupils were fixed and dilated and his liver was 3 cm below the costal
margin. On arrival at the Texas Children’s Hospital ED, his pH was 7.12 and he
had a platelet count of 51 000/ L, a prolonged PTT, and elevated liver enzymes
(Table 1). Anoncontrast brain CT showed no hemorrhage or skull fracture, but
hypodense areas of both posterior temporal and parietal lobes were indeterminate
for infarct or edema versus white matter immaturity. Askeletal survey
demonstrated periosteal new bone of the left humeral midshaft and mild cortical
irregularity of the left medial tibial cortex for which a traumatic cause could
not be excluded (Fig 3). Periosteal new bone formation of the medial right tibia
seemed to be physiologic. Ventilatory support, fluid resuscitation, transfusions
of hemoglobin and platelets, plus infusions of fresh-frozen plasma corrected
some of these abnormalities. The patient had multiple seizures. Repeat
noncontrast brain CT performed 2 days after admission revealed severe brain
edema without herniation or bleed and extensive areas of hypodensity in the deep
gray nuclei. Because of
the suspicion of HLH, a serum ferritin was drawn and found to be 20 286 ng/mL.
Abone marrow aspirate was diagnostic of HLH, and treatment was initiated with
dexamethasone and VP-16 after
obtaining informed consent from the parents. No family history of consanguinity
or possible HLH was determined. Unfortunately, this child’s neurologic condition
continued to deteriorate and the parents agreed to withdrawal of life support.
Permission for a postmortem examination was declined.
DISCUSSION
The preceding case reports illustrate that HLH can present with symptoms similar
to child abuse and
that clinicians may have significant difficulty diagnosing HLH, especially when
the presentation is atypical. In the first 2 cases, an older sibling was removed
from parental custody because of the suspicion of abuse, causing additional
stress and trauma or the family. Although not always part of the classic
presentation for HLH, CNS events have been previously described by numerous
authors as occurring in 20% to 100% of HLH patients.3–5 Patients may present
with primarily CNS findings and be treated for presumed infectious encephalitis
before the correct diagnosis is made.6 Those with meningeal symptoms receive a
diagnosis, on the average, in the first 7 months of life, and those with other
neurologic symptoms receive a diagnosis by 16 months of life. Reported CNS
symptoms include hypo- or hypertonia, opisthotonus, irregularities of heart rate
or respirations, seizures, ataxia, cranial nerve findings, and other nonspecific
signs of raised intracranial pressure. 3 Frequently described radiologic
manifestations include abnormal leptomeningeal enhancement, focal necrosis with
parenchymal volume loss, and atrophy.4,5 The leptomeninges are infiltrated by
lymphocytes and histiocytes, associated with a sterile CSF lymphocytosis and
elevated protein levels.4 With more extensive involvement, the perivascular
spaces are infiltrated with astrocytic and microglial cell proliferation
affecting the white matter most extensively. Areas of necrosis and focal or
diffuse demyelination may follow. Henter and Nennesmo’s4 report of 23 patients
revealed focal hemorrhage in the leptomeninges of 1 patient and of the basal
ganglia in another. Although Haddad et al5 did not specifically describe
hemorrhages in their patients, 2 were found to have subdural space dilation. The
unenhanced CT (Fig 2A) of the Haddad paper showed a subdural effusion that had
similar imaging characteristics of the hemorrhage seen in our patient Fig 2. A,
Wright-Geimsa–stained section of the subdural hemorrhage in patient 2 with many
CD68 positive (brown) macrophages present. B, Higher power view of a
CD68-positive macrophage from the retinal hemorrhage demonstrating
hemophagocytosis. e638
CENTRAL NERVOUS SYSTEM HEMOPHAGOCYTIC SYNDROME VERSUS CHILD
ABUSE
1 (Fig 1). Cases 1 and 2 in our report probably represent the extreme result of
tissue necrosis and blood vessel destruction caused by the perivascular
infiltrations of lymphocytes and macrophages. The hemorrhages were facilitated
by the coagulopathy manifested by the prolonged PTTs in all 3 patients. Ocular
findings, prominent in our first and second cases, have also been described.7–11
Liao and Thompson10 described a case of a teenage boy who presented with fever
and visual disturbances. On examination, he was found to have scattered flame
hemorrhages, which subsequently resolved as the patient was treated for HLH.
Autopsy evaluations have identified lymphohistiocytic infiltration of the optic
nerve, iris, choroids, and perivascular structures in other patients.7–9 Retinal
hemorrhages, often considered 1 of the hallmarks of shaken infant syndrome, were
misleading in the cases presented here. Our first patient presented with several
findings characteristic of abuse but were most likely from CNS HLH. The
child protective services department cleared the family of the abuse charges
after a thorough investigation and realization of the HLH diagnosis as well as
the fact that the child continued to require hospitalization for symptoms
(diarrhea) that could not be linked to abuse. Thus, the weight of evidence
greatly diminishes the probability that this was shaken infant syndrome in
addition to HLH. The third case presents a picture of HLH that often creates
suspicion as an abuse case in pediatric EDs, with the sudden lack of
responsiveness and subsequent asystole in an otherwise healthy child. Given the
nonspecific periosteal elevation of the humerus and cortical irregularity of the
tibia, nonaccidental trauma could not be excluded. Apossible explanation in this
case, however, is periosteal elevation as a result of marrow infiltration. Had
the treating physicians not been aware of HLH and appropriately
explored it as an alternative explanation for the child’s condition, the family
or child care center may
well have had to face a murder charge. Hepatosplenomegaly in 2 of the cases and
abnormal laboratory findings in all 3 at the time of presentation could
have alerted clinicians to an underlying systemic illness. Striking
elevation of the PTT was present in all 3 patients on initial presentation. Two
had markedly elevated liver enzymes (patients 2 and 3). One patient was anemic
and another was thrombocytopenic. It is known that patients with severe brain
injury may have disseminated intravascular coagulation and elevations of the PT
or PTT.12 Patients reported in that series, however, had traumatic injuries
primarily from automobile accidents and penetrating or blunt trauma, not shaken
infant syndrome. Likewise hepatosplenomegaly, cytopenias, abnormal liver
function tests, and electroencephalogram findings of diffuse encephalopathy are
not usual findings in child abuse. One might suspect a coincident viral
infection in some instances of cytopenias. However, the constellation of
hepatosplenomegaly, CNS abnormalities, and the above noted laboratory findings
should alert a clinician to the possibility that HLH could be the correct
diagnosis. It is imperative that clinicians be aware of HLH in all of its
manifestations because HLH can be confused with other diagnoses besides child
abuse, including hepatitis, fever of unknown origin, and sepsis. 13 Screening
for HLH with a complete blood count, liver function tests, triglyceride level,
and serum ferritin levels as well as possibly bone marrow aspiration and biopsy
can be accomplished in a relatively easy and expedient manner, even in a
critically ill child. The infiltrating features of CNS lesions in HLH are easily
seen by T2-weighted or fluidattenuated inversion recovery MRI images and thus
can further differentiate HLH from child abuse. Subsequent institution of
appropriate therapy can be life saving. Although child abuse is unfortunately a
more common entity than HLH, the false accusation of this can be devastating for
a family. Heightened clinical awareness and basic laboratory evaluations may
help prevent such an error when HLH is the cause of unusual CNS abnormalities in
young children.
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