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Abstract

We report a case of IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) with acquired hemophilia A (AHA) in a pediatric patient. An 11-year-old female presented with intermittent swelling of the bilateral upper eyelids and neck areas. Clinical examination revealed bilateral swollen upper eyelids with palpable mass lesions in the lacrimal fossa. The submandibular and sublingual glands were enlarged, tender, and movable. Neck ultrasound showed bilateral gland enlargement with irregular hypoechoic parenchyma. Maxillofacial magnetic resonance imaging (MRI) revealed bilateral lacrimal glands enlargement, homogeneous enlarged bilateral submandibular and parotid glands, measuring 4.7 × 3.9 cm. Laboratory investigation showed increased activated partial prothromboplastin time (80.9 s), markedly decreased FVIII activity (0.6%), a high titer of FVIII inhibitor (480 Bethesda units/mL), and a remarkable increase in serum IgG4 level (1005.68 mg/dL). A left submandibular gland biopsy revealed marked lympho-plasmacytic infiltration with scattered eosinophils. Immunohistochemical staining for IgG4 showed numerous IgG4-positive plasma cells (>100 per high-power field), with a ratio of IgG4-positive to IgG-positive cells >40%. The symptoms were markedly relieved following corticosteroid therapy. IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) with acquired hemophilia A (AHA) can also be seen in the pediatric population and should be considered a differential diagnosis in patients with relevant symptoms.

Keywords

acquired hemophilia A IgG4-related disease pediatric

Introduction

Immunoglobulin G4-related disease (IgG4-RD), a systemic condition, is characterized by tumefactive lesions, dense lympho-plasmacytic infiltration, abundant IgG4-positive plasma cells, storiform fibrosis, and frequently elevated serum IgG4 levels.¹ IgG4-RD has been described in virtually all organs, including salivary glands, periorbital tissues, and pancreas.^1–3 The typical patient with IgG4-RD is a middle-aged to elderly male. Although rare, IgG4-RD can occur in children with a median age of 13 years (from 22 months to 17 years) and 64% being female. Pediatric IgG4-RD often exhibits in orbit, pancreas, lung, biliary tree, and lymph node.⁴

Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by an autoantibody to coagulation factor VIII, partially or completely neutralizing its coagulant function.⁵ The autoantibodies are mostly IgG1 and IgG4.⁶ AHA may be associated with pregnancy, autoimmune diseases, malignancy, infection, or drug allergies.^6,7 Several cases of AHA co-occurring with IgG4-RD have been reported in adults, though the underlying mechanism remains unknown.^8–11 Here, we report a case of pediatric IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) with acquired hemophilia A (AHA).

Case presentation

An 11-year-old female from an ethnic minority presented with 8 months of intermittent swelling of the bilateral upper eyelids and neck areas. Clinical examination revealed bilateral swollen upper eyelids with palpable mass lesions in the lacrimal fossa; submandibular and sublingual glands were enlarged, tender, and movable (Figure 1a and b). Her visual acuity, intraocular pressure, and eye movement were not affected. No erythema or signs of acute skin infection were found. She had no symptoms of dry eyes and mouth. She had no family history of a bleeding disorder.

Figure 1.

Clinical appearance showed bilateral upper eyelids swelling submandibular and sublingual gland enlargement (a, b). No erythema or signs of acute infection of the overlying skin. Lacrimal, parotid, and submandibular gland swelling improved markedly at follow-up 2 months after continuation of prednisone (c, d).

Neck ultrasound showed enlarged bilateral salivary glands (including parotid, submandibular, and sublingual glands) with irregular hypoechoic parenchyma. Maxillofacial magnetic resonance imaging (MRI) revealed bilateral lacrimal glands enlargement; homogeneous, enlarged bilateral submandibular, and parotid glands, measuring 4.7 × 3.9 cm. Moreover, she had bilateral maxillary sinusitis (Figure 2). The entire resection biopsy of the left submandibular gland was performed. However, after the biopsy procedure, a prolonged subcutaneous hematoma and bruising in the left mandibular and neck region developed.

Figure 2.

Maxillofacial magnetic resonance imaging (MRI). Axial (a, b) images of the patient show the enlargement of the lacrimal gland (dacryoadenitis, yellow arrow) and bilateral submandibular parotid gland (sialadenitis, black star). Moreover, she had bilateral maxillary sinusitis. There is no abnormal lymphadenopathy.

