Main Text
Introduction
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of
lymphocyte apoptosis, characterized by nonmalignant lymphadenopathy,
splenomegaly, immune dysregulation, and autoimmune
cytopenias1,2. There are known genetic defects
associated with ALPS, although they are not required for
diagnosis3. ALPS can be challenging to diagnose, as
clinical presentations can vary or be incomplete. This syndrome usually
presents early in life, and treatment aims to improve the constellation
of symptoms. Treatment modalities include corticosteroids, rituximab,
sirolimus, and mycophenolate mofetil4,5. The
dysregulated cell division in ALPS also places patients at increased
risk for developing lymphoid malignancies6.
Langerhans cell histiocytosis (LCH) is a neoplasm of myeloid precursor
cells that is frequently characterized by a mutation of the MAPK gene
pathway7. LCH primarily presents as bone, soft tissue,
lung, skin, and pituitary lesions. A BRAF V600E mutation has been
reported in 57% of patients with LCH, and pathology confirms the
diagnosis with granulomatous lesions that are CD207
positive8,9. LCH is often treated with conventional
chemotherapy, such as vinblastine and prednisone10.
This case report describes the unique presentation of a patient
diagnosed with ALPS and LCH in short succession.
Results (Case Report)
A 10-month-old female was admitted to our hospital for several weeks of
persistent fevers. Her past medical history was remarkable for four
separate urinary tract infections (UTI), all of which grew E.
coli and were successfully treated with antibiotics. Additionally, she
had intermittent bloody stools before her presentation.
During her first hospitalization at our institution, she was diagnosed
with an E. coli UTI , and voiding cystourethrogram revealed
vesicoureteral reflux. She had normocytic anemia with a hemoglobin of
5.7 gm/dl and a reticulocyte count of 3.9%. Her peripheral blood smear
revealed thrombocytopenia, reactive lymphocytes, and monocytosis. These
results were attributed to anemia of chronic disease, as well as
gastrointestinal bleeding of unknown etiology. She was also noted to
have failure to thrive (FTT) and delayed developmental milestones. She
was discharged home to complete a course of cephalexin for her UTI.
Five days after discharge, she was readmitted for persistent fevers
despite compliance with the prescribed antibiotics. Her hemoglobin had
decreased to 4.8 gm/dl, her reticulocyte count had increased to 9.2%,
and she was transfused with packed red blood cells. A bone marrow
aspiration and biopsy revealed rare hemophagocytosis with no other
significant findings. Abdominal imaging revealed splenomegaly. Ferritin
was normal (129 ng/mL). Soluble interleukin-2 receptor was elevated at
12900 pg/ml (reference range <1033 pg/ml). The remainder of
her workup was unremarkable or non-contributory, including renal
ultrasound, echocardiogram, celiac panel, preliminary immunological
studies, and an extensive infectious disease workup. Due to persistent
diarrhea in the setting of prolonged antibiotic usage, C.
difficile treatment was initiated with oral vancomycin, but there was
no improvement in her intermittently loose, bloody stools.
Esophagogastroduodenoscopy and colonoscopy revealed erythema and
friability throughout the colon, and multiple biopsies showed
nonspecific, diffuse inflammation. Her fevers resolved, and her
gastrointestinal symptoms eventually improved without additional
intervention.
Genetic testing revealed a c.1567T>C mutation inCASP10 , diagnostic of ALPS-caspase (CASP)10. TCRαβ+ CD4- CD8-
cell count was normal. Subsequently, she was started on sirolimus
therapy.
Approximately two months after starting sirolimus therapy, she was
hospitalized for progressive left-sided facial swelling and dry, flaky
scalp changes. Imaging confirmed an erosive lesion involving most of the
sphenoid bone, bilateral inferior orbital walls, and bilateral squamous
portions of temporal bones. Additional smaller lesions in the right
mandible and right mastoid air cells were observed. Biopsy revealed LCH
with a BRAF V600E mutation. Positron emission tomography revealed
fluorodeoxyglucose-avid regions localized to the skull and facial bones.
The patient began treatment with vinblastine and prednisolone with
subsequent resolution of the facial swelling and cytopenias.
Discussion
To our knowledge, this is the first patient to be described with both
ALPS and LCH. The diagnosis of multifocal LCH was made less than three
months after starting sirolimus for ALPS. Initiation of prednisolone for
the treatment of LCH led to the resolution of facial swelling, but also
led to resolution of bloody stools and cytopenias, which were her
primary symptoms related to ALPS. This is notable because
corticosteroids are also first-line treatments for
ALPS4.
While both ALPS and LCH are characterized by inflammatory and cellular
dysregulation, the cellular pathways leading to these diagnoses are
quite different. The pathophysiology of LCH is characterized by
alterations in myeloid precursor cells, while ALPS is characterized by
molecular signaling disruptions in lymphoid cells. ALPS patients are
known to have a higher risk of malignancy, including leukemia, Hodgkin
lymphoma, and non-Hodgkin lymphoma6,11; however, ALPS
has not been explicitly linked to LCH.
As this case illustrates, it is often challenging to diagnose ALPS, and
frequently an extensive workup is obtained before diagnosis. Indeed,
this patient had an incomplete diagnosis for ALPS (Table
1)1. While she was found to have a pathologic germline
mutation of CASP10, autoimmune cytopenias, and
hypergammaglobulinemia (all of which are common in ALPS), she did not
have elevated numbers of peripheral TCRαβ+ CD4- CD8- cells. AlthoughCASP10 mutations typically have autosomal dominant inheritance,
patients with mutations in CASP10 can have variable
presentations, and these patients may not exhibit classic diagnostic
features for ALPS, thus requiring genetic confirmation to make the
diagnosis11,12.
Our patient initially presented with FTT, fever, and cytopenias, each
reported in ALPS-CASP10 and LCH4,11,13,14. The patient
also had persistent fevers, prompting hospitalization. ALPS and LCH, as
with other malignancies, can and should be considered in the setting of
persistent fevers and FTT. This also calls into question whether LCH was
present at the time of ALPS diagnosis. The dry patches on the patient’s
scalp were present before her presentation and initially attributed to
seborrheic dermatitis; however, they were likely a manifestation of LCH
and are a common presentation of LCH13.
This case exemplifies an unusual presentation resulting in the
concurrent diagnosis of LCH and ALPS and emphasizes the importance of
continued evaluation when a patient’s clinical presentation does not
entirely meet diagnostic criteria. Genetic testing and further workup
were ultimately needed to lead to the correct diagnosis and treatment of
ALPS. Once treatment began for LCH, the patient had significant
improvement in symptoms related to both LCH and ALPS. While some cases
have highlighted a link between ALPS and other diagnoses of
histiocytosis, including Rosai-Dorfman Disease and histiocytic
sarcoma,15,16 concurrent diagnosis of ALPS and LCH has
not been reported previously, and these diagnoses share no known
association. Further research is needed to explore any potential
associations.
Conflict of Interest Statement: No authors have a conflict of interest.
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