eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

von Hippel-Lindau Disease: Differential Diagnoses & Workup

Author: Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Contributor Information and Disclosures

Updated: Apr 20, 2009

Differential Diagnoses

Birt-Hogg-Dube (BDH) Syndrome
Polycystic Kidney Disease
Multiple Endocrine Neoplasia
Tuberous Sclerosis
Multiple Paraganglioma Syndrome
Neurofibromatosis
Pheochromocytoma

Other Problems to Be Considered

Retinal and CNS hemangioblastomas are pathognomonic for von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, and their presence is a critical clue to diagnosis. These lesions also clearly differentiate von Hippel-Lindau disease from similar entities that can confuse the practitioner.

While a diagnosis of pheochromocytoma should prompt consideration of both von Hippel-Lindau disease and multiple endocrine neoplasia type 2, the latter is easily differentiated from von Hippel-Lindau by the presence of parathyroid tumors and medullary thyroid carcinoma.

Multiple paragangliomas are observed in individuals with mutations in the succinate dehydrogenase gene, subunits B, C, and D.3 Paragangliomas are endocrinologically active tumors of the sympathetic nervous system that are histologically identical to pheochromocytomas. These paragangliomas occur in the head and neck region, which distinguishes them from the usual locations of pheochromocytomas. Paragangliomas are not part of the spectrum of manifestations seen in von Hippel-Lindau disease.

Multiple renal cysts are found in patients with autosomal dominant polycystic kidney disease (ADPKD), and these cysts are more numerous than in patients with von Hippel-Lindau disease. The architecture of the kidneys is distorted, adversely affecting renal function. Little potential for malignant change is noted in ADPKD. Although CNS lesions are seen in both disorders, the lesions in ADPKD consist of arterial aneurysms and not hemangioblastomas, as is seen in von Hippel-Lindau disease. Hepatic cysts are frequent in ADPKD but rare in von Hippel-Lindau disease, whereas the converse is true for pancreatic cysts.

An autosomal dominant predisposition to renal cell carcinoma, as described in Birt-Hogg-Dube syndrome, is occasionally seen. This genetic etiology not caused by von Hippel-Lindau mutations. However in patients with renal cell carcinoma, ruling out the presence of other manifestations is always important.

Tuberous sclerosis complex (TSC) should also be considered in the differential diagnosis of multiple renal lesions. Although renal cysts occur in both TSC and von Hippel-Lindau disease, the renal tumor typically seen in TSC is the angiomyolipoma, which has a characteristic appearance on abdominal CT and MRI. Unlike von Hippel-Lindau disease, TSC is a neurocutaneous disorder characterized by dermatologic findings, such as hypopigmented macules (ash-leaf spots), shagreen patches, periungual fibromas, and adenoma sebaceum. Seizure disorders and learning disabilities are also seen in TSC.

Workup

Laboratory Studies

Conduct the following annual laboratory studies in individuals with von Hippel-Lindau (VHL) disease, or von Hippel-Lindau syndrome, in patients in whom von Hippel-Lindau disease is suspected, and in relatives who are at risk for von Hippel-Lindau disease:

  • CBC count to look for evidence of polycythemia vera due to erythropoietin expression by renal cysts and cerebellar hemangioblastomas.
  • Measurement of urinary catecholamine metabolites (inclusive of vanillylmandelic acid (VMA), metanephrines and total catecholamines) to detect for pheochromocytomas, even in the absence of hypertension.
  • Urinalysis for hematuria, which can be indicative of a renal abnormality.
  • Urine cytology to detect for clear cell renal carcinoma.

Imaging Studies

  • Annual abdominal imaging studies are suggested for individuals diagnosed with von Hippel-Lindau disease, for individuals in whom von Hippel-Lindau disease is suspected, and for at-risk relatives of a patient with von Hippel-Lindau disease.
    • Abdominal ultrasound to identify lesions in kidneys, adrenal glands and/or pancreas.
    • CT scanning of the abdomen with and without contrast is recommended for additional clarification of abdominal lesions; however, MRI may be of equal or greater efficacy, depending on expertise of the personnel performing and interpreting these imaging studies.
  • Periodic imaging to detect hemangioblastomas of the brain and spinal cord is usually not required. These tumors are typically benign; therefore, imaging is needed only if concerning neurologic symptoms or signs are present upon examination.
  • The American College of Radiology has established guidelines for the assessment of indeterminate renal masses.4

More on von Hippel-Lindau Disease

Overview: von Hippel-Lindau Disease
Differential Diagnoses & Workup: von Hippel-Lindau Disease
Treatment & Medication: von Hippel-Lindau Disease
Follow-up: von Hippel-Lindau Disease
Multimedia: von Hippel-Lindau Disease
References
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References

  1. Turturro F. Beyond the Knudson's hypothesis in von Hippel-Lindau (VHL) disease-proposing vitronectin as a "gene modifier". J Mol Med. Apr 8 2009;[Medline].

  2. Krzysztolik K, Cybulski C, Sagan L, Nowacki P, Lubinski J. Endolymphatic sac tumours and von Hippel-Lindau disease - case report, molecular analysis and histopathological characterization. Folia Neuropathol. 2009;47(1):75-80. [Medline].

  3. Boedeker CC, Erlic Z, Richard S, et al. Head and Neck Paragangliomas in Von Hippel-Lindau Disease and Multiple Endocrine Neoplasia Type 2. J Clin Endocrinol Metab. Mar 31 2009;[Medline].

  4. Israel GM, Francis IR, Baumgarten DA, et al. Indeterminate renal mass. Reston, VA: ACR; 2007.

  5. Chan-Smutko G, Plon SE, Iliopoulos O. Clinical features, diagnosis, and management of von Hippel-Lindau disease. UpToDate. Available at www.utdol.com/online/content/topic.do?topicKey=brain_ca/15247. Accessed 01/06/2009.

  6. Decker HJ, Weidt EJ, Brieger J. The von Hippel-Lindau tumor suppressor gene. A rare and intriguing disease opening new insight into basic mechanisms of carcinogenesis. Cancer Genet Cytogenet. Jan 1997;93(1):74-83. [Medline].

  7. Huson SM, Rosser EM. Von Hippel-Lindau disease. In: Rimoin DL, Connor JM, Pyeritz RE, Emery AE, eds. Emery and Rimoin's Principles and Practice of Medical Genetics. 3rd ed. Churchill Livingston; 1996:2290-5.

  8. Johns Hopkins University. #193300. OMIM. Available at http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300. Accessed June 3, 2002.

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  13. Richards FM, Webster AR, McMahon R, et al. Molecular genetic analysis of von Hippel-Lindau disease. J Intern Med. Jun 1998;243(6):527-33. [Medline].

  14. Schimke NR, Collins DL, Stolle CA. Von Hippel-Lindau Syndrome. GeneReviews. Available at www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vhl. Accessed January 6, 2009.

  15. Schimke RN, Collins DL, Stolle CA. von Hippel-Lindau Syndrome. GeneTests GeneClinics. Available at http://www.geneclinics.org. Accessed December 1, 2004.

  16. Schoenfeld AR, Davidowitz EJ, Burk RD. Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products. Proc Natl Acad Sci U S A. Jul 18 2000;97(15):8507-12. [Medline]. [Full Text].

  17. Sun X, Kanwar JR, Leung E, Vale M, Krissansen GW. Regression of solid tumors by engineered overexpression of von Hippel-Lindau tumor suppressor protein and antisense hypoxia-inducible factor-1alpha. Gene Ther. Dec 2003;10(25):2081-9. [Medline].

  18. VHL Family Alliance. Available at www.vhl.org/aboutvhlfa/index.php. Accessed January 6, 2009.

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Further Reading

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Keywords

von Hippel-Lindau disease, von Hippel-Lindau syndrome, VHL syndrome, VHL, von Hippel-Lindau's disease, Hippel disease, Hippel's disease, Hippel-Lindau disease, VHL gene, chromosome 3, 3p26-p25, VHL proteins, pVHL, Knudson's theory of carcinogenesis, retinocerebral angiomatosis, Lindau disease, Lindau's disease, retinal hemangioblastomas, CNS hemangioblastomas, central nervous system hemangioblastomas, pheochromocytomas, renal cyst, pancreatic cyst, renal carcinoma, renal cancer, renal cell carcinoma, RCC, endolymphatic sac tumors, ELSTs, epididymal papillary cystadenomas, treatment, diagnosis, retinal detachment, macular edema, glaucoma, tinnitus

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Contributor Information and Disclosures

Author

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: Ambulatory Pediatric Association and American Academy of Pediatrics
Disclosure: Nothing to disclose.

Medical Editor

Erawati V Bawle, MD, FAAP, FACMG, Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan; Professor (Clinician-Educator), Department of Pediatrics, Wayne State University School of Medicine
Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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