Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, severe immunodeficiency, and predisposition to lymphoid malignancy. In this report, we describe a case of a 9-year-old boy, previously diagnosed with NBS and symptoms of dyspnea, dry cough, and fever. Despite initial recognition of pneumonia, there was no response to broad spectrum antimicrobial treatment, negative results from microbiological tests, and unclear changes in lung imaging were observed. Therefore, further diagnostics were focused on suspected lymphoid malignancy and involved lung biopsy. Unexpectedly, histopathological examination revealed noncaseating granulomas. The introduction of systemic steroids resulted in significant improvement of the patient’s clinical condition. This is the first description of primary pulmonary noncaseating granulomas without nodular involvement in a child with NBS.

Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive disorder characterized by progressive microcephaly with characteristic face, growth retardation, immunodeficiency, and high predisposition to malignancy. It is caused by mutations in the NBS1 (also known as NBN) gene located on chromosome 8q21, which encodes for nibrin, a protein responsible for repairing double strand breaks (DSBs) in DNA. Because “physiological” DSBs occur during V(D)J recombination and immunoglobulin class switch, nibrin activity is especially important in maturation and differentiation of immunocompetent B and T cells. Therefore, NBS1 mutations result in combined immunodeficiency (CVID), with increased susceptibility to severe infections, mostly affecting respiratory, gastrointestinal, or urinary tracts, as well as granulomatous reaction.1,3 However, the main complication of DSBs is chromosomal instability leading to the development of cancer, mainly of lymphoid origin.4,5 

A 9-year-old boy with previously recognized NBS was admitted to the local hospital because of nonproductive cough, dyspnea, and fever up to 38.5°C, with a suspicion of a third episode of pneumonia in a short period, within 1 year. Previous medical history of this patient included several mild respiratory tract infections during early childhood, severe enterocolitis of rotavirus etiology at the age of 3, and 2 cases of pneumonia at the ages of 8 and 8.5. After the second case of pneumonia, because of a low level of immunoglobulin G (IgG), the patient qualified for monthly intravenous immunoglobulin (IVIg) supplementation, which, however, was irregular.

According to the patient’s available medical records, he was the first child of nonconsanguineous Polish parents, from an uncomplicated pregnancy, delivered at term. The body weight at birth was 3300 g, body length was 57 cm, and head circumference was 32 cm (<3rd percentile). Because of the increasing head circumference (up to 36 cm within 2 days), the patient was subjected to ultrasound and computed tomography, which revealed a cerebral defect–related hydrocephalus. Over the next 3 years, the patient developed facial dysmorphia, strabismus, sparse hair, dry skin, parakeratosis on arms and tights, micropenis, hypospadias, and cryptorchidism. Together with the presence of cerebral defects, mild growth retardation, and intellectual disability, a genetic disorder was suspected (Fig 1). Therefore, at the age of 3, the patient was subjected to further tests, which eventually revealed a c.657del5 deletion in both alleles of exon 6 in the NBS1 gene. Despite both of the parents being carriers of the mutation, the patient has a younger brother who is healthy.

FIGURE 1

Picture of the child at the age of 4 years.

FIGURE 1

Picture of the child at the age of 4 years.

Close modal

On admission to the local hospital, the patient revealed symptoms characteristic for pneumonia: moderate respiratory distress with 60 breaths per minute, oxygen saturation in room air was 88% (up to 95% with oxygen supplementation), heart rate was 110 beats per minute, and body temperature was 38.0°C. During auscultation, a vesicular breath sound with disseminated crackles and wheezes was heard. A lung ultrasound scan revealed disseminated consolidations. In initial laboratory tests, a marked eosinophilia (1140/mm3, corresponding to 9.7% of white blood cells) and relatively low level of the C-reactive protein (3.45 mg/dL, at the normal level <1.0 mg/dL) were observed. The results of microbiological blood cultures were negative.

Initial treatment started with intravenous co-amoxicillin, inhaled steroids, and bronchodilators. However, after 3 days of such treatment, respiratory distress worsened and a lung ultrasound revealed progression. Despite a change of the antimicrobial treatment to clarithromycin and fluconazole, no improvement was observed. Therefore, further diagnostics concerned mycobacteriosis (interferon-γ release assays) and pneumocystosis (bronchoalveolar lavage for cytopathologic testing), but all tests were negative. Although regular infusion of IVIg was added to the therapy, the patient’s clinical condition still worsened. A chest radiograph revealed disseminated consolidations over the whole lungs (Fig 2). Hence, the patient was referred to the Pulmonology Department for further diagnostics and treatment.

FIGURE 2

Posteroanterior chest radiograph picture with disseminated consolidation over whole lungs.

