[RX] Trapped Neutrophil Syndrome in a Border Collie

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<p>ONLINE CASE REPORTS</p><p>Trapped Neutrophil Syndrome in a Border Collie</p><p>Ashley K. Hegler, DVM, Amy M. Grooters, DVM, Shannon D. Dehghanpir, DVM, MS, Rebekah A. Gallaher, DVM,</p><p>Lorrie E. Gaschen, DVM</p><p>ABSTRACT</p><p>A 10 wk old female border collie was presented for hemorrhagic diarrhea and pelvic limb lameness. Examination revealed</p><p>pain and effusion in multiple appendicular joints and pyrexia. Clinicopathologic testing revealed moderate neutropenia as</p><p>well as nondegenerate neutrophilic inflammation in multiple joints. Radiographs showed capsular joint swelling and hetero-</p><p>geneous metaphyseal lucencies in the distal radius, ulna, femur, and tibia. Genetic testing confirmed a mutation in the</p><p>vacuolar protein sorting-associated protein 13B gene and a diagnosis of trapped neutrophil syndrome (TNS). Within 24 hr</p><p>of initiating prednisone therapy (1 mg/kg, per os, q 12 hr), the dog was afebrile and nonpainful with normal ambulation.</p><p>Lameness recurred twice over the next 5 mo. At 9 mo of age, diagnostics showed severe erosive polyarthritis of both stifles</p><p>with an inflammatory leukogram and arthrocentesis findings consistent with septic arthritis, and the dog died despite</p><p>antibiotic therapy. This is the first case of TNS described in the North American literature, and it is unique in that we had</p><p>the opportunity to document progression of radiographic abnormalities over more than 6 mo. TNS should be considered in</p><p>young border collies with signs suggestive of immune-mediated polyarthritis, septic arthritis, or hypertrophic osteodystrophy,</p><p>combined with neutropenia or gastrointestinal signs. (J Am Anim Hosp Assoc 2020; 56:e563-04. DOI 10.5326/JAAHA-MS-6981)</p><p>Introduction</p><p>Trapped neutrophil syndrome (TNS) is a rare autosomal recessive</p><p>genetic disease of border collies that has been documented in Australia,</p><p>New Zealand, Japan, the United Kingdom, and Israel.1–6 Affected dogs</p><p>develop lameness, joint swelling, and neutropenia before 4 mo of age.</p><p>Although allele prevalence in border collies is estimated to be 6–12%</p><p>worldwide, there have been no North American cases described to</p><p>date.7,8 In addition, although the radiographic findings associated with</p><p>TNS are distinctive and their recognition is paramount to making a</p><p>diagnosis, radiographic images available in the veterinary literature are</p><p>currently limited to a single image of an atypical finding (metaphyseal</p><p>fracture).1 This report is the initial description of TNS in a North</p><p>American border collie and documents multiple radiographic abnor-</p><p>malities, including their progression over more than 6 mo.</p><p>Case Report</p><p>A 10 wk old female border collie was presented for evaluation of</p><p>hemorrhagic diarrhea, lethargy, and left pelvic limb lameness that had</p><p>progressed to nonambulation. Physical examination revealed pyrexia</p><p>(103.38F, 39.68C) and moderate swelling and pain in both carpi, tarsi,</p><p>and stifles, most severe in the left pelvic limb. On complete blood count</p><p>(CBC), the patient’s leukogram was unremarkable with an absolute</p><p>segmented neutrophil count within the reference interval (4.1 cells 3</p><p>103/mL; reference interval 3–11.5 cells 3 103/mL).