Int J Hematol DOI 10.1007/s12185-014-1621-z
CASE REPORT
A possible familial lymphoproliferative disorder in two male siblings of children with recurrent wheezing and lung infections since infancy Shih-Hsiang Chen • Shao-Hsuan Hsia • Jainn-Jim Lin • Kin-Sun Wong • Chih-Wei Wang Lee-Yung Shih • Wen-I Lee
•
Received: 20 February 2014 / Revised: 11 June 2014 / Accepted: 11 June 2014 Ó The Japanese Society of Hematology 2014
Abstract Malignancies that result in wheezing in infants are very uncommon. Given its rarity in children, the diagnosis is challenging, and in the absence of a high index of suspicion, delayed diagnosis is not uncommon. Here we report two male siblings of children who presented with recurrent wheezing and recurrent lung infections since infancy. Both children showed no laboratory evidence of immunodeficiency. Lymphocytic interstitial pneumonia or hypersensitivity pneumonitis was histologically suspected in lung biopsy specimens from the older brother. He subsequently developed Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis and died. Based on the family history, we screened mutations among PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes for the younger brother, but did not identify any mutations. He also underwent lung biopsy, which showed interstitial infiltration of lymphoid cells. In situ hybridization for
Electronic supplementary material The online version of this article (doi:10.1007/s12185-014-1621-z) contains supplementary material, which is available to authorized users. S.-H. Chen (&) Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin Street, Kwei-Shan 333, Taoyuan, Taiwan e-mail: [email protected] S.-H. Hsia J.-J. Lin Division of Critical Care and Emergency Medicine, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan K.-S. Wong Division of Pulmonology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
EBV-encoded RNA showed a positive nuclear signal in the lymphoid cells. The presence of clonal B-cell proliferations was detected by clonally rearranged immunoglobulin studies. Lymphomatoid granulomatosis grade 3 was finally diagnosed. The progression of disease was rapid, and the patient died, despite rituximab therapy. The similar clinical manifestations in two male siblings suggest the possibility that a previously undescribed genetic defect contributed to these familial lymphoproliferative malignancies. Keywords Children Familial lymphoproliferative malignancy Lymphomatoid granulomatosis Recurrent wheezing X-linked
Introduction Lymphoproliferative disorders in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, lymphoid neoplasms that occur in the setting of immune dysfunction. Familial lymphoproliferative disorC.-W. Wang Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan L.-Y. Shih Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan W.-I. Lee Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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ders have been described in association with a variety of primary immunodeficiency disorders (PIDs). The incidence ranges from 0.7 to 15 % [1]. Specific PIDs have associations with particular lymphoproliferations. For example, patients with ataxia-telangiectasia predispose to developing T-cell leukemias and lymphomas, and in Wiskott–Aldrich syndrome there is a tendency for lymphomatoid granulomatosis (LYG) [1]. LYG is an angiocentric and angiodestructive lymphoproliferative disorder. It is a rare condition and usually presents in adult life (generally between the ages of 30 and 50). But it may be seen in children with immunodeficiency disorders. Pulmonary involvement occurs in over 90 % of patients and is usually present at initial diagnosis [2]. Patients frequently present with respiratory symptoms, such as cough, dyspnea, and chest pain. Wheezing is seldom observed. The course of LYG tends to be fulminant and the reported mortality rate is above 50 % [3–5]. Given its rarity in children, the diagnosis is challenging, and delayed diagnosis is not uncommon without a high index of suspicion. Herein, we report two male siblings of children who presented with recurrent wheezing and lung infections since early infancy. Immunodeficiency was not evident in both children. They subsequently died of Epstein-Barr virus (EBV) associated lymphoproliferative disorders. A previously undescribed genetic defect contributing to familial lymphoproliferative malignancies was highly suspected.
