Diffuse Pancreatic Cystic Disease as the Initial Phenotypic Clue to Von Hippel-Lindau Syndrome

Abstract

Introduction:

Von Hippel-Lindau syndrome (VHL) is a rare autosomal dominant tumour predisposition syndrome with highly variable clinical expression. Pancreatic cystic lesions are common in VHL, but they are often incidental and only occasionally represent the initial clue to diagnosis.

Methods:

We report the case of a 29-year-old woman who presented with intermittent pelvic pain. Clinical examination disclosed epigastric fullness. Pelvic ultrasonography suggested a septated ovarian cyst. Magnetic resonance imaging revealed hydrocephalus, diffuse multifocal pancreatic cystic lesions, and a large pelvic cystic lesion corresponding to an ovarian cyst. The patient underwent laparoscopic ovarian cystectomy and cholecystectomy. Histopathological examination showed a benign serous papillary cystadenoma.

Results:

Because the association of diffuse pancreatic cystic disease and neurologic imaging abnormalities in a young adult was unusual, an inherited tumour syndrome was suspected. Molecular analysis identified a heterozygous pathogenic VHL variant, NM_000551.4(VHL):c.500G>A (p.Arg167Gln), confirming the diagnosis of VHL syndrome.

Conclusion:

This case highlights that diffuse pancreatic cystic disease may represent the initial phenotypic clue to VHL syndrome and underlines the diagnostic value of syndromic pattern recognition in young adults, with important implications for surveillance and genetic counselling.

Introduction

Von Hippel-Lindau syndrome (VHL) is a multisystem hereditary tumour predisposition syndrome caused by pathogenic variants in the VHL tumour suppressor gene on chromosome 3p25.3.^[1] It is characterised by age-dependent penetrance and marked variability in organ involvement, with manifestations including retinal hemangioblastomas, central nervous system hemangioblastomas, renal cell carcinoma, pheochromocytoma/paraganglioma, pancreatic cysts, pancreatic neuroendocrine tumours, and genital tract cystadenomas.^[2,3] The molecular basis of the disease involves defective degradation of hypoxia-inducible factor alpha, resulting from loss of normal pVHL function.^[4]

Pancreatic involvement is common in VHL and usually includes simple cysts or serous cystadenomas, often detected incidentally during abdominal imaging.^[2,3,5] However, diffuse pancreatic cystic disease as the dominant presenting clue remains uncommon in routine clinical practice.^[6,7] We report a young woman in whom multifocal pancreatic cystic lesions, together with hydrocephalus and a pelvic cystic lesion, led to the diagnosis of VHL syndrome.

Case Report

A 29-year-old woman was referred for evaluation of intermittent pelvic pain evolving over 6 months. Her history was notable for an ovarian cyst. No contributory family history of hereditary tumour syndromes was documented at presentation.

On physical examination, she was hemodynamically stable. Abdominal examination revealed epigastric fullness without tenderness or palpable organomegaly. No focal neurologic deficit was identified.

Pelvic ultrasonography suggested a septated ovarian cyst. Subsequent magnetic resonance imaging demonstrated hydrocephalus [Figure 1A], diffuse multifocal pancreatic cystic lesions involving a large part of the pancreatic parenchyma [Figure 1B], and a large pelvic cystic lesion corresponding to an ovarian cyst [Figure 1C]. Associated gallbladder lithiasis was also noted. Routine laboratory investigations were unremarkable.

Figure 1.

Radiologic findings in the present case. (A) Axial brain MRI demonstrating hydrocephalus with ventricular dilatation. (B) Abdominal MRI showing diffuse multifocal pancreatic cystic lesions consistent with VHL-associated pancreatic involvement. (C) Sagittal pelvic MRI showing a large ovarian cystic lesion

Because of the symptomatic adnexal lesion and associated gallbladder disease, the patient underwent laparoscopic ovarian cystectomy and cholecystectomy. Histopathological examination of the ovarian lesion demonstrated a benign serous papillary cystadenoma, with no evidence of malignancy.

The coexistence of extensive pancreatic cystic disease and neurologic imaging abnormalities in a young adult raised suspicion for an underlying hereditary tumour syndrome. Molecular analysis of the VHL gene identified a heterozygous pathogenic missense variant, NM_000551.4(VHL):c.500G>A (p.Arg167Gln), thereby confirming the diagnosis of VHL.

