Abstract
Arginine vasopressin deficiency (AVP-D) is an uncommon disorder caused by deficient vasopressin production due to hypothalamic or pituitary gland dysfunction resulting in hypotonic polyuria, whose etiology oftentimes remains elusive. We present the case of a 20-year-old male patient evaluated for polyuria and polydipsia. Laboratory evaluation demonstrated hypernatremia, elevated serum osmolality, and inappropriately dilute urine with symptomatic improvement following initiation of desmopressin, consistent with AVP-D. Initial pituitary magnetic resonance imaging (MRI) showed a small enhancing lesion with pituitary stalk thickening (PST), raising concern for inflammatory or infiltrative etiologies. Extensive autoimmune and pituitary infiltrative disease work-up was unrevealing, and serial imaging remained inconclusive. Given diagnostic uncertainty, a transsphenoidal pituitary biopsy was performed, which proved consistent with a germinoma with evidence of human chorionic gonadotropin secretion. Subsequent staging studies, including spinal MRI and cerebrospinal fluid analysis, raised concern for possible disseminated disease. The patient was treated with craniospinal irradiation and continues close multidisciplinary follow-up for hypopituitarism and AVP-D. This case highlights the need for continued surveillance in patients presenting with AVP-D and nonspecific imaging findings, as early identification of etiology is critical for timely treatment and optimal outcomes.
Keywords: arginine vasopressin deficiency, germinoma, hypopituitarism
Introduction
Arginine vasopressin (AVP) disorders are characterized by the excretion of large volumes of hypotonic urine, with an estimated prevalence of approximately 1 in 25 000 individuals [1]. Arginine vasopressin deficiency (AVP-D), caused by deficient vasopressin production either from hypothalamic or pituitary gland dysfunction, is the most common subtype. Most cases are acquired and may result from autoimmune infundibuloneurohypophysitis, primary or secondary tumors, infiltrative disorders such as sarcoidosis, or iatrogenic injury, including neurosurgery [2]. Despite thorough evaluation, the etiology remains unknown in a substantial proportion of patients.
Intracranial germ cell tumors (IGCTs), broadly classified as germinomas or non-germinomatous germ cell tumors (NGGCTs), are among the most frequent neoplastic causes of AVP-D in adolescents and young adults, with germinomas being the predominant subtype [3]. Diagnosis can be challenging, as initial imaging may reveal only pituitary stalk thickening (PST) or small lesions, and definitive confirmation often requires histopathologic analysis.
We report a 20-year-old male patient presenting with AVP-D, whose initial magnetic resonance imaging (MRI) findings were subtle, with subsequent work-up excluding autoimmune and infiltrative etiologies. Transsphenoidal pituitary biopsy and cerebrospinal fluid (CSF) studies confirmed a human chorionic gonadotropin (HCG)-secreting germinoma, and staging studies raised concern for possible CSF dissemination, prompting treatment with craniospinal irradiation. This case highlights several important points: AVP-D can be the initial manifestation of a germinoma presenting with subtle imaging findings, and early recognition of potential dissemination is critical for appropriate management. It underscores the diagnostic complexity and necessity of a multidisciplinary approach to optimize outcomes in young adults with AVP-D.
Case presentation
We present a case of a 20-year-old male patient with no prior medical history, who presented to our clinic with a 2-month history of polydipsia and polyuria. The patient had been referred to endocrinology for evaluation of possible AVP disorder by a gastroenterologist who was following the patient for incidental mild transaminitis.
On initial evaluation, the patient reported drinking around 11.3 L and voiding 12.5 L in less than 24 hours. He also reported associated fatigue, xerostomia, decreased libido and morning erections, and hot flashes, but denied any other symptoms, including headaches, lightheadedness, visual disturbances, nausea, anorexia, weight changes, fevers, or night sweats. The patient reported frequent exercise and consuming whey protein, but otherwise denied use of other medications or supplements, alcohol consumption, tobacco use, or recreational drug use. He denied a prior history of head injury, diabetes, kidney disease, autoimmune disorders, psychiatric illness, or neurosurgery. Family history was noncontributory.
