526 Case report
A severe systemic presentation of pigmented villonodular synovitis in a child with underlying Chediak–Higashi syndrome Victoria L. Truea, Fergal P. Monsellb, Tanya A. Smitha, Simon C. Parkee, David J. Grierc, Marion E. Schneiderf and Colin G. Stewardd Pigmented villonodular synovitis (PVNS), a condition of synovial hyperproliferation that mostly affects large joints, is rare in children and conventionally lacks systemic symptoms. This report describes a complex paediatric patient who underwent bone marrow transplantation to control the accelerated phase of the Chediak–Higashi syndrome. Diffuse PVNS developed in one knee 2.75 years later. Progression of PVNS was accompanied by the development of severe systemic symptoms, which resolved rapidly following subtotal surgical debridement. The patient remains well with minimal elevation of inflammatory marker levels 10.5 years later. As PVNS and Chediak–Higashi syndrome are both very rare diseases we propose a potential unifying hypothesis for this combination. J Pediatr
Case presentation An 18-month-old child presented with recurrent infections, eczema, axillary pustules, gingivitis and inflamed bleeding gums. She was found to be neutropenic, with enlarged cytoplasmic granules in her neutrophils on a blood film. These appearances are pathognomonic of Chediak–Higashi syndrome (CHS), a disease characterized by partial albinism (pale skin, underpigmented irises causing photophobia and blonde hair with a metallic sheen) [1,2]. There is also a major propensity to develop a form of hemophagocytic lymphohistiocytosis (HLH), where lymphocytes and histiocytes/ macrophages become highly activated and proliferate because of abnormal lysosomal granule transport/formation. This complication, known as ‘accelerated phase’ disease, typically causes fever, lymphadenopathy, pancytopenia and widespread lymphohistiocytic infiltration of the reticuloendothelial system; involvement of the central nervous system (CNS) may also occur. This is a potentially lifethreatening disorder and requires urgent chemotherapy and immune suppression, followed by haemopoietic stem cell transplantation (HSCT) from a healthy donor to prevent recurrence [3]. Accelerated phase disease occurred in an isolated form at 4.1 years of age in this patient, who presented with profound cerebellar dysfunction and neurological deterioration with diffuse white matter changes on MRI (Smith TA et al., manuscript in preparation). Bone marrow examination at this time excluded hemophagocytic involvement, but cytogenetic analysis revealed incidental Turner mosaicism (45X/47XXX), further confirmed by somatic 1060-152X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Orthop B 24:526–529 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Journal of Pediatric Orthopaedics B 2015, 24:526–529 Keywords: Chediak–Higashi syndrome, haematopoietic stem cell transplantation, pigmented villonodular synovitis a
University of Bristol Medical School, bDepartment of Orthopaedics, cDepartment of Radiology, dBone Marrow Transplant Unit, Royal Hospital for Children, Bristol, e Department of Paediatrics, Royal Devon and Exeter Hospital, Exeter, UK and f Section of Experimental Anaesthesiology, Ulm University, Germany Correspondence to Colin G. Steward, FRCPCH, PhD, Bone Marrow Transplant Unit, Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin St., Bristol BS2 8BJ, UK Tel: + 44 117 342 8102; e-mail: [email protected]
DNA analysis. Remission of this accelerated phase neurological disease was achieved through conventional HLH therapy (etoposide, dexamethasone, cyclosporine and intrathecal methotrexate) [4]. She underwent bone marrow transplantation (BMT) from a matched unrelated male donor to consolidate remission at 4.7 years of age. At 2.75 years after BMT, when her CHS disease was otherwise well controlled, a soft-tissue swelling developed on the medial side of her right knee without any preceding history of injury or bruising. MRI showed a soft-tissue thickening, and the mass was initially thought to represent an inflammatory or vascular condition. Biopsy was performed, and histological examination showed sheets of histiocytes with a papillary architecture and extensive hemosiderin deposition, consistent with a diagnosis of pigmented villonodular synovitis (PVNS). There was no evidence of infection (on histology or culture), lymphohistiocytosis or neoplasia. The patient then developed systemic features uncharacteristic of PVNS [5,6]: for over 8 months she experienced episodes of low-grade fever (≤ 38°C), weight loss and severe night sweats, and progressive anaemia of chronic disease (nadir of haemoglobin 8.0 g/dl). Her C-reactive protein (CRP) levels fluctuated in the range 100–290 mg/l, and her erythrocyte sedimentation rate (ESR) was in the range 75–120 mm/h. During this period, there was a further increase in the size of the soft-tissue swelling; it became erythematous and tender, and affected her joint movement to the extent that she developed in-toeing while walking. DOI: 10.1097/BPB.0000000000000190
