Histologically confirmed immunoglobulin G4-related hypophysitis in an adolescent girl: a case report with review of literature

Abstract

Hypophysitis is an extremely rare inflammatory condition in children that affects the pituitary gland and infundibulum. Immunoglobulin G4-related hypophysitis (IgG4-RH) is an IgG4-related disease (IgG4-RD) typified by the infiltration of IgG4-positive plasma cells into the pituitary gland, leading to fibrosis and damage. Although IgG4-RD was recently recognized as a defined clinical entity, pediatric cases of IgG4-RD are extremely rare. This report describes a histologically confirmed case of IgG4-RH in a 13-year-old girl. The patient became anorectic after several months of nonspecific symptoms such as headache and fatigue. Detailed examinations, including brain computed tomography (CT), did not detect any causes. However, repeated brain CT revealed pituitary enlargement. Further investigations identified an elevated serum IgG4 level (234 mg/dL, normal range: <118 mg/dL). Pituitary biopsy revealed increased IgG4-positive plasma cell counts in the anterior pituitary gland, fulfilling the diagnostic criteria for IgG4-RH. Steroid treatment dramatically improved her symptoms and reversed pituitary enlargement. A literature review identified 128 pediatric cases of IgG4-RD but only seven cases of pediatric IgG4-RH including our case. Although ophthalmic disease was the most common manifestation, broad clinical presentations were observed, even in pediatric cases. A slight female predominance was suggested in pediatric populations with IgG4-RD, whereas a male predominance was reported in adults. Pediatricians should consider IgG4-RH in the differential diagnosis when encountering patients with nonspecific symptoms because early diagnosis could improve the prognosis of pituitary function. Consequently, necessitating the diseases awareness.

Introduction

Hypophysitis, a rare inflammatory condition with an incidence of approximately 1 per 9 million people, affects the pituitary gland and infundibulum, and it is extremely rare in pediatric populations [1]. Because its pathogenesis is incompletely understood, the disease is classified according to the anatomical location of pituitary involvement, its histological appearance, and its cause [2]. Recently, novel pathologies such as immunoglobulin G4-related disease (IgG4-RD), immunotherapy-induced hypophysitis, and paraneoplastic pituitary-directed auto immunity have been recognized, thereby widening the hypophysitis disease spectrum [3].

IgG4-related hypophysitis (IgG4-RH) is an IgG4-RD characterized by the infiltration of IgG4-positive plasma cells into the pituitary gland, resulting in pituitary fibrosis and damage. This disease was first histologically confirmed in 2007 [4]. Large case series revealed that IgG4-RH constitutes 1.3% of all primary hypophysitis cases and predominantly affects men aged approximately 50–63 years [5]. However, considering that the recent increasing awareness of the disease has led to the identification of several cases, it is possible that the prevalence of IgG4-RH has been underestimated. In fact, a previous clinical study in Japan identified seven patients with isolated IgG4-RH among 23 cases of primary hypophysitis when they re-examined 170 consecutive outpatients with hypopituitarism [6].

Although IgG4-RD was recently recognized as a defined clinical entity, pediatric cases of this disease are exceedingly rare. Previous reviews found that the characteristics of IgG4-RD differ between pediatric and adult cases with regard to sex predominance and involved organs [7-9]. According to these reviews, the sex distribution of pediatric population with IgG4-RD differed among reports, and the localized form was reported more often than the systemic form. Meanwhile, IgG4-RH is extremely rare in children, with only six histologically confirmed cases among patients <18 years old [10]. Therefore, an additional case should be presented to better understand this extremely rare entity. In this report, we present a case of histologically confirmed IgG4-RH in a 13-year-old girl; a literature review was conducted to enrich our understanding of the characteristics of pediatric IgG4-RD and IgG4-RH. The patient provided written informed consent for the publication of details regarding her medical case and any accompanying images.

Case Presentation

The patient was delivered at 40 weeks’ gestation with a birth weight of 2,974 g (0.3 SD) and a body length of 49 cm (0 SD). She was diagnosed with congenital deafness after birth and underwent a bilateral cochlear implant for sensorineural deafness at 22 months of age. Her brother also had congenital deafness. Although a genetic disorder was suspected, a genetic analysis was not performed because her parents did not desire further investigation.

