Pituitary dysfunction in trans-sellar encephalocele: a two-case report and a literature review

Abstract

Trans-sellar encephalocele (TSE) is a rare congenital anomaly of the cranial base characterized by herniation of intracranial contents through the sellar floor. Although clinical presentations are diverse, the prevalence and characteristics of endocrine dysfunction due to hypothalamic–pituitary involvement are unclear. This study aimed to clarify endocrine function in patients with TSE and emphasized the importance of multidisciplinary management. Here, we present two adult cases of TSE with progressive visual impairment and evident pituitary hormone deficiencies, and conducted a comprehensive literature review to investigate endocrine function and its postoperative outcomes in patients with TSE. Both cases presented with growth hormone (GH) deficiency and diabetes insipidus and showed deterioration in GH secretion, which was postoperatively assessed using dynamic testing, despite minimal or no direct manipulation of the pituitary gland. In a literature review, 87 cases from 41 case reports and 3 review articles were identified. Among the 87 cases, pituitary dysfunction was identified in 41 (47.1%); however, detailed hormonal assessments were performed in only 25 (28.7%) of the cases. In 33 cases with documented preoperative and postoperative endocrine status, pituitary function worsened in 16 (48.5%), improved in 6 (18.2%), and remained unchanged in 11 (33.3%) postoperatively. Pituitary dysfunction occurred in nearly half of patients with TSE, but was frequently underdiagnosed due to inadequate endocrine assessment. Comprehensive endocrine evaluation, including dynamic GH testing, performed at diagnosis and perioperatively, may be essential in optimizing patient outcomes.

Graphical Abstract

Introduction

Trans-sellar encephalocele (TSE) is a rare congenital anomaly characterized by herniation of intracranial contents through a defect in the skull base at the level of the sella turcica, often extending into the sphenoid sinus or nasopharynx. Patients with TSE present with diverse symptoms, including respiratory distress, nasal obstruction, visual impairment, cerebrospinal fluid (CSF) leakage, meningitis, cranial nerve palsy, feeding difficulties, and, notably, endocrine dysfunction due to hypothalamic–pituitary involvement. TSE has been reported in multiple specialties, including neurosurgery, otorhinolaryngology, endocrinology, plastic surgery, pediatrics, and radiology [1-45].

Endocrine dysfunction is a clinically significant yet underrecognized feature of TSE, particularly among physicians outside the fields of pituitary neurosurgery and endocrinology. These hormonal disturbances may be present at diagnosis or develop later in life, often asymptomatically, and are frequently overlooked without targeted endocrine evaluation. Moreover, surgical repair, often required for progressive symptoms, such as visual deterioration or CSF leakage, can further affect pituitary function, highlighting the need for careful perioperative endocrine assessment.

We previously reported TSE in two adults with progressive visual impairment and reviewed neurosurgical cases, focusing on surgical interventions [42]. In this study, we revisited the same two cases to detail their evident pituitary hormone deficiencies, reviewed 85 previously reported cases to clarify the endocrinological spectrum of TSE, and emphasized the importance of multidisciplinary awareness and long-term endocrine follow-up.

Materials and Methods

We examined two cases of symptomatic TSE associated with progressive visual impairment, focusing on their endocrine function. The cases were those of a 26-year-old woman and a 32-year-old man, both of whom underwent transnasal surgery performed by the first author (K Amano). Additionally, a literature review of TSE published over the last quarter century was conducted using PubMed and Google Scholar. We identified 41 case reports and three review articles on TSE [1-45] (Tables 1, 2). In this study, TSE was defined based on the presence of a bony defect in the sella turcica, irrespective of the extent of encephalocele protrusion, as our focus was on evaluating pituitary function. The 41 case reports included 85 individual cases; together with our two additional cases, we analyzed 87 cases in this study.

Table 1. Summary of reported and present cases of trans-sellar encephalocele and associated review articles.

