Hereditary renal cell carcinoma

The recognised syndromes associated with hereditary RCC follow autosomal dominant inheritance. Affected individuals carry one germline pathogenic variant in the relevant predisposition gene. Mosaicism is described as a less common alternative pattern in carriers of a TSC1/2 variant.

Diagnosis combines the renal histological subtype with extrarenal features and family history to direct syndrome-specific molecular genetic testing. Multigene panel testing covering the recognised RCC-predisposition genes identifies the causative germline variant and assigns the specific syndrome.

Main differential diagnoses include:

• Sporadic (non-hereditary) RCC: the most common mimic, typically later-onset, unilateral and unifocal, without syndromic extrarenal features or a supportive family history; no germline predisposition gene.
• : renal angiomyolipomata and, less commonly, RCC, with cutaneous, neurological and pulmonary features; TSC1, TSC2.
• (Cowden syndrome): RCC with macrocephaly, mucocutaneous lesions and breast, thyroid and endometrial tumour risk; PTEN.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.
• In Birt-Hogg-Dubé syndrome, a confirmed diagnosis supports life-long renal cancer surveillance.

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