FIGURE 2

Posteroanterior chest radiograph picture with disseminated consolidation over whole lungs.

Close modal

Because of the persisting symptoms and necessity of oxygen therapy, the patient was subjected to extended diagnostic protocol. Because the results of repeated laboratory blood tests revealed leukocytosis with marked eosinophilia and low concentrations of IgG, immunoglobulin A, and immunoglobulin M despite recent IVIg infusion, the patient received broad spectrum antibiotics (piperacillin with tazobactam) and another dose of IVIg. The results of repeated microbiological assessments of blood and bronchoalveolar lavage fluid for bacteria (including mycobacteriosis), fungal, or parasite infections were all negative. Also, the results of a molecular screening of the patient’s blood for main viral pathogens (Epstein-Barr virus, cytomegalovirus, and influenza) with polymerase chain reaction were negative. The results of a flow cytometry assessment of the main lymphocyte populations in circulating blood revealed a mild increase of the CD3+CD8+ T population and a significant decrease of CD19+ B cells (Table 1).

TABLE 1

Selected Immunologic Parameters of the Patient

ParameterResultNormal Range (Age 5–10)
Immunoglobulins (g/L)   
 IgG 6.65 8.53–14.4 
 IgA 0.17 0.38–2.35 
 IgM 0.29 0.36–1.98 
Lymphocytes/µL (%) 2932 1700–3600 
 CD3+ 2633 (89.8%) 1000–2600 (52%–77%) 
  CD4+ 899 (47.6%) 500–1500 (26%–46%) 
  CD8+ 1396 (30.7%) 300–1000 (15%–35%) 
  CD16+CD56+ 272 (9.3%) 140–690 (6%–30%) 
 CD19+ 16 (0.5%) 300–600 (10%–23%) 
ParameterResultNormal Range (Age 5–10)
Immunoglobulins (g/L)   
 IgG 6.65 8.53–14.4 
 IgA 0.17 0.38–2.35 
 IgM 0.29 0.36–1.98 
Lymphocytes/µL (%) 2932 1700–3600 
 CD3+ 2633 (89.8%) 1000–2600 (52%–77%) 
  CD4+ 899 (47.6%) 500–1500 (26%–46%) 
  CD8+ 1396 (30.7%) 300–1000 (15%–35%) 
  CD16+CD56+ 272 (9.3%) 140–690 (6%–30%) 
 CD19+ 16 (0.5%) 300–600 (10%–23%) 

IgA, immunoglobulin A; IgM, immunoglobulin M.

To avoid excessive radiograph exposure in a child with NBS, nuclear magnetic resonance (NMR) imaging was performed instead of chest computed tomography. It confirmed previously recognized disseminated consolidations in both lungs, without lymphadenopathy (Figs 3 and 4). On the basis of an equivocal clinical picture and considering NBS-related high risk of malignancy, the patient was qualified for open-lung biopsy. Samples were taken from a first segment of the left lung at a place corresponding to the most intense lung changes. Again, microbiological assessments of tissue samples for bacteria, fungi, and viruses returned negative results. Unexpectedly, a routine histopathological examination revealed noncaseating granulomas composed of giant and epithelioid cells with abundant lymphoid cells infiltration and no features of malignancy (Fig 5).

FIGURE 3

Nuclear MRI. Coronal plane, T2 tse dixon; in phase- and water-sensitive images from initial examination. The size and distribution of the lesions are better appreciated on fat-saturated T2-dixon water-sensitive images (right).

FIGURE 3

Nuclear MRI. Coronal plane, T2 tse dixon; in phase- and water-sensitive images from initial examination. The size and distribution of the lesions are better appreciated on fat-saturated T2-dixon water-sensitive images (right).

Close modal
FIGURE 4

Nuclear MRI. On diffusion-weighted images, 1 of the biggest granulomas located in the right apex revealed high diffusion restriction signal on diffusion-weighted images b800 (left) and low on apparent diffusion coefficient map (right).

FIGURE 4

Nuclear MRI. On diffusion-weighted images, 1 of the biggest granulomas located in the right apex revealed high diffusion restriction signal on diffusion-weighted images b800 (left) and low on apparent diffusion coefficient map (right).

Close modal
FIGURE 5

Histopathological examination of lung biopsies, hematoxylin, and eosin staining: A, disseminated granulomas may be seen in the whole biopsy specimen, low magnification (×100). B, Granulomas composed of epithelioid and giant cells (marked with arrows) in bronchiolar wall and in surrounding lung tissue, high magnification (×400). C, Granulomas markedly infiltrated with lymphoid cells, high magnification (×400).