At 13 years and 5 months of age, the patient began to experience occasional headaches that gradually increased in frequency. At 13 years and 9 months of age, the headaches were accompanied by fatigue with a slight fever of approximately 37°C. At 13 years and 10 months of age, she became anorectic; thus, she was referred to the previous hospital by her primary care physician. Then, a routine blood test was performed, which showed a mild inflammatory response as evidenced by a white blood cell count of 13,200/μL (normal range, 3,300–8,600/μL) and a C-reactive protein (CRP) level of 0.66 mg/dL (normal range, <0.14 mg/dL). Give our suspicions for chronic inflammatory condition based on her clinical history, her serum IgG level and erythrocyte sedimentation rate were also evaluated. The revealed serum IgG level of 1,878 mg/dL (normal range: 870–1,700 mg/dL) and erythrocyte sedimentation rate of 47 mm/h (normal range: 3–15 mm/h) confirmed our suspicions. Cervical, chest and abdominal ultrasound and brain computed tomography (CT; Fig. 1A) revealed no abnormal findings. Two weeks after referral, her body temperature increased to 39°C, and her serum CRP level reached 7.3 mg/dL. She was admitted to the previous hospital to investigate the cause of her fever and chronic illness. Cervical, chest and abdominal CT and gallium scintigraphy did not reveal any causes, but lumbar puncture revealed an increased cerebrospinal fluid cell count (16.3/μL, normal range: <5/μL). Although mononuclear cell counts in her cerebrospinal fluid were predominantly increased, she was empirically treated with intravenous antibiotics (cefotaxime sodium 4.5 g/day). After the treatment, her temperature decreased to near the afebrile range but had fluctuated approximately 37°C. However, her headache and fatigue persisted. Meanwhile, her serum CRP level had reduced to the normal range. During these examinations, brain CT was not repeated because it had been performed 2 weeks before. However, they decided to perform a repeat brain CT owing to the persistence of her headache and fatigue and the unavailability of brain magnetic resonance imaging (MRI) for patients with cochlear implants at the hospital. This revealed pituitary enlargement (Fig. 1B) compared with the findings of the preceding examination (Fig. 1A). Additional laboratory investigations of pituitary function revealed low levels of basal pituitary hormones [luteinizing hormone (LH), <0.10 mIU/mL; follicle stimulating hormone (FSH), 1.4 mIU/mL; and thyroid-stimulating hormone (TSH), 0.041 μIU/mL]. She did not menstruate that month. At 13 years and 11 months of age, she was transferred to our hospital to further investigate the cause of pituitary enlargement.

Fig. 1  Enlarged pituitary detected on brain computed tomography (CT)

(A) Brain CT at the initial visit to the previous hospital. (B) Brain CT 3 weeks after the first examination

After transfer, polyurea became apparent, and a water deprivation test revealed arginine vasopressin deficiency (AVP-D, formally termed central diabetes insipidus; Table 1). Anterior pituitary functions were evaluated by growth hormone-releasing peptide-2, thyrotropin-releasing hormone, and gonadotropin-releasing hormone provocation tests, which revealed deficiencies of growth hormone (GH), TSH, LH, and FSH (Table 1). MRI was attempted using an applicable device for her cochlear implant, but only partial series were available because of her headache and fatigue during MRI (Fig. 2A). Laboratory examinations revealed an elevated serum IgG4 level (234 mg/dL, normal range: <118 mg/dL), whereas autoantibodies including antinuclear antibody, anti-neutrophil cytoplasmic antibody, and anti-thyroid peroxidase antibody, were negative. Abdominal contrast-enhanced CT identified no abnormal findings. IgG4-RH was suspected based on these findings. For further investigation, pituitary biopsy was performed through transsphenoidal surgery. An extremely thickened dura and pale anterior pituitary were observed during surgery, suggesting remarkable inflammation in this gland (Fig. 3A). Pathological studies revealed that the anterior pituitary was highly infiltrated by lymphocytes and plasma cells (Fig. 3B). Flow cytometry using cell surface markers (CD 4, CD 5, CD 8, CD 10, CD 16, CD 19, CD 20, CD 22, CD 23, CD 33, CD 38, CD 45, CD 56, and CD 64) revealed an absence of abnormal cell clusters within these cells (κ/λ light chain ratios: 1.1–1.5), and immunohistochemistry revealed the presence of >100 IgG4-positive plasma cells per high-power field and 50% proportion of IgG4-positive cells among IgG-positive cells (Fig. 3C), fulfilling the diagnostic criteria for IgG4-RH in terms of pathological findings [11, 12]. Considering these pathological findings and the elevated serum IgG4 level without any findings in other organs, we diagnosed her with isolated IgG4-RH. Steroid treatment (prednisolone 0.6 mg/kg/day: 30 mg/day) was administered, which dramatically improved her symptoms. MRI was performed after her symptoms improved, confirming amelioration of pituitary enlargement compared with the findings at transfer (Fig. 2A, B). Her basal pituitary function, excluding arginine vasopressin, normalized 1 month after treatment initiation, and menstruation resumed 2 months later; however, central adrenal insufficiency could not be evaluated given that she was receiving steroids as pharmacological treatment. The dose of prednisolone was gradually reduced to 5 mg/day over a period of 6 months, accompanied by a reduction in the patient’s serum IgG4 level to approximately 150 mg/dL. Therefore, the treatment was switched from prednisolone to hydrocortisone at a dose of 15 mg/day, an amount representing near-physiological steroid replacement.