</p><p>Radiographs of the right carpus (Figures 1A, B) showed cap-</p><p>sular soft tissue swelling with a region of ill-defined lucency at the</p><p>right distal radial and ulnar metaphyses just proximal to the distal</p><p>physes. Radiographs of the right femorotibial joint (Figure 2)</p><p>showed capsular swelling as well as a large heterogeneous area of</p><p>lucency with surrounding sclerosis in the cranial and proximal as-</p><p>pect of the distal femoral metaphysis. The distal femoral physis was</p><p>irregular and indistinct. The right femoral condyles were irregularly</p><p>marginated and the femoral epiphysis was diffusely mottled. There</p><p>was a thin, irregularly marginated, ill-defined lucency in the right</p><p>distal tibial metaphysis just proximal to and parallel with the distal</p><p>physis. Radiographs of the left pelvic limb showed capsular swelling</p><p>From Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana</p><p>State University, Baton Rouge, Louisiana.</p><p>Correspondence: agroot1@lsu.edu (A.M.G.)</p><p>CBC (complete blood count); CS (Cohen syndrome); HOD (hypertrophic</p><p>osteodystrophy); PO (per os); TNS (trapped neutrophil syndrome)</p><p>The online version of this article (available at jaaha.org) contains sup-</p><p>plementary data in the form of one figure.</p><p>Accepted for publication: June 18, 2019.</p><p>ª 2020 by American Animal Hospital Association JAAHA.ORG e563-04</p><p>Jo</p><p>ur</p><p>na</p><p>l o</p><p>f</p><p>th</p><p>e</p><p>A</p><p>m</p><p>er</p><p>ic</p><p>an</p><p>A</p><p>ni</p><p>m</p><p>al</p><p>H</p><p>os</p><p>pi</p><p>ta</p><p>l A</p><p>ss</p><p>oc</p><p>ia</p><p>tio</p><p>n</p><p>D</p><p>ow</p><p>nl</p><p>oa</p><p>de</p><p>d</p><p>fr</p><p>om</p><p>ja</p><p>ah</p><p>a.</p><p>or</p><p>g</p><p>by</p><p>U</p><p>ni</p><p>ve</p><p>rs</p><p>ity</p><p>o</p><p>f</p><p>E</p><p>di</p><p>nb</p><p>ur</p><p>gh</p><p>L</p><p>ib</p><p>ra</p><p>ry</p><p>o</p><p>n</p><p>03</p><p>/2</p><p>0/</p><p>20</p><p>. F</p><p>or</p><p>p</p><p>er</p><p>so</p><p>na</p><p>l u</p><p>se</p><p>o</p><p>nl</p><p>y.</p><p>mailto:agroot1@lsu.edu</p><p>http://jaaha.org</p><p>of the left femorotibial joint and a thin, irregularly marginated, and</p><p>ill-defined lucency in the distal femoral metaphysis parallel to and</p><p>just proximal to the physis. The epiphysis was heterogeneous with</p><p>an irregular articular border. In addition, there was capsular soft</p><p>tissue swelling of the left tibiotarsal joint associated with a thin,</p><p>irregularly marginated, ill-defined lucency with adjacent sclerosis</p><p>just proximal to the distal tibial physis.</p><p>Cytologic examination of joint fluid from the left stifle and carpus</p><p>showednondegenerate neutrophilic inflammation; aerobic culture of joint</p><p>fluid was negative. A single oral dose of carprofen (2 mg/kg) was ad-</p><p>ministered and treatment with clindamycin (15 mg/kg, IV, q 12 hr) and</p><p>ampicillin sulbactam (30 mg/kg, IV, q 8 hr) was initiated. Three days</p><p>after the initial presentation, there was no clinical improvement and a</p><p>recheck CBC showed mild neutropenia (2.9 cells 3 103/mL; reference</p><p>interval 3–11.5 cells 3 103/mL). The neutropenia in combination with</p><p>the signalment, radiographic findings, and lack of response to antibiotic</p><p>therapy raised suspicion for trapped neutrophil syndrome (TNS),</p><p>prompting treatment with prednisone (1.4 mg/kg, per os [PO], q 12 hr),</p><p>omeprazole (1 mg/kg, PO, q 12 hr, for 14 days), and tramadol (5 mg/kg,</p><p>PO, q 8–12 hr, for 10 days). Within 24 hr, the dog showed significant</p><p>improvement. When discharged the following day, 4 days after presen-</p><p>tation, the dog was afebrile, was eating and drinking normally, and was</p><p>nonpainful with normal ambulation. Blood submitted for gene se-</p><p>quencing to the Veterinary Genetics Laboratorya showed that the dog</p><p>was homozygous for the TNS mutation of the VPS13B gene. A recheck</p><p>CBC 1 wk after discharge (11 days after presentation) showed neu-</p><p>tropenia (2.4 cells 3 103/mL; reference interval 3–11.5 cells 3 103/mL).