
Von Hippel-Lindau (VHL) disease is a rare autosomal dominantly inherited familial cancer-predisposition syndrome with an incidence of 1 in 36,000 live births. VHL disease is caused by a germline mutation of
Although 80% of VHL disease are autosomal dominantly inherited from an affected parent, 20% of VHL disease cases are a
Herein, we are reporting a genetically confirmed case of VHL disease with brainstem HB in an 11-year-old girl without a family history who could be suspected and diagnosed of VHL disease in asymptomatic state due to incidentally found multiple pancreatic cysts.
An 11-year-old girl was admitted with prolonged fever lasting for more than 10 days, sore throat, and cervical lymphadenopathy. She did not have a past medical history of admission or family history of cysts or malignancy.
On admission, she had a fever (temperature up to 38.5°C), and physical examination showed throat injection with palatine tonsillar hypertrophy, multiple cervical lymph-node enlargement on both neck levels II and III with a size smaller than 1.5 cm. Other physical examination findings including a neurologic examination were normal.
Initial CBC showed WBC 3,750/μL, Hb 13.7 g/dL, platelet 293,000/μL, absolute neutrophil count 2,088/μL, revealing mild leukopenia. Blood chemistry showed elevation in liver enzymes, including aspartate aminotransferase (AST, 111 IU/L), alanine aminotransferase (ALT, 208 IU/L), and lactate dehydrogenase (LDH, 412 IU/L), but amylase (75 U/L) and lipase (16 U/L) were normal. For the work-up of fever and hepatitis, C-reactive protein and cultures in blood, urine, cerebrospinal fluid, and throat were all negative. Virus studies and immunologic studies yielded negative results.
Neck ultrasonography (USG) was done for cervical lymph-node enlargement, and she was diagnosed as having benign reactive cervical lymphadenitis. Hepatobiliary USG was done, and multiple pancreatic cysts and mild fatty liver were observed (Fig. 1). For further evaluation of the pancreatic cysts, we did magnetic resonance cholangiopancreatography (MRCP), which showed multiple cystic lesions involving the whole pancreas, with cyst sizes up to 1.6 cm, but no neuroendocrine tumors of the pancreas, other tumors, or renal cysts were observed (Fig. 2). The MRCP finding implied an association of a genetic disorder, such as VHL disease. Therefore,
The fever subsided after 16 days, and a follow-up laboratory examination showed improvement in leukopenia, AST, ALT, and LDH level before discharge on the 9th day of hospitalization, which was finally normalized 4 months later at our outpatient clinic.
After genetic confirmation as VHL disease, we did surveillance for VHL disease-associated tumors. In brain magnetic resonance imaging (MRI), a 9.2×4.5×8.1 mm sized well-defined enhancing lesion was detected in the posterior aspect of the medulla of the brainstem, suspected of HB (Fig. 4). After consultation with neurosurgery, we planned to follow up with a brain MRI every year and considered surgical excision if symptoms developed or size of the HB increases.
The
VHL disease is classified as type 1 and type 2 with different genotype-phenotype manifestation. Type 1 VHL results from a loss-of-function mutation, such as truncation mutation of the
The mean age of initial tumor diagnosis in VHL disease is 26 years (range 1-70 years) [7], but different tumors develop typically at different mean ages. Cerebellar HBs are diagnosed in the 3rd decade (at a mean age of 29 years), and brainstem and spinal HBs develop rarely in the younger population (less than 40 years of age), but in multiple location. RCCs are diagnosed in the 4th decade, but can be as early as at 16 years of age, presenting with hematuria, flank pain, or a palpable mass. Pheochromocytomas are diagnosed at a mean age of 28 years, presenting with secondary hypertension or stroke. Pancreatic lesions in VHL disease are diverse, including simple cysts within pancreatic parenchyma, serous cystadenomas, and PNETs. Simple pancreatic cysts are benign and typically asymptomatic, but surgical treatment is indicated when they are symptomatic because of compression or obstruction.
Surveillance guidelines have been developed by the VHL disease Family Alliance and are recommended for VHL disease patients diagnosed by
Our patient could be suspected and genetically diagnosed as VHL disease because of incidentally found multiple pancreatic cysts by abdominal USG and MRCP. By using the surveillance protocol for VHL disease-associated tumors, we could diagnose brainstem HB before progression. We plan to conduct a
In one previous study of 55 VHL disease in Korea, there were 7 pediatric cases genetically diagnosed at age of 10 to 18 years [13]. Amongst 7 pediatric patients, 4 patients manifested as CNS HB and either pancreatic cysts or tumor, or renal or hepatic cyst, and 3 patients manifested as either retinal or CNS HB [13]. In another study of 26 VHL disease in Korea, there were 3 pediatric cases genetically diagnosed at age of 12, 11 and 14 years [14]. Amongst 3 pediatric patients, 12 year old male patient with family history manifested with CNS HB, RCC, pancreatic lesion and renal cyst, 11 year old male patient manifested with symptomatic CNS HB, pancreatic and renal cysts, and 14 year old male patient manifested with symptomatic pancreatic cysts and retinal HB [14]. In our 11-year-old VHL disease case without family history, multiple pancreatic cysts found incidentally in asymptomatic state became a clue to VHL disease. When there is symptomatic or asymptomatic multiple pancreatic cysts with or without renal or hepatic cysts, VHL disease must be suspected and surveillance protocol for VHL disease-associated tumors is recommended.
The authors have no conflict of interest to declare.