Case presentation Case 1 Case 1 is the elder brother of case 2. According to the medical summary provided by his parents, he had refractory wheezing and recurrent lung infections since infancy. No definite cause of wheezing was identified after many laboratory and radiologic evaluations. PID was, therefore, suspected. He was born to healthy non-consanguineous parents with no family history of early death or immunodeficiency. His two sisters were healthy (Fig. 1a). He received extensive immunologic evaluations and medical treatment at another hospital. Serum immunoglobulin (Ig) level was normal. Lymphocyte subset studies revealed 15.9 % CD19? lymphocytes, 69 % CD3?, 30.5 % CD4?, 34.6 % CD8?, and 8.8 % CD16/CD56?. The polymorphonuclear leukocytes (PMN) function (chemotaxis and phagocytosis) was normal. He received lung biopsy at around 2 years of age. The histology showed interstitial infiltration with a mixed population of lymphocytes, plasma cells, histiocytes, and eosinophils. Lymphocytic
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interstitial pneumonia or hypersensitivity pneumonitis was suspected. Unfortunately, he developed fever, pancytopenia, hepatosplenomegaly, hypertriglycemia, hyperferritinemia at 3 years of age. The serology for EBV showed positive for viral capsid antigen (VCA)-IgM, VCA-IgG, early antigen, and nuclear antigen. Natural killer (NK) cell activity was not measured. EBV-associated hemophagocytic lymphohistiocytosis (HLH) was diagnosed based on the Histiocyte Society HLH-2004 protocol [6]. High dose of intravenous immunoglobulin was applied. The clinical course was so fulminant that he died of respiratory failure despite intensive medical treatment. Case 2 Case 2 had presented with recurrent wheezing suspicious of infantile asthma and recurrent lung infections since 4 months of age. He had been treated by periodic steroid for wheezing with partial benefit. As his elder brother (case 1), no definite cause of wheezing was identified. PID was suspected, but serum immunoglobulin level checked at 7 months of age was normal. In May 2009, he had fever lasting for 4 days and respiratory distress, requiring pediatric intensive care unit admission with nasal intermittent mandatory ventilation at another hospital. Immunodeficiency with severe infection was impressed. Intravenous immunoglobulin and antibiotic therapy were applied. For further evaluation and management of his underlying disease, he was referred to our hospital. On examination, the 13-month-old boy appeared ill and pale. The temperature was 38.6 °C, pulse 152/min, and respiratory rate 30/min. Auscultation of chest revealed bilateral rales and wheezing. There was no evidence of rashes, lymphadenopathy, or hepatosplenomegaly. Plain chest radiograph showed increased bilateral perihilar infiltration without cardiomegaly. The hemogram revealed hemoglobin 9.6 g/dL, platelets 239 9 109/L, and white blood cell 30 9 109/L with 78.5 % segmented neutrophils, 3.5 % band neutrophils, 9 % lymphocytes, 8 % monocytes, and 1 % eosinophil. We performed a series of laboratory tests to evaluate his immune function. Serum immunoglobulin level was normal. The total lymphocyte count was 2.7 9 109/L. Lymphocyte subset studies revealed 21.3 % CD19? lymphocytes, 74.6 % CD3?, 49.5 % CD4?, 18.2 % CD8?, and 2.1 % CD16/CD56?. NK cell activity was not evaluated. The PMN function (chemotaxis, phagocytosis, and H2O2 production) was normal. The serology for EBV showed positive for VCA-IgM, VCA-IgG, early antigen, and nuclear antigen. EBV DNA analysis in blood was negative. A bone marrow examination was normal. Other laboratory investigations did not support the diagnosis of EBV-associated HLH. Familial HLH or X-linked
LPD in 2 male siblings of children Fig. 1 a The family pedigree of case 1 and case 2. b CT scan of lung. Linear nodular lesions in bilateral lung fields. c Diffuse interstitial infiltration of small to large atypical lymphoid cells with a marked peribronchiolar pattern (Hematoxylin-eosin stain). d The Compressed bronchiole and CD20? lymphoid cells. e Positive EBVencoded small ribonucleic acid in situ hybridization in lymphoid cells
lymphoproliferative disease (XLP) was highly suspected based on his family history. After obtaining the informed consent from his parents, total RNA was isolated from his peripheral mononuclear cells and was further analyzed for the mutations of PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes (Supplementary Table 1). No mutation in the above mentioned genes was identified. The computed tomography of chest showed normal structure of trachea, bronchus, and great vessels. He was