Table 1 Provocative tests for pituitary function at transfer

GHRP-2 provocation test
Clinical test items	0 min	15 min	30 min	45 min	60 min
GH (ng/mL)	1.8	5.6	8.3	8.9	9.1
ACTH (pg/mL)	37.9	195	131	120	117
Cortisol (μg/dL)	13.7	17.8	20.5	21.7	22.8
TRH and GnRH provocation tests
Clinical test items	0 min	30 min	60 min	90 min	120 min
TSH (μIU/mL)	0.023	0.098	0.079	0.059	0.047
PRL (ng/mL)	45.3	76.7	65.0	61.0	59.5
LH (mIU/mL)	0.2	3.4	2.8	2.5	2.7
FSH (mIU/mL)	2.2	4.3	5.8	6.4	7.6
Water deprivation test
Clinical test items			Baseline	4 h after restriction
Weight (kg)			47.3	45.8
Urine osmolality (mOsm/kg)			76	210
Plasma osmolality (mOsm/kg)			ND	298
Arginine vasopressin (pg/mL)			ND	0.7

ND: not determined

Fig. 2  Improvement of pituitary enlargement in pituitary magnetic resonance imaging (MRI)

(A) Pituitary MRI at the time of transfer to our hospital. (B) Pituitary MRI at discharge from our hospital. Given that only partial pituitary images were available at transfer owing to the patient’s headache and fatigue, locations in the images were slightly inconsistent between panels A and B. The maximum pituitary diameters were 17.3 and 10.0 mm in panels A and B, respectively.

Fig. 3  Immunoglobulin G4-related hypophysitis (IgG4-RH) confirmed by pituitary biopsy

(A) Intraoperative macroscopic findings. An extremely thickened dura and pale anterior pituitary were observed, suggesting remarkable inflammation in the pituitary. (B) Hematoxylin–eosin staining of the anterior pituitary. The anterior pituitary was highly infiltrated by lymphocytes and plasma cells. (C) Immunostaining of IgG4 (left) and IgG (right). More than 100 IgG4-positive plasma cells were detected per high-power field, and IgG4-positive cells comprised 50% of all IgG-positive cells, meeting the diagnostic criteria for IgG-RH.

Subsequently, the patient’s serum IgG4 and CRP levels gradually increased, and she experienced occasional dizziness. Brain MRI was repeated 1 and 2 years after the commencement of steroid treatment, revealing no changes. Careful follow-up was performed through blood testing and assessing symptoms other than hypophysitis. However, after 2.5 years, the patient experienced severe headache, nausea, and abdominal pain. Laboratory examinations disclosed elevated levels of serum IgG4 (370 mg/dL) and CRP (2.0 mg/dL). Additionally, slight elevation of alanine aminotransferase (49 U/L, normal range: 7–23) and γ-glutamyl transferase (76 U/L, normal range: 9–32) was detected. Although brain CT did not detect any change in her pituitary, abdominal ultrasound revealed a small high echoic lesion (3 mm) in her liver. Therefore, we considered that IgG4-RD had relapsed in the liver instead of the pituitary. However, it might be difficult to interpret such a small high echoic lesion as a clinical sign for IgG4-RD at this stage. Consequently, her steroid treatment was switched from hydrocortisone to 15 mg/day prednisolone, which significantly improved her symptoms.