</p><p>Onemonth after initial presentation, at 3.5mo of age, the dog was</p><p>clinically normal and received a rabies vaccine. Prednisone was con-</p><p>tinued at 1 mg/kg, PO, q 12 hr. One week later, the dog was presented</p><p>for acute lameness and right carpal swelling with no known history of</p><p>trauma. Examination showed moderate, diffuse soft tissue swelling of</p><p>the right thoracic limb distal to the elbow. A small crust was present</p><p>on the lateral aspect of the right thoracic limb just distal to the elbow.</p><p>A CBC revealed moderate neutropenia (1.8 cells 3 103/mL; reference</p><p>interval 3–11.5 cells 3 103/mL). Radiographs showed extracapsular</p><p>soft tissue swelling of the right carpus (Figures 1C, D). The previously</p><p>noted regions of lucency in the right distal radial and ulnar meta-</p><p>physes were no longer present. The dog was discharged on amoxicillin</p><p>FIGURE 1</p><p>Right carpus at initial evaluation at 2.5 mo of age (A, B) and after 1 mo of</p><p>therapy at 3.5 mo of age (C, D). Initial dorsopalmar (A) and mediolateral</p><p>(B) radiographic images show capsular soft tissue swelling with regions of</p><p>ill-defined lucency (arrows) at the right distal radial and ulnar metaphyses</p><p>just proximal to the distal physes. Recheck dorsopalmar (C) and medio-</p><p>lateral (D) radiographic images obtained 1 mo later showed severe cap-</p><p>sular soft tissue swelling of the carpus. The previously noted areas of</p><p>ill-defined</p><p>lucency in the distal metaphyses are no longer present.</p><p>FIGURE 2</p><p>Right femorotibial joint on day 2 after initial presentation at approx-</p><p>imately 2.5 mo of age. Mediolateral (A) and caudocranial (B) radio-</p><p>graphic images show femorotibial joint distention (black arrowheads)</p><p>associated with mottled lysis of the distal femoral metaphysis (white</p><p>arrows) and irregular margination of the physis. The articular borders</p><p>of the femoral condyles are irregularly marginated (black arrow) and</p><p>the femoral epiphysis is diffusely mottled. A thin, irregularly margin-</p><p>ated, ill-defined lucency is evident in the right distal tibial metaphysis</p><p>(white arrowheads) just proximal to the distal physis and parallel to</p><p>the physis with an adjacent band of sclerosis.</p><p>e563-04 JAAHA | 56:3 May/Jun 2020</p><p>Jo</p><p>ur</p><p>na</p><p>l o</p><p>f</p><p>th</p><p>e</p><p>A</p><p>m</p><p>er</p><p>ic</p><p>an</p><p>A</p><p>ni</p><p>m</p><p>al</p><p>H</p><p>os</p><p>pi</p><p>ta</p><p>l A</p><p>ss</p><p>oc</p><p>ia</p><p>tio</p><p>n</p><p>D</p><p>ow</p><p>nl</p><p>oa</p><p>de</p><p>d</p><p>fr</p><p>om</p><p>ja</p><p>ah</p><p>a.</p><p>or</p><p>g</p><p>by</p><p>U</p><p>ni</p><p>ve</p><p>rs</p><p>ity</p><p>o</p><p>f</p><p>E</p><p>di</p><p>nb</p><p>ur</p><p>gh</p><p>L</p><p>ib</p><p>ra</p><p>ry</p><p>o</p><p>n</p><p>03</p><p>/2</p><p>0/</p><p>20</p><p>. F</p><p>or</p><p>p</p><p>er</p><p>so</p><p>na</p><p>l u</p><p>se</p><p>o</p><p>nl</p><p>y.</p><p>clavulanate (24 mg/kg, PO, q 12 hr, for 14 days), tramadol (5 mg/kg,</p><p>PO, q 8–12 hr, for 14 days), and continued prednisone therapy. At re-</p><p>evaluation 3 days later, the dog was ambulatory and nonpainful and</p><p>had decreased swelling of the right forelimb.