Most patients diagnosed with Birt-Hogg-Dube (BHD) syndrome exhibit fibrofolliculomas and pneumothorax, but only 30–45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest reported onset of RCC in a BHD patient has been age 20 (Benusiglio et al., 2014). In a new case study, Schneider et al. (2017) report the case of a 14-year-old patient with a FLCN mutation leading to an early-onset RCC that could not be classified according to typical histology. This is the youngest patient with reported BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC at an early age.

BHD-associated renal tumours can present with different histological subtypes and for BHD patients, baseline imaging of the kidneys is recommended at age 20 (Menko et al., 2009). This new case reports a 14-year-old girl presenting with a renal cell carcinoma (RCC) of the left kidney that had been histologically unclassified. Apart from the tumour, physical examination was unremarkable, including the absence of skin lesions. Her past medical history included only a surgically repaired patent ductus arteriosus. Family history was unremarkable for RCC. An abdominal CT demonstrated a large 21 cm solid mass arising from the inferior pole of the left kidney causing severe hydronephrosis. The patient underwent a unilateral nephrectomy without complications. Histological examination showed that the viable tumour cells formed tubular, trabecular and focally follicular structures. The differential diagnosis based on routine histology included mucinous tubular spindle cell carcinoma (MTSC) and thyroid-like follicular carcinoma. In the patient’s age group, consideration was also given to metanephric adenoma and MiTF family translocation RCC. The tumour showed no morphological features to suggest MiTF translocation carcinoma. MTSC was not supported by the histology or protein markers expression. In addition, the thyroid follicles were too focal to suggest thyroid-like follicular carcinoma. Wilms’ tumour and metanephric adenoma were also not supported by marker expression. No neuroendocrine marker expression was found to suggest carcinoid tumour. On the basis of the morphological features and immunophenotype, the tumour did not fit into any of the typical diagnostic categories. Genetic testing was offered to the patient and a panel of kidney cancer susceptibility genes was examined for mutations. The results revealed a germline FLCN p.Gly84_Glu-132del mutation of exon 5 and the patient was diagnosed with BHD syndrome. To assess the functional significance of this novel in-frame mutation on FLCN function the authors stably re-introduced wild type and mutant FLCN gene into the FTC133 FLCN-null cell line and used a xenograft mouse assay to show that the in-frame deletion inactivates the tumour suppressor effect of the encoded protein. Testing of both parents revealed that her father also carried the same mutation. An abdominal MRI examination was offered to the father and no renal cysts or masses were identified. Neither the patient nor the father had fibrofolliculomas or history of spontaneous pneumothorax.

The authors describe a case of early-onset BHD syndrome caused by a novel inherited deletion of exon 5 of the FLCN gene. This case is unusual in the young age of onset of initial manifestation of disease and the atypical histology. Deletion of just exon 5 has not been reported so far to cause BHD syndrome and very little is known about a possible correlation between the genotype and the risk to develop RCC. It is becoming more evident that there is a wide clinical variability in BHD syndrome and this case report demonstrates the importance of genetic testing especially in patients with an uncommon clinical presentation and histology. In the paediatric population, RCC constitutes a small fraction of renal tumours and up to 25% are considered histologically unclassified. This raises the question of whether FLCN mutations are especially under diagnosed in this population. This study highlights the need to revisit the appropriate age to initiate surveillance for RCC in BHD patients.