treated with periodic steroid, bronchodilators, and prokinetic agents. But the respiratory symptoms were not responsive well to above therapies, especially when steroid was tapered or discontinued. Followed-up computed tomography of the chest revealed progressive nodular opacities in both lung fields (Fig. 1b). A thoracoscopic lung biopsy was performed. The histologic examination revealed diffuse interstitial infiltration of small to large atypical lymphoid cells with a
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Fig. 2 The presence of homoduplex bands for IgH: VH-JH (FR2), IgH: VH-JH (FR3), IgK Vk-Jk, and IgK Vk/intron-Kde by heteroduplex analysis with corresponding monoclonal peaks by gene scanning
marked peribronchiolar pattern. The bronchiole was significantly compressed and some alveoli were stuffed with lymphoid cells. These lymphoid cells were reactive for anti-CD4, CD8, and CD20, which was the most strongly positive (Fig. 1c, d). An in situ hybridization (ISH) for EBV-encoded nuclear RNA (EBER) disclosed strong positivity of the nuclei of infiltrated lymphoid cells ([50/ high power field) (Fig. 1e). We extracted DNA from the paraffin-embedded lung biopsy specimen. Clonal rearrangements of the Ig heavy chain gene were detected using
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the polymerase chain reaction (PCR) (Fig. 2). LYG grade 3 was then diagnosed. The patient was more tachypneic with persistent wheezy breathing sound, like acute exacerbation of asthma. His consciousness became drowsy and his eyes were protruded gradually. The whole-body computed tomography revealed soft-tissue lesions at the lateral sides of bilateral orbital cavities which resulted in proptosis, poor differentiation of gray and white matter, increased number of nodular lesions and multiple patchy opacities and consolidation over
LPD in 2 male siblings of children
bilateral lung fields, and several small hypodense nodular lesions in the liver, spleen, and kidneys. Although we did not perform biopsy from these lesions, LYG in progression was clinically impressed. Rituximab was given on a weekly basis at a dose of 375 mg/m2. Unfortunately, the patient died of respiratory failure related to his disease progression after applying 2 doses of rituximab.
Discussion Wheezing is a common presenting symptom of respiratory disease in children. It has been reported that 25–30 % of infants will have at least one episode of wheezing [7], nevertheless not all the children with wheezing are caused by asthma. The younger the child, the broader the differential diagnosis, highlighting the importance of a higher index of suspicion for other causes of wheezing in preschool-aged children [8]. Respiratory tract infections, anatomic anomalies of the airway (e.g. tracheomalacia), extrinsic impingement of the airway (e.g. vascular ring), gastroesophageal reflux, and foreign body aspiration are usually considered when evaluating the child with recurrent wheezing. Importantly, physicians need to be alert to other rare causes of recurrent wheezing such as immunodeficiencies or malignancies if the common causes are not identified. Recurrent sinopulmonary infections usually lead physicians to the suspicion of immunodeficiency. Since there was a family history of male siblings with HLH, familial HLH and XLP should be considered in the little brother. We and others have shown that familial HLH is rare in Southeast Asia [9–11]. XLP is a genetic disorder that affects young boys and is characterized by severe dysregulation of the immune system, often, but not always, in response to EBV infection. The three most common clinical manifestations of XLP are fulminant infectious mononucleosis (some may develop HLH), dysgammaglobulinemia, and lymphoma, usually of B-cell origin [12]. XLP is caused by mutations in SH2D1A and XIAP genes. It may also occur in rare instances with no identified underlying genetic cause [13]. LYG is a very rare EBV-driven lymphoproliferative disease. It predominantly affects extranodal sites. Histologically, it composes predominantly of atypical lymphocytes admixed with plasmacytoid cells, immunoblasts, and histiocytes [3]. It usually manifests between the ages of 30 and 50. In a recent review of LG in children, the median age at diagnosis was 12 years [5]. Most commonly involved organs were lung (82 %), central nervous system (51 %), liver (25 %), skin (22 %), lymph nodes (16 %), kidneys (13 %), and spleen (8 %). Pulmonary symptoms were the main presenting symptoms. In contrast to adults,
