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hepatopathy and hyperferritinemia. Our primary diagnosis
of a catheter-related sepsis seemed from episode to
episode unlikely, as the blood-cultures stayed negative
each time. The suspicious laboratory �ndings, especially
the high ferritin levels �nally lead us to the diagnosis. In
general, making the diagnosis of a HLH is sometimes not
quite easy. As shown, the patient’s symptoms may be misinterpreted
as an infection, leading to a severe in�ammatory
response (SIRS), or an underlying infection might be
the activator of the overwhelming immune response. On
the other hand, as in our case, not enough criteria according
to the HLH 2004 guidelines might be ful�lled and
an «incomplete HLH syndrome» must be considered. According
to the HLH 2004 study group, �ve out of eight
diagnostic criteria must be ful�lled, in order to make the
diagnosis of HLH (see Tab. 2). Once our patient ful�lled
enough criteria, the diagnosis was made, and an anti-in-
�ammatory therapy was installed. Shortly afterwards the
symptoms dissolved.
Even if the diagnosis of HLH can be made, it still remains
a challenge to distinguish between the genetic and the acquired
form. In both forms, the clinical features and laboratory
�ndings of HLH are a result of the cytokine storm
and an immune cell in�ltration in practically every organ.
The genetic mutations found in HLH almost exclusively
occur in the genes for cytotoxic granule exocytosis or in
the perforin gene. These defects in the lymphocytes and
natural killer cells result in an impaired apoptosis in the
target cell as well as in the antigen-presenting cell. A persistence
of the antigen-presenting cell keeps the activation
of T-lymphocytes going and therefore the in�ammation.
On the contrary the exact mechanisms leading to the acquired
form of HLH are not completely understood yet.
According to the HLH 2004 study group, irrespective on
the form, the diagnosis criteria include (see Tab. 2): Fever,
not following a certain course of the day is induced by IL-
1, TNF alpha and IL-6. Elevated concentrations of TNF
alpha, INF gamma and hemophagocytosis in the bone
marrow cause the pancytopenia. A splenomegaly caused
by an in�ltration of activated immune cells and a follow-
Diagnostic criteria
Fever
Splenomegaly
Bicytopenia: Hb < 90 G/l, thrombocytes < 100 G/l, neutrophil granulocytes < 1 G/l
Triglycerides ≥ 3.0 mmol/l and/or Fibrinogen< 1.5 g/l
Hemophagocytosis
Ferritin ≥ 500 ng/ml
NK cell activity defect or absence
sCD25 ≥ 2400 UI/ml
Tab. 2. Diagnostic criteria of HLH
ing hypersplenism might contribute to the pancytopenia.
Hepatic involvement manifests as a hepatomegaly with
elevated levels of transaminases, bilirubin and cholestasis
parameters. The in�ltration of the immune cells can cause
a chronic hepatitis-like �brosis of the portal �elds. High
TNF alpha levels alter on the one hand the albumin production
leading to a decreased serum albumin levels and
decrease on the other hand the activity of the lipoprotein
lipase leading to a hypertriglyceridemia. Activated macrophages
secret ferritin explaining the hyperferritinemia
and also plasminogen activator resulting in low �brinogen
levels. Moderately increased cell count and protein
content in the cerebrospinal �uid can be found and might
be accompanied by meningitis-like symptoms, encephalitis-like
symptoms, seizures and cranial nerve palsy. These
neurological �ndings are properly caused by cerebral in�ltration
of immune cells. Less common symptoms of HLH
are gastrointestinal symptoms as diarrhea, nausea and
emesis, cardiopulmonary symptoms as altered myocardial
function, pleural effusion and ARDS due to edemas by
capillary leak and seldom skin manifestations as erythema
and purpura.
During the course of the �ve fever episodes, the boy developed
more and more features of HLH, leading us to the
diagnosis. As a common genetic cause of the lymphohistiocytosis
could be excluded, the question remained, if our
patient’s dysmorphic syndrome still might be associated
with a yet unknown form of a genetic lymphohistiocytosis.
So an association of HLH with the dysmorphic features
of our patient and the CIOS was searched in the databases
of OMIM and PubMed. One paper reported the case of a
young child suffering from HLH who also showed some
dysmorphic features similar to our patient’s dysmorphic
features and similar to patients suffering from Crouzon
syndrome. The authors drew a possible connection to the
underlying mutations leading to Morbus Crouzon, which
is mostly caused by a mutation in the �broblast growth
factor receptor 2. The authors postulated a possible association
between the �broblast growth factor receptor
two gene and the gene causing one genetic form of HLH
140 Schweizer Krebsbulletin � Nr. 2/2012