</p><p>Approximately 5 mo after diagnosis, at 7.5 mo of age, the dog</p><p>was presented for recurrent lameness and swelling of both stifles and</p><p>tarsi. Repeat CBC showed neutropenia (2.6 cells3 103/mL; reference</p><p>interval 3–11.5 cells 3 103/mL) and moderate monocytosis (5.0</p><p>cells 3 103/mL; reference interval 0.1–1.4 cells 3 103/mL). Radio-</p><p>graphs of both carpi showed sclerosis surrounding the distal ulnar</p><p>and radial physes with resolution of the previously identified soft</p><p>tissue swelling. Radiographs of both femorotibial joints showed</p><p>severe intracapsular swelling of the right stifle joint (Figure 3). The</p><p>previous irregularity of the epiphysis and articular margin had</p><p>progressed to severe lysis of the medial aspect of the right distal</p><p>femoral condyle affecting the articular margin with a surrounding</p><p>rim of sclerosis. Similar but less severe changes were present at the</p><p>medial aspect of the left femoral condyle and medial tibial condyle.</p><p>Additional diagnostics were declined by the owner, and the dog</p><p>received amoxicillin-clavulanate for 14 days, tramadol for 5 days,</p><p>and continued prednisone therapy (0.6 mg/kg, PO, q 12 hr).</p><p>Six weeks later, 6.5 mo after the initial presentation and at</p><p>approximately 9 mo of age, the dog was re-presented for lameness.</p><p>She was small (8.7 kg) and short in stature for her age and breed, had</p><p>severe effusion of both stifles, and was nonambulatory in the pelvic</p><p>limbs. A CBC showed a segmented neutrophil count that was within</p><p>the reference interval (11 cells 3 103/mL; reference interval 3–11.5</p><p>cells 3 103/mL) with increased band neutrophils (1.4 cells 3 103/</p><p>mL; reference interval 0–0.3 cells 3 103/mL). Non–contrast en-</p><p>hanced computed tomography at 0.625 cm slice thickness in a bone</p><p>algorithm of both femorotibial joints was performed to obtain a</p><p>more complete assessment of the osseous lesions for diagnostic and</p><p>prognostic reasons. Severe lysis of the medial femoral condyles with</p><p>surrounding sclerosis was present bilaterally and was more extensive</p><p>on the right (Supplementary Figure I). Severe erosive polyarthritis</p><p>was diagnosed. Cytology of synovial fluid from the stifles showed</p><p>mildly degenerate neutrophilic inflammation. Aerobic culture of</p><p>synovial fluid yielded a small number of colonies of Staphylococcus</p><p>pseudintermedius from the right stifle but not the left. Sepsis sec-</p><p>ondary to septic arthritis was suspected and antibiotic therapy was</p><p>reinstituted, but the dog died the following day. Necropsy was de-</p><p>clined by the owner.</p><p>Discussion</p><p>Similar to the dog described here, dogs with TNS typically develop</p><p>failure to thrive, fever, gastrointestinal signs, lameness, joint swelling,</p><p>and neutropenia between 6 and 12 wk of age.1–6 They are often small</p><p>compared with litter mates and may have abnormal craniofacial</p><p>development characterized by a narrow, elongated skull or “ferret-</p><p>like” features.1–5 Cytologically, the polyarthritis associated with TNS</p><p>is most often characterized by nondegenerate neutrophilic inflam-</p><p>mation, consistent with immune-mediated polyarthritis.3 However,</p><p>septic arthritis can also occur, presumably secondary to persistent</p><p>neutropenia.</p><p>The mutation that causes TNS is a 4 base pair deletion in exon</p><p>19 of the VPS13B gene on chromosome 13, which codes for a trans-</p><p>membrane protein used for vesicle-mediated transport and sorting</p><p>within the cell and is specifically involved in Golgi glycosylation and</p><p>endo-lysosomal maintenance.7,9 In people, mutations in VPS13B</p><p>lead to the rare autosomal recessive disorder Cohen syndrome (CS),</p><p>which is characterized by delayed development, microcephaly,</p><p>neutropenia, and facial dysmorphism typified by a beak-shaped</p><p>nose and grimace.10</p><p>Based on the nine previously described cases, the neutropenia</p><p>associated with TNS is typically mild to moderate and occurs despite</p><p>myeloid hyperplasia in the bone marrow, hence the name of the</p><p>FIGURE 3</p><p>Right femorotibial joint 5 mo after initial presentation at approxi-</p><p>mately 7.5 mo of age. Mediolateral (A) and caudocranial (B) radio-</p><p>graphic images show progressive, severe intracapsular swelling of the</p><p>femorotibial joint. There is moderate lysis of the medial aspect of the</p><p>distal femoral condyle (arrows) affecting the articular margin with a</p><p>surrounding rim of sclerosis.