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
PVNS complicating HSCT in Chediak–Higashi syndrome True et al. 527
The initial suspicion was that these symptoms represented a form of atypical solid-tissue hemophagocytic relapse analogous to her presentation with isolated CNS disease. However, analysis of serum samples showed a marked elevation in cytokine levels [interleukin-1β (IL-1β), 46.7 pg/ml (normal range, < 5 pg/ml); IL-6, 161 pg/ml (normal range < 6 pg/ml); and IL-8, 1923 pg/ml (normal range, < 70 pg/ml)] but no increase in sCD25 or HLA-DR expression – a pattern more in keeping with macrophage activation syndrome than with typical acute HLH. Prednisolone therapy was commenced at a dose of 2 mg/kg per day, and cyclosporine was added as a steroidsparing agent 1 week later. The steroid therapy effected a major reduction in inflammatory marker levels (CRP levels fell to a nadir of 56 mg/l over 1 week); however, this response was not maintained (see Fig. 1).
CD20-positive B cells. Histologically, the mass had the classical appearance of PVNS, comprising sheets of mixed histiocytes and synovial lining cells. These were associated with significant fibrosis, hemosiderin pigment deposition, a few scattered multinucleated giant cells and foamy macrophages; there was no evidence of hemophagocytosis. The femoral bone adjacent to this mass was involved, and five areas of abnormal bone measuring up to 1.3 × 0.9 × 0.2 cm were easily curetted out. Microscopically, these fragments showed extensive fat necrosis within the marrow cavity, patches of chronic inflammation and a focus of osteonecrosis and new bone formation. Subsequent cytogenetic testing showed that the cultured tissue from the PVNS mass consisted of a majority of female cells with the Turner mosaic karyotype found previously (45X/47XXX), despite 100% of peripheral blood cells being of male donor origin.
Three months later, it was decided that conventional surgical extirpation must be attempted. MRI performed 5 days before the surgery suggested the presence of a solid mass at the distal end of the right femur (see Figs 2, 3a and b). A total synovectomy and extensive surgical debridement of this mass were therefore performed at 1 year after presentation (age 8.25 years). A 4.5 × 4.0 cm disc of firm brown tissue with a fatty cut surface was removed at operation. There was also extensive fat necrosis and engulfment of the distal aspect of the sartorius muscle by diseased tissue; the muscle mass contained a dense inflammatory cell infiltrate of medium-sized lymphoid cells. These lymphocytes were predominantly CD4-positive T cells, with relatively few
Despite achieving only an estimated 80% resection of the PVNS material, the patient showed a radical response, with rapid resolution of her systemic symptoms and a decline in her inflammatory marker levels (Fig. 1). CRP levels reduced from 287 to 22 mg/l within 2 weeks. She showed excellent postoperative recovery, rapidly becoming pain-free and being able to mobilize normally, although she suffered an insufficiency fracture of the left upper tibia 1 month after the operation (presumed to be due to a combination of joint underuse and osteoporosis due to steroids). Repeat MRI of the affected knee is still unremarkable at 10.5 years after excision. Despite this, inflammatory marker levels remain persistently slightly
Fig. 1
Inflammatory marker level
CRP
ESR
350 300
Started prednisolone
Surgical resection
250 200 150 100 50 Started cyclosporine 0 20 34 41 51 76 107 131 132 133 135 139 143 150 157 164 174 178 185 192 199 217 230 237 246 254 296 335 390
0 Soft-tissue swelling right knee
Time point (days)
Time profile of the inflammatory markers CRP and ESR. This demonstrates the progressive increase in the inflammatory marker levels from the initial presentation of soft-tissue swelling. It shows the transient inflammatory response achieved by prednisolone and cyclosporine and a well-maintained decline in inflammatory markers following surgical debridement. CRP, C-reactive protein (mg/l); ESR, erythrocyte sedimentation rate (mm/h).