On her blood examination, the serum IgG level was 42.31 g/L (normal range 6.5–12.3), IgE level was 271.5 IU/mL (normal range 0–170), and IgG4 level was 1005.68 mg/dL (normal range 1.6–115). The activated partial thromboplastin time (APTT) was prolonged to 80.9 s (s) with a normal platelet count and prothrombin time (11.6 s, normal range 10.2–20). In addition, FVIII activity was markedly decreased at 0.6% (normal range 60–150), and the FVIII inhibitor level was elevated to 480 BU/mL (Table 1).

Table 1.

Laboratory findings at presentation.

Complete blood counts		Biochemistry		Immunology
WBC	9,2.10⁹/L	Total protein	98.1 g/L	IgM	3.12 g/L
Neutrophil	33.3%	Albumin	34.3 g/L	IgA	1.25 g/L
Lymphocyte	28.6%	GOT	22.3 U/L	IgE	271.5 IU/mL
Monocyte	6.6%	GPT	26.8 U/L	IgG	42.31 g/L
Eosinophil	30.4%	CRP	0.31 mg/L	IgG4	10056.8 mg/L
Basophil	1.1%	Ure	2.4 mmol/L	C3	0.67 g/L
RBC	4,75.10¹²/L	Creatinin	34.73 μmol/L	C4	0.08 g/L
Hb	134 g/L	Cortisol	318 nmol/L	Anti-ANA	Negative
Hct	37.2%	ACTH	5.82 pmol/L	Anti-RNP 70	8.3 AU/mL
PLT	410.10⁹/L	LDH	242 U/L	Anti-SSA (Ro)	5.2 AU/mL
Coagulation		Tryglyceride	0.76 mmol/L	Anti-SSB (La)	<3.0 AU/mL
PT	11.6 s			Anti-phospholipid IgG/IgM	5.2/2.5
INR	1.04	Glucose	5.8 mmol/L
APTT	77.5 s	Calci	2.15 mmol/L
Mix APTT*	72.8 s
		Clotting factor activity
		Factor VIII activity	0.6%
		Factor VIII inhibitor	480 BU/mL

WBC: white blood cell; RBC: red blood cell; Hb: hemoglobin; Hct: hematocrit; PLT: platelet count; PT: prothrombin time; INR: international normalized ratio; APTT: activated partial thromboplastin; GOT: glutamic oxaloacetic transaminase; GPT: glutamic pyruvic transaminase; CRP: c-reactive protein; ACTH: Adrenocorticotropic hormone; LDH: lactate dehydrogenase; ANA: anti-nuclear antibody; RNP: ribonucleoprotein; SSA: Sjogren’s syndrome A; SSB: Sjogren’s syndrome B.

Normal control/patient: 50/50, 37°C, at 0 and 2 h.

The histopathological examination showed increased interlobar and periductal fibrosis, marked lympho-plasmacytic infiltration around the lobules, and occasionally, lymph follicles formed with clear germ centers. The lobular structure of the salivary gland is preserved. In addition, scattered eosinophils infiltration in the stroma. Immunohistochemical staining for IgG4 revealed diffuse IgG4-positive plasma cells with an average of 350 per high-power field (HPF) and a ratio of IgG4-positive to IgG-positive cells >40% (Figure 3). The clinical and histopathological findings were consistent with IgG4-related dacryoadenitis and sialadenitis with AHA. After the final diagnosis was made, we treated bleeding at the biopsy site due to AHA with a fresh frozen plasma infusion, recombinant factor VIIa (90 mcg/kg every 6 h), IV methylprednisolone (4 mg/kg/day), and oral cyclophosphamide (2 mg/kg/day). After 4 days, the wound stopped bleeding. We discontinued recombinant factor VIIa and gradually reduced the dose of IV methylprednisolone to 4 mg/kg/day, along with oral cyclophosphamide at 2 mg/kg/day. Following 2 weeks of treatment, the lacrimal and salivary glands significantly decreased in size with minimal swelling. APTT was within normal limits, and FVIII activity was 147%. Subsequently, we discharged the patient and maintained oral prednisolone at 1 mg/kg/day combined with cyclophosphamide at 2 mg/kg/day. The patient visited our hospital 18 days after discharge due to swelling in the lacrimal and salivary glands and non-compliance with prescribed medication. The APTT was prolonged to 86.7 s. We readmitted the patient and initiated oral treatment with prednisolone (1 mg/kg/day) combined with cyclophosphamide (2 mg/kg/day). After 1 week of treatment, the gland size significantly decreased, and the APTT test showed 53.2 s, with a blood concentration IgG4 level of 289 mg/L (Table 2, Figure 1c, d). Following this discharge, our patient refused any treatment and used Vietnamese herbs. Unfortunately, she died after 24 months.