</p><p>Trapped Neutrophil Syndrome</p><p>JAAHA.ORG e563-04</p><p>Jo</p><p>ur</p><p>na</p><p>l o</p><p>f</p><p>th</p><p>e</p><p>A</p><p>m</p><p>er</p><p>ic</p><p>an</p><p>A</p><p>ni</p><p>m</p><p>al</p><p>H</p><p>os</p><p>pi</p><p>ta</p><p>l A</p><p>ss</p><p>oc</p><p>ia</p><p>tio</p><p>n</p><p>D</p><p>ow</p><p>nl</p><p>oa</p><p>de</p><p>d</p><p>fr</p><p>om</p><p>ja</p><p>ah</p><p>a.</p><p>or</p><p>g</p><p>by</p><p>U</p><p>ni</p><p>ve</p><p>rs</p><p>ity</p><p>o</p><p>f</p><p>E</p><p>di</p><p>nb</p><p>ur</p><p>gh</p><p>L</p><p>ib</p><p>ra</p><p>ry</p><p>o</p><p>n</p><p>03</p><p>/2</p><p>0/</p><p>20</p><p>. F</p><p>or</p><p>p</p><p>er</p><p>so</p><p>na</p><p>l u</p><p>se</p><p>o</p><p>nl</p><p>y.</p><p>syndrome.1 Although the specific mechanism for neutropenia is</p><p>unknown, the importance of vacuolar protein sorting genes in</p><p>granulocytic development is reinforced by the finding of neu-</p><p>tropenia in VPS45-deficient people.11 Studies of bone marrow and</p><p>neutrophil function in people with CS revealed normal marrow</p><p>cellularity without granulocytic dysplasia or maturation arrest and</p><p>with appropriate superoxide anion release.12,13 However, neutrophils</p><p>from people with CS were found to have increased adhesion</p><p>capacity and decreased expression of L-selectin (CD62L) and B2</p><p>integrin (CD11b), suggestive of increased neutrophilic margin-</p><p>ation.13 Although these studies have yet to be performed in dogs</p><p>with TNS, it can be speculated that the mechanism of neutropenia is</p><p>similar because bone marrow evaluation from dogs with TNS has</p><p>largely been unremarkable.2,3</p><p>The most common radiographic and computed tomographic</p><p>abnormalities previously described in border collies with TNS are</p><p>similar to those identified in the dog described here, and they include</p><p>intracapsular joint swelling and metaphyseal lucencies surrounded by</p><p>sclerosis, most often in the distal femur, tibia, radius, and ulna.</p><p>However, lesion severity has ranged from the absence of radiographic</p><p>abnormalities4,5 to fractures associated with metaphyseal lysis,1 and</p><p>locations have also included proximal humerus,1,3 distal fibula,2 and</p><p>phalanges.5 Histologically, areas of radiographic metaphyseal lu-</p><p>cency have corresponded to areas of hypercellularity associated with</p><p>marked neutrophilic infiltration, hemorrhage, and osteonecrosis</p><p>with variable loss of the trabecular bone.1 Segmental necrosis of the</p><p>physis has also been described and may account for the physeal</p><p>sclerosis and irregularity observed radiographically in our patient.1</p><p>The case described here was unique in that there was an op-</p><p>portunity to evaluate the progression of radiographic abnormalities</p><p>over more than 6 mo. Lesions were initially characterized by capsular</p><p>joint swelling and heterogeneous areas of metaphyseal lucency and</p><p>sclerosis in the distal radius, ulna,</p><p>femur, and tibia but progressed to</p><p>include bilateral epiphyseal lysis of the distal femur and tibia as well as</p><p>articular lysis of both stifles. Although previous reports have de-</p><p>scribed lysis at the joint margin and articular swelling associated with</p><p>nonseptic inflammation, articular lysis has not been previously</p><p>reported in dogs with TNS and may reflect changes secondary to</p><p>septic arthritis or may be a newly described feature due to progression</p><p>of disease. The distal radial and ulnar metaphyseal lucencies resolved</p><p>in this dog after initial therapy, and it is unclear whether some</p><p>component of hypertrophic osteodystrophy (HOD) caused the ra-</p><p>diographic features and were self-limiting, as was suspected in one</p><p>previously described dog with TNS,2 or whether immunosuppressive</p><p>therapy contributed to their resolution.