A pediatric case of central diabetes insipidus and hypopituitarism after COVID-19 suspected with lymphocytic hypophysitis with positive anti-rabphilin-3A antibodies

Abstract

Lymphocytic hypophysitis (LYH) is a rare autoimmune disorder characterized by lymphocytic infiltration of the pituitary gland, leading to central diabetes insipidus (CDI) and hypopituitarism. Although distinguishing LYH from other diseases presenting with pituitary enlargement is challenging, the use of anti-rabphilin-3A antibody (RPH3A-Ab) in the diagnosis of LYH has been recently reported. Case reports of LYH following coronavirus disease 2019 (COVID-19) infection in adult and adolescent patients have been accumulated. Here, we present the first case confirming the presence of RPH3A-Abs in pediatric CDI following COVID-19. A 4-yr-old girl developed CDI one week after COVID-19, and anterior hypopituitarism was confirmed 14 mo later. Head magnetic resonance imaging (MRI) revealed progressive pituitary stalk thickening, which subsequently improved. Although other disease-specific markers did not increase, serological testing confirmed the presence of RPH3A-Ab, supporting the clinical diagnosis of LYH. It has previously reported that RPH3A-Ab demonstrate high sensitivity and specificity in differential diagnosis of LYH, and RPH3A-Ab are also identified as positive in pediatric cases of LYH with a biopsy. Additionally, this is the first documented prepubertal case of LYH following COVID-19. Our case study indicates that LYH can occur in children after COVID-19, and RPH3A-Ab may be useful in its diagnosis.

Highlights

● We report the first pediatric case of RPH3A-Ab-positive CDI after COVID-19.

● This is also the first prepubertal case of LYH following COVID-19.

● RPH3A-Ab may be valuable in suspecting post-COVID-19 LYH even in children.

Introduction

Lymphocytic hypophysitis (LYH) is a rare inflammatory disorder characterized by lymphocytic infiltrates invading the pituitary gland, and the underlying cause may be due to an autoimmune process (1, 2). LYH is classified into three types: lymphocytic adenohypophysitis (LAH), lymphocytic infundibuloneurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) (2). Depending on the type of disease and case, LYH can cause central diabetes insipidus (CDI), hypopituitarism, and neurological symptoms, such as headache and visual field disturbances (2). Differentiating LYH from other conditions presenting with a pituitary enlargement or pituitary stalk thickening, such as germinoma and Langerhans cell histiocytosis, is challenging.

Recent studies indicate that serum anti-rabphilin-3A antibodies (RPH3A-Abs) may serve as a valuable diagnostic marker for LYH in adult and pediatric populations (3,4,5,6,7). Although pituitary biopsies have been the gold standard for diagnosing LYH, RPH3A-Ab testing offers a less invasive alternative, particularly beneficial for pediatric patients (4,5,6).

LYH is a rare complication following coronavirus disease 2019 (COVID-19) infection (7,8,9,10,11). COVID-19 is an infectious disease caused by the SARS-CoV-2 virus and well known for its respiratory complications. Moreover, it can also lead to extrapulmonary manifestations, including endocrinological symptoms, such as hypophysitis (7,8,9,10,11,12), although the exact pathogenesis remains unclear.

Here, we present the first case of prepubertal CDI and hypopituitarism following COVID-19, wherein the presence of RPH3A-Ab was indicative of LYH.

