Von Hippel-Lindau Type Research Articles

8338 A Case Series of 3 Patients with Unusual Miliary Lung Metastases in Paraganglioma: Diagnostic Workup, Treatment Challenges and Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G>T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C>G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively.Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

8338 A Case Series Of 3 Patients With Unusual Miliary Lung Metastases In Paraganglioma: Diagnostic Workup, Treatment Challenges And Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G>T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C>G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively. Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

Genotype-phenotype associations in Von-Hippel Lindau Syndrome: implications for screening

Abstract Background Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease with an estimated incidence of 1:36,000. The type of germline VHLI alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genomic subtype. We aim to assess genotype-phenotype association among an institutional cohort of VHL patients. Methods We conducted a retrospective cohort study of 69 patients (27 families) at the University of Utah and Huntsman Cancer Institute from 1998- December 2023. 41 patients had documented germline testing in our system to define VHL type. VHL Type 1 was defined as those with nonsense mutations, deletions, and duplications and Type 2 as those with missense and splice mutations. Mean follow-up was 86- and 59-months for VHL type 1 and 2 respectively. We then evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). Results We identified 24 unique VHL alterations among 41 patients. 83% (29/41) patients had missense mutations, 7.5% (3/41) had nonsense mutations, 17% (6/41) had splice mutations, and 3% (3/41) had a deletion. The median age at VHL diagnosis was 43 years old for type 1 (range 19-76) and 38 for VHL type 2 (range 4-67). VHL Type 2 was more common, 85% (35/41). All VHL Type 1 patients (6/6) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the 35 patients diagnosed with VHL Type 2, 20% (7/35) were diagnosed with PheoPara, 9% (3/35) with RCC, 31% (n = 11) with HB, and 37% (n = 13) were asymptomatic. No VHL Type 1 patients were asymptomatic. Conclusions VHL type 2 comprised the majority of VHL diagnoses in our cohort. Individuals diagnosed with VHL type 2 have the highest penetrance for: hemangioblastoma (hb), Pheo-Para, and renal cell carcinoma (RCC). In our study, 37% of VHL type 2 participants did not demonstrate any VHL manifestation. VHL type 1 had a high prevalence for RCC and HB, with a notable absence of PheoPara manifestation. However, majority of these patients (75%) were below the age of 20, and thus likely did not develop a manifestation yet. This cohort add to evidence supporting utilizing genetic VHL Types to personalize surveillance guidelines. Validation in larger cohorts with longer follow-up suggest that VHL type 1 patients could forgo pheo/para screening.

Abstract 2559: Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening

Abstract Introduction and Objectives: Von Hippel-Lindau (VHL) is an autosomal dominant genetic disease. The type of VHL alteration has been shown to impact downstream VHL expression and clinical phenotype. However, current screening practices do not differ based on VHL genetic subtype. We aim to define the genotype-phenotype association among an institutional cohort of VHL patients. Methods: We conducted a retrospective cohort study of 69 patients (27 families) with von Hippel-Lindau at the Huntsman Cancer Institute from 1998-2023. 55% (38/69) patients have documented VHL variants for review. We evaluated the association of VHL type with risk of pheochromocytoma (Pheo), renal cancer (RCC), and hemangioblastoma (HB). t test and Fisher’s exact test were used to assess differences in clinicopathologic characteristics by VHL Type. P-value < 0.05 was considered significant. Results: We identified 24 unique VHL alterations among 38 patients. 66% (25/38) of patients had missense mutations, 10% (4/38) nonsense mutations, 21% (8/38) splice mutations, and 3% (1/38) deletion/duplication (Table 1). The median age at VHL diagnosis was 31 years old (range 4-76). VHL Type 2 was more common, 87% (33/38). All VHL Type 1 patients (5/5) developed RCC and HB. No patients with VHL Type 1 developed PheoPara. Of the VHL Type 2 patients, 39% (13/33) have not developed any VHL-associated clinical manifestations. Of the 33 patients diagnosed with VHL Type 2, 18% (6/33) were diagnosed with PheoPara, 30% (10/33) with RCC, and 48% (16/33) with HB. Conclusion: VHL type 2 comprised the majority of VHL diagnoses in our cohort with a notable absence of PheoPara phenotype. VHL Type 1 had higher penetrance and a higher prevalence for RCC and hemangioblastoma. With validation in larger cohorts, this cohort supports utilizing VHL genetic subtypes to personalize surveillance. Additional VHL testing for the remainder of the cohort is ongoing. Clinicopathologic characteristics of von Hippel-Lindau Syndrome cohort with known genetic mutations All (n=38) Type 1 (n=5) Type 2 (n=33) p-value AgeMean (Median) 33.1 (31) 42 (28) 31.7 (31) 0.38 White, n (%) 92% (n=35) 5 (100%) 30 (91%) 1 Hispanic, n (%) 8% (n=3) - 3 (9%) 1 VHL alteration, n (%) - Missense 25 (66%) - 25 (76%) Nonsense 4 (10%) 4 (80%) - Splice site 8 (21%) - 8 (24%) Deletion/Duplication 1 (3%) 1 (20%) - Penetrance, n (%) 25 (66%) 5 (100%) 20 (61%) 0.14 Phenotype, n (%) PheoPara 6 (16%) - 6 (18%) 0.57 RCC 15 (39%) 5 (100%) 10 (30%) 0.006 Hemangioblastoma 21 (55%) 5 (100%) 16 (48%) 0.26 Citation Format: Nicole Murray, Colton Leavitt, Noah Shepard, Zera Gonzales, Jiaming Li, Brock O'Neil, Christopher Dechet, Bogdana Schmidt, Benjamin L. Maughan, Kristen Pauley, Anne Naumer, Wendy Kohlmann, Alejandro Sanchez. Genotype-phenotype associations in von hippel-lindau syndrome: Implications for screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2559.