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
528 Journal of Pediatric Orthopaedics B 2015, Vol 24 No 6
Fig. 2
Fig. 3
Coronal short tau inversion recovery (STIR) image right distal femur. The image shows a lobular mass with increased signal density adjacent to the metaphysis and epiphysis on the medial side (see arrow).
elevated (CRP in the range of 7–58 mg/l, mean 24 mg/l; ESR 6–74 mm/h, mean 38 mm/h) after over 10 years of follow-up, suggesting that subclinical disease may still be present.
Discussion PVNS is a locally aggressive disorder of the synovium, tendon sheaths and bursae, usually presenting between 20 and 40 years of age, and it is rare in children [5,7]. There are two broad classifications for PVNS presentation: localized (with involvement of a single synovial nodule) and diffuse (destruction of the entire joint synovium) [5]. The clinical manifestations observed are highly variable and may be nonspecific, including joint stiffness, a dull ache and a palpable mass [7,8]. There remains much uncertainty concerning the underlying pathogenesis, with a range of hypotheses proposed such as chronic inflammation and tissue reaction to hemarthrosis or trauma [6]. This patient’s presentation of diffuse PVNS was unique for a number of reasons. First, PVNS usually follows an episode of trauma, but our patient had no such history. Second, PVNS is not classically associated with systemic symptoms or raised inflammatory marker levels, yet in this case it was accompanied by severe weight loss, intermittent high fever, anaemia of chronic disease, night sweats and highly elevated CRP levels and ESRs – all of which resolved or improved markedly after surgical debridement
(a, b) Axial image of the right distal femur. Axial MRI images of the right distal femur, showing a lobular soft-tissue mass (arrowed) adjacent to the medial aspect of the distal femur of (a) low signal on the T1 image and (b) high signal on the short tau inversion recovery (STIR) image.
of the majority of diseased tissue [9,10]. Third, considering the emphasis placed on complete surgical debridement to prevent the otherwise high rate of disease relapse in diffuse PVNS, it is interesting that a subtotal surgical resection achieved ongoing relapse-free survival sustained for more than 10 years. Finally, unique to this patient, the PVNS mass contained an area of florid lymphocytic infiltration that was skewed towards a population of T cells, rather
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
PVNS complicating HSCT in Chediak–Higashi syndrome True et al. 529
than being the usual mixed inflammatory infiltrate of B and T lymphocytes. To the best of our knowledge, no previous familial link or genetic association has been shown between PVNS and either Turner’s/Turner’s mosaic karyotype or CHS (or other similar diseases predisposing to lymphohistiocytosis) [11]. However it is surprising that a child with underlying CHS, a disease with less than 500 cases reported worldwide [1], should also develop PVNS, which affects only one in 1.8 million people [7]. As such, it may be more likely that their etiopathogenesis is interlinked. This could result from ongoing dysregulated histiocyte function/control as replacement of recipient histiocytes with those from the donor is extremely slow after transplant. For example, in mouse BMT models, only 30% of CNS microglial cell (which are specialized tissue histiocytes) are of donor origin by 1 year after transplant [12]. It could be postulated that this patient’s problems did start off with very minor unidentified trauma, possibly causing a small localized haemorrhage. If so, this could in turn have caused activation of persisting recipient fixed tissue histiocytes rather than the recurrent hemophagocytic process that was initially suspected. This would have explained the poor response to steroids and cyclosporine. There are no reports of atypical, unexplained inflammatory syndromes occurring after BMT for CHS. However, long-term follow-up has demonstrated that these patients develop progressive neurological deterioration, which may culminate in profound cerebellar and other CNS problems during adult life [13]. It has been presumed that this is due to primary problems with granule formation or transport in neurones or Schwann cells. However, it may alternatively be possible that brain histiocytes of recipient origin (including microglial cells) remain susceptible to excitation by external phenomena such as infections or trauma, and that this patient is showing an orthopaedic correlate of that behaviour. Our observations in this patient raise the question of whether subtle defects in histiocyte control – either inherited or acquired – could underpin other cases of
PVNS, which never reach the extent that we have described because of either early appropriate surgical debridement or a lesser degree of immune dysregulation.