Materials and Methods

Case report

A 4-yr-old girl with an unremarkable family history of particular illnesses developed COVID-19 diagnosed using an antigen test. Fever and respiratory symptoms improved in several days without specific treatment. After a week, her parents noticed that she had polydipsia and polyuria. Her height and weight were 98.1 cm (standard deviation [SD], −1.2) and 14.2 kg (−1.0 SD), respectively. She had no headache and no visual field defect. Her blood count and serum chemistry profile, including anterior pituitary function, were within the reference range (Table 1). A water deprivation test showed a poor elevation of urine osmolality (82 to 98 mOsm/kg) when the body weight was reduced by 4% after 180 min. We administered vasopressin acetate at 2 units subcutaneously, resulting in an increase in urine osmolality at 520 mOsm/kg. Two weeks after the CDI onset, T1-weighted magnetic resonance imaging (MRI) revealed no high-intensity signal of the posterior lobe, with no evidence of enlarged pituitary gland or thickened pituitary stalk (Figs. 1a and b). The diagnosis of CDI was made, and her polyuria was controlled after starting desmopressin acetate hydrate. However, repeat head MRI showed pituitary stalk thickening 7 mo after the CDI onset (Figs. 1c and d), and another baseline endocrine evaluation with blood test was conducted (Table 1). After 2 mo, she underwent a head CT scan because of persistent vomiting which subsequently resolved following intravenous fluid therapy. The CT scan revealed no specific abnormalities, and the patient was diagnosed with ketotic hypoglycemia. MRI taken 10 mo after the CDI onset showed that the lesion of the pituitary stalk shrank slightly (Figs. 1e and f), although her responses to arginine, CRH, TRH, and LH-RH loading tests were abnormal 16 mo after the CDI onset (Tables 1 and 2). Anterior hypopituitarism was confirmed, and hormone replacement with levothyroxine and hydrocortisone was initiated. During the follow-up, her growth rate stagnated (Fig. 2). However, growth hormone replacement therapy has not yet been initiated due to parental intention.

Table 1. Laboratory data at the first visit, 7 and 16 mo after CDI onset.

Fig. 1.

Changes in magnetic resonance imaging (MRI) findings over time. (a, b) T1-weighted MRI images 2 wk after central diabetes insipidus (CDI) onset, showing no high-intensity signal for the posterior or enlargement of the pituitary stalk (arrowheads). (c, d) Seven months after CDI onset. The pituitary stalk thickened. The stalk width was 6.5 and 5.6 mm for the coronal and sagittal sections, respectively. (e, f) Ten months after CDI onset. Contrast-enhanced MRI showed that the enlargement slightly shrank. The stalk width was 5.2 and 4.5 mm for the coronal and sagittal sections, respectively. (g, h) Seventeen months after CDI onset. Contrast-enhanced MRI showed that the lesion had been shrinking over time. The stalk width is 3.4 and 3.4 mm for the coronal and sagittal sections, respectively. (a, c, e, g) Sagittal section, (b, d, f, h) coronal section. Scale bars indicate 10 mm.

Table 2. Pituitary function test 16 mo after CDI onset.

Fig. 2.

Growth curve of the patient.

Human chorionic gonadotropin β-subunit (β-hCG), α-fetoprotein (AFP) in serum, or β-hCG, AFP, or placental alkaline phosphatase (PLAP) in the cerebrospinal fluid (CSF) was not elevated (Table 3). She had negative results for serological screenings for IgG4-related disease, sarcoidosis, systemic lupus erythematosus, syphilis, and tuberculosis (Table 3). Lytic bone lesions on skull radiograph or skin lesions were not found. Pituitary biopsy was pending because of its invasive nature. Western blotting was used to evaluate RPH3A-Ab, as previously reported (3). The antibody was detected in the patient’s serum, leading to a clinical diagnosis of LPH. The pituitary stalk thickening decreased in size at 17 mo after developing polyuria (Figs. 1g and h). Glucocorticoid therapy for suppression of pituitary inflammation was not indicated because the patient had no symptoms associated with tumor-induced compression, such as headache or visual field disturbances.

Table 3. Markers for the differential diagnosis.

Informed consent for the publication of this case report was obtained from the patient and her parents, and the institution’s ethical committee approved the publication.

Discussion

We present the first prepubertal case suspected of having COVID-19-related LYH. The patient demonstrated clinical features of CDI and hypopituitarism, and subsequent MRI findings and the presence of RPH3A-Ab strongly supported the possibility of LYH.

