What are RTRS?

RTRS are a group of rare diseases genetically determined from birth and that affect approximately 5 in 10,000 people or less worldwide. Patients suffering from RTRS have a high risk of developing cancer and transmitting the disease to their descendants. Particularly if undiagnosed (asymptomatic) or non-surveilled, RTRS patients can develop particularly aggressive cancers.

Currently, the genetic and heritable defects causing RTRS are already known for many of these syndromes. This information provides the opportunity to spot high-risk carriers before disease development and to define the conditions (target organs, age, gender cancer onset and recurrence) associated with each syndrome. Only by combining this knowledge, it is possible to predict when and which cancer an asymptomatic RTRS patient will develop, establish effective disease prevention measures, and increase survival rates. Additionally, this integrative analysis allows to identify, characterise, and prospect the costs for tailoring condition-specific pathways of care for each RTRS.

Types of RTRS

Birt-Hogg-Dubé Syndrome (BHDS)

Definition

Birt-Hogg-Dubé syndrome (BHDS) is a rare genetic disorder characterised by the development of multiple benign skin lesion- called fibrofolliculomas-, lungs cysts, and kidney tumours as shown in Figure 1. It is inherited in an autosomal dominant manner, meaning that an affected individual has a 50% chance of passing the mutated gene to each of their children.

Figure 1 Main manifestations by BHDS

Frequency

Birt-Hogg-Dubé Syndrome is an infrequent genetic condition, occurring in approximately 1 in 100,000 individuals in over 400 families.

Genes

BHDS is caused by mutations in the FLCN (folliculin) gene, located on chromosome 17. The FLCN gene normally acts as a tumour suppressor, helping to regulate cell growth and prevent the formation of tumours. The diagnosis of BHDS involves observing clinical symptoms and identifying mutations in one of the two copies of the FLCN gene. Major criteria for diagnosing BHDS include the presence of multiple fibrofolliculomas or trichodiscomas (skin lesions), pulmonary cysts or spontaneous pneumothorax, and renal cancer or renal tumours. Minor criteria include a family history of BHDS, multiple lung cysts without spontaneous pneumothorax, a first-degree relative with BHDS and/or characteristic skin lesions, and the presence of parotid oncocytoma or multiple oncocytic tumours of the parotid gland. A confirmed diagnosis often requires genetic testing to identify pathogenic mutations in the FLCN gene.

Symptoms or Manifestations

BHDS is mainly characterised by skin manifestations such as multiple fibrofolliculomas, lung cysts, and an increased risk of developing several types of kidney cancer, presenting a spectrum of clinical manifestations that affect the skin, lungs, and kidneys.

Treatment and Surveillance

The severity of symptoms and the age at which they appear can vary among affected individuals. It is important for individuals with a suspected or confirmed diagnosis of BHDS to undergo regular medical monitoring and screenings to detect and manage potential complications, such as the development of tumours. Genetic counselling is also recommended for individuals with BHDS and their families to better understand the inheritance pattern and make informed decisions about their health.

Patient Association

UK: https://www.bhdsyndrome.org/ and https://ikcc.org/about-ikcc/
Czech Republic: http://arcus-oc.org/
France: http://geneticancer.org
Italy: https://mutagens.it/
Portugal: http://www.evitacancro.org
Spain:
• Birt-Hogg-Dubé European Association BIHDA (https://twitter.com/Birt_Hogg_Dube)
• Asociación para la Información e Investigación sobre Enfermedades Renales Genéticas (https://airg-e.org)
• Asociación de Mama y Ovario Hereditario AMOH (https://amohasociacion.org)
• Afectados por el Síndrome de Peutz-Jeghers (http://sindromedepeutzjeghers.blogspot.com)
• Fundación Anemia de Fanconi (https://anemiadefanconi.org)
• Barcelona PID Fundation (http://www.pidfoundationbcn.org)
• Federación Española de Enfermedades Raras | FEDER (https://enfermedades-raras.org/)
• Federació Catalana de Malalties Minoritàries – FECAMM (http://www.fecamm.org)

Your Contribution

Individuals affected by BHDS might search for the nearest healthcare personnel and engage in the patient organisation(s) by contributing to the well-being of others facing the same or similar conditions. You may update your information by following our social media and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis).