children with LG had a higher incidence of neurological symptoms. Protracted wheezing has been reported as one of the abnormal physical findings in an old woman with LYG who presented with a hilar mass encasing and narrowing the bronchus [14]. In our patient, we could not find any extrinsic compression of airway leading to his wheezing. It is speculated that wheezing in our patient may result from the compressed bronchioles by surrounding infiltration of the atypical lymphoid cells. Histologically, LYG is characterized by large atypical CD20? B cells and numerous background lymphocytes. Most lymphocytes are CD3? T cells, with CD4? cells more frequent than CD8? cells [2]. Therefore, the precise identification of these potentially malignant cells from a prominent inflammatory background may depend on the subjective assessment and the experience of the pathologist. By the advanced progress of molecular technique, the component of malignant lymphoma can be identified more precisely as the presence of a clonal rearrangement of the Ig gene or T-cell receptor gene. Most cases of LYG are reported to have clonal Ig gene rearrangement from the atypical lymphoid cells [15, 16]. In our patient, we were unable to distinguish marked inflammatory reactions or lymphoproliferative disorders until the presence of a clonal Ig gene rearrangement was demonstrated by PCR-based clonality analysis. As a result, clonality analysis of antigen receptor genes is helpful in the diagnosis if the immunohistochemistry study is not informative enough. Treatment of LYG remains a challenge, and there is no standard protocol. The treatment outcomes of LYG are variable, but generally dismal in adults with a median survival of 14 months and a mortality rate of 65–90 % [3, 4]. In children, the mortality rate was around 50 %, and the median interval between diagnosis and death was 8 months [5]. Treatment with prednisolone or rituximab as a single agent has variable success [17–19]. Rituximab in combination with intensive chemotherapy are usually recommended for grade 3 lesions due to the high rate of rapid progression into EBV-positive large B-cell lymphoma [20]. However, many patients were refractory to therapy and died of disease progression shortly after diagnosis [20]. LYG is rarely reported within family members. Rogers et al. [21] reported a familial lymphoproliferative disorder presenting with primary pulmonary manifestations. They studied a family in which lymphoproliferative disorders with primary pulmonary involvement occurred in three male siblings. All three siblings received lung biopsy. Lymphocytic interstitial pneumonia was diagnosed in one. The histology findings in the remaining two siblings showed similar angiocentric, nodular polymorphic infiltrates resembling LYG. However, EBV was not demonstrated in any of the pulmonary lesions. At the moment of their report, the latter two siblings had rapid disease
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progression and died. The first sibling also had progressive pulmonary lesions and appeared radiographically similar to his brothers. There is some resemblance between the clinical course of the two siblings in our report and the report from Rogers et al. An unknown genetic cause in such familial lymphoproliferative disease needs further investigation. Acknowledgments This work was supported in part by the grants CMRPG4A0041-43 from Chang Gung Memorial Hospital, Taiwan, the grants NCS-100-2314-B-182A-063 from the National Science Council, Taiwan, and grants DOH102-TD-C-111-006 from the National Health Research Institute, Taiwan. Conflict of interest
None declared.
References 1. Tran H, Nourse J, Hall S, Green M, Griffiths L, Gandhi MK. Immunodeficiency-associated lymphomas. Blood Rev. 2008;22(5): 261–81. 2. Pittaluga S, Wilson WH, Jaffe ES. Lymphomatoid granulomatosis. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 ed. Lyon: IARC Press; 2008. p. 247–9. 3. Katzenstein AL, Doxtader E, Narendra S. Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol. 2010;34(12):e35–48. 4. Sheehy N, Bird B, O’Briain DS, Daly P, Wilson G. Synchronous regression and progression of pulmonary nodules on chest CT in untreated lymphomatoid granulomatosis. Clin Radiol. 2004; 59(5):451–4. 5. Tacke ZC, Eikelenboom MJ, Vermeulen RJ, van der Knaap MS, Euser AM, van der Valk P, et al. Childhood lymphomatoid granulomatosis: a report of 2 cases and review of the literature. J Pediatr Hematol Oncol 2014. [Epub ahead of print]. 6. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. 7. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first 6 years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3): 133–8. 8. Weiss LN. The diagnosis of wheezing in children. Am Fam Physician. 2008;77(8):1109–14.