Recent studies have emphasized the significance of RPH3A-Ab as a diagnostic marker for LYH, particularly for LINH and LPH (3,4,5,6,7). Although evidence has accumulated in adults, the usefulness of RPH3A-Ab for LYH diagnosis has also been reported in pediatric cases (4,5,6). Considering that our patient was only 4 yr old, a noninvasive diagnostic approach was crucial. Recently, a 4-yr-old child has been reported as the youngest documented case of probable or definitive LINH with RPH3A-Ab positivity (13). Murai reported a case of a 12-yr-old girl with RPH3A-Ab-positive LPH diagnosed by pituitary biopsy and revealed that the antibody had an 88.9% sensitivity for LINH and LPH, with 97.4% specificity for distinguishing sellar/suprasellar masses (4). The primary advantage of RPH3A-Ab lies in its noninvasive nature. Combined with its high sensitivity and specificity (4), RPH3A-Ab is a promising tool for LYH diagnosis in pediatric cases, emphasizing the importance of minimizing invasive procedures and ensuring careful follow-up in pediatric LYH. We didn’t perform a pituitary biopsy and couldn’t obtain a definitive pathological diagnosis. According to a national clinical practice consensus guideline, biopsy of the pituitary stalk may be considered when there is significant stalk thickening (≥ 6.5–7.0 mm), progressive enlargement, progressive hypopituitarism, or visual deterioration (14). In our case, while the hypopituitarism was progressive, the stalk was not markedly enlarged and there was no visual impairment. Furthermore, the patient was clinically suspected to have LYH. Given these considerations, we concluded that the patient was unlikely to benefit significantly from an invasive pituitary biopsy. If the lesion had been a germinoma, it might be the case that the radiation from the head CT scan partially treated the lesion (15, 16). Since the possibility of germinoma cannot be completely ruled out, careful follow-up with head MRI is essential. However, other serum or CSF markers related to infection, tumor, or vasculitis were negative and the improved MRI findings during the clinical course strengthened the suspicion of LPH.

LYH is a rare but significant complication following COVID-19 (8–12), and to date, only one middle-aged case with positive RPH3A-Ab has been reported (7). LYH, as the sequelae of COVID-19, has been observed in adolescents and adults (7,8,9,10,11), but not in prepubertal patients. In previous reports, the patients with LYH following COVID-19 presented with headache, visual disturbance, CDI, and hypopituitarism (7,8,9,10,11). Although our case had no headache or visual symptoms, she may not have been able to report certain symptoms because of her age. The time between COVID-19 symptoms and hypophysitis onset varied between 2 and 3 wk in most adult and adolescent patients (11), whereas our patient developed CDI one week after COVID-19. Whether the relatively early disease onset is related to our patient being a preadolescent is unclear. Our patient developed CDI initially, followed by the manifestation of anterior pituitary dysfunction. The complication rates of posterior and anterior hypopituitarism in LYH after COVID-19 infection is 71% and 42%, respectively, with 85% of patients developing either of the two (11). Currently, which patients are more likely to have posterior or anterior lobe hypofunction with post-COVID-19 LYH is unclear, and further studies are required to elucidate this question.

The pathogenesis of LYH is thought to be immune-mediated (2), and the involvement of RPH3A and RPH3A-Ab has been suggested (17, 18). The association between RPH3A-Ab and LYH has been reported mainly in non-COVID-19 cases, and the specific mechanism of LYH following SARS-CoV-2 infection remains unknown. Herein, the positive RPH3A-Ab in the present case might indicate that the pathogenesis of LYH was common with general LYH, rather than a COVID-19-specific mechanism. It is plausible that the immune response to SARS-CoV-2 may also cross-react with RPH3A, further resulting in pituitary inflammation. Whether SARS-CoV-2 is more likely to elicit this immune-mediated mechanism than other pathogens, or which patients tend to develop pituitary inflammation after COVID-19 remains unknown. Conversely, evidence revealed that SARS-CoV-2 can directly injure the pituitary gland (12, 19, 20) by entering the central nervous system through the olfactory nerve or circumventricular organs (19). Moreover, angiotensin-converting enzyme 2 (ACE2) receptor which are expressed in the pituitary gland, allow SARS-CoV-2 to enter cells (12). SARS-CoV-2 has been detected in the pituitary gland during autopsy (20). In the present case, CDI occurred only one week after COVID-19, and the first MRI already showed a loss of high signal intensity in the posterior pituitary, that suggests a rapid progression compared to typical cases of CDI. The timeline raises the possibility that the viral direct injury to the pituitary compounded the canonical autoimmune process characteristic of LYH. Unfortunately, we couldn’t reach a definitive conclusion, because histological or virological assessment of the pituitary lesion was not performed. Further studies based on accumulated cases are needed to elucidate the LYH mechanism after SARS-CoV-2 infection.

Conclusion

We present a prepubertal case of CDI and hypopituitarism developing after COVID-19, which was strongly suspected to be LPH with RPH3A-Ab. The present case study proposes that RPH3A-Ab may serve as a diagnostic marker for pediatric LPH, even in the context of COVID-19 sequelae.

Conflict of interests

The authors have nothing to declare.