FIGURE 5

Histopathological examination of lung biopsies, hematoxylin, and eosin staining: A, disseminated granulomas may be seen in the whole biopsy specimen, low magnification (×100). B, Granulomas composed of epithelioid and giant cells (marked with arrows) in bronchiolar wall and in surrounding lung tissue, high magnification (×400). C, Granulomas markedly infiltrated with lymphoid cells, high magnification (×400).

Close modal

The patient received oral corticosteroid (prednisone 1 mg/kg), and weekly subcutaneous immunoglobulin replacement therapy was introduced instead of IVIg. After 1 week of such treatment, the patient’s clinical condition significantly improved and normal oxygen saturation was noted. A control lung NMR and ultrasound scan revealed marked regression of pulmonary changes (Fig 6). He received steroids in the dose mentioned above for 8 subsequent weeks. Regrettably, every attempt to taper the dose resulted in worsening of the lung ultrasound image and a decrease of exercise tolerance. After consultation with an oncologist, a therapy with cyclosporine being used as a steroid-sparing drug was introduced together with patient preparation for hematopoietic stem cell transplantation (HSCT).

FIGURE 6

Nuclear MRI. In initial MRI of the chest, T2-weighted images in axial plane present disseminated, massive T2-hyperintense lesions in both lungs (arrows in left). Partial regression of the lesions in follow-up examination (right).

FIGURE 6

Nuclear MRI. In initial MRI of the chest, T2-weighted images in axial plane present disseminated, massive T2-hyperintense lesions in both lungs (arrows in left). Partial regression of the lesions in follow-up examination (right).

Close modal

As mentioned previously, the NBS1 mutation affects development and function of T and B lymphocytes. Therefore, patients with NBS reveal CVID, with high susceptibility to infections. Usually, these infections involve the respiratory system, including chronic sinusitis, recurrent bronchitis, and pneumonia. In addition to “typical” pathogens, opportunistic infections induced by rare microorganisms may appear. Tuberculosis was reported in individuals with NBS as a pulmonary form, but also as generalized type, or was restricted to the skin only. Furthermore, in some patients, prolonged antibiotic treatment may result in colonization by drug-resistant pathogens (eg, Pseudomonas aeruginosa).4 

In the case described above, the results of all tests for typical or atypical pathogens were negative. Therefore, because of an unclear ultrasound and radiograph picture of the lungs, the constant deterioration of the patient’s condition, and no response to broad spectrum antibiotics and antifungal treatment, the malignancy was considered in further diagnostics.

According to the molecular background of NBS, the high risk of malignancy is associated with chromosomal instability. In the majority of patients with NBS, lymphomas are diagnosed before the age of 15, and they are a main cause of death in that group.1,5 The most common are non-Hodgkin lymphomas, predominantly diffuse large B-cell lymphoma, and T-cell lymphoblastic lymphoma. However, Burkitt and Burkitt-like lymphomas may also be found.

It is noteworthy that among main symptoms of lymphoma, which usually include enlarged lymph nodes, fever, drenching sweats, and unintended weight loss, the presented patient had only fever and moderate leukocytosis. The lung NMR imaging revealed disseminated consolidations without lymph node involvement. Nevertheless, although extremely rare, the extranodal location of primary pulmonary non-Hodgkin lymphoma was already described in a 6-year-old boy with NBS.6 Therefore, we have decided to verify the nature of lung changes using open-lung biopsy. The results of a molecular screening of lung biopsy for Epstein-Barr virus, which often is involved in lymphoid malignancies,7 was negative. Unexpectedly, the histopathological examination of excised tissues revealed noncaseating granulomas, composed of giant and epithelioid cells, with strong lymphoid cells infiltration, but it did not confirm malignant character of studied samples.

Granulomas consist of focal aggregations of inflammatory cells, activated macrophages (epithelioid histiocytes), Langhans giant cells, and lymphocytes. However, the minimum requirement of a granuloma is aggregation of histiocytes.8 Differential diagnosis for lung noncaseating granulomas contained infectious and noninfectious diseases. Because infection is the most common cause of pulmonary granulomas, we carefully excluded an infectious etiology. Furthermore, in the absence of specific clinical data or histologic features, several diseases such as aspiration pneumonia, hypersensivity pneumonitis, Churg-Strauss syndrome, Wegener granulomatosis, or rheumatoid nodules could be excluded. On the basis of a normal serum level of calcium and angiotensin-converting enzymes and a lack of an involvement of lymph nodes, childhood sarcoidosis was also excluded.