Tumor renal de células claras como debut de la enfermedad de Von Hippel-Lindau: reporte de caso

Antecedentes: La enfermedad de Von Hippel Lindau se debe a mutaciones del gen VHL (un supresor tumoral) que provoca aparición de distintas neoplasias en sistema nervioso central, ojo y abdomen. Su incidencia es baja y su importancia estriba en que el carcinoma renal de células claras representa la entidad con mayor tasa de letalidad en pacientes afectados por esta enfermedad.
 Caso clínico: Femenino de 45 años que presenta múltiples antecedentes familiares de neoplasias del sistema nervioso central y abdomen, que acude por aparición de tumoración abdominal. Se corrobora por imagen una neoplasia renal por lo que se somete a nefrectomía radical izquierda y se confirma el diagnóstico de carcinoma renal de células claras. En su abordaje posterior se integra el diagnóstico de Enfermedad de Von Hippel Lindau tipo I.
 Conclusiones: La enfermedad de Von Hippel Lindau presenta diversas manifestaciones neoplásicas de las cuales el carcinoma renal de células claras representa la entidad con mayor morbimortalidad, por lo que su detección temprana cuando existen antecedentes familiares es esencial para mejorar el pronóstico y diagnosticar a tiempo otras neoplasias vistas en la enfermedad.

Clear cell renal cell carcinoma detection leading to von Hippel-Lindau disease diagnosis: A case report

Background: Von Hippel-Lindau disease is caused by mutations of the VHL tumor-suppressor gene and results in the development of different neoplasias in the central nervous system, eye, and abdomen. Its incidence is low, but patients that develop clear cell renal cell carcinoma have the highest mortality rate. 
 Clinical case: A 45-year-old woman, with a family history of central nervous system and abdominal neoplasias, sought medical attention due to a progressively growing mass in the left flank. A kidney tumor was corroborated through an imaging study, and she underwent left radical nephrectomy. The diagnosis of clear cell renal cell carcinoma was confirmed. In the subsequent approach, she was also diagnosed with von Hippel-Lindau type I disease. 
 Conclusions: Von Hippel-Lindau disease presents with different neoplastic manifestations, and that of clear cell renal cell carcinoma has the highest morbidity and mortality rates. When there is a family history, its early detection is essential for improving outcome and opportunely diagnosing other neoplasias resulting from the disease.

Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease

Inherited germline mutations in the VHL gene cause predisposition to Von Hippel-Lindau (VHL) disease. Patients exhibit benign and cancerous lesions in multiple tissues, including hemangioblastomas, clear cell renal cell carcinoma, cysts in kidneys and pancreas, and pheochromocytomas. Although pathogenic germline mutations in the VHL gene have been widely described in different populations, only a single mutation was previously reported in a family from mixed Arab-Persian ethnicity. Here, we present five Arab patients with two new and two recurrent germline mutations in the VHL gene. These mutations include three in-frame deletions and a missense mutation. Infrequent in-frame deletions in previously described patients from other populations, as well as the presence of new mutations, suggests a distinct spectrum of VHL gene mutations in Arab patients. While pulmonary manifestation has been described rarely in VHL disease, we have identified two patients with a recurrent p.Phe76del in-frame deletion exhibiting multiple nodules in lungs. We also describe a first-ever in-frame deletion in the VHL gene in a patient with VHL type 2C disease, exhibiting bilateral pheochromocytoma. Overall, the study provides an insight into the genotype-phenotype relationship of VHL disease in Arab patients and provides a comparison with previously described patients from other ethnicities.