References

  1. Tavares E. et al. Birt-Hogg-Dubé Syndrome – report of two cases with two new mutations. Journal of Dermatological Case Reports. 2017. DOI: 10.3315/jdcr.2017.1242.
  2. Winship I.M. et al. Update of penetrance estimates in Birt-Hogg-Dubé syndrome. Journal of Medical Genetics; 2023. DOI: 10.1136/jmg-2022-109104

More Information

  1. Birt-Hogg-Dubé Syndrome (BHD Syndrome) by ERN Genturis
  2. Birt-Hogg-Dubé syndrome by MedlinePlus
  3. Birt-Hogg-Dubé syndrome by GARD

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Li-Fraumeni Syndrome (LFS)

Definition

Li-Fraumeni Syndrome (LFS) is a rare and inherited genetic disorder characterised by a substantially heightened risk of developing diverse cancers, often at an early age.  Predominantly linked with soft tissue sarcoma, osteosarcoma, breast cancer in young women, brain tumour, adrenocortical carcinoma, and leukaemia, depicted in the Figure 6. LFS has also been associated with various other cancer types.

Figure 6 Organs affected by LFS

Frequency

The incidence of causal TP53 germline variant at birth is estimated between 1 in 5,000 and 20,000, according to studies but it is probably underestimated and the prevalence could reach 0.2%.

Genes

This syndrome is caused by pathogenic / likely pathogenic (P/LP) variant in the TP53 gene, located on chromosome 17. TP53 is  a tumour suppressor gene which encodes the p53 protein, regulating cell growth and preventing tumour formation.  LFS follows an autosomal dominant inheritance pattern, meaning inheriting one mutated copy of the TP53 gene is adequate to increase cancer risk. In some infrequent but not rare situations, the TP53 P/LP variant is de novo, meaning not inherited (no family history) but as a result of a mutational event in the parental gametes or in embryonic cell layers The percentage of individuals with a newly occurring germline TP53 P/LP  variant varies  between 7% and 20%, according to studies but could be higher. It’s crucial to note that not all individuals with a P/LP variant in TP53 will develop cancer, but the risks are substantially higher than in the general population. Upon a diagnosis of LFS in a patient, it is essential for  family members to undergo genetic counselling and surveillance for early cancer.

Symptoms or Manifestations

Individuals with LFS have a higher likelihood of developing a wide range of cancers at a young age, and multiple primary tumours These may include sarcoma (bone and soft tissue tumours), breast cancer, brain tumour, adrenal gland tumour, and others.

Treatment and Surveillance

LFS patients require a lifelong commitment to vigilant cancer surveillance and personalised management strategies, with avoidance of radiation when possible Genetic counselling serves as a critical support mechanism, offering information on cancer risks and empowering individuals and families to make informed decisions about their healthcare in the face of this rare and complex genetic disorder.

Patient Associations

Française du syndrome de Li-Fraumeni (LFS France) : https://www.association-lfsfrance.org/

The American LFS Association has several EU chapters:

Chapter France: https://www.lfsassociation.org/france/

Chapter Germany: https://www.lfsassociation.org/germany/

Chapter Netherlands: https://www.lfsassociation.org/netherlands/

Chapter Italy : https://www.lfsassociation.org/italy/

Your Contribution

Individuals affected by LFS might search genetic test and genetic counselling in nearest healthcare personnel and engage in the patient organisation(s) by contributing to the well-being of others facing the same or similar conditions. You may update your information by following our social media and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis).

References

  1. Bougeard G, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015. doi: 10.1200/JCO.2014.59.5728. PMID: 26014290.
  2. Renaux-Petel M, et al. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 2018. doi: 10.1136/jmedgenet-2017-104976. PMID: 29070607.
  3. Kasper E, et al. Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations. Eur J Cancer. 2018. doi: 10.1016/j.ejca.2018.06.011. PMID: 30072235.
  4. Gargallo P, et al. Li-Fraumeni syndrome heterogeneity. Clin Transl Oncol. 2020. doi: 10.1007/s12094-019-02236-2. PMID: 31691207.
  5. Frebourg T, et al.; European Reference Network GENTURIS. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020. doi: 10.1038/s41431-020-0638-4. PMID: 32457520.
  6. Raad S, et al. Blood functional assay for rapid clinical interpretation of germline TP53 variants. J Med Genet. 2021. doi: 10.1136/jmedgenet-2020-107059. PMID: 33051313
  7. Thariat J, et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes. Lancet Oncol. 2021 doi: 10.1016/S1470-2045(21)00425-3. PMID: 34856153.
  8. Rocca V, et al. Li-Fraumeni Syndrome: Mutation of TP53 Is a Biomarker of Hereditary Predisposition to Tumor: New Insights and Advances in the Treatment. Cancers (Basel). 2022. doi: 10.3390/cancers14153664. PMID: 35954327.

More Information

  1. Li-Fraumeni syndrome by MedlinePlus
  2. Li-Fraumeni syndrome by GARD
  3. Heritable TP53-related cancer syndrome (hTP53rc syndrome)/Li Fraumeni syndrome (LFS) by ERN Genturis

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