Most of all, the granulomatous reaction pattern frequently appears in patients with various immunodeficiency disorders, including chronic granulomatous disease, ataxia-telagniectasia, and severe CVID. Granulomatous disease occurs in up to 22% of patients with CVID, with lungs as the prominent location.9 The etiopathogenesis of granulomas in immunodeficiency is poorly understood. Some authors postulate the possible role of unidentified fastidious pathogens and functional impairment of humoral and cellular immunity because of the increased level of chromosomal damage.10,12 

Most commonly, granulomas appear in visceral form with lymphadenopathy. In children with NBS, the incidents of isolated involvement reported so far concerned only cutaneous granulomas,2,3,13,14 whereas, according to data from the European Society for Immunodeficiencies registry, the isolated lung granulomas have not been yet described.15 

The optimal treatment of granulomatous disease in primary immunodeficiency is unknown. Therefore, the decision regarding the patient’s treatment was based on the clinical and pathologic similarities to the granulomatous-lymphocytic interstitial lung disease.16 In this disorder, the restoration of IgG level to a normal range is usually followed by oral glucocorticoids. Second-line therapies include azathioprine, rituximab, and mycophenolate.17 Alternative options involve tumor necrosis factor–α blocking agents because of their beneficial effect in some patients with CVID and combined therapies.18,19 Cyclosporine is also of note because of the reported beneficial effect in lymphoid interstitial pneumonitis.20 

Because an appropriate treatment in which immunosuppressive drugs are used is a particular challenge in the presence of a high risk of hematologic malignancy, HSCT is also considered as an alternative option.1 Therefore, the presented patient was scheduled for HSCT because tapering the dose of glucocorticoids, even after adding cyclosporine to the therapy, was not possible.

It is noteworthy that the presence of extensive granulomatous lesions may complicate the diagnosis of lymphoma and thus may lead to a delay in the diagnosis and treatment of hematologic malignancy. The granulomatous component in malignant disease may be connected with T-cell–mediated immune response to tumor antigen.21 Hence, a careful microscopic evaluation that is focused on the presence of any atypical cells is of great importance. For example, immunochemistry can highlight the Reed-Sternberg cells or Reed-Sternberg variant with strong reactions to CD15 or CD30 and thus confirm Hodgkin disease.22 

Therefore, the increased number and percentage of CD3+CD8+ lymphocytes in the presented patient requires constant vigilance because it may be the early manifestation of developing systemic granulomas or lymphoma.6,13 The patient was scheduled for close follow-up.

The case described above illustrates some difficulties in diagnostics of unique granulomatous lung inflammation, found in a patient with an already known immunodeficiency and a high risk of malignancy. We present for the first time and shortly discuss the association of NBS with pulmonary granulomas, without any other manifestations of systemic granulomatosis or lymphoid malignancy.

     
  • CVID

    combined immunodeficiency

  •  
  • DSB

    double strand breaks

  •  
  • HSCT

    hematopoietic stem cell transplantation

  •  
  • IgG

    immunoglobulin G

  •  
  • IVIg

    intravenous immunoglobulin

  •  
  • NBS

    Nijmegen breakage syndrome

  •  
  • NMR

    nuclear magnetic resonance

Dr Marczak contributed to study design, clinical data collection and analysis, and manuscript preparation; Dr Heropolitańska-Pliszka contributed to immunologic data collection and analysis and manuscript preparation; Dr Langfort contributed to preparation and assessment histopathological preparations and manuscript preparation; Dr Roik contributed to radiological assessment and manuscript preparation; Dr Grzela contributed to study design, coordination and supervision of data collection, data analysis, and manuscript preparation; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