An Autopsy Case Report of Von Hippel-Lindau Syndrome-Type 2C Masquerading as Pre-eclampsia and Resulting in Maternal and Foetal Mortality

A 23-year-old female with seven months pregnancy, presented with gestational hypertension associated with mild proteinuria and was diagnosed clinically as pre-eclampsia and referred to tertiary care centre. She also had progressive breathlessness and giddiness. On examination, pallor, Blood pressure (BP) of 180/100 mm Hg and crepitations in left lower lung were noted. Laboratory investigations revealed neutrophilic leucocytosis and a profile of Disseminated Intravascular Coagulation (DIC). An ultrasound (USG) of the abdomen showed a gravid uterus with Intrauterine Foetal Death (IUFD) and a left adrenal mass. The clinical diagnosis was acute hypertensive heart failure with severe pre-eclampsia. She was put on three anti-hypertensives and ventilatory support, but she succumbed to her illness, within three days of admission. A complete autopsy was performed. The autopsy revealed hypertensive heart disease with marked left ventricular hypertrophy, severe coronary atherosclerosis, cystic bilateral adrenal pheochromocytoma, a cystic para-aortic paraganglioma, a pancreatic Neuroendocrine Tumour (NET) with lymph node metastasis. Hence, a diagnosis of DIC with refractory hypertension in Type 2C Von Hippel-Lindau (VHL) syndrome was established. VHL syndrome is an autosomal dominant disorder caused by germline VHL mutation which leads to development of various tumours. VHL disease is classified into four subtypes and VHL type 2C has predominantly pheochromocytomas without haemangioblastoma and Renal Cell Carcinoma (RCC). As the patient mimicked pre-eclampsia clinically, the diagnosis of VHL was missed. Bilateral adrenal cystic masses with gestational hypertension should be thoroughly evaluated, at the earliest, for familial pheochromocytomas or VHL syndromes as they may prove fatal.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel-Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline VHL mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B VHL mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by VHL type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.

Von Hippel-Lindau "Black Forest" mutation inherited in a large Chinese family.

The Von Hippel-Lindau (VHL) p.Tyr98His (Y98H) mutation is designated as the "Black Forest" founder mutation and has been previously reported in Western countries. This study reports the first recorded Chinese VHL family with the "Black Forest" mutation in Asia. Paired whole-exome sequencing (WES), Sanger sequencing and immunohistochemistry (IHC) were performed on samples from a large Chinese family to confirm the causative mutation and mutation carriers in the family. Clinical manifestations of the family were summarized and compared with those reported from other patients with the VHL Y98H mutation. The Chinese pheochromocytoma (PCC) family was identified as a VHL type 2 family with a Y98H mutation. There were 4 VHL patients and 11 currently healthy individuals with the mutation. Copy number analysis and SDHB IHC were performed to exclude interference from other pathogenic genes of PCC or paraganglioma (PGL). We report the first recorded instance of a Chinese VHL type 2 family with the "Black Forest" mutation by using WES and Sanger sequencing, which widens the currently recorded presence of the "Black Forest" mutation to China and potentially elsewhere in Asia and indicates that the "Black Forest" mutation does not uniquely evolve in occidental countries. A personalized surveillance approach, which may be more appropriate for affected families, has been recommended to improve quality of life.

Dexmedetomidine for anaesthetic management of phaeochromocytoma in a child with von Hippel-Lindau type 2 syndrome.

Phaeochromocytoma is a rare neoplasm in the paediatric population with fewer than 20% of diagnosed cases.[1] We describe the use of dexmedetomidine infusion for successful management of an 11-year-old male child with von Hippel-Lindau type 2 syndrome (VHL), who underwent bilateral adrenalectomy for phaeochromocytoma.