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9. Lee WI, Chen SH, Hung IJ, Yang CP, Jaing TH, Chen CJ, et al. Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J. 2009;28(1):30–4. 10. Zhizhuo H, Junmei X, Yuelin S, Qiang Q, Chunyan L, Zhengde X, et al. Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2012;58(3):410–4. 11. My LT, le Lien B, Hsieh WC, Imamura T, Anh TN, Anh PN, et al. Comprehensive analyses and characterization of haemophagocytic lymphohistiocytosis in Vietnamese children. Br J Haematol. 2010;148(2):301–10. 12. Kanegane H, Yang X, Zhao M, Yamato K, Inoue M, Hamamoto K, et al. Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis. Pediatr Allergy Immunol. 2012;23(5):488–93. 13. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041–52. 14. Mohyuddin GR, Sultan F, Khaleeq G. A rare presentation of a rare disease: pulmonary lymphomatoid granulomatosis. Case Rep Pulmonol. 2012;2012:371490. 15. Nishihara H, Tateishi U, Itoh T, Nagashima K, Tanaka S. Immunohistochemical and gene rearrangement studies of central nervous system lymphomatoid granulomatosis. Neuropathology. 2007;27(5):413–8. 16. Beaty MW, Toro J, Sorbara L, Stern JB, Pittaluga S, Raffeld M, et al. Cutaneous lymphomatoid granulomatosis: correlation of clinical and biologic features. Am J Surg Pathol. 2001;25(9): 1111–20. 17. Jordan K, Grothey A, Grothe W, Kegel T, Wolf HH, Schmoll HJ. Successful treatment of mediastinal lymphomatoid granulomatosis with rituximab monotherapy. Eur J Haematol. 2005;74(3): 263–6. 18. Jaffre S, Jardin F, Dominique S, Duet E, Hubscher P, Genevois A, et al. Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab. Eur Respir J. 2006;27(3):644–6. 19. Saruta H, Tsuruta D, Hashikawa K, Ohyama B, Ishii N, Furumura M, et al. Old-aged case of indolent grade III lymphomatoid granulomatosis successfully treated only with oral prednisolone. J Dermatol. 2013;40(11):942–3. 20. Gitelson E, Al-Saleem T, Smith MR. Review: lymphomatoid granulomatosis: challenges in diagnosis and treatment. Clin Adv Hematol Oncol. 2009;7(1):68–70. 21. Rogers BB, Browning I, Rosenblatt H, McClain K, Kemp J, Glasser LL, et al. A familial lymphoproliferative disorder presenting with primary pulmonary manifestations. Am Rev Respir Dis. 1992;145(1):203–8.
CASE REPORT
A possible familial lymphoproliferative disorder in two male siblings of children with recurrent wheezing and lung infections since infancy Shih-Hsiang Chen • Shao-Hsuan Hsia • Jainn-Jim Lin • Kin-Sun Wong • Chih-Wei Wang Lee-Yung Shih • Wen-I Lee
•
Received: 20 February 2014 / Revised: 11 June 2014 / Accepted: 11 June 2014 Ó The Japanese Society of Hematology 2014
Abstract Malignancies that result in wheezing in infants are very uncommon. Given its rarity in children, the diagnosis is challenging, and in the absence of a high index of suspicion, delayed diagnosis is not uncommon. Here we report two male siblings of children who presented with recurrent wheezing and recurrent lung infections since infancy. Both children showed no laboratory evidence of immunodeficiency. Lymphocytic interstitial pneumonia or hypersensitivity pneumonitis was histologically suspected in lung biopsy specimens from the older brother. He subsequently developed Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis and died. Based on the family history, we screened mutations among PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes for the younger brother, but did not identify any mutations. He also underwent lung biopsy, which showed interstitial infiltration of lymphoid cells. In situ hybridization for
Electronic supplementary material The online version of this article (doi:10.1007/s12185-014-1621-z) contains supplementary material, which is available to authorized users. S.-H. Chen (&) Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 5 Fu-Shin Street, Kwei-Shan 333, Taoyuan, Taiwan e-mail: [email protected] S.-H. Hsia J.-J. Lin Division of Critical Care and Emergency Medicine, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan K.-S. Wong Division of Pulmonology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
EBV-encoded RNA showed a positive nuclear signal in the lymphoid cells. The presence of clonal B-cell proliferations was detected by clonally rearranged immunoglobulin studies. Lymphomatoid granulomatosis grade 3 was finally diagnosed. The progression of disease was rapid, and the patient died, despite rituximab therapy. The similar clinical manifestations in two male siblings suggest the possibility that a previously undescribed genetic defect contributed to these familial lymphoproliferative malignancies. Keywords Children Familial lymphoproliferative malignancy Lymphomatoid granulomatosis Recurrent wheezing X-linked
Introduction Lymphoproliferative disorders in children represent a heterogeneous group of expanding, monoclonal or oligoclonal, lymphoid neoplasms that occur in the setting of immune dysfunction. Familial lymphoproliferative disorC.-W. Wang Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan L.-Y. Shih Division of Hematology/Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan W.-I. Lee Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
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ders have been described in association with a variety of primary immunodeficiency disorders (PIDs). The incidence ranges from 0.7 to 15 % [1]. Specific PIDs have associations with particular lymphoproliferations. For example, patients with ataxia-telangiectasia predispose to developing T-cell leukemias and lymphomas, and in Wiskott–Aldrich syndrome there is a tendency for lymphomatoid granulomatosis (LYG) [1]. LYG is an angiocentric and angiodestructive lymphoproliferative disorder. It is a rare condition and usually presents in adult life (generally between the ages of 30 and 50). But it may be seen in children with immunodeficiency disorders. Pulmonary involvement occurs in over 90 % of patients and is usually present at initial diagnosis [2]. Patients frequently present with respiratory symptoms, such as cough, dyspnea, and chest pain. Wheezing is seldom observed. The course of LYG tends to be fulminant and the reported mortality rate is above 50 % [3–5]. Given its rarity in children, the diagnosis is challenging, and delayed diagnosis is not uncommon without a high index of suspicion. Herein, we report two male siblings of children who presented with recurrent wheezing and lung infections since early infancy. Immunodeficiency was not evident in both children. They subsequently died of Epstein-Barr virus (EBV) associated lymphoproliferative disorders. A previously undescribed genetic defect contributing to familial lymphoproliferative malignancies was highly suspected.