1
Chrzanowska
KH
,
Gregorek
H
,
Dembowska-Bagińska
B
,
Kalina
MA
,
Digweed
M
.
Nijmegen breakage syndrome (NBS).
Orphanet J Rare Dis
.
2012
;
7
:
13
2
Vogel
CA
,
Stratman
EJ
,
Reck
SJ
,
Lund
JJ
.
Chronic noninfectious necrotizing granulomas in a child with Nijmegen breakage syndrome.
Pediatr Dermatol
.
2010
;
27
(
3
):
285
289
[PubMed]
3
Yoo
J
,
Wolgamot
G
,
Torgerson
TR
,
Sidbury
R
.
Cutaneous noncaseating granulomas associated with Nijmegen breakage syndrome.
Arch Dermatol
.
2008
;
144
(
3
):
418
419
[PubMed]
4
Wolska-Kuśnierz
B
,
Gregorek
H
,
Chrzanowska
K
, et al;
Inborn Errors Working Party of the Society for European Blood and Marrow Transplantation and the European Society for Immune Deficiencies
.
Nijmegen breakage syndrome: clinical and immunological features, long-term outcome and treatment options - a retrospective analysis.
J Clin Immunol
.
2015
;
35
(
6
):
538
549
[PubMed]
5
The International Nijmegen Breakage Syndrome Study Group
.
Nijmegen breakage syndrome.
Arch Dis Child
.
2000
;
82
(
5
):
400
406
[PubMed]
6
Moreno Pérez
D
,
García Martín
FJ
,
Vázquez López
R
, et al
.
Nijmegen breakage syndrome associated with pulmonary lymphoma [in Spanish].
An Esp Pediatr
.
2002
;
57
(
6
):
574
577
[PubMed]
7
Pasic
S
,
Kandolf-Sekulovic
L
,
Djuricic
S
,
Zolotarevski
L
,
Simic
R
,
Abinun
M
.
Necrobiotic cutaneous granulomas in Nijmegen breakage syndrome.
J Investig Allergol Clin Immunol
.
2012
;
22
(
2
):
138
140
[PubMed]
8
Mukhopadhyay
S
,
Gal
AA
.
Granulomatous lung disease: an approach to the differential diagnosis.
Arch Pathol Lab Med
.
2010
;
134
(
5
):
667
690
[PubMed]
9
Ardeniz
O
,
Cunningham-Rundles
C
.
Granulomatous disease in common variable immunodeficiency.
Clin Immunol
.
2009
;
133
(
2
):
198
207
[PubMed]
10
Shoimer
I
,
Wright
N
,
Haber
RM
.
Noninfectious granulomas: a sign of an underlying immunodeficiency?
J Cutan Med Surg
.
2016
;
20
(
3
):
259
262
[PubMed]
11
Lun
KR
,
Wood
DJ
,
Muir
JB
,
Noakes
R
.
Granulomas in common variable immunodeficiency: a diagnostic dilemma.
Australas J Dermatol
.
2004
;
45
(
1
):
51
54
[PubMed]
12
Chiam
LY
,
Verhagen
MM
,
Haraldsson
A
, et al
.
Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation?
Dermatology
.
2011
;
223
(
1
):
13
19
[PubMed]
13
Liana
RA
,
Dan
G
,
Nicolae
M
.
Cutaneous sarcoid-like granulomas in a child known with Nijmegen breakage syndrome.
Iran J Pediatr
.
2013
;
23
(
1
):
100
104
[PubMed]
14
Pasic
S
,
Vujic
D
,
Fiorini
M
,
Notarangelo
LD
.
T-cell lymphoblastic leukemia/lymphoma in Nijmegen breakage syndrome.
Haematologica
.
2004
;
89
(
8
):
ECR27
[PubMed]
15
European Society for Immunodeficiencies
. New ESID registry. Available at: https://esid.org/Working-Parties/Registry/New-ESID-Registry. Accessed August 21, 2017
16
Park
JH
,
Levinson
AI
.
Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID).
Clin Immunol
.
2010
;
134
(
2
):
97
103
[PubMed]
17
Hurst
JR
,
Verma
N
,
Lowe
D
, et al
.
British Lung Foundation/United Kingdom Primary Immunodeficiency Network consensus statement on the definition, diagnosis, and management of granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders.
J Allergy Clin Immunol Pract
.
2017
;
5
(
4
):
938
945
[PubMed]
18
Kähler
CM
,
Heininger
P
,
Loeffler-Ragg
J
,
Vogelsinger
H
.
Infliximab therapy in pulmonary sarcoidosis.
Am J Respir Crit Care Med
.
2007
;
176
(
4
):
417
; author reply 417–418
[PubMed]
19
Chase
NM
,
Verbsky
JW
,
Hintermeyer
MK
, et al
.
Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID).
J Clin Immunol
.
2013
;
33
(
1
):
30
39
[PubMed]
20
Davies
CW
,
Juniper
MC
,
Gray
W
,
Gleeson
FV
,
Chapel
HM
,
Davies
RJ
.
Lymphoid interstitial pneumonitis associated with common variable hypogammaglobulinaemia treated with cyclosporin A.
Thorax
.
2000
;
55
(
1
):
88
90
[PubMed]
21
Nyunt
WW
,
Wong
YP
,
Wan Jamaludin
WF
,
Abdul Wahid
SF
.
Diffuse large B cell lymphoma with chronic granulomatous inflammation.
Malays J Pathol
.
2016
;
38
(
1
):
55
59
[PubMed]
22
Al-Maghrabi
JA
,
Sawan
AS
,
Kanaan
HD
.
Hodgkin’s lymphoma with exuberant granulomatous reaction.
Saudi Med J
.
2006
;
27
(
12
):
1905
1907
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.