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an inherited tumor syndrome caused by germline mutations in the VHL tumor suppressor gene. It is characterized by hemangioblastoma in the central nervous system and retina, renal cell carcinoma, pancreatic tumor and cysts, and pheochromocytoma. In this study, we detected 26 germline mutations in the VHL gene of Korean patients, of which 1 was a novel mutation, c.417_418insT. We also integrated our data from this study with the published literature to identify 55 VHL germline mutations in Koreans, and identified a unique hotspot at codon 70. Nine unrelated patients (9/55, 16.4%) had the same amino-acid substitution at codon 70 (Glu70Lys) and showed VHL type 1 phenotypes. Although this mutation was shown to have a mild effect on VHL function, four of the nine patients (44.4%) subsequently developed multiple central nervous system hemangioblastomas or retinal hemangioblastoma. However, this hotspot has not been identified in Chinese or Japanese patients. This study provides information on the spectrum of VHL mutations in Korean VHL disease and contributes to a better understanding of VHL disease in terms of improvements in the clinical management of VHL families.

Clinical presentation of Von Hippel Lindau syndrome type 2B associated with VHL p.A149S mutation in a large Turkish family

Von Hippel Lindau (VHL) syndrome is an autosomal dominant disorder characterized by benign and malignant tumors. This study presents the clinical and genetic features of VHL syndrome in a Turkish family. For the diagnosis of pheochromocytoma-related diseases, 49 family members from three generations were evaluated between March 2008 and January 2013. Family members were examined to identify components of pheochromocytoma-related genetic syndromes through physical examination, laboratory tests, and imaging methods. For the causative mutation, sequence analysis of VHL gene was performed. Nine patients were diagnosed with pheochromocytoma. Lumbal spinal hemangioblastoma and pancreatic neuroendocrine tumor without pheochromocytoma were detected in one patient. In patients with pheochromocytoma, additional tumors, such as retinal angioma, renal cell carcinoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors were detected. All patients were diagnosed as VHL syndrome type 2B. Sequence analysis of VHL gene revealed heterozygous p.A149S mutation in all symptomatic patients and in seven of the asymptomatic family members. This is the first study that identified VHL p.A149S mutation in a Turkish family with VHL syndrome. However, VHL p.A149S mutation was identified in an American family by Atuk et al. (J Clin Endocrinol Metab, 83:117-120, 14) and the family was defined as VHL type 2A. In our study, the family was identified as VHL type 2B. This variability in the phenotypic features suggests that further studies are required to beter assess the genotype-phenotype correlation in such cases.

A novel missense mutation (N78D) in a family with von Hippel–Lindau disease with central nervous system haemangioblastomas, pancreatic and renal cysts

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome caused by mutations in the VHL tumor suppressor gene. In a family with VHL, we identified a novel missense mutation (N78D), which affects a fully conserved residue in the VHL protein. Interestingly, several other missense mutations reported at same codon in the VHL protein that might be associated with a low risk of renal cell carcinoma (RCC) but not pheochromocytoma appear to be associated with a VHL type 1 phenotype. At the moment, RCC is present in none of the affected mutation carriers in the family described here. In contrast to other missense changes at codon 78, the change in our VHL family is predicted to have a mild effect on VHL function, which apparently is insufficient to cause predisposition to RCC. Our findings suggest that the risk of RCC in VHL is attributable to the severity of the amino acid substitution at this particular codon in the VHL protein.

Identification and In Silico Analysis of Novel von Hippel-Lindau (VHL) Gene Variants from a Large Population

Mutational inactivation of the VHL gene is the cause of von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary cancer syndrome predisposing to haemangioblastomas, pheochromocytomas and clear-cell renal carcinomas. The gene product (pVHL) functions as an adapter in cellular processes including cell growth and apoptosis. VHL mutation analysis was carried out in 426 unrelated subjects with phenotypes ranging from VHL syndrome, to isolated VHL-related tumours that could represent the first manifestation of the disease. A total of 111 individuals were found to carry alterations, with large deletions representing 40% of the variants. Eighteen of the 95 detected variants were novel, seemingly disease-causing mutations; their pathogenic role has been evaluated in silico for effects on protein folding and interactions. Putative regions of interaction between pVHL and proteins involved in common pathways have been identified, assessing possible implications for the presence of mutations in these regions. All new variants predicted to truncate or cause complete pVHL loss of structure were associated with phenotypes consistent with VHL type 1. Seven of the new amino acid substitutions are disease-causing mutations, one is a neutral variant, whereas the results for two remain ambiguous. Our combined molecular and in silico approach for the evaluation of putative disease-causing mutations contributes to the interpretation of the potential pathogenicity of these novel variants.