Acknowledgements We would like to thank the patient and her family for providing consent for submitting data concerning the case for publication. Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
10
11 12
13
Lozano ML, Rivera J, Sánchez-Guiu I, Vicente V. Towards the targeted management of Chediak–Higashi syndrome. Orphanet J Rare Dis 2014; 9:132. Introne WJ, Westbroek W, Golas GA, Adams D. Chediak–Higashi Syndrome. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews. Seattle, WA: University of Washington; 2009. Eapen M, DeLaat CA, Baker KS, Cairo MS, Cowan MJ, Kurtzberg J, et al. Hematopoietic cell transplantation for Chediak–Higashi syndrome. Bone Marrow Transplant 2007; 39:411–415. Haddad E, Sulis ML, Jabado N, Blanche S, Fischer A, Tardieu M. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood 1997; 89:794–800. Kubat O, Mahnik A, Smoljanović T, Bojanić I. Arthroscopic treatment of localized and diffuse pigmented villonodular synovitis of the knee. Coll Antropol 2010; 34:1467–1472. Sharma H, Rana B, Mahendra A, Jane MJ, Reid R. Outcome of 17 pigmented villonodular synovitis (PVNS) of the knee at 6 years mean follow-up. Knee 2007; 14:390–394. Akinci O, Akalin Y, İncesu M, Eren A. Long-term results of surgical treatment of pigmented villonodular synovitis of the knee. Acta Orthop Traumatol Turc 2011; 45:149–155. Baroni E, Russo BD, Masquijo JJ, Bassini O, Miscione H. Pigmented villonodular synovitis of the knee in skeletally immature patients. J Child Orthop 2010; 4:123–127. Toro FG, Paulos JA, Fuentes DL, Sancy KL. Total shoulder arthroplasty in pigmented villonodular synovitis: a case report. J Shoulder Elbow Surg 2002; 11:188–190. Gangane N, Anshu, Shivkumar VB, Sharma SM. Intranuclear inclusions in a case of pigmented villonodular synovitis of the ankle. Diagn Cytopathol 2003; 29:349–351. Mankin H, Trahan C, Hornicek F. Pigmented villonodular synovitis of joints. J Surg Oncol 2011; 103:386–389. Kennedy DW, Abkowitz JL. Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 1997; 90:986–993. Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, Fischer A. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood 2005; 106:40–42.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
A severe systemic presentation of pigmented villonodular synovitis in a child with underlying Chediak–Higashi syndrome Victoria L. Truea, Fergal P. Monsellb, Tanya A. Smitha, Simon C. Parkee, David J. Grierc, Marion E. Schneiderf and Colin G. Stewardd Pigmented villonodular synovitis (PVNS), a condition of synovial hyperproliferation that mostly affects large joints, is rare in children and conventionally lacks systemic symptoms. This report describes a complex paediatric patient who underwent bone marrow transplantation to control the accelerated phase of the Chediak–Higashi syndrome. Diffuse PVNS developed in one knee 2.75 years later. Progression of PVNS was accompanied by the development of severe systemic symptoms, which resolved rapidly following subtotal surgical debridement. The patient remains well with minimal elevation of inflammatory marker levels 10.5 years later. As PVNS and Chediak–Higashi syndrome are both very rare diseases we propose a potential unifying hypothesis for this combination. J Pediatr
Case presentation An 18-month-old child presented with recurrent infections, eczema, axillary pustules, gingivitis and inflamed bleeding gums. She was found to be neutropenic, with enlarged cytoplasmic granules in her neutrophils on a blood film. These appearances are pathognomonic of Chediak–Higashi syndrome (CHS), a disease characterized by partial albinism (pale skin, underpigmented irises causing photophobia and blonde hair with a metallic sheen) [1,2]. There is also a major propensity to develop a form of hemophagocytic lymphohistiocytosis (HLH), where lymphocytes and histiocytes/ macrophages become highly activated and proliferate because of abnormal lysosomal granule transport/formation. This complication, known as ‘accelerated phase’ disease, typically causes fever, lymphadenopathy, pancytopenia and widespread lymphohistiocytic infiltration of the reticuloendothelial system; involvement of the central nervous system (CNS) may also occur. This is a potentially lifethreatening disorder and requires urgent chemotherapy and immune suppression, followed by haemopoietic stem cell transplantation (HSCT) from a healthy donor to prevent recurrence [3]. Accelerated phase disease occurred in an isolated form at 4.1 years of age in this patient, who presented with profound cerebellar dysfunction and neurological deterioration with diffuse white matter changes on MRI (Smith TA et al., manuscript in preparation). Bone marrow examination at this time excluded hemophagocytic involvement, but cytogenetic analysis revealed incidental Turner mosaicism (45X/47XXX), further confirmed by somatic 1060-152X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Orthop B 24:526–529 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Journal of Pediatric Orthopaedics B 2015, 24:526–529 Keywords: Chediak–Higashi syndrome, haematopoietic stem cell transplantation, pigmented villonodular synovitis a