Figure 3.

IgG4-related sialadenitis (submandibular gland). Hematoxylin-eosin staining demonstrates increased interlobar and periductal fibrosis (black arrow), marked lymphoplasmacytic cell infiltration around the lobules, and occasionally, lymph follicles form with a clear germ center. The lobular structure of the salivary gland is preserved. In addition, scattered eosinophils infiltration in the stroma. Immunohistochemical staining for IgG4 revealing diffuse IgG4 positive plasma cells with an average of 350 per high-power field (a, b: ×40, d, e: ×100, c, f: ×400).

Table 2.

Clinical course of our patient.

Date	PT (%)	APTT (s)	IgG4 (mg/dL)	FVIII activity (%)	FVIII inhibitor (BU/mL)
10-12-2018	90	75
12-12-2018		80.9	1005.68
14-12-2018*	94	69		0.6	480
16-12-2018		60.2
17-12-2018		57.2
19-12-2018	135	58.9		3.1	441
23-12-2018		61.6
26-12-2018	102	36.7		2	480
02-01-2019		29.4
23-01-2019**		86.7		3	314
30-01-2019***		53.2	289	21.7	450

FVIII: factor VIII; IgG4: immunoglobulin G4; APTT: activated partial thromboplastin time; PT: Prothrombin.

After biopsy. **Hospitalized after discontinuing treatment. ***Discharge, continuation of prednisone after 1 week.

Discussion

Immunoglobulin G4-related disease (IgG4-RD) can manifest in various organs and frequently has elevated serum IgG4 levels.¹ In 1892, Mikulicz et al. first reported a patient with symmetrical swelling of the lacrimal, parotid, and submandibular glands, with massive infiltration of mononuclear cells, later named Mikulicz’s disease. Mikulicz’s disease is now recognized as IgG4-related dacryoadenitis and sialadenitis in a representative part of the IgG4-RD spectrum.^1,12

In our case, IgG4-RD was diagnosed in accordance with the comprehensive diagnostic criteria, including (1) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs; (2) hematological examination showing elevated serum IgG4 concentrations (>135 mg/dL); and (3) histopathological examination showing (i) marked lymphocyte and plasmacyte infiltration and fibrosis, and (ii) infiltration of IgG4⁺ plasma cells with the ratio of IgG4⁺/IgG⁺cells >40% and >10 IgG4⁺plasma cells/HPF.¹³ The comprehensive diagnostic criteria combined with organ-specific diagnostic criteria increase the sensitivity of diagnosis to 100% for IgG4-related dacryoadenitis and sialoadenitis.^3,13

IgG4-RD occurs predominantly in elderly males, and the male-to-female ratio was 3.2. Exceptions are patients with IgG4-related dacryoadenitis and sialadenitis, in whom sex distribution is almost equal.^1,14,15 Children have not been included in larger IgG4-RD studies and have been discussed mainly in case reports. In the pediatric population, the median age is 13 years (ranging from 22 months to 17 years old), and more than 60% are females.⁴ Most pediatric patients have orbital disease.^4,16,17 Other manifestations include the pancreas, lung, biliary tract, thyroid gland, salivary gland, lacrimal gland, liver, and lymph node.^4,18–21 The differential diagnoses for IgG4-related dacryoadenitis and sialadenitis include Sjogren’s syndrome, infection, other autoimmune diseases (such as systemic lupus erythematosus), and lymphoma.^2,12

AHA is a rare autoimmune disorder caused by an autoantibody to coagulation factor VIII, partially or completely neutralizing its coagulant function. It can occur in both males and females without a previous personal or family history of bleeding. AHA typically affects the elderly, with a median age of 64–78 years, but it can also occur in pediatric cases. Although most cases are idiopathic, AHA has been associated with cancers, autoimmune diseases, medications, or pregnancy.^5,22,23 Typically, AHA presents with acute or recent bleeding symptoms without a previous history of bleeding. Laboratory investigations show an isolated prolonged activated partial thromboplastin time (APTT), reduced FVIII activity, and the presence of autoantibodies detected by the Bethesda assay or by enzyme-linked immunosorbent assay (ELISA).