Literature Review

To better understand IgG4-RD in the pediatric population, we performed a literature review using PubMed targeting studies published through February 2025. The search terms were [“IgG4-related disease,” “IgG4,” “IgG4-related hypophysitis,” “Mikulicz disease,” “Riedel thyroiditis,” or “Küttner tumor” (title or abstract)] and [“children,” “child,” “adolescent,” “adolescence,” “pediatric,” “boy,” or “girl” (title or abstract)], with additional reviews and papers cited by each article, including any patients with IgG4-RD aged <18 years. In total, 128 patients aged <18 years, including our patient, were identified through our literature review [8, 10, 13-83], and nearly all cases were histologically confirmed.

Table 2 summarizes the clinical characteristics of pediatric patients with IgG4-RD in comparison with adult patients [84, 85]. The median age at diagnosis was 15 years (range: 1.25–17). Slight female predominance was observed (52.3%). The median serum IgG4 level was 207 mg/dL (range: 3–2,970), and 32.7% of patients had a serum IgG4 level <135 mg/dL. Multiple organs were involved in 32.0% of cases. Steroid treatment was a mainstay, being received by 84.2% of patients. Table 3 presents the organ manifestations detected in pediatric patients with IgG4-RD in comparison with adult patients [84, 85], which affected nearly all systemic organs with different frequencies. Ophthalmic disease was the most common manifestation (39.4%), followed by lymphadenopathy (19.7%), sclerosing cholangitis and hepatopathy (18.1%), and pancreatis (15.7%). Other manifestations included kidney involvement (9.4%), lung involvement (7.9%), salivary gland involvement (7.1%), pachymeningitis and neural involvement (6.3%), hypophysitis (5.5%), colitis (5.5%), sinusitis (3.1%), thyroiditis (3.1%), mastoid involvement (2.4%), cardiovascular involvement (2.4%), peritoneum involvement (0.8%), pleural involvement (0.8%), and muscle involvement (0.8%).

Table 2 Clinical characteristics of pediatric patients with IgG4-related disease

Variables	N	Characteristics	Reported characteristics in adults [84, 85]
Age (years) [median (range)]	128	15 (1.25–17)	Peak age at 50–70
Sex (male/female) [n (%)]	128	61 (47.7%)/67 (52.3%)	Male dominance at 61–80%
Serum IgG4 level (mg/dL) [median (range)]	95	207 (3–2,970)	Variable according to affected organs
Patients without an elevated serum IgG4 level (<135 mg/dL) [n (%)]	98*	32 (32.7%)	One-third of patients
Single-organ involvement [n (%)]	128	87 (68.0%)	10–40%
Multiorgan involvement [n (%)]	128	41 (32.0%)	60–90%
Steroid treatment [n (%)]	120	101 (84.2%)	First-line treatment

*The data of serum IgG4 level were described in 98 patients from literatures.

Table 3 Organ manifestations detected in pediatric patients with IgG4-related disease

Organ manifestations (N = 128)	Number of patients**	Proportion	Frequency in adults [84, 85]
Ophthalmic disease	50	39.4%	Occasional
Lymphadenopathy	25	19.7%	Frequent
Sclerosing cholangitis and hepatopathy	23	18.1%	Occasional
Pancreatis	20	15.7%	Frequent
Kidney involvement	12	9.4%	Occasional
Lung involvement	10	7.9%	Occasional
Salivary gland involvement	9	7.1%	Frequent
Pachymeningitis and neural involvement*	8	6.3%	Infrequent
Hypophysitis	7	5.5%	Infrequent
Colitis	7	5.5%	Infrequent
Sinusitis	4	3.1%	Infrequent
Thyroiditis	4	3.1%	Infrequent
Mastoid involvement	3	2.4%	Infrequent
Cardiovascular involvement	3	2.4%	Infrequent
Peritoneum involvement	1	0.8%	Frequent
Pleural involvement	1	0.8%	Infrequent
Muscle involvement	1	0.8%	Infrequent

*The category does not include hypophysitis.