University of Bristol Medical School, bDepartment of Orthopaedics, cDepartment of Radiology, dBone Marrow Transplant Unit, Royal Hospital for Children, Bristol, e Department of Paediatrics, Royal Devon and Exeter Hospital, Exeter, UK and f Section of Experimental Anaesthesiology, Ulm University, Germany Correspondence to Colin G. Steward, FRCPCH, PhD, Bone Marrow Transplant Unit, Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Upper Maudlin St., Bristol BS2 8BJ, UK Tel: + 44 117 342 8102; e-mail: [email protected]
DNA analysis. Remission of this accelerated phase neurological disease was achieved through conventional HLH therapy (etoposide, dexamethasone, cyclosporine and intrathecal methotrexate) [4]. She underwent bone marrow transplantation (BMT) from a matched unrelated male donor to consolidate remission at 4.7 years of age. At 2.75 years after BMT, when her CHS disease was otherwise well controlled, a soft-tissue swelling developed on the medial side of her right knee without any preceding history of injury or bruising. MRI showed a soft-tissue thickening, and the mass was initially thought to represent an inflammatory or vascular condition. Biopsy was performed, and histological examination showed sheets of histiocytes with a papillary architecture and extensive hemosiderin deposition, consistent with a diagnosis of pigmented villonodular synovitis (PVNS). There was no evidence of infection (on histology or culture), lymphohistiocytosis or neoplasia. The patient then developed systemic features uncharacteristic of PVNS [5,6]: for over 8 months she experienced episodes of low-grade fever (≤ 38°C), weight loss and severe night sweats, and progressive anaemia of chronic disease (nadir of haemoglobin 8.0 g/dl). Her C-reactive protein (CRP) levels fluctuated in the range 100–290 mg/l, and her erythrocyte sedimentation rate (ESR) was in the range 75–120 mm/h. During this period, there was a further increase in the size of the soft-tissue swelling; it became erythematous and tender, and affected her joint movement to the extent that she developed in-toeing while walking. DOI: 10.1097/BPB.0000000000000190
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
PVNS complicating HSCT in Chediak–Higashi syndrome True et al. 527
The initial suspicion was that these symptoms represented a form of atypical solid-tissue hemophagocytic relapse analogous to her presentation with isolated CNS disease. However, analysis of serum samples showed a marked elevation in cytokine levels [interleukin-1β (IL-1β), 46.7 pg/ml (normal range, < 5 pg/ml); IL-6, 161 pg/ml (normal range < 6 pg/ml); and IL-8, 1923 pg/ml (normal range, < 70 pg/ml)] but no increase in sCD25 or HLA-DR expression – a pattern more in keeping with macrophage activation syndrome than with typical acute HLH. Prednisolone therapy was commenced at a dose of 2 mg/kg per day, and cyclosporine was added as a steroidsparing agent 1 week later. The steroid therapy effected a major reduction in inflammatory marker levels (CRP levels fell to a nadir of 56 mg/l over 1 week); however, this response was not maintained (see Fig. 1).
CD20-positive B cells. Histologically, the mass had the classical appearance of PVNS, comprising sheets of mixed histiocytes and synovial lining cells. These were associated with significant fibrosis, hemosiderin pigment deposition, a few scattered multinucleated giant cells and foamy macrophages; there was no evidence of hemophagocytosis. The femoral bone adjacent to this mass was involved, and five areas of abnormal bone measuring up to 1.3 × 0.9 × 0.2 cm were easily curetted out. Microscopically, these fragments showed extensive fat necrosis within the marrow cavity, patches of chronic inflammation and a focus of osteonecrosis and new bone formation. Subsequent cytogenetic testing showed that the cultured tissue from the PVNS mass consisted of a majority of female cells with the Turner mosaic karyotype found previously (45X/47XXX), despite 100% of peripheral blood cells being of male donor origin.