Case presentation Case 1 Case 1 is the elder brother of case 2. According to the medical summary provided by his parents, he had refractory wheezing and recurrent lung infections since infancy. No definite cause of wheezing was identified after many laboratory and radiologic evaluations. PID was, therefore, suspected. He was born to healthy non-consanguineous parents with no family history of early death or immunodeficiency. His two sisters were healthy (Fig. 1a). He received extensive immunologic evaluations and medical treatment at another hospital. Serum immunoglobulin (Ig) level was normal. Lymphocyte subset studies revealed 15.9 % CD19? lymphocytes, 69 % CD3?, 30.5 % CD4?, 34.6 % CD8?, and 8.8 % CD16/CD56?. The polymorphonuclear leukocytes (PMN) function (chemotaxis and phagocytosis) was normal. He received lung biopsy at around 2 years of age. The histology showed interstitial infiltration with a mixed population of lymphocytes, plasma cells, histiocytes, and eosinophils. Lymphocytic
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interstitial pneumonia or hypersensitivity pneumonitis was suspected. Unfortunately, he developed fever, pancytopenia, hepatosplenomegaly, hypertriglycemia, hyperferritinemia at 3 years of age. The serology for EBV showed positive for viral capsid antigen (VCA)-IgM, VCA-IgG, early antigen, and nuclear antigen. Natural killer (NK) cell activity was not measured. EBV-associated hemophagocytic lymphohistiocytosis (HLH) was diagnosed based on the Histiocyte Society HLH-2004 protocol [6]. High dose of intravenous immunoglobulin was applied. The clinical course was so fulminant that he died of respiratory failure despite intensive medical treatment. Case 2 Case 2 had presented with recurrent wheezing suspicious of infantile asthma and recurrent lung infections since 4 months of age. He had been treated by periodic steroid for wheezing with partial benefit. As his elder brother (case 1), no definite cause of wheezing was identified. PID was suspected, but serum immunoglobulin level checked at 7 months of age was normal. In May 2009, he had fever lasting for 4 days and respiratory distress, requiring pediatric intensive care unit admission with nasal intermittent mandatory ventilation at another hospital. Immunodeficiency with severe infection was impressed. Intravenous immunoglobulin and antibiotic therapy were applied. For further evaluation and management of his underlying disease, he was referred to our hospital. On examination, the 13-month-old boy appeared ill and pale. The temperature was 38.6 °C, pulse 152/min, and respiratory rate 30/min. Auscultation of chest revealed bilateral rales and wheezing. There was no evidence of rashes, lymphadenopathy, or hepatosplenomegaly. Plain chest radiograph showed increased bilateral perihilar infiltration without cardiomegaly. The hemogram revealed hemoglobin 9.6 g/dL, platelets 239 9 109/L, and white blood cell 30 9 109/L with 78.5 % segmented neutrophils, 3.5 % band neutrophils, 9 % lymphocytes, 8 % monocytes, and 1 % eosinophil. We performed a series of laboratory tests to evaluate his immune function. Serum immunoglobulin level was normal. The total lymphocyte count was 2.7 9 109/L. Lymphocyte subset studies revealed 21.3 % CD19? lymphocytes, 74.6 % CD3?, 49.5 % CD4?, 18.2 % CD8?, and 2.1 % CD16/CD56?. NK cell activity was not evaluated. The PMN function (chemotaxis, phagocytosis, and H2O2 production) was normal. The serology for EBV showed positive for VCA-IgM, VCA-IgG, early antigen, and nuclear antigen. EBV DNA analysis in blood was negative. A bone marrow examination was normal. Other laboratory investigations did not support the diagnosis of EBV-associated HLH. Familial HLH or X-linked