</p><p>The clinical signs and radiographic lesions associated with TNS</p><p>have a number of similarities to those caused by HOD, and as a result,</p><p>TNS may be misdiagnosed as severe HOD that fails to resolve.2</p><p>Similar to TNS, the signs associated with HOD typically develop at</p><p>2–8 mo of age and include lameness, lethargy, fever, and an-</p><p>orexia.14,15 Radiographically, both diseases cause metaphyseal lesions</p><p>in long bones, including irregular, faint, radiolucent bands aligned</p><p>parallel to the physis in the distal radius, ulna, and tibia. However,</p><p>there are a number of differences between the radiographic features</p><p>associated with these diseases. First, swelling of the distal extremities</p><p>is often the result of intracapsular joint effusion in dogs with TNS,</p><p>whereas in HOD, swelling is typically extracapsular and is most</p><p>prominent at the physis. Second, HOD is infrequently described in</p><p>the distal femur, with the most common sites being the distal radius,</p><p>ulna, and tibia,15 whereas distal femoral lysis is common in dogs</p><p>with TNS. Third, in addition to the faint, lucent metaphyseal</p><p>bands typically associated with HOD, metaphyseal lysis associated</p><p>with TNS often has an indistinct, moth-eaten appearance with</p><p>surrounding sclerosis consistent with osteomyelitis1,3 and may ex-</p><p>tend to the metaphyseal/diaphyseal junction1 or into the epiphysis,</p><p>as was seen in our patient. Finally, the progressive articular lysis of</p><p>the stifles observed in the dog described here has not previously</p><p>been associated with HOD.</p><p>A clinical diagnosis of TNS can be made on the basis of sig-</p><p>nalment combined with typical clinical features, including fever,</p><p>neutropenia despite myeloid hyperplasia, effusive polyarthropathy,</p><p>and radiographic evidence of osteolytic and sclerotic irregular</p><p>metaphyseal lesions in long bones. Because of their clinical simi-</p><p>larities, TNS should be considered in any young border collie with</p><p>signs consistent with HOD, especially when gastrointestinal signs,</p><p>neutropenia, or joint effusion are present. The diagnosis of TNS can</p><p>be confirmed by gene sequencing that indicates the animal is ho-</p><p>mozygous for the VPS13B gene mutation.7 In the United States,</p><p>there are at least three laboratories that offer testing for TNS from</p><p>blood samples or cheek swabsa,b,c. Results can differentiate normal</p><p>dogs from those that are carriers (heterozygous for the mutation) or</p><p>affected (homozygous for the mutation).</p><p>Unfortunately, the long-term prognosis for dogs with TNS is</p><p>guarded to poor, with therapy aimed at controlling clinical signs,</p><p>improving neutropenia, and treating secondary bacterial infections.