Diagnostic assessment
Initial laboratory work-up prior to endocrinology evaluation included a complete metabolic panel, a urinalysis (UA), urine electrolytes, and a glycated hemoglobin A1c (HbA1c), with notable results summarized in Table 1 (second column). The presence of hypotonic urine, mild hypernatremia, preserved renal function, normal glycemic control, in addition to a negative UA, supported a diagnosis of AVP disorder, prompting further endocrine evaluation.
Table 1.
Results of chemistry and urine laboratories prior to initial endocrinology evaluation
| Parameters | Values at initial laboratory work-up | Values following water deprivation test | Reference range |
|---|---|---|---|
| HbA1c | 36 mmol/mol (5.4%) | — | 20-42 mmol/mol (4.8-5.6%) |
| Sodium | 146 mmol/L (146 mEq/L) | 154 mmol/L (154 mEq/L) | 135-145 mmol/L (135-145 mEq/L) |
| eGFR | 97 mL/min/1.73 | 94 mL/min/1.73 | >59 mL/min/1.73 |
| Urine specific gravity | ≤1.005 (≤1.005) | — | 1.005-1.030 |
| Urine sodium | <20 mmol/L (<20 mEq/L) | — | Not established |
| Urine osmolality | — | 153 mmol/kg (153 mOsm/kg) | 50-1200 mmol/kg (50-1200 mOsm kg) |
| Serum osmolality | — | 321 mmol/kg (321 mOsm/kg) | 278-305 mmol/kg (278-305 mOsm/kg) |
Abbreviations: eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin A1c.
The patient was subsequently evaluated by endocrinology, with initial physical examination notable for dry mucous membranes. Given the patient's preference to avoid hospitalization, an overnight outpatient water deprivation test was performed, followed by morning laboratory testing. Results (see Table 1, third column) demonstrated worsening hypernatremia, elevated serum osmolality, and inappropriately low-normal urine osmolality, further supporting the working diagnosis. A pituitary panel (Table 2, second column) revealed hypogonadotropic hypogonadism; all other pituitary hormones were found within normal limits.
Table 2.
Results of pituitary hormone panels at time of initial endocrinology evaluation, 2 months before biopsy, 1 week before biopsy, and 7 months after biopsy
| Parameters | Values at initial evaluation | Values 2 mo before biopsy | Values 1 wk before biopsy | Values 7 mo after biopsy | Reference range |
|---|---|---|---|---|---|
| TT | 1.94 nmol/L (56 ng/dL) | 0.36 nmol/L (10 ng/dL) | <0.10 nmol/L (<3 ng/dL) | 36.92 nmol/L (1064 ng/dL) | 9.16-31.79 nmol/L (264-916 ng/dL) |
| FT | 26.7 pmol/L (7.7 pg/mL) | 4.2 pmol/L (1.2 pg/mL) | 1.04 pmol/L (0.3 pg/mL) | 38.5 pmol/L (11.1 pg/mL) | 32.2-91.5 pmol/L (9.3-26.5 pg/mL) |
| LH | 0.9 IU/L (0.9 mIU/mL) | 0.4 IU/L (0.4 mIU/mL) | 0.3 IU/L (0.3 mIU/mL) | — | 1.5-9.3 IU/L (1.5-9.3 mIU/mL) |
| FSH | <0.7 IU/L (<0.7 mIU/mL) | <0.7 IU/L (<0.3 mIU/mL) | <0.3 IU/L (<0.3 mIU/mL) | — | 1.6-8.0 IU/L (1.6-8.0 mIU/mL |
| Am cortisol | 728 nmol/L (26.4 µg/dL) | 369.8 nmol/L (13.4 µg/dL) | 193.1 nmol/L (7.0 µg/dL) | — | 110-607 nmol/L (4.0-22.0 µg/dL) |
| ACTH | 9.7 pmol/L (44 pg/mL) | 6.3 pmol/L (28.5 pg/mL) | 3.4 pmol/L (15.6 pg/mL) | — | 1.3-11.0 pmol/L (6-50 pg/mL) |
| TSH | 2.54 mIU/L (2.54 µIU/mL) | 1.71 mIU/L (1.71 µIU/mL) | 0.99 mIU/L (0.99 µIU/mL) | 0.022 mIU/L (0.022 µIU/mL | 0.40-4.50 mIU/L (0.40-4.50 µIU/mL) |
| FT4 | 15.4 pmol/L (1.2 ng/dL) | 9.7 pmol/L (0.75 ng/dL) | 16.5 pmol/L (1.28 ng/dL) | 14.2 pmol/L (1.1 ng/dL) | 10.2-23.2 pmol/L (0.8-1.8 ng/dL) |
| TT3 | 1.85 mmol/L (120 ng/dL) | — | — | — | 1.2-2.78 mmol/L (76-181 ng/dL) |
| IGF-1 | 24.1 nmol/L (184 ng/mL) | 21.6 nmol/L (165 ng/mL) | — | 6.3 nmol/L (48 ng/mL) | 14.3-46.1 nmol/L (109-353 ng/mL) |
| Prolactin | 9.4 µg/L (9.4 ng/mL) | 41.9 µg/L (41.9 ng/mL) | — | 15.4 µg/L (15.4 ng/mL) | 2.0-18.0 µg/L (3.6-31.5 ng/mL) |
For context, the values in the second column, values at initial evaluation, were obtained 7 months prior to biopsy.