**Multiple organs were involved in 41 patients (32.0%).

Discussion

This report discussed the case of a 13-year-old girl with histologically confirmed IgG4-RH. It was extremely difficult to diagnose her with hypophysitis before pituitary enlargement was detected by repeated brain CT because her symptoms were nonspecific and hypophysitis, especially IgG4-RH, is an extremely rare disease in pediatric populations. Fewer than 1% of pediatric patients with pituitary stalk thickening or AVP-D developed immunological or autoimmune hypophysitis [86]. In the current case, the patient’s anterior pituitary functions recovered to a level that precluded the need for hormone replacement treatment because steroid treatment resulted in a dramatic improvement in hypopituitarism, although AVP-D was permanent. Because steroid treatment is usually effective for IgG4-RH [87, 88], early diagnosis is vital for preserving pituitary functions in patients with IgG4-RH before fibrosis in the pituitary gland leads to irreversible organ damage. Therefore, this extremely rare entity should be remembered in clinical practices for pediatricians encountering patients with nonspecific symptoms suggesting hypopituitarism.

IgG4-RD can cause fibroinflammatory lesions in almost any organ [89]. Our literature review confirmed the broad clinical presentations of this disease even in pediatric populations (Table 3). The previous reviews revealed that the localized form is reported more often than the systemic form in pediatric patients [7-9]. However, our review uncovered frequent internal involvement, with sclerosing cholangitis and hepatopathy, pancreatis, kidney involvement, and lung involvement being detected at rates of 18.1%, 15.7%, 9.4%, and 7.9%, respectively, in pediatric patients, although ophthalmic disease was the most common presentation (39.4%). Therefore, clinicians should be aware of internal organ involvement even in pediatric populations. Meanwhile, male predominance was detected in adult patients with IgG4-RD [5], whereas the sex distribution in pediatric patients with IgG4-RD differed among prior reports [7, 9, 13, 55, 56]. However, a prospective study involving 737 patients with IgG4-RD reported that the proportion of males increased with age [56], and a slight female predominance has been observed in pediatric populations in large sample-based studies [9], consistent with our results (Table 2). Accordingly, the sex distribution of IgG4-RD apparently differs between pediatric and adult populations.

The first systematic review of pediatric patients with IgG4-RD conducted in 2016 [7] only identified 25 cases, whereas we found 128 pediatric cases in the published literature. This implies that children have been increasingly diagnosed with IgG4-RD in response to increasing awareness of the disease over the past 10 years. Nevertheless, only seven pediatric cases, including our case, involved histologically confirmed IgG4-RH [10], comprising 5.5% of all pediatric cases of IgG4-RD. One reason for the rarity of IgG4-RH is that pituitary biopsy is invasive, and it can only be performed in limited clinical institutes. A more complicated issue in diagnosing IgG4-RH is that the presence of IgG4-positive plasma cells in the pituitary gland is not specific to this disease. These cells have also been reported in Rathke’s cleft cyst and granulomatosis with polyangiitis, which can fulfill diagnostic criteria for IgG4-RH in terms of pathological findings [90, 91]. A careful differential diagnosis is mandatory before diagnosing IgG4-RH.

In the seven reported pediatric cases of IgG4-RH, isolated disease was found in four patients, whereas multiorgan involvement was detected in three patients, including our case [10]. Involved organs in the other two patients were submandibular and parotid glands in one patient, and pancreas, lacrimal glands, liver, and lymph nodes in another patient, respectively. The patients included five girls and two boys, suggesting female dominance. An elevated serum IgG4 level was observed in only two patients including our case, which was not surprising given that IgG4 elevation is not specific to IgG4-RD [92]. Although steroids were used in five patients, only two received steroids alone. Considering these observations, it is challenging to define the clinical characteristics of patients with pediatric IgG4-RH at this stage. Therefore, additional cases of pediatric IgG4-RH should be shared.

In conclusion, we identified a 13-year-old girl with histologically confirmed IgG4-RH. We also described the clinical characteristics of pediatric patients with IgG4-RD by reviewing 128 pediatric patients in the literature. Although IgG4-RH is extremely rare, pediatricians should consider this disease in the differential diagnosis when encountering patients with nonspecific symptoms, as awareness of this entity could improve the prognosis of pituitary function through early diagnosis (Graphical Abstract).

Graphical Abstract 

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

Funding sources: The work submitted did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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