VHL is a well-described familial cancer syndrome with well-established clinical characteristics and a database of mutations (http://www.umd.be/VHL/). However, there is limited data from the Indian population.

The average age at presentation in our cohort was 27.2 years which is comparable to previously reported data [5]. Pheochromocytomas constituted the most common tumor seen in 49% (34/69) subjects. This contrasts previous reports including the Indian study by Vikkath et al. 2015 where pancreatic cysts and hemangioblastomas were the most common presentations [14]. Overall diagnostic yield was 46.3% in our cohort which included VHL and isolated tumors associated with VHL. Out of 12 patients, who met the diagnostic criteria at the time of presentation, pathogenic variations in VHL gene were detected in 11 patients (92% yield). However, pathogenic variations were also identified in 21 patients who did not meet diagnostic criteria at the time of presentation (yield 37%). This stresses the limitations of relying on the criteria especially in young patients where the full spectrum of the disorder has not manifested. Out of 37 patients with isolated PPGLs (Pheochromocytomas and Paragangliomas), pathogenic variation in VHL gene was found in 16 patients (43%). PPGLs are caused by a germline pathogenic mutation in one of the 27 susceptibility genes which include RET, NF1, MET, KIF1B, MAX, etc. besides VHL [15]. A mutation in one of these remaining genes may be causative. In an Indian study by Khadilkar et al. on PPGLs VHL gene was among the 5 genes they studied. In their study, VHL accounted for 33.3% and 13.18% PPGLs cases in pediatric and adult patients, respectively [16]. In a similar Indian study by Lomte et al. on patients with PPGLs, missense mutation was found in 81% and the rest were small indels or large deletions. However, their study was a retrospective study of mutation positive cases only and did not take in to account the yield of each test unlike our study [17].

In our cohort, diagnostic yields for CNS hemangioblastoma and renal cell carcinoma were 45% (9/21) and 60% (3/5), respectively. Of particular interest was a 14-year-old girl (Case 11) who had only endolymphatic sac tumor at presentation. So, VHL germline mutation testing should be offered even to those who do not fulfill the diagnostic criteria and have seemingly sporadic tumors.

Most of the 22 pathogenic variations identified in this study are clustered in exons 1 and 3 of VHL (NM_000551, Fig. 2). Of these only one is novel. The mother of proband with this novel variant was deceased at 55 years of age with unknown cause and father at 75 years of age. In extended family history recently, proband’s niece is found to have pheochromocytoma; however, sample was not available for molecular testing. This variant is predicted to be deleterious by in-silico prediction tools and protein homology modeling. The variants c.499C > T, c.500G > A and c.556G > A were each present in three unrelated families.

Fig. 2
figure 2

Distribution of Mutations across VHL gene along with the tumors at presentation (NM_000551)

To facilitate genotype–phenotype correlations, VHL disease was categorized into Type 1 and Type 2, according to the absence or presence of pheochromocytoma. As previously reported, we also found that missense substitutions were associated with a higher risk of pheochromocytoma while truncating mutations and large genomic rearrangements were associated with renal tumors [18, 19]. Patients with the same mutation presented with different tumors. This was evident even in the same family. Patient 12, 28-year-old male, presented with pancreatic cyst, while his father and paternal uncles presented with CNS hemangioblastomas.

Pathogenic mutations were identified in all the 7 familial cases. Nine at-risk relatives were found to harbor the pathogenic variant found in the respective probands. Thus, we were able to counsel these patients and also put them on appropriate surveillance. Early detection and management of tumors have been shown to improve the outcome. Anxiety of mutation-negative at-risk relatives was allayed, and they were prevented from undergoing unnecessary surveillance.

Though, a multigene panel by next-generation sequencing (NGS), to look for VHL and VHL-associated tumors is being employed exceedingly, Sanger sequencing of VHL gene should be the first step, considering the small size of the gene and high yield of the test, especially in resource constraint settings.

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