Abbreviations: ACTH, adrenocorticotropin; Am cortisol, serum cortisol obtained during specific sampling times (0700-0900 hours); FSH, follicle-stimulating hormone; FT, free testosterone; FT4, free thyroxine; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; TSH, thyrotropin; TT, total testosterone; TT3, total triiodothyronine.
Given these findings, MRI of the brain with and without contrast was performed, revealing a 2.5-mm hypoenhancing lesion at the base of the pituitary infundibulum (Fig. 1). Neurosurgical review noted PST, raising concern for sarcoidosis, lymphocytic hypophysitis, or other autoimmune etiologies. However, subsequent rheumatologic evaluation for such etiologies was unremarkable.
Figure 1.
A, Sagittal with B, close-up coronal images from the initial MRI brain noting 2.5-mm pituitary stalk hypoenhancement. MRI, magnetic resonance imaging.
Given the lack of conclusive findings and the patient's stability on 1-deamino-8-D-arginine vasopressin, or desmopressin acetate (DDAVP), the patient was closely monitored with serial MRIs. MRI of the brain 3 months after initial imaging demonstrated slight interval growth of the pituitary stalk hypoenhancement area, from 2.5 mm to 3.3 mm (Fig. 2). CSF analysis was obtained to help differentiate between pure germinoma and NGGCT etiologies, and to identify the presence of disease dissemination. CSF analysis revealed unremarkable alkaline phosphatase, α-fetoprotein (AFP), HCG, protein, glucose, germ cell marker levels, cytology, and flow cytometry. Given the inability to exclude malignancy, a transsphenoidal biopsy of the pituitary stalk lesion was performed. Histopathology revealed large pleomorphic tumor cells with vesicular chromatin and abundant eosinophilic cytoplasm, intermixed with dense mature lymphocytic infiltrate. Immunohistochemistry showed tumor cells positive for placental alkaline phosphatase, stem cell factor receptor c-KIT (c-KIT, also known as CD117), and octamer-binding transcription factor 3/4 (OCT 3/4), negative for AFP, and focally positive for CD30—findings diagnostic of germinoma. Repeat CSF studies suggested an HCG-secreting germinoma, with CSF HCG levels of 9.96 mIU/mL (SI: 9.96 IU/L) (reference range, 0-3 mIU/mL [SI: 0-3 IU/L]). Serum HCG levels were less than 1 mIU/mL (SI: 9.96 IU/L) (reference range, 0-3 mIU/mL [SI: 0-3 IU/L]).
Figure 2.
A, Coronal images with B, close-up of follow up pituitary MRI 3 months later with an interval increase of pituitary stalk hypoenhancement to 3.3 mm. MRI, magnetic resonance imaging.
Staging imaging was performed, showing questionable enhancement of the cauda equina, and nodular enhancement within the sacral canal on MRI (Fig. 3). Given concern for CSF dissemination vs postbiopsy inflammation, neuro-oncology recommended repeating MRI and lumbar puncture (LP); the former showed slight improvement in nodular enhancement and the latter demonstrated resolving pleocytosis. Although these findings favored a resolving inflammatory process, disseminated disease could not be definitively excluded. Treatment was initiated to avoid further delays.
Figure 3.
Sagittal image from MRI of the lumbar spine showing nodular enhancement within cauda equina and sacral canal. MRI, magnetic resonance imaging.
