Familial Malignant Melanoma (FMM)

Definition

Familial Malignant Melanoma (FMM) is characterised by a familial predisposition to melanoma -a type of skin cancer-, and in some cases also pancreatic cancer, as illustrated in Figure Affected organs by FMM Individuals with a family history of melanoma have an increased risk of developing the disease themselves.

Figure Affected organs by FMM

Frequency

Approximately 8% of individuals recently diagnosed with melanoma have a first-degree relative who also has melanoma. A smaller proportion, around 1% to 2%, has two or more close relatives affected by melanoma. People in families predisposed to melanoma often exhibit atypical moles known as dysplastic nevi.

Genes

The genetic basis of FMM is complex, and several genes have been associated with an increased risk of familial melanoma. CDKN2A and CDK4 are the most important high-penetrance melanoma genes.

CDKN2A (p16INK4a): Pathogenic variants in the CDKN2A gene are associated with a high risk of melanoma. This gene is also linked to an increased risk of pancreatic cancer.
CDK4: Pathogenic variants in the CDK4 gene give the same phenotype as pathogenic variants in CDKN2A, but are far less common.

It is important to note that not all cases of FMM can be attributed to known genetic mutations, and there may be other as-yet-unidentified genetic factors involved.

Symptoms or Manifestations

It’s important to note that early detection and prompt medical attention are crucial for better outcomes of melanoma. Some general symptoms and manifestations associated with melanoma are change in moles, asymmetry, border irregularity, colour variation, diameter, evolving or changing lesions, satellite lesions, itching or pain and ulceration.

Treatment and Surveillance

Genetic testing may be recommended to assess the risk and provide personalised recommendations for monitoring and preventive measures. Participation in intensive skin surveillance programs is recommended for individuals with pathogenic variants in CDKN2A/CDK4. Early detection and intervention can significantly improve the prognosis for individuals with melanoma.

Patient Association

Czech Republic: http://arcus-oc.org/

France: http://geneticancer.org

Italy: https://mutagens.it/

Portugal: http://www.evitacancro.org

Spain: http://actitudfrentealcancer.org

Sweden: http://www.melanomapatientnetworkeu.org/home.html

Belgium: https://pancreaticcancereurope.eu/

Find Your Support

Individuals affected by FMM can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you will gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Leachman S.A. et al. Population-based analysis of prognostic factors and survival in familial melanoma. Journal of Clinical Oncology. 2005. DOI: 10.1200/JCO.2005.11.999
2. Puntervoll HE et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013 doi: 10.1136/jmedgenet-2012-101455.
3. Fargnoli M.C. et al. Familial Melanoma: Diagnostic and Management Implications. Dermatology Practical & Conceptual. 2019. DOI: 10.5826/dpc.0901a03

More Information

1. Melanoma by MedlinePlus
2. Familial malignant melanoma by ERN Genturis
3. Familial malignant melanoma by cancer.net
4. Familial Melanoma by orpha.net

 

 

 

 

Gastrointestinal Stromal Tumours (GIST)

Definition

Gastrointestinal Stromal Tumours (GISTs) are a type of soft tissue sarcoma that typically occurs in the gastrointestinal (GI) tract (Figure Gastrointestinal tract system), which includes the stomach, small intestine, and oesophagus. GISTs arise from specialized cells in the wall of the GI tract called interstitial cells of Cajal, which play a role in regulating the digestive system.

Figure Gastrointestinal tract system

Frequency

GISTs are rare, and there are notable discrepancies in reported incidence rates, ranging from 0.4 to 2 cases per 100,000 per year.

Genes

GISTs are a type of tumour that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. Most cases of GIST are sporadic and are not inherited. In some cases, it is caused by the mutation of KIT/PDGFRA genes inherited by autosomal dominant inheritance (Figure 1) and the mutations of the four genes related to the succinate dehydrogenase (SDH) enzyme complex. The specific location and type of mutation within these genes can influence the behaviour of GISTs. Some mutations are associated with more aggressive tumours, while others may result in slower-growing, indolent forms of GIST.

Symptoms or Manifestations

GISTs symptoms may include abdominal pain, gastrointestinal bleeding, a feeling of fullness or bloating, and sometimes, the presence of a palpable mass in the abdomen.  In cases with KIT mutations, additional symptoms include pigmented skin macules, urticaria pigmentosa, and diffuse hyperplasia of the interstitial cells of Cajal. The diagnosis often involves imaging studies, such as CT scans or endoscopy, and a biopsy to confirm the presence of GIST.

Treatment and Surveillance

Treatment for GISTs typically involves surgical removal of the tumour. In cases where surgery is not feasible or the tumour has spread, targeted therapy with drugs like imatinib (Gleevec) may be used. Imatinib specifically targets the abnormal proteins produced by the mutated genes in GISTs, helping to control tumour growth. GISTs are relatively rare, but they are the most common mesenchymal tumours of the GI tract. Due to advancements in understanding the molecular biology of GISTs, targeted therapies have significantly improved the prognosis for many patients with this condition.

Patient Association

Czech Republic: http://arcus-oc.org/

France: http://geneticancer.org

Italy: https://mutagens.it/ and https://viveresenzastomaco.org/chi-siamo/

Portugal: http://www.evitacancro.org and http://www.europacolon.pt/

Spain: http://actitudfrentealcancer.org

Belgium: https://digestivecancers.eu/for-patients/

Find Your Support

Individuals affected by GISTs can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you will gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Briceno-Delgado J. et al. Gastrointestinal stromal tumors: A multidisciplinary challenge. Wordl Journal of Gastroenterology. 2018. DOI: 10.3748/wjg.v24.i18.1925
2. Liegl-Atzwanger B. et al. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics. 2021. DOI: 10.3390/diagnostics11020194
3. Casali P.G et al. Gastrointestinal stromal tumours: ESMOeEURACANeGENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology: official journal of the European Society for Medical Oncology. DOI:10.1016/j.annonc.2021.09.005

More Information

1. Gastrointestinal stromal tumor by MedlinePlus
2. Gastrointestinal stromal tumor by GARD

 

Hereditary Diffuse Gastric Cancer (HDGC)

Definition

Hereditary Diffuse Gastric Cancer (HDGC) is a rare genetic condition characterised by an increased risk of developing diffuse gastric cancer- a type of stomach cancer -, and  lobular breast cancer as illustrated in Figure Illustration organs affected by HDGC.