Pheochromocytoma and Von Hippel–Lindau in Pregnancy

Pheochromocytoma is an infrequent but well-acknowledged primary cause of malignant hypertension in pregnancy. Although the majority of pheochromocytomas are sporadic, those that present as bilateral or multifocal tumors may be a manifestation of a rare cancer susceptibility syndrome, such as Von Hippel-Lindau (VHL). Gravidae with unrecognized pheochromocytoma are at risk for recurrent paroxysmal hypertensive crises with ensuant maternal and fetal risks. To further illustrate the challenges of management of pheochromocytoma and VHL in pregnancy, we present two illustrative cases. In the first, a multigravida presented with an intrauterine fetal demise and malignant hypertension and a concurrent diagnosis of bilateral pheochromocytomas. A missense mutation in exon 3 of the VHL gene was identified, confirming the diagnosis of VHL type 2C. In the second case, a multigravida with a prior diagnosis of VHL syndrome but sporadic follow-up underwent renal and adrenal imaging surveillance as part of her prenatal care. Although she was normotensive and clinically asymptomatic, such imaging enabled the detection of bilateral pheochromocytomas. In summary, in this report we discuss our management in gravidae with pheochromocytoma and VHL, emphasizing current recommendations pertaining to obstetric management, genetic testing, and long-term follow-up.

VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo

Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma, and pheochromocytoma. Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-α regulation. Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl2B/2B) displayed preserved physiologic regulation of both HIF factors with slightly more normoxic dysregulation of HIF-2α. Differentiated Vhl2B/2B-derived teratomas over-expressed the joint HIF targets Vegf and EglN3 but not the HIF-1α-specific target Pfk1 and displayed a growth advantage over Vhl-/--derived teratomas, suggestive of a tight connection between perturbations in the degree and ratio of HIF-1α and HIF-2α stabilization and cell growth. Vhl2B/2B mice displayed mid-gestational embryonic lethality, while adult Vhl2B/+ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at twelve months. Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development, and tumor predisposition.

Germline mutations in the von Hippel–Lindau disease (VHL) gene in mainland Chinese families

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. To date, more than 500 VHL families have been reported worldwide. However, few information is available about VHL germline mutations in mainland Chinese families. To provide some preliminary information about the germline VHL mutations in mainland Chinese population. A total of 27 index patients suspected of having VHL disease from unrelated Chinese families were studied by using direct DNA sequencing analysis and universal primer quantitative fluorescent multiplex polymerase chain reaction. The VHL germline mutations were detected in 26 (96%) probands. A total of 20 intragenic mutations (77%) were identified consisting of 12 missenses, 5 nonsenses, 2 micro-deletions and 1 novel intron mutation (IVS1-38C>T). Six large deletions (23%) were detected including four partial deletions and two complete deletions. Furthermore, a C>T substitution at nucleotide 470 (Pro86Leu) was observed in two unrelated Chinese families. Of note, two mutations (Asn78Ser and Ser80Ile) previously characterized as VHL type I mutations in Western VHL were associated with the type II Chinese family. In addition, a VHL germline mutation was also identified in a proband who did not fulfill the clinical diagnostic criteria for VHL disease. The spectrum of VHL germline mutations in mainland Chinese population is similar to that observed in Western population, and Genetic testing can be powerful in diagnosis and clinical management of VHL disease.

A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL) syndrome type 2C

BackgroundVon Hippel-Lindau (VHL) disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership.Case presentationA 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser) in exon 1 of the VHL gene on chromosome 3 (p25 – p26) was shown in the patient, her father and her daughter confirming the diagnosis of VHL.ConclusionIn almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

VHL mutation analysis in patients with isolated central nervous system haemangioblastoma

Haemangioblastomas of the CNS are a cardinal feature of von Hippel-Lindau (VHL) disease, a dominantly inherited multisystem familial cancer syndrome caused by germline mutation of the VHL tumour suppressor gene. We investigated the frequency of VHL mutations in 188 patients presenting with a single haemangioblastoma, no family history of VHL disease and no evidence of retinal or abdominal manifestations of the disease at the time of diagnosis. We found that approximately 4% of patients had a detectable VHL mutation and all of these cases presented age 40 years or less. Although the identification of a germline VHL mutation has important consequences for the patient (e.g. risk of further CNS and extra-CNS tumours) and their relatives, four patients had germline VHL missense mutations [C162Y, D179N and R200W (two patients)] that may represent haemangioblastoma-only and/or low penetrance mutations. Approximately 5% of patients without a detectable VHL mutation subsequently developed a further 'VHL type tumour' (in most cases a further CNS haemangioblastoma). These findings suggest that a subset of patients with apparently sporadic CNS haemangioblastoma will have a germline VHL mutation but may not be at risk for developing classical VHL disease and a further group may be mosaic for a germline VHL mutation that cannot be detected in blood cells.