Treatment
Soon after the water deprivation test, the patient was started on DDAVP 0.1 mg twice daily, with improvement in polydipsia and polyuria; dosing was subsequently titrated to clinical response. He was also started on testosterone cypionate injections given hypogonadotropic hypogonadism. Two months before biopsy was obtained, the patient developed evidence of central hypothyroidism (see Table 2, third column) and began levothyroxine at 75 mcg once daily, further titrated according to biochemical response. Additionally, given the patient's nausea, fatigue, low-normal morning cortisol level (see Table 2, fourth column), and the upcoming pituitary stalk lesion biopsy, empirical hydrocortisone was started and subsequently adjusted according to clinical response.
Given the uncertainty about metastatic disease, the patient was treated with craniospinal irradiation (CSI). While whole-ventricle radiotherapy may have been sufficient for localized disease, CSI was chosen given the concern for potential metastatic disease. The patient was treated with once-daily proton beam therapy for 5 weeks, receiving an estimated total radiation dose of 47 Gy (relative biological effectiveness).
Eventually, 7 months after biopsy (5 months after CSI initiation), the patient also developed growth hormone (GH) deficiency (see Table 2, fifth column), raising concern for panhypopituitarism. However, after a risk vs benefit discussion, the patient declined GH supplementation.
Outcome and follow-up
The transsphenoidal biopsy was complicated by bitemporal hemianopsia; subsequent endoscopic exploration revealed optic chiasm compression and a small hematoma, requiring decompression, evacuation, and washout, with near-complete resolution of hemianopsia. Shortly after CSI initiation, the patient's visual acuity worsened; he began a 100-mg daily prednisone taper for suspected inflammation and surgical scarring displacing the optic chiasm. The taper was completed with a near-complete resolution of his visual deficits.
Currently, he is being monitored with surveillance MRIs of the pituitary and spine every 6 months. Thus far, imaging has shown stable postoperative changes since biopsy (Fig. 4), without new or increased enhancement that would pose concern for neoplastic recurrence, and near-complete resolution of the previously noted sacral nodular enhancement (Fig. 5). He continues to follow up with endocrinology for hypopituitarism and AVP-D and remains stable on the medications. Fig. 6 provides a flowchart summarizing the patient's clinical course and outcomes.
Figure 4.
Sagittal image of MRI brain post treatment with CSI, noting stable postbiopsy changes of the pituitary, without any enhancement concerning for neoplastic recurrence. CSI, craniospinal irradiation; MRI, magnetic resonance imaging.
Figure 5.
Sagittal image of MRI lumbar spine post treatment with CSI, showing near complete resolution of sacral nodular enhancement. CSI, craniospinal irradiation; MRI, magnetic resonance imaging.
Figure 6.
Flowchart diagram summarizing the patient's clinical course and outcomes. AVP-D, arginine vasopressin deficiency; CSF, cerebrospinal fluid; CSI, craniospinal irradiation; GH, growth hormone HCG, human chorionic gonadotropin; IHC, immunohistochemistry; LP, lumbar puncture; MRI, magnetic resonance imaging.
Discussion
Evaluation of AVP-D begins by confirming the presence of hypotonic polyuria and excluding primary polydipsia or solute diuresis by obtaining serum and urine electrolytes. While the water deprivation test remains the gold standard for diagnostic confirmation, plasma copeptin—a stable vasopressin surrogate—is increasingly used where available [4].
Once AVP-D is confirmed, etiologic evaluation should include a comprehensive history and physical examination, assessment of other pituitary axes, and obtaining hypothalamic-pituitary MRI to identify structural causes. While approximately 30% to 50% of adult cases have historically been labeled as idiopathic, improved MRI resolution and antibody testing now frequently reveal autoimmune or infiltrative etiologies [4, 5].
As this case illustrates, AVP-D can be the first sign of a pituitary germinoma. Several reports describe germinomas initially presenting with nonspecific MRI findings, resulting in diagnostic delay. In one adult case, AVP-D with PST was initially misattributed to infundibuloneurohypophysitis, with germinoma ultimately diagnosed after biopsy [6]. Occult neurohypophyseal germinomas can present with absent initial MRI findings, requiring repeat imaging and close follow-up in idiopathic AVP-D [7]. In pediatric and adult cohorts, isolated PST or elevated CSF HCG levels have been shown to precede detectable lesions [8]. A retrospective study on a series of adults with AVP-D and PST noted a higher malignancy risk in patients in which both were present, with germinomas being a relatively common neoplastic etiology [9]. Consequently, “idiopathic” AVP-D requires vigilant longitudinal follow-up with serial imaging.