	Case or publication	Values
Reporting specialty, N (%)	45 publications
Neurosurgery		25 (55.6%)
Otolaryngology		5 (11.1%)
Endocrinology		4 (8.9%)
Radiology		3 (6.7%)
Plastic surgery		3 (6.7%)
Pediatrics		3 (6.7%)
Ophthalmology		1 (2.2%)
Genetics		1 (2.2%)
Demographics	87 cases
Male sex, N (%)		57 (65.5%)
Age range		Neonate to 73 years
Patients under 6 years, N (%)		46 (55.4%)
Pediatric patients (0–17 years), N (%)		63 (72.4%)
Treatment modality, N (%)	87 cases
Surgery		71 (81.6%)
Conservative management		16 (18.4%)
Endocrine function before surgery	87 cases
Not described		16 (18.4%)
Normal		30 (34.5%)
Impaired		41 (47.1%)
Hypopituitarism		16 (18.4%)
Axis-specific hormonal evaluation*		25 (28.7%)
GH deficiency		16 (18.4%)
Central hypothyroidism		14 (16.1%)
Central hypogonadism		13 (14.9%)
Central adrenal insufficiency		13 (14.9%)
Diabetes insipidus		8 (9.2%)
Hyperprolactinemia		3 (3.4%)
Reported postoperative outcomes	33 cases
Worsened		16 (48.5%)
Unchanged		11 (33.3%)
Improved		6 (18.2%)

* Multiple hormonal abnormalities may coexist in a single patient.

Abbreviation: GH, Growth hormone

Table 2. Reported and present cases of trans-sellar encephaloceles with endocrine status.

Case	Reference	Department	Sex	Age	Pituitary function
					Pre-operation	Post-operation
1	Tsutsumi et al. (1999) [1]	Neurosurgery	M	6 y	Hypopituitary dwarfism	No change
2			M	3 m	Normal	GH, Ad
3	Abe et al. (2000) [2]	Neurosurgery	F	26 y	DI, hPRL	Ad, DI
4	Komiyama et al. (2000) [4]	Neurosurgery	M	29 y	Panhypopituitarism	(No surgery)
5	Koral et al. (2000) [5]	Radiology	M	15 y	GH, Th, Ad	(No surgery)
6			F	6 y	Short stature	Th, Ad
7	Van Esch et al. (2004) [8]	Genetics	M	adolescence	GH, Th, Go, Ad	(Not mentioned)
8	Spacca et al. (2009) [14]	Neurosurgery	M	12 y	Th, Go	No further deterioration
9			M	18 y	Panhypopituitarism	Improved
10			F	3 y	GH	(No surgery)
11			M	14 y	Panhypopituitarism	No further deterioration
12			M	5 y	GH, hypopituitarism	(No surgery)
13			M	9 y	Panhypopituitarism, DI	No further deterioration
14	Kohan et al. (2010) [15]	Plastic surgery	M	6 y	DI, endocrine abnormalities	(Not mentioned)
15	Holanda et al. (2011) [16]	Neurosurgery	F	9 y	GH	(Not mentioned)
16	Tanimoto et al. (2011) [20]	Endocrinology	M	21 y	GH, Th, Go, Ad	(No surgery)
17	Rabelink et al. (2012) [21]	Endocrinology	F	38 y	hPRL	(No surgery)
18	Saito et al. (2012) [22]	Neurosurgery	M	36 y	Mild panhypopituitarism	Hormonal replacement
19	Ogiwara et al. (2013) [23]	Neurosurgery	M	2 m	Normal	GH
20			F	2 m	Normal	GH
21			F	36 m	Normal	GH
22			F	2 m	Th, Ad	GH, Th, Ad
23			M	13 m	Th, Ad	GH,Th, Ad
24			M	69 m	GH, Th, Ad	GH, Th, Ad
25			F	6 m	Normal	GH
26	Sanjari et al. (2013) [24]	Neurosurgery	M	17 y	GH, Go, Ad	(Not mentioned)
27	Bayram et al. (2014) [25]	Endocrinology	M	10 y	GH	(No surgery)
28	Yang et al. (2015) [27]	Neurosurgery	M	3 y	Th, Go, Ad	Hormone improved
29			F	5 y	hPRL	Normal
30			M	2 y	Th, Ad	Hormone improved
31			M	17 y	Go	Hormone improved
32			M	6 y	Th, Go, Ad	Hormone improved
33			M	28 y	Th, Go, Ad	(No surgery)
34	Rao et al. (2017) [28]	Ophthalmology	F	3 y	GH	(No surgery)
35	Zeinalizadeh et al. (2017) [29]	Neurosurgery	M	24 m	DI	(Not mentioned)
36	Bhaisora et al. (2018) [30]	Neurosurgery	M	18 m	Th	(Not mentioned)
37	Kasim et al. (2018) [32]	Endocrinology	F	14 y	GH, Th, Go, Ad	(No surgery)
38	Harrison et al. (2020) [34]	Otolaryngology	F	22 y	Hypopituitarism	(Not mentioned)
39	Kelsch et al. (2020) [35]	Radiology	F	20 y	DI, oligomenorrhea	(Not mentioned)
40			M	31 y	Hypogonadism	(No surgery)
41			F	14 y	Short stature, Th, oligomenorrhea	(No surgery)
42	Morishima et al. (2020) [36]	Pediatrics	M	8 y	GH, Go, DI	(No surgery)
43	Morota et al. (2020) [37]	Neurosurgery	M	4 m	Normal	GH
44			M	22 m	Normal	GH
45			F	1 m	Normal	GH
46			M	25 d	Normal	GH
47	Pavanello et al. (2021) [39]	Neurosurgery	M	6 y	(Not mentioned)	GH, Th
48	Azab et al. (2022) [40]	Neurosurgery	M	15 y	Panhypopituitarism	(Not mentioned)
49	Basheer et al. (2023) [41]	Neurosurgery	M	4 m	Congenital hypopituitarism	No development
50	Present cases [42]	Neurosurgery	F	26 y	GH, Go, DI	GH, Go, DI
51			M	32 y	GH, DI	GH, DI