</p><p>The mainstay of treatment is immunosuppressive therapy, which in</p><p>the few cases that have been described has often resolved the signs</p><p>associated with polyarthropathy and improved neutropenia in the</p><p>short term.1,3–5 Glucocorticoids have been used successfully to de-</p><p>crease joint effusion and increase neutrophil counts, but signs</p><p>typically recur as immunosuppressive therapy is tapered. It is sus-</p><p>pected that glucocorticoid administration promotes neutrophil</p><p>demargination and migration from the bone marrow into the pe-</p><p>ripheral circulation by decreasing gene transcription of L-selectin.16</p><p>e563-04 JAAHA | 56:3 May/Jun 2020</p><p>Jo</p><p>ur</p><p>na</p><p>l o</p><p>f</p><p>th</p><p>e</p><p>A</p><p>m</p><p>er</p><p>ic</p><p>an</p><p>A</p><p>ni</p><p>m</p><p>al</p><p>H</p><p>os</p><p>pi</p><p>ta</p><p>l A</p><p>ss</p><p>oc</p><p>ia</p><p>tio</p><p>n</p><p>D</p><p>ow</p><p>nl</p><p>oa</p><p>de</p><p>d</p><p>fr</p><p>om</p><p>ja</p><p>ah</p><p>a.</p><p>or</p><p>g</p><p>by</p><p>U</p><p>ni</p><p>ve</p><p>rs</p><p>ity</p><p>o</p><p>f</p><p>E</p><p>di</p><p>nb</p><p>ur</p><p>gh</p><p>L</p><p>ib</p><p>ra</p><p>ry</p><p>o</p><p>n</p><p>03</p><p>/2</p><p>0/</p><p>20</p><p>. F</p><p>or</p><p>p</p><p>er</p><p>so</p><p>na</p><p>l u</p><p>se</p><p>o</p><p>nl</p><p>y.</p><p>The dosage of prednisone used in the dog described here was based</p><p>on dosages that were deemed effective for control of clinical signs in</p><p>previously described cases.3,5 Although this dog’s clinical signs im-</p><p>proved initially, the neutropenia was persistent and signs of poly-</p><p>arthropathy recurred twice despite therapy. In addition, it was not</p><p>possible to reevaluate the dog frequently. Therefore, rather than</p><p>attempting to more aggressively taper the dosage of prednisone, we</p><p>elected to maintain the same tablet size of prednisone over the</p><p>course of treatment. Because of the dog’s growth, this resulted in a</p><p>decrease in the prednisone dosage over 6.5 mo from 1.4 mg/kg q</p><p>12 hr to 0.6 mg/kg q 12 hr.</p><p>Of the nine dogs with TNS previously described in the literature,</p><p>four died or were euthanized before 1 yr of age because of persistent</p><p>neutropenia, recurrent bacterial infection, sepsis, or recurrent pol-</p><p>yarthritis.1,2,4 However, one report described a dog that was treated</p><p>for at least 3 yr,3 and a second report described two cases that were</p><p>managed for 3 and 6 yr, respectively,5 so longer outcomes are pos-</p><p>sible. In the two dogs described in the second report, azathioprine</p><p>was used in addition to prednisone for immunosuppression, but the</p><p>authors concluded that its use did not improve clinical signs or</p><p>allow lowering of the prednisone dosage.5 The addition of newer</p><p>immunosuppressive agents such as mycophenolate may be consid-</p><p>ered for these purposes in future cases. In the dog described here, it</p><p>is possible that earlier identification of potential septic arthritis and</p><p>reinstitution of antibiotic therapy may have delayed the outcome;</p><p>however, the necessity for ongoing immunosuppressive therapy</p><p>combined with recurrent or persistent neutropenia makes long-</p><p>term management of patients with TNS challenging.</p><p>Conclusion</p><p>Trapped neutrophil syndrome is a rare, autosomal recessive, heritable</p><p>disease of border collies that has not previously been described in a</p><p>dog fromNorth America, despite the fact that estimates of worldwide</p><p>allele prevalence in the breed are 6–12%.7,8 It is our hope that the</p><p>description of clinicopathologic and radiographic findings in this</p><p>case will raise awareness in North America and prompt veterinar-</p><p>ians to include TNS as a differential diagnosis when a young border</p><p>collie with signs consistent with HOD, immune-mediated poly-</p><p>arthritis, or septic arthritis is encountered, especially when com-</p><p>bined with gastrointestinal signs or neutropenia. Veterinarians who</p><p>counsel US border collie breeders should consider recommending</p><p>that genetic testing for the TNS mutation be included when</p><p>screening breeding animals for heritable diseases.