LPD in 2 male siblings of children Fig. 1 a The family pedigree of case 1 and case 2. b CT scan of lung. Linear nodular lesions in bilateral lung fields. c Diffuse interstitial infiltration of small to large atypical lymphoid cells with a marked peribronchiolar pattern (Hematoxylin-eosin stain). d The Compressed bronchiole and CD20? lymphoid cells. e Positive EBVencoded small ribonucleic acid in situ hybridization in lymphoid cells
lymphoproliferative disease (XLP) was highly suspected based on his family history. After obtaining the informed consent from his parents, total RNA was isolated from his peripheral mononuclear cells and was further analyzed for the mutations of PRF1, Munc13-4, STX11, SH2D1A, and XIAP genes (Supplementary Table 1). No mutation in the above mentioned genes was identified. The computed tomography of chest showed normal structure of trachea, bronchus, and great vessels. He was
treated with periodic steroid, bronchodilators, and prokinetic agents. But the respiratory symptoms were not responsive well to above therapies, especially when steroid was tapered or discontinued. Followed-up computed tomography of the chest revealed progressive nodular opacities in both lung fields (Fig. 1b). A thoracoscopic lung biopsy was performed. The histologic examination revealed diffuse interstitial infiltration of small to large atypical lymphoid cells with a
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Fig. 2 The presence of homoduplex bands for IgH: VH-JH (FR2), IgH: VH-JH (FR3), IgK Vk-Jk, and IgK Vk/intron-Kde by heteroduplex analysis with corresponding monoclonal peaks by gene scanning
marked peribronchiolar pattern. The bronchiole was significantly compressed and some alveoli were stuffed with lymphoid cells. These lymphoid cells were reactive for anti-CD4, CD8, and CD20, which was the most strongly positive (Fig. 1c, d). An in situ hybridization (ISH) for EBV-encoded nuclear RNA (EBER) disclosed strong positivity of the nuclei of infiltrated lymphoid cells ([50/ high power field) (Fig. 1e). We extracted DNA from the paraffin-embedded lung biopsy specimen. Clonal rearrangements of the Ig heavy chain gene were detected using
123
the polymerase chain reaction (PCR) (Fig. 2). LYG grade 3 was then diagnosed. The patient was more tachypneic with persistent wheezy breathing sound, like acute exacerbation of asthma. His consciousness became drowsy and his eyes were protruded gradually. The whole-body computed tomography revealed soft-tissue lesions at the lateral sides of bilateral orbital cavities which resulted in proptosis, poor differentiation of gray and white matter, increased number of nodular lesions and multiple patchy opacities and consolidation over
LPD in 2 male siblings of children
bilateral lung fields, and several small hypodense nodular lesions in the liver, spleen, and kidneys. Although we did not perform biopsy from these lesions, LYG in progression was clinically impressed. Rituximab was given on a weekly basis at a dose of 375 mg/m2. Unfortunately, the patient died of respiratory failure related to his disease progression after applying 2 doses of rituximab.
