DISCUSSION
Orf virus is a member of the Parapoxvirus family, and generally
causes highly contagious zoonotic infections [6]. The virus causes
sore mouth disease in sheep and goats [6]. In healthy individuals,
especially in people who are handling sheep and goats, this virus may
cause orf nodules in hands named as contagious ecthyma or contagious
pustular dermatitis [6,13]. Orf virus causes skin lesions via direct
contact of damaged skin with infected animals or fomites indirectly
[6]. The disease course is usually self-limited, and it is not
expected to cause disseminated disease, but there are very rare cases of
disseminated exanthems, fever and lymphadenopathies [11]. It may,
however, cause systemic disease or unexpected giant lesions in primary
immunodeficiency patients [12]. Although there is susceptibility to
mostly fungal infections in patients with STAT1 gain of function (GOF)
defects, there has been a case of a STAT1 GOF mutation who had developed
an orf virus infection [12]. Orf virus was reported to be associated
with lobular capillary hemangioma in burn patients [13-15]. This may
be attributed to the local immunosupression related to burn. It has been
shown that the VEGF-E protein produced by orf infections causes
epithelial growth in mice models [14]. It may be suggested that
virally expressed VEGF-E protein may responsible for proliferative skin
lessions. The presented patient had multiple giant lobular capillary
hemangiomas which are infected with orf virus.
Epidermodysplasia verruciformis is a rare, autosomal recessive skin
disorder, reported a total 501 patients in literature [16]. It is
characterized by high susceptibility to certain types of human
papillomaviruses. Patients develops flat-topped, wart-like papular
lesions similar to verrucae planae on the extremities [17]. Patients
have an increased risk of developing non-melanoma skin cancers [17].
The pathogenesis is not completely understood but it is thought to be
related to agent selective immunodeficiency [16]. Our patient’s skin
biopsy showed epidermodysplasia verruciformis. The presented patient had
extensive orf virus infected giant lobular capillary hemangiomas and
epidermodysplasia verruciformis lessions.
DOCK8 deficiency is a combined immunodeficiency characterized by
recurrent infections, atopy, autoimmunity and cancer [3,4]. It is
most commonly seen in Arabic and Turkish populations [3]. Severe
cutaneous and invasive viral infections such as varicella zoster,
molluscum contagiosum, HSV and HPV are seen [3,4,5]. Viral
infections may be systemic or involves deep tissues [3]. DOCK8
deficiency may cause virally-driven malignencies such as HPV-related
squamous cell carcinoma, EBV-related smooth muscle tumors or lymphomas
[3]. This unusual occurance of orf virus infected giant lessions and
epidermodysplasia verruciformis raised our suspicion towards an
underlying combined or agent spesific immunodeficiency. Our patient also
had eosinophilia and elevated IgE levels. Further investigations
revealed DOCK8 deficiency in our patient. The presented case is first
case to with DOCK8 deficiency, epidermodysplasia verruciformis and orf
virus infection.
Castleman disease is a disease of unknown etiology and seen very rare in
childhood [1]. The literature is mainly focused on adult population
and small case series have been reported. Clinical and pathologic
abnormalities are heterogeneous and overlap with a wide range of other
immunologic disorders [2]. Whether autoimmune, autoinflammatory,
neoplastic or infectious mechanism make the most contribution is not
certain [2]. Our patient hyaline vasculary type CD and clinically
had iMCD-NOS. Although the role of HHV8 in HHV8-MCD is relatively well
understood, the pathogenesis of iMCD-NOS is unclear [2]. It has been
showed that IL-6 overexpression may play a role in disease [18].
Interestingly, VEGF expression is also elevated in iMCD patients
[19]. No certain relationship between a virus other that HIV or
HHV-8 was shown to date [20]. The presented patient had multiple
thoracic, cervical and abdominal lymphadenopathies. Lymph node biopsy of
the conglomerated abdominal lymph nodes were performed and revealed
hyaline vascular variant of multicentric Castleman disease. Our patient
met the inclusion criteria for iMCD-NOS.
This patient is the first case with iMCD-NOS and DOCK8 deficiency.
Drolet et al. reported a case of CD in a child with common variable
immunodeficiency (CVID) [8]. Castleman disease has also been
reported to occur in patients with HIV, which is an acquired T-cell
deficiency. Guihot et al. documented polyfunctional effector memory
HHV-8 specific CD8+ T cells in MCD and suggested that HHV-8 specific T
cell responses may play a role in the pathogenesis of MCD [9].
Elevated effector memory (CD4+CCR7-CD45RA-) in our patient supports this
hypothesis. Leroy et al reported a child born to consanguineous parents
with proven HHV-8 associated MCD in the absence of an immunodeficiency.
He suggested that MCD in childhood may be related to rare inborn errors
of immunity against HHV-8 infection [10].
There are no definitive guidelines for treatment of CD and regimens vary
among different institutions. The options include steroids, rituximab,
anakinra, siltuximab, tocilizumab, conventional cytotoxic chemotherapy,
R-CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone) and
radiotherapy [2]. The presented patient responded to R-CHOP
treatment very well. Our patient also had underlying DOCK8 deficiency.
Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8
deficiency. IFN-α treatment may also be beneficial [4]. After
remission induction, we planned HSCT to our patient but unfortunatelly,
our patient died because of neutropenic sepsis.
In conclusion, our case is the first case with DOCK8 deficiency,
iMCD-NOS and orf virus infection. Each of these diseases are rarely seen
in childhood. Our findings suggest that inborn errors of immunity may
play a role in the occurrence of iMCD-NOS, and orf virus may trigger CD
in the presence of an underlying immunodeficiency. Further
investigations are required for understanding the immunologic basis of
the disease.
Aknowledgements: We are thankful to our staff who contributed
to this patient’s care.
Ethical approval : Informed consent was obtained from the
patient’s family to publish the details and images of this case.
Conflict of Interest Disclosures: None reported.