Following molecular confirmation of VHL syndrome, the patient underwent baseline syndrome-oriented evaluation. Funduscopic examination showed no retinal angioma, blood pressure assessment revealed no hypertension, and audiologic/otolaryngologic evaluation was unremarkable. The patient was referred for genetic counselling and multidisciplinary surveillance. Biochemical screening for pheochromocytoma/paraganglioma was not performed at the initial evaluation; however, this investigation is part of the recommended baseline assessment in patients with suspected or confirmed VHL syndrome.

Discussion

This case is clinically relevant because the diagnosis of VHL was not initially suggested by the classical retinal, renal, or adrenal manifestations, but rather by diffuse pancreatic cystic disease associated with hydrocephalus in a young woman. Although pancreatic lesions are well recognised in VHL, they are often considered incidental when they are asymptomatic and unaccompanied by overt endocrine symptoms or renal masses.^[2,3,5] In young adults, however, multifocal or diffuse pancreatic cystic involvement should raise suspicion for a syndromic disorder, particularly when additional abnormalities are present on neuroimaging or abdominal imaging.

The VHL gene encodes pVHL, a substrate-recognition component of the VCB-CUL2 E3 ubiquitin ligase complex involved in the regulation of hypoxia-inducible factor alpha.^[4] Loss of normal VHL function leads to persistent activation of hypoxia-responsive pathways and promotes angiogenesis and tumorigenesis across multiple organ systems.^[4] In the present patient, the variant NM_000551.4(VHL):c.500G>A (p.Arg167Gln) confirmed the diagnosis, but the main educational value of the case lies in the clinical and radiologic pattern rather than in the molecular detail alone. Variants affecting codon 167 are recognised in VHL disease and may be associated with clinically relevant genotype-phenotype correlations.^[8,9]

Pancreatic manifestations of VHL include simple cysts, serous cystadenomas, and pancreatic neuroendocrine tumours.^[5–7,10] Simple cystic lesions are usually benign and asymptomatic, whereas pancreatic neuroendocrine tumours carry the main malignant potential.^[10] From a practical standpoint, diffuse pancreatic cystic disease in a young patient is unusual in sporadic settings and should prompt targeted evaluation for inherited tumour predisposition syndromes. In our patient, the pancreatic phenotype was the major abdominal clue, while hydrocephalus on brain imaging further supported the suspicion of a multisystem disorder.

The differential diagnosis of diffuse pancreatic cystic disease includes sporadic simple cysts, serous cystadenomatosis, intraductal papillary mucinous neoplasms, cystic degeneration of pancreatic neuroendocrine tumours, and cystic lesions associated with other inherited disorders. Several features favoured a syndromic diagnosis in this patient, including young age at presentation, multifocal pancreatic involvement, neurologic imaging abnormalities, and the coexistence of another pelvic cystic lesion. Although the ovarian lesion itself was not diagnostic of VHL, the overall constellation of findings justified molecular investigation.

Recognition of VHL has important implications for long-term management. Once diagnosed, affected individuals require structured surveillance including ophthalmologic evaluation, periodic central nervous system imaging, abdominal imaging focused on renal and pancreatic lesions, blood pressure assessment, and biochemical screening for pheochromocytoma or paraganglioma.^[5,8,9] Audiologic assessment may also be considered according to the clinical context. In our patient, baseline funduscopic examination, blood pressure assessment, and audiologic/otolaryngologic evaluation were normal. Although biochemical screening for catecholamine excess was not performed at the initial evaluation, it remains an important component of the recommended syndrome-oriented workup. Early diagnosis is clinically decisive because it allows the timely detection of potentially serious manifestations and enables genetic counselling, as well as counselling and testing of at-risk relatives.

The main clinical message of this report is that diffuse pancreatic cystic disease in a young adult should not be dismissed as an incidental abdominal finding, particularly when associated with abnormalities outside the pancreas. In such settings, syndromic pattern recognition remains essential and may lead to early diagnosis of VHL syndrome before more typical complications become clinically apparent.

Conclusion

Diffuse pancreatic cystic disease may represent the initial phenotypic clue to VHL. In the present case, the association of multifocal pancreatic cysts, hydrocephalus, and a pelvic cystic lesion prompted further investigation and molecular confirmation of VHL syndrome. Recognition of this presentation is important because early diagnosis changes surveillance strategy, supports genetic counselling and family screening, and may allow timely detection of other potentially serious VHL-related manifestations.