Discussion Wheezing is a common presenting symptom of respiratory disease in children. It has been reported that 25–30 % of infants will have at least one episode of wheezing [7], nevertheless not all the children with wheezing are caused by asthma. The younger the child, the broader the differential diagnosis, highlighting the importance of a higher index of suspicion for other causes of wheezing in preschool-aged children [8]. Respiratory tract infections, anatomic anomalies of the airway (e.g. tracheomalacia), extrinsic impingement of the airway (e.g. vascular ring), gastroesophageal reflux, and foreign body aspiration are usually considered when evaluating the child with recurrent wheezing. Importantly, physicians need to be alert to other rare causes of recurrent wheezing such as immunodeficiencies or malignancies if the common causes are not identified. Recurrent sinopulmonary infections usually lead physicians to the suspicion of immunodeficiency. Since there was a family history of male siblings with HLH, familial HLH and XLP should be considered in the little brother. We and others have shown that familial HLH is rare in Southeast Asia [9–11]. XLP is a genetic disorder that affects young boys and is characterized by severe dysregulation of the immune system, often, but not always, in response to EBV infection. The three most common clinical manifestations of XLP are fulminant infectious mononucleosis (some may develop HLH), dysgammaglobulinemia, and lymphoma, usually of B-cell origin [12]. XLP is caused by mutations in SH2D1A and XIAP genes. It may also occur in rare instances with no identified underlying genetic cause [13]. LYG is a very rare EBV-driven lymphoproliferative disease. It predominantly affects extranodal sites. Histologically, it composes predominantly of atypical lymphocytes admixed with plasmacytoid cells, immunoblasts, and histiocytes [3]. It usually manifests between the ages of 30 and 50. In a recent review of LG in children, the median age at diagnosis was 12 years [5]. Most commonly involved organs were lung (82 %), central nervous system (51 %), liver (25 %), skin (22 %), lymph nodes (16 %), kidneys (13 %), and spleen (8 %). Pulmonary symptoms were the main presenting symptoms. In contrast to adults,
children with LG had a higher incidence of neurological symptoms. Protracted wheezing has been reported as one of the abnormal physical findings in an old woman with LYG who presented with a hilar mass encasing and narrowing the bronchus [14]. In our patient, we could not find any extrinsic compression of airway leading to his wheezing. It is speculated that wheezing in our patient may result from the compressed bronchioles by surrounding infiltration of the atypical lymphoid cells. Histologically, LYG is characterized by large atypical CD20? B cells and numerous background lymphocytes. Most lymphocytes are CD3? T cells, with CD4? cells more frequent than CD8? cells [2]. Therefore, the precise identification of these potentially malignant cells from a prominent inflammatory background may depend on the subjective assessment and the experience of the pathologist. By the advanced progress of molecular technique, the component of malignant lymphoma can be identified more precisely as the presence of a clonal rearrangement of the Ig gene or T-cell receptor gene. Most cases of LYG are reported to have clonal Ig gene rearrangement from the atypical lymphoid cells [15, 16]. In our patient, we were unable to distinguish marked inflammatory reactions or lymphoproliferative disorders until the presence of a clonal Ig gene rearrangement was demonstrated by PCR-based clonality analysis. As a result, clonality analysis of antigen receptor genes is helpful in the diagnosis if the immunohistochemistry study is not informative enough. Treatment of LYG remains a challenge, and there is no standard protocol. The treatment outcomes of LYG are variable, but generally dismal in adults with a median survival of 14 months and a mortality rate of 65–90 % [3, 4]. In children, the mortality rate was around 50 %, and the median interval between diagnosis and death was 8 months [5]. Treatment with prednisolone or rituximab as a single agent has variable success [17–19]. Rituximab in combination with intensive chemotherapy are usually recommended for grade 3 lesions due to the high rate of rapid progression into EBV-positive large B-cell lymphoma [20]. However, many patients were refractory to therapy and died of disease progression shortly after diagnosis [20]. LYG is rarely reported within family members. Rogers et al. [21] reported a familial lymphoproliferative disorder presenting with primary pulmonary manifestations. They studied a family in which lymphoproliferative disorders with primary pulmonary involvement occurred in three male siblings. All three siblings received lung biopsy. Lymphocytic interstitial pneumonia was diagnosed in one. The histology findings in the remaining two siblings showed similar angiocentric, nodular polymorphic infiltrates resembling LYG. However, EBV was not demonstrated in any of the pulmonary lesions. At the moment of their report, the latter two siblings had rapid disease
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progression and died. The first sibling also had progressive pulmonary lesions and appeared radiographically similar to his brothers. There is some resemblance between the clinical course of the two siblings in our report and the report from Rogers et al. An unknown genetic cause in such familial lymphoproliferative disease needs further investigation. Acknowledgments This work was supported in part by the grants CMRPG4A0041-43 from Chang Gung Memorial Hospital, Taiwan, the grants NCS-100-2314-B-182A-063 from the National Science Council, Taiwan, and grants DOH102-TD-C-111-006 from the National Health Research Institute, Taiwan. Conflict of interest
None declared.
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