AHA may be associated with pregnancy, autoimmune diseases, malignancy, infection, or drug allergies.^5–7 Four cases of AHA associated with IgG4-RD were reported^8–11 (Table 3). In all cases, AHA associated with IgG4-related disease occurred mainly in the elderly, with various organ involvements (including lymph node, biliary tree, pancreas, urinary tract, lung, and salivary gland), elevated serum IgG4 concentration, and typical histopathological features for IgG4-RD. AHA usually onsets with hemorrhagic symptoms (frequently subcutaneous bleeding and muscle hematomas) associated with a markedly prolonged APTT, low factor VIII (FVIII) activity level, and a high titer of FVIII inhibitor. All patients were treated with oral corticosteroids, frequently combined with recombinant activated factor VII, or activated prothrombin complex concentrate. Additionally, one case of AHA associated with elevated serum IgG4 level was reported.²⁴ Although the serum IgG4 level is associated with AHA and IgG4-RD, its relevance to the etiology of IgG4-RD disease and AHA remains poorly understood.

Table 3.

Previous AHA associated with IgG4-RD published in the literature.

Case	Year	Authors	Reference	Sex	Age	Organ of IgG4-RD
1	2012	Keishi Sugino	8	Male	65	Lung, pancreas, biliary tree
2	2016	Xiaoyan Li	9	Male	55	Lung, lymph node, biliary tree, pancreas, urinary tract
3	2018	Taisuke Narazaki	10	Female	64	Pancreas, salivary gland
4	2020	Sébastien Sanges	11	Male	75	Salivary gland, lymph node

Factor VIII autoantibodies may be oligoclonal in origin with a mixed composition of IgG subtypes, including IgG1, IgG2, IgG3, and IgG4.²⁵ The overall prevalence of factor VIII-binding antibodies in healthy individuals is reported to be 19% because the antibodies can bind to non-functional domains of factor VIII and lack neutralizing capacity.²⁶ The main IgG subtypes of factor VIII-binding antibodies in healthy individuals were IgG1 and IgG3. In contrast, IgG1 and IgG4 were reported to be the major components of anti-factor VIII antibodies in patients with AHA.^25,26 It is considered that there is an association between AHA and IgG4-RD. Recently, Sanges et al. published the pathophysiological hypothesis that the anti-FVIII autoantibody production could result from broken tolerance to endogenous FVIII and bystander polyclonal IgG4-positive plasma cell proliferation.¹¹

Treatment is still controversial, but glucocorticoids are accepted as first-line therapy for IgG4-RD, including in the pediatric population.^4,27 Recently, the efficacy of rituximab for treating IgG4-RD has been reported.^1,2 Disease recurrence tends to be higher among younger patients.²⁸ Longstanding periods without treatment may lead to irreversible fibrotic damage.^1,29 Moreover, IgG4-RD has been associated with various types of malignancy (such as lung cancer, colon cancer, and lymphoma), especially in patients with high serum IgG4 levels, regardless of treatment with corticosteroids.³⁰ AHA associated with IgG4-RD is responsive to corticosteroid therapy and can be combined with by-passing agents and immunosuppressive drugs. Our patient was treated with methylprednisolone combined with recombinant cyclophosphamide, and she responded well to the treatment.

Conclusion

We report a case of Acquired Hemophilia A associated with IgG4-related dacryoadenitis and sialadenitis in an 11-year-old female who presented with unusual clinical features and systemic manifestations. Awareness of such an entity is necessary as it is a curable disease, and timely treatment could be life-saving. Corticosteroids remain the mainstay of the treatment. Documentation of such rare cases will help in further characterizing the pathogenesis of this rare disorder.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethics approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed consent

Written informed consent was obtained from the patient for their anonymized information to be published in this article.

Trial registration

Not applicable.

ORCID iD

Khuyen Nguyen Thi

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Pediatric IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) with acquired hemophilia A: A case report and review of literature

Abstract

Keywords

Introduction

Case presentation

Discussion

Conclusion

Footnotes

Declaration of conflicting interests

Funding

Ethics approval

Informed consent

Trial registration

ORCID iD

References