Birt-Hogg-Dubé Syndrome and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome: An Effective Multidisciplinary Approach to Hereditary Renal Cancer Predisposing Syndromes.

Simon Wood,Andrew John Mallett,Helen Marfan,Mohammad Al-Shinnag,Rachel Susman,Jan Wakeling,Sonja Gustafson

doi:10.3389/fonc.2021.738822

Abstract

AimWe aimed to describe and analyse clinical features, characteristics, and adherence to surveillance guidelines in an Australian Birt-Hogg-Dubé syndrome (BHD) and hereditary leiomyomatosis and renal cell cancer (HLRCC) cohort.MethodsAll identified patients with a diagnosis of BHD or HLRCC at RBWH 01/01/2014-01/09/2019 were included (HREC/17/QRBW/276). All patients were initially assessed and counselled by a clinical geneticist and then referred to an adult nephrologist. Baseline and incidental clinical variables were extracted and analysed.ResultsFifty-seven patients were identified (28 BHD, 29 HLRCC) with a median age of 47 years. The median and cumulative follow-up were 1 and 99 years, respectively. Baseline renal MRI occurred in 40/57 patients, and 33/57 had regular MRI as per the national guidelines (eviQ). Of 18/57 without baseline imaging, nine were yet to have imaging, seven were lost follow-up, and two patients had logistic difficulties. RCC was diagnosed in 11/57 patients: two of 28 with BHD were diagnosed with RCC aged 73 and 77, both prior to commencement of surveillance. Nine of 29 patients with HLRCC were diagnosed with RCC (one of 29 during surveillance at 47 years of age) and eight of 29 prior to commencement of surveillance (11–55 years). Amongst BHD patients, cutaneous fibrofolliculomas were noted in 15 patients, lung cysts were detected in seven patients, spontaneous pneumothoraces in five patients, and parotid oncocytoma in two of 28. Amongst those with HLRCC, cutaneous leiomyomas were noted in 19/29, cutaneous leiomyosarcoma diagnosed in one of 29, and uterine fibroids in 13 female patients.ConclusionEvidence-based RCC screening in BHD and HLRCC cohort is feasible and able to identify incidental renal lesions. Multidisciplinary patient management enables expedited genetic counselling, diagnosis, longitudinal screening, and RCC management. The success of this clinical model warrants consideration of undertaking longitudinal screening of BHD and HLRCC patients by nephrologists.

Highlights

It is estimated that hereditary forms of renal cell cancer (RCC) account for 2%–4% of renal cancer [1]
The diagnosis of BHD can be suspected in the presence of one major or two minor criteria as proposed by Menko et al [2], but a definitive diagnosis requires the identification of a pathogenic FLCN variant [4]
All identified patients had been previously referred to the state clinical genetic service, Genetic Health Queensland (GHQ) and had been assessed by a clinical geneticist before being referred to an adult nephrologist for ongoing clinical assessment and surveillance

Summary

Introduction

It is estimated that hereditary forms of renal cell cancer (RCC) account for 2%–4% of renal cancer [1]. Within that small proportion of all cases of RCC, there are many monogenic disorders that have been linked to RCC, including BHD and HLRCC (Table 1). BHD is caused by heterozygous germline pathogenic variants in FLCN-encoding folliculin. It is inherited in an autosomal dominant pattern, characterised by skin fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax, and RCC [2]. Over 600 families with pathogenic FLCN variants have been reported worldwide [3], indicating its significant rarity and the need for further research and characterisation. The diagnosis of BHD can be suspected in the presence of one major or two minor criteria as proposed by Menko et al [2], but a definitive diagnosis requires the identification of a pathogenic FLCN variant [4]

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