</p><p>FOOTNOTES</p><p>a Veterinary Genetics Laboratory, School of Veterinary Medicine,</p><p>University of California, Davis, Davis, California</p><p>b OptiGen, LLC, Ithaca, New York</p><p>c Animal Genetics Inc, Tallahassee, Florida</p><p>REFERENCES</p><p>1. Allan FJ, Thompson KG, Jones BR, et al. Neutropenia with a probable</p><p>hereditary basis in Border Collies. N Z Vet J 1996;44:67–72.</p><p>2. Gans Z. Confirmed trapped neutrophil syndrome in a Border Collie</p><p>puppy in Israel. Isr J Vet Med 2015;70:45–48.</p><p>3. Mason SL, Jepson R, Maltman M, et al. Presentation and management of</p><p>trapped neutrophil syndrome (TNS) in UK border collies. J Small Anim</p><p>Pract 2014;55:57–60.</p><p>4. Mizukami K, Shoubudani T, Nishimoto S, et al. Trapped neutrophil</p><p>syndrome in a border collie dog: clinical, clinicopathologic, and mo-</p><p>lecular findings. J Vet Med Sci 2012;74:797–800.</p><p>5. Wouda RM, Mackay BM. Long-term management of trapped neutrophil</p><p>syndrome in two border collies. Aust Vet Pract 2010;40:58–63.</p><p>6.</p><p>Black VL, Whitworth FJS, Adamantos S. Pyrexia in juvenile dogs: a re-</p><p>view of 140 referred cases. J Small Anim Pract 2019;60:116–20.</p><p>7. Shearman JR, Wilton AN. A canine model of Cohen syndrome: trapped</p><p>neutrophil syndrome. BMC Genomics 2011;12:258.</p><p>8. Mizukami K, Yabuki A, Kohyama M, et al. Molecular prevalence of</p><p>multiple genetic disorders in border collies in Japan and recommenda-</p><p>tions for genetic counseling. Vet J 2016;214:21–3.</p><p>9. Duplomb L, Duvet S, Picot D, et al. Cohen syndrome is associated with</p><p>major glycosylation defects. Hum Mol Genet 2014;23:2391–9.</p><p>10. Rodrigues JM, Fernandes HD, Caruthers C, et al. Cohen syndrome:</p><p>review of the literature. Cureus 2018;10:e3330.</p><p>11. Vilboux T, Lev A, Malicdan MC, et al. A congenital neutrophil defect syn-</p><p>drome associated with mutations in VPS45. N Engl J Med 2013;369:54–65.</p><p>12. Donadieu J, Beaupain B, Fenneteau O, et al. Congenital neutropenia in</p><p>the era of genomics: classification, diagnosis, and natural history. Br J</p><p>Haematol 2017;179:557–74.</p><p>13. Olivieri O, Lombardi S, Russo C, et al. Increased neutrophil adhesive</p><p>capability in Cohen syndrome, an autosomal recessive disorder associ-</p><p>ated with granulocytopenia. Haematologica 1998;83:778–82.</p><p>14. Safra N, Johnson EG, Lit L, et al. Clinical manifestations, response to</p><p>treatment, and clinical outcome for Weimaraners with hypertrophic osteo-</p><p>dystrophy: 53 cases (2009-2011). J Am Vet Med Assoc 2013;242:1260–6.</p><p>15. Demko J, McLaughlin R. Developmental orthopedic disease. Vet Clin</p><p>North Am Small Anim Pract 2005;35:1111–35.</p><p>16. Weber PS, Toelboell T, Chang LC, et al. Mechanisms of glucocorticoid-</p><p>induced down-regulation of neutrophil L-selectin in cattle: evidence for</p><p>effects at the gene-expression level and primarily on blood neutrophils. J</p><p>Leukoc Biol 2004;75:815–27.</p><p>Trapped Neutrophil Syndrome</p><p>JAAHA.ORG e563-04</p><p>Jo</p><p>ur</p><p>na</p><p>l o</p><p>f</p><p>th</p><p>e</p><p>A</p><p>m</p><p>er</p><p>ic</p><p>an</p><p>A</p><p>ni</p><p>m</p><p>al</p><p>H</p><p>os</p><p>pi</p><p>ta</p><p>l A</p><p>ss</p><p>oc</p><p>ia</p><p>tio</p><p>n</p><p>D</p><p>ow</p><p>nl</p><p>oa</p><p>de</p><p>d</p><p>fr</p><p>om</p><p>ja</p><p>ah</p><p>a.</p><p>or</p><p>g</p><p>by</p><p>U</p><p>ni</p><p>ve</p><p>rs</p><p>ity</p><p>o</p><p>f</p><p>E</p><p>di</p><p>nb</p><p>ur</p><p>gh</p><p>L</p><p>ib</p><p>ra</p><p>ry</p><p>o</p><p>n</p><p>03</p><p>/2</p><p>0/</p><p>20</p><p>. 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