Three months later, it was decided that conventional surgical extirpation must be attempted. MRI performed 5 days before the surgery suggested the presence of a solid mass at the distal end of the right femur (see Figs 2, 3a and b). A total synovectomy and extensive surgical debridement of this mass were therefore performed at 1 year after presentation (age 8.25 years). A 4.5 × 4.0 cm disc of firm brown tissue with a fatty cut surface was removed at operation. There was also extensive fat necrosis and engulfment of the distal aspect of the sartorius muscle by diseased tissue; the muscle mass contained a dense inflammatory cell infiltrate of medium-sized lymphoid cells. These lymphocytes were predominantly CD4-positive T cells, with relatively few
Despite achieving only an estimated 80% resection of the PVNS material, the patient showed a radical response, with rapid resolution of her systemic symptoms and a decline in her inflammatory marker levels (Fig. 1). CRP levels reduced from 287 to 22 mg/l within 2 weeks. She showed excellent postoperative recovery, rapidly becoming pain-free and being able to mobilize normally, although she suffered an insufficiency fracture of the left upper tibia 1 month after the operation (presumed to be due to a combination of joint underuse and osteoporosis due to steroids). Repeat MRI of the affected knee is still unremarkable at 10.5 years after excision. Despite this, inflammatory marker levels remain persistently slightly
Fig. 1
Inflammatory marker level
CRP
ESR
350 300
Started prednisolone
Surgical resection
250 200 150 100 50 Started cyclosporine 0 20 34 41 51 76 107 131 132 133 135 139 143 150 157 164 174 178 185 192 199 217 230 237 246 254 296 335 390
0 Soft-tissue swelling right knee
Time point (days)
Time profile of the inflammatory markers CRP and ESR. This demonstrates the progressive increase in the inflammatory marker levels from the initial presentation of soft-tissue swelling. It shows the transient inflammatory response achieved by prednisolone and cyclosporine and a well-maintained decline in inflammatory markers following surgical debridement. CRP, C-reactive protein (mg/l); ESR, erythrocyte sedimentation rate (mm/h).
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
528 Journal of Pediatric Orthopaedics B 2015, Vol 24 No 6
Fig. 2
Fig. 3
Coronal short tau inversion recovery (STIR) image right distal femur. The image shows a lobular mass with increased signal density adjacent to the metaphysis and epiphysis on the medial side (see arrow).
elevated (CRP in the range of 7–58 mg/l, mean 24 mg/l; ESR 6–74 mm/h, mean 38 mm/h) after over 10 years of follow-up, suggesting that subclinical disease may still be present.
Discussion PVNS is a locally aggressive disorder of the synovium, tendon sheaths and bursae, usually presenting between 20 and 40 years of age, and it is rare in children [5,7]. There are two broad classifications for PVNS presentation: localized (with involvement of a single synovial nodule) and diffuse (destruction of the entire joint synovium) [5]. The clinical manifestations observed are highly variable and may be nonspecific, including joint stiffness, a dull ache and a palpable mass [7,8]. There remains much uncertainty concerning the underlying pathogenesis, with a range of hypotheses proposed such as chronic inflammation and tissue reaction to hemarthrosis or trauma [6]. This patient’s presentation of diffuse PVNS was unique for a number of reasons. First, PVNS usually follows an episode of trauma, but our patient had no such history. Second, PVNS is not classically associated with systemic symptoms or raised inflammatory marker levels, yet in this case it was accompanied by severe weight loss, intermittent high fever, anaemia of chronic disease, night sweats and highly elevated CRP levels and ESRs – all of which resolved or improved markedly after surgical debridement
(a, b) Axial image of the right distal femur. Axial MRI images of the right distal femur, showing a lobular soft-tissue mass (arrowed) adjacent to the medial aspect of the distal femur of (a) low signal on the T1 image and (b) high signal on the short tau inversion recovery (STIR) image.
