A 29-year-old woman underwent progressive worsening headaches and difficulty swallowing, then she was admitted to a local hospital. Her laryngoscopy was normal and the gastroscope showed chronic superficial gastritis. Despite receiving symptomatic treatment and being diagnosed with “vascular headache” based on two normal brain CT scans, the patient’s condition did not improve. Two weeks later, the patient was admitted to our hospital’s neurology department, and her clinical course is detailed in. A neurological examination revealed a positive kernig sign, stiff neck, absent pharyngeal reflex, poor soft palate elevation, and water swallow test level III. The patient has a 6-year-old son and was pregnant again 1 year ago but induced abortion due to fetal death at 16 weeks of gestation. The cerebrospinal fluid (CSF) was colorless and transparent, with a pressure of 400+ mmH2O. CSF analysis revealed the following: karyocytes, 2/μL; red cells, 0/μL; protein, 0.329 g/L (normal range, 0.150-0.450 g/L); glucose, 4.8 mmol/L (normal range, 2.5-4.5 mmol/L); and chloride, 114 mmol/L (normal range, 120-132 mmol/L). No abnormalities were detected in the blood samples aside from high cholesterol levels. A cranial magnetic resonance imaging (MRI) showed space-occupying lesions in the medulla oblongata (), ultrasound scans revealed multicentric renal cysts in both kidneys, and a cystic solid mixed density mass in the pancreas was later identified as PanNENs through enhanced CT (), chest radiograph shows thickened pleura, and Sanger sequencing identified a heterozygous mutation site in the VHL gene, leading to a diagnosis of VHL syndrome. The patient underwent Ommaya implantation for the first time in Huashan Hospital Affiliated with Fudan University in 2006, then underwent craniotomy for tumor resection 2 weeks later. 2 masses were resected in the dorsal medulla oblongata and C1 segment of the cervical cord, measured 3×3×1cm, 2×2×1cm, respectively. The histopathological results of the tumor: purplish-brown tissue as seen by the naked eye. Microscopically, foam cells were seen dispersed between CD34, SMA immunolabelled positive vascular tufts, scattered KP1 and LCA positive cells with GFAP positive gliosis at the margins, the pathological diagnosis was hemangioblastoma. She was diagnosed with renal occupancy in 2008 and underwent resection of the target lesion, which was confirmed as RCC by postoperative pathology (). In 2015, she developed neck pain, weakness of the right limb, and urinary and fecal disorders, then multiple occupying lesions were detected by spinal cord MRI (), and a total of 3 masses in C1, C2-3, and C6-7 were surgically resected, measured 2×1×2mm, 3×2×4mm, 2×1.5×1.0mm, respectively. Pathological findings were considered a HBs, homologous with medulla oblongata occupancy. In 2021, the patient suffered dizziness, headache, and unsteady gait again, and imaging revealed space-occupying lesions in the right cerebellar hemisphere, junction of the medulla oblongata and cervical medulla (), 3 masses were surgically resected, measured 2.5×2×2cm, 1.5×1×1.5cm, 5×6×2mm, which were confirmed to be HBs by postoperative pathology. Up to now, the patient survived without significant discomfort and possessed a complete social function. The patient’s maternal grandparents are related as cousins (I 1 and I 2). Her maternal grandfather died at the age of 40 due to severe headaches. In 1987, her mother(II 2) experienced numbness in her left hand and unstable walking, but she did not seek medical attention. Later, she suffered from blindness in her left eye. In 2020, the patient’s mother was diagnosed with a “hemangioma” in the thoracic medulla by post-surgical pathology (), which occupied the T8-T10 region, resulting in bilateral lower limb paraplegia and urinary and fecal disorders. The patient’s maternal aunt (II 3) was diagnosed with both “renal cyst” and “pancreatic cyst” and underwent a nephrectomy on the left side in her forties. After obtaining consent from the patient and other family members, peripheral blood samples were collected from a total of eight individuals, including the patient, her mother, her son, her brothers and sister, and her three nephews, for VHL gene testing, the family lineage chart is available in. Additionally, 187 individuals from the healthy population were selected as normal controls for VHL gene testing. The polymerase chain reaction was employed to amplify the VHL gene exons from genomic DNA, with primer pairs listed in. To confirm the presence of any mutations in the VHL gene, Sanger DNA sequencing was utilized, with each exon analyzed using forward and reverse analysis. Our findings revealed a missense mutation c.353T > C on exon 2 of the short arm in chromosome 3 of the patient. This specific mutation leads to the replacement of leucine with proline at amino acid 118 of the encoded protein, which may primarily account for the VHL syndrome that occurred in the proband (). Our results indicated that this mutation was also present in the patient’s mother and son. However, this mutation was not detected in other family members and the 187 healthy controls. 17 years follow-up was conducted in the family. Despite the multi-organ involvement and several relapses during the disease, early and aggressive surgery led to the patient’s survival well, with no impairment of social behavior. The patient’s mother remained disabled as previously and no new lesions in her brain and spinal cord were detected on her recent physical examination. Her son, who is now 23 years old, remains apparently healthy, he had not undergone whole-body multiorgan imaging until now. The patient’s maternal aunt, a patient with suspected VHL syndrome, was diagnosed with “renal cyst” and “pancreatic cyst”, then underwent a nephrectomy on the left side in her forties. Unfortunately, she did not consent to the invitation to undergo genetic testing and refused to provide detailed physical examination data during our long-term clinical follow-up. Up to now we learned that she did not undergo another surgical procedure and later and died of acute renal failure in 2015 at age 58. The other members of the family remained healthy without similar abnormalities.