Abbreviations: GH, growth hormone deficiency; Th, central hypothyroidism; Go, central hypogonadism; Ad, central adrenal insufficiency; DI, diabetes insipidus; hPRL, hyperprolactinemia

This study was approved by the Ethics Committee of Tokyo Women’s Medical University (approval number: 2021-0063) and Hamamatsu University School of Medicine (approval number: 20-279), and conducted in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained from all the patients.

Categorical variables were compared using binomial tests. A p value of <0.05 was considered statistically significant. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Japan).

Results

Case Presentation

Case 1 (Case 50 in Table 2)

A 26-year-old woman who was followed-up by a pediatrician since early childhood, presented with progressive visual impairment and nasal obstruction. At 17 years of age, she was diagnosed with primary amenorrhea and was initiated on hormone replacement therapy for hypogonadotropic hypogonadism. Over subsequent years, the patient developed worsening polydipsia, polyuria, and dry mouth, leading to a diagnosis of central diabetes insipidus, for which she was placed on desmopressin therapy. At 24 years of age, she developed anosmia, bilateral nasal obstruction, and progressive visual field defects, and was referred to our clinic. Endocrinological evaluation revealed growth hormone (GH) deficiency, based on the low peak GH response (5.06 ng/mL) to GH-releasing peptide-2 (GHRP-2) (low GH response is defined as peak GH of <9 ng/mL) [46], hypogonadism (estradiol, 12.8 pg/mL; luteinizing hormone (LH)/follicle-stimulating hormone (FSH), 2.5/4.9 mIU/mL), and diabetes insipidus. Preoperative magnetic resonance imaging (MRI) demonstrated a large defect in the sella turcica and TSE herniating inferiorly into the nasopharyngeal cavity (Fig. 1a, b).

Fig. 1. First case (Case 50 in Table 2).

Preoperative coronal gadolinium-enhanced T1-weighted (a) and sagittal T2-weighted (b) magnetic resonance imaging (MRI) revealed a trans-sellar encephalocele. Postoperative coronal T1-weighted (c) and sagittal T2-weighted (d) MRI showed reduction of the encephalocele and a patent nasal cavity (↔).

Transnasal surgery was performed for the encephalocele to resolve her progressive visual impairment and nasal obstruction. Intraoperatively, the TSE was not resected; instead, plication with sutures was performed to reduce its volume, redirect CSF, and create a patent nasal airway.

Postoperative MRI revealed a reduction in the size of the encephalocele and an open nasal cavity (Fig. 1c, d). The patient was able to breathe through her nose, her sense of smell was restored, progression of the visual field impairment ceased, and photophobia resolved.

Endocrinological evaluation after surgery demonstrated worsening GH levels (peak GH response to GHRP-2, 1.26 ng/mL [Fig. 2a]) and gonadotropin secretion (estradiol 43.7 pg/mL; LH/FSH, 1.5/2.9 mIU/mL), and a decreased desmopressin dose.

Fig. 2. Pre- and postoperative GHRP-2 stimulation tests.

GH response to growth hormone-releasing peptide-2 (GHRP-2) administration of the first case (a) and second case (b) before and after surgery.

Notably, she conceived naturally and delivered a healthy child five years after the surgery. The TSE remained reduced in size for 14 years post-operation.

Case 2 (Case 51 in Table 2)

A 32-year-old man experienced blurred vision in his right eye six months prior to presentation, and his visual impairment gradually worsened. His left eye was functionally blind since childhood. Endocrinological evaluation revealed GH deficiency (peak GH response to GHRP-2, 8.05 ng/mL [Fig. 3b]) and reduced arginine vasopressin levels (<0.4 pg/mL). Preoperative MRI and computed tomography revealed a defect in the sellar floor and a TSE protruding into the nasopharynx, which was partially covered with fat (Fig. 3a–c).

Fig. 3. Second case (Case 51 in Table 2).

Preoperative coronal gadolinium-enhanced T1-weighted (a) and sagittal T2-weighted (b) MRI revealed a trans-sellar encephalocele. Sagittal computed tomography (CT) with a bone window (c) demonstrated absence of the sellar floor. Postoperative coronal T1-weighted (d) and sagittal T2-weighted (e) MRI showed a reduced encephalocele. Sagittal CT with a bone window (f) demonstrated a newly reconstructed sellar floor (arrow).

Transnasal surgery was performed to treat the encephalocele and resolve the progressive visual impairment. An incision was made in the fat at the inferior aspect of the sphenoid sinus, and a portion protruding into the nasopharynx was detached. Postoperative MRI confirmed a reduction in encephalocele size (Fig. 3d–f).

Right hemianopsia partially improved, and endocrinological evaluation after surgery demonstrated worsening of GH deficiency (peak GH response to GHRP-2, 2.95 ng/mL [Fig. 2b]) and diabetes insipidus.

Literature Review

A literature review of TSE identified 41 case reports and three review articles. Including our own cases, these 45 publications originated from various specialties: neurosurgery (25 publications), otolaryngology (five publications), endocrinology (four publications), radiology (three publications), plastic surgery (three publications), pediatrics (three publications), ophthalmology (one publication), and genetics (one publication) (Tables 1, 2).

Eighty-seven cases of TSE were reported (57 men and 30 women), with ages ranging from neonates to 73 years. Forty-six (55.4%) patients were <6 years of age, and 63 (72.4%) were pediatric cases (aged 0–17 years). Endocrine function was not mentioned in 16 cases (18.4%), normal in 30 cases (34.5%), and dysfunctional in 41 cases (47.1%). Of the 41 cases with pituitary dysfunction, 16 were identified based on abstract-level descriptors (e.g., “short stature” or “hypopituitarism”), while 25 were assessed using detailed clinical evaluations specifying hormonal axes.

Among the 25 cases with detailed hormonal assessments, overlapping deficiencies across multiple pituitary axes were common. Specific hormonal abnormalities were as follows: GH deficiency (including short stature) in 16 (64%), central hypothyroidism in 14 (56%), central hypogonadism in 13 (52%), central adrenal insufficiency in 13 (52%), diabetes insipidus in 8 (32%), and hyperprolactinemia in 3 (12%) patients.

Of the 87 patients, 71 underwent surgical treatment, and 16 were managed conservatively. Postoperative pituitary function was described in 33 of the 71 surgical cases (46.5%). Among the 33 patients with postoperative endocrine follow-up, pituitary function worsened in 16 (48.5%), remained unchanged in 11 (33.3%), and improved in six (18.2%). When comparing only patients with functional deterioration or improvement (n = 22), postoperative deterioration occurred more frequently than improvement (p = 0.033) (Table 1). Among the 87 patients, pituitary function was reported in 51 patients, either preoperatively, postoperatively, or both (Table 2).

Discussion

TSE are rare cranial base defects characterized by herniation of the brain tissue and/or meninges through the sellar floor into the sphenoid sinus or nasopharyngeal region [43-45]. Although most previous reports have focused on structural characteristics and surgical interventions, relatively little attention has been paid to pituitary function, despite its crucial role in determining long-term quality of life [1-41]. In this study, we present two cases of TSE with progressive visual impairment and review 85 previously reported cases across various specialties. Particular attention was paid to pituitary function, its evaluation, and the management of endocrine dysfunction, an area that remains under-recognized.

Characteristics of Endocrine Function in Patients with TSE

Among the 25 patients with axis-specific endocrine evaluations, GH deficiency (n = 16), central hypothyroidism (n = 14), central hypogonadism (n = 13), and central adrenal insufficiency (n = 13) were the most common, followed by diabetes insipidus (n = 8) and hyperprolactinemia (n = 3). This distribution highlights the multisystem involvement of TSE-associated pituitary dysfunction and underscores the need for a comprehensive endocrine assessment, including evaluation of all the anterior and posterior pituitary axes. Importantly, the combined anterior pituitary hormone deficits suggest that TSE can result in global hypopituitarism, rather than isolated axis failure. Therefore, clinicians should maintain a high index of suspicion even in the absence of overt endocrine symptoms. These findings emphasize that endocrinology consultation and appropriate hormonal assessments, including dynamic testing, are mandatory for all patients diagnosed with TSE, regardless of age or overt symptoms.

Inadequate Endocrine Assessment in Patients with TSE

Our review showed that at least 47.1% of the 87 patients with TSE had impaired pituitary function, indicating a considerable prevalence of endocrine dysfunction. However, as pituitary function was not addressed in 18.4% of the cases, it is presumed that no hormonal assessment was performed. Furthermore, in many cases classified as “normal,” it remains unclear whether comprehensive testing, including dynamic stimulation, was conducted. Only 25 of the 87 reviewed cases (28.7%) underwent a comprehensive endocrine evaluation. Asymptomatic patients with pituitary dysfunction, such as case 51, may not have received adequate endocrine evaluation. Therefore, the prevalence of impaired pituitary function in patients with TSE may underrepresent the true burden of hormonal impairment.

Endocrine Function Deterioration Following Pituitary Surgery

Another important finding of our analysis was the risk of deterioration of endocrine function after surgical intervention. Among the 33 patients with documented preoperative and postoperative endocrine status, 48.5% experienced postoperative worsening. In conventional pituitary tumor resection, the pituitary gland is typically visualized on preoperative imaging, and various techniques are used to preserve its function [47]. However, in TSE, preoperative identification of the gland is often challenging. In our first case, the sac was opened; however, the pituitary gland could not be visualized endoscopically. In the second case, the sac was not opened, and the pituitary gland was not directly manipulated. Nevertheless, postoperative GHRP-2 stimulation tests revealed deterioration of GH deficiency in both cases. These observations suggest that pituitary function may deteriorate postoperatively, even in the absence of direct manipulation, and that preoperative endocrine assessment and postoperative endocrine follow-up may be important. Accordingly, the primary purpose of surgery may be to resolve symptoms such as visual impairment, CSF leakage, and cranial nerve palsies rather than pituitary dysfunction. Our study suggests that pituitary dysfunction may not be considered a primary indication for surgery in patients with TSE because postoperative improvement in pituitary function is uncommon. As the cause of postoperative deterioration in pituitary function remains unclear, further studies are required to investigate whether the lack of postoperative improvement or deterioration in pituitary function is attributable to surgical complications or to underlying congenital abnormalities in pituitary development or hormone secretion.