of the majority of diseased tissue [9,10]. Third, considering the emphasis placed on complete surgical debridement to prevent the otherwise high rate of disease relapse in diffuse PVNS, it is interesting that a subtotal surgical resection achieved ongoing relapse-free survival sustained for more than 10 years. Finally, unique to this patient, the PVNS mass contained an area of florid lymphocytic infiltration that was skewed towards a population of T cells, rather
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
PVNS complicating HSCT in Chediak–Higashi syndrome True et al. 529
than being the usual mixed inflammatory infiltrate of B and T lymphocytes. To the best of our knowledge, no previous familial link or genetic association has been shown between PVNS and either Turner’s/Turner’s mosaic karyotype or CHS (or other similar diseases predisposing to lymphohistiocytosis) [11]. However it is surprising that a child with underlying CHS, a disease with less than 500 cases reported worldwide [1], should also develop PVNS, which affects only one in 1.8 million people [7]. As such, it may be more likely that their etiopathogenesis is interlinked. This could result from ongoing dysregulated histiocyte function/control as replacement of recipient histiocytes with those from the donor is extremely slow after transplant. For example, in mouse BMT models, only 30% of CNS microglial cell (which are specialized tissue histiocytes) are of donor origin by 1 year after transplant [12]. It could be postulated that this patient’s problems did start off with very minor unidentified trauma, possibly causing a small localized haemorrhage. If so, this could in turn have caused activation of persisting recipient fixed tissue histiocytes rather than the recurrent hemophagocytic process that was initially suspected. This would have explained the poor response to steroids and cyclosporine. There are no reports of atypical, unexplained inflammatory syndromes occurring after BMT for CHS. However, long-term follow-up has demonstrated that these patients develop progressive neurological deterioration, which may culminate in profound cerebellar and other CNS problems during adult life [13]. It has been presumed that this is due to primary problems with granule formation or transport in neurones or Schwann cells. However, it may alternatively be possible that brain histiocytes of recipient origin (including microglial cells) remain susceptible to excitation by external phenomena such as infections or trauma, and that this patient is showing an orthopaedic correlate of that behaviour. Our observations in this patient raise the question of whether subtle defects in histiocyte control – either inherited or acquired – could underpin other cases of
PVNS, which never reach the extent that we have described because of either early appropriate surgical debridement or a lesser degree of immune dysregulation.
Acknowledgements We would like to thank the patient and her family for providing consent for submitting data concerning the case for publication. Conflicts of interest
There are no conflicts of interest.
References 1
2
3
4
5
6
7
8
9
10
11 12
13
Lozano ML, Rivera J, Sánchez-Guiu I, Vicente V. Towards the targeted management of Chediak–Higashi syndrome. Orphanet J Rare Dis 2014; 9:132. Introne WJ, Westbroek W, Golas GA, Adams D. Chediak–Higashi Syndrome. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews. Seattle, WA: University of Washington; 2009. Eapen M, DeLaat CA, Baker KS, Cairo MS, Cowan MJ, Kurtzberg J, et al. Hematopoietic cell transplantation for Chediak–Higashi syndrome. Bone Marrow Transplant 2007; 39:411–415. Haddad E, Sulis ML, Jabado N, Blanche S, Fischer A, Tardieu M. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood 1997; 89:794–800. Kubat O, Mahnik A, Smoljanović T, Bojanić I. Arthroscopic treatment of localized and diffuse pigmented villonodular synovitis of the knee. Coll Antropol 2010; 34:1467–1472. Sharma H, Rana B, Mahendra A, Jane MJ, Reid R. Outcome of 17 pigmented villonodular synovitis (PVNS) of the knee at 6 years mean follow-up. Knee 2007; 14:390–394. Akinci O, Akalin Y, İncesu M, Eren A. Long-term results of surgical treatment of pigmented villonodular synovitis of the knee. Acta Orthop Traumatol Turc 2011; 45:149–155. Baroni E, Russo BD, Masquijo JJ, Bassini O, Miscione H. Pigmented villonodular synovitis of the knee in skeletally immature patients. J Child Orthop 2010; 4:123–127. Toro FG, Paulos JA, Fuentes DL, Sancy KL. Total shoulder arthroplasty in pigmented villonodular synovitis: a case report. J Shoulder Elbow Surg 2002; 11:188–190. Gangane N, Anshu, Shivkumar VB, Sharma SM. Intranuclear inclusions in a case of pigmented villonodular synovitis of the ankle. Diagn Cytopathol 2003; 29:349–351. Mankin H, Trahan C, Hornicek F. Pigmented villonodular synovitis of joints. J Surg Oncol 2011; 103:386–389. Kennedy DW, Abkowitz JL. Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood 1997; 90:986–993. Tardieu M, Lacroix C, Neven B, Bordigoni P, de Saint Basile G, Blanche S, Fischer A. Progressive neurologic dysfunctions 20 years after allogeneic bone marrow transplantation for Chediak-Higashi syndrome. Blood 2005; 106:40–42.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