Current guidelines for evaluation of AVP-D with initial inconclusive imaging are limited. One 20-year retrospective review suggests a stepwise approach: excluding autoimmune and infiltrative causes while concurrently obtaining CSF studies to screen for IGCT presence; whenever the cause remains elusive, the authors recommend obtaining serial MRIs every 3 to 6 months [10]. A UK-based multidisciplinary group developed guidelines aiming to improve outcomes in patients younger than 19, suggesting that a PST greater than 3 mm at the insertion or 4 mm at the optic chiasm is potentially pathological, especially with concomitant endocrinopathies and/or visual deficits [11]. If first-line tests are inconclusive, the authors propose that PST greater than 6.5 mm, presence of AVP-D, pituitary dysfunction, visual deficits, or any combination of these should prompt CSF analysis, and whole-body FDG-PET (2-[fluorine-18]fluoro-2-deoxy-d-glucose–positron emission tomography) to rule out Langerhans cell histiocytosis [11].
This unique case of a pituitary stalk germinoma documents a rare temporal evolution from marker-negative to marker-positive status. Initially, the patient presented with atypical hypoenhancing imaging and negative CSF HCG, showing elevated levels only after serial enlargement and subsequent biopsy. This progression may challenge the assumption that HCG-secreting tumors are detectable from the onset, suggesting HCG may rise only after interval evolution from an “occult phase.” An alternate interpretation for this observed sequence, however, is biopsy-related release from potential tumor architecture manipulation or blood-brain barrier disruption. Nevertheless, this case may argue for serial CSF marker surveillance—not just imaging—in idiopathic AVP-D cases, as a single negative LP does not permanently exclude a germinoma that may later become marker positive. Lastly, this case emphasizes the need for rigorous, longitudinal evaluation to identify underlying etiologies in AVP-D patients who initially present with nonspecific or normal hypothalamic-pituitary imaging.
Learning points
Neurohypophyseal germinomas can present with hypoenhancement rather than the classically described avid contrast enhancement, particularly in the early or transitional phase of disease.
Serial MRI surveillance for interval growth remains essential in patients with unexplained PST and AVP-D.
A multidisciplinary approach is critical for etiology evaluation, management of potential concomitant hypopituitarism, and optimizing patient outcomes.
Abbreviations
- AFP
α-fetoprotein
- AVP-D
arginine vasopressin deficiency
- CSF
cerebrospinal fluid
- CSI
craniospinal irradiation
- DDAVP
desmopressin acetate
- GH
growth hormone
- HbA1c
glycated hemoglobin, or hemoglobin A1c
- HCG
human chorionic gonadotropin
- IGCTs
intracranial germ cell tumors
- IHC
immunohistochemistry
- LP
lumbar puncture
- MRI
magnetic resonance imaging
- NGGCTs
nongerminomatous germ cell tumors
- PST
pituitary stalk thickening
- UA
urinalysis
Contributor Information
Rolando Vargas Santiago, Department of Internal Medicine, Mount Sinai South Nassau, Oceanside, NY 11572, USA.
Simran Kaur, Department of Internal Medicine, Mount Sinai South Nassau, Oceanside, NY 11572, USA.
Effie Tsomos, Department of Endocrinology, Mount Sinai South Nassau, Oceanside, NY 11572, USA.
Contributors
All authors made joint contributions to authorship. R.V.S., S.K., and E.T. made substantial contributions to the conception of the work and acquisition, analysis, and interpretation of data for the work; drafted the work and reviewed it critically for important intellectual content; worked on final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. E.T. was involved in the diagnosis and management of the patient.
Funding
No public or commercial funding.
Disclosures
None declared.
Informed patient consent for publication
Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.
Data availability
Original data generated and analyzed for this case report are included in this published article.
Current affiliation
R.V.S. current affiliation: HealthproMed Foundation Inc, Ave Borinquen 2020, San Juan, PR, 00915, USA.
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Data Availability Statement
Original data generated and analyzed for this case report are included in this published article.