Congenital and Pediatric Predominance

A notable finding of our review is that >70% of reported cases of TSE occurred in pediatric patients, with more than half diagnosed before the age of 6 years. This distribution suggests a congenital etiology and supports the hypothesis that TSE may result from developmental defects in the midline skull base formation. Pituitary development begins during the fourth to fifth weeks of embryogenesis, coinciding with the developmental timeline of the surrounding midline cranial base structures [48]. Although a small number of cases have been diagnosed in adulthood, they likely represent delayed recognition rather than true adult-onset disease. These findings highlight the importance of considering TSE in the differential diagnosis of congenital hypopituitarism or unexplained endocrine dysfunction in infants and young children.

Challenges of Multidisciplinary Endocrine Management

These findings suggest that the clinical specialty responsible for the treatment and follow-up of TSE may be a critical determinant of patient outcomes. In our review of 45 publications, only 4 were reported by endocrinologists. This distribution likely reflects the variability in the initial clinical presentation and diagnostic pathways, which determine which department assumes primary responsibility. For example, patients presenting with diabetes insipidus are often managed by endocrinologists [49]. When TSE is primarily treated by pituitary neurosurgeons, as in our two cases, pituitary dysfunction is typically anticipated, and appropriate referral to endocrinologists is generally undertaken. Omissions of endocrine assessment may pose a risk to a patient’s development and long-term quality of life. Clinicians other than endocrinologists should recognize that TSE can impair the pituitary function and may require endocrine assessment.

Our experience suggests that pituitary function may deteriorate over time, as observed in our first case. We hypothesized that this decline may be due to the mechanical traction of the pituitary gland from CSF pulsation or descent of the sac. A similar mechanism is observed in empty sella syndrome, in which increased CSF pulsation leads to pituitary gland distortion and dysfunction [50]. For such patients, close collaboration with endocrinologists, including thorough endocrine evaluation at diagnosis and regular follow-ups, may be essential.

Limitations

Our study has several limitations. First, as this was a two-case report and literature review, statistical analysis was limited. Second, this literature review is subject to publication bias, as severe cases with obvious symptoms may be more likely to be reported. Therefore, further cohort studies are required to clarify the prevalence and long-term course of endocrine dysfunction in patients with TSE. Third, we used a GHRP-2 test to evaluate GH secretion in two cases (cases 50 and 51). GHRP-2 testing is considered a convenient and safe diagnostic procedure in Japan [51], but it is not available in most countries. In future cohort studies, a standardized evaluation of GH secretion, such as an insulin tolerance test, will be recommended.

In conclusion, pituitary dysfunction occurs in nearly half of patients with TSE, but is frequently underdiagnosed due to inadequate endocrine assessment (Graphical Abstract). Comprehensive endocrine evaluations, including dynamic stimulation testing, should be performed in all patients at the time of diagnosis and at regular intervals thereafter. Early identification and hormone replacement therapy can markedly improve functional outcomes and quality of life. Given the potential for postoperative deterioration, especially in cases requiring surgical intervention, routine collaboration with endocrinologists and long-term hormonal follow-up are integral components of TSE management.

Graphical Abstract.

Abbreviations

CSF

cerebrospinal fluid

FSH

follicle-stimulating hormone

GH

growth hormone

GHRP-2

GH-releasing peptide-2

LH

luteinizing hormone

MRI

magnetic resonance imaging

TSE

trans-sellar encephalocele

Disclosure

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

Declarations of Interest

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

Author Contributions Statement

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by KA. The first draft of the manuscript was written by KA and reviewed and edited by YS. This study was supervised by KK, AI, and TK. All authors read and approved the final manuscript.