Clinical Guidance

Four general VHL phenotypes (type 1, type 2A, type 2B, type 2C) have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma. Many lines of research support the conclusion that the molecular etiology of pheochromocytomas appears to be distinct from other VHL lesions. Therefore, the most relevant genotype-phenotype correlations rely mostly on scoring the presence/absence of pheochromocytomas associated with a given allele. The following discussion summarizes the genotype-phenotype studies published to date, with the cautionary note that further investigation is needed. Note: Patterns are not clear-cut, and genotype-phenotype correlations have no current diagnostic or therapeutic value; they are used for academic purposes only. VHL type 1.

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Penetrance

VHL pathogenic variants are highly penetrant. Almost all individuals who have a VHL pathogenic variant are symptomatic by age 65 years .

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Diagnostic Criteria

Clinical diagnostic criteria for von Hippel-Lindau syndrome (VHL) have been proposed and vary slightly between Dutch or Danish guidelines . Suggestive Findings VHL should be suspected in individuals with or without a family history of VHL who have: • Retinal angioma, especially in a young individual • Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years • Adrenal or extra-adrenal pheochromocytoma • Renal cell carcinoma diagnosed at age ≤40 years • Multiple renal and pancreatic cysts • Multiple neuroendocrine tumors of the pancreas • Endolymphatic sac tumors • Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament Establishing the Diagnosis The clinical diagnosis of VHL can be established in proband according to Danish or Dutch guidelines , or the molecular diagnosis can be established by identification of a heterozygous pathogenic (or likely pathogenic) variant in VHL on molecular genetic testing . Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making . Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous VHL variant of uncertain significance does not establish or rule out the diagnosis. Table 1. Von Hippel-Lindau Syndrome Clinical Diagnostic Criteria

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Differential Diagnosis

Isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma. The clinical sensitivity of molecular genetic testing of VHL makes it possible to effectively rule out von Hippel-Lindau syndrome (VHL) with a high degree of certainty in individuals with (1) isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma and (2) no detectable germline VHL pathogenic variant. Somatic mosaicism for a VHL pathogenic variant could still be considered in such individuals (an estimated 5% of individuals with VHL have a somatic mosaicism ). A younger individual, especially one with multiple lesions, is more likely to have a germline VHL pathogenic variant than an older individual with a single lesion . The differential diagnosis for an individual suspected of having VHL depends on the further clinical presentation (see and ). Pheochromocytoma. Up to 40% of individuals with pheochromocytoma have a heterozygous pathogenic variant in one of several genes: SDHB, SDHD, VHL, RET, and NF1 (most prevalent) or SDHA, SDHAF2, MAX, FH, and TMEM127 (less prevalent). Germline VHL pathogenic variants are rare in simplex cases of unilateral pheochromocytoma (i.e., an affected individual with no family history of VHL), unless the individual is younger than age 20 years. Table 3a. Genetic Disorders Associated with an Increased Risk of Pheochromocytomas

Management Guidelines

The first von Hippel-Lindau syndrome (VHL) care pathway was recently published by a multidisciplinary team from the Netherlands .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with VHL, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Von Hippel-Lindau Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| • Neurologic history physical exam

• Brain total spine MRI

| To assess for evidence of CNS or peripheral nerve hemangioblastomas

Eyes | Ophthalmologic eval | To assess for retinal hemangioblastomas

Renal/pancreatic cysts tumors

| Abdominal ultrasound in those age ≥16 yrs | Evaluate suspicious lesions in kidney, adrenal gland, or pancreas by more sophisticated techniques (e.g., CT, MRI).

Endocrine

| • Blood pressure measurement

• Measurement of 24-hr urine fractionated metanephrines catecholamine metabolites or plasma free fractionated metanephrines

| In those age ≥5 yrs to evaluate for pheochromocytoma

ENT | Audiologic eval | To assess for hearing loss assoc w/endolymphatic sac tumors

MRI of internal auditory canals | At age 15-20 yrs to assess for ELST or earlier in those w/hearing loss, tinnitus, or vertigo

Psychological

| Assess psychosocial needs. | Refer to social worker or psychologist as needed

Genetic counseling

| By genetics professionals1 | To obtain a pedigree inform affected persons their fam...

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Clinical Guidance

Avoid the following:

• Tobacco products, as they are considered a risk factor for kidney cancer

• Chemicals and industrial toxins known to affect VHL-involved organs

• Contact sports if adrenal or pancreatic lesions are present

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Therapies Under Investigation

Certain VHL pathogenic variants fail to downregulate hypoxia-inducible factor alpha (HIF), leading to overexpression of downstream effectors such as vascular endothelial growth factor (VEGF), which contribute to pathogenesis. Many experimental therapies target these misregulated signaling pathways. An intravitreal VEGF receptor inhibitor, ranibizumab, has been used with some success in individuals with retinal hemangioblastomas who have either failed local therapy or whose lesions are not amenable to local therapy . Intravitreal injections of bevacizumab, another VEGF inhibitor, have also proven effective in treating retinal hemangioblastomas in individuals with VHL . Stabilization of some (but not all) CNS hemangioblastomas has also been demonstrated .

Source: GeneReviews — "Von Hippel-Lindau Syndrome"

Surveillance Guidelines

In the United States, the VHL Alliance has worked extensively with health care professionals to assemble guidelines that are generally accepted worldwide (see VHL Resources – Active Surveillance Guidelines). Additional guidelines originate from Denmark and the Netherlands . Individuals with VHL and first-degree relatives who have not undergone DNA-based testing need regular clinical surveillance by a physician or medical team familiar with VHL . Table 5. Von Hippel-Lindau Syndrome: Recommended Surveillance

Source: GeneReviews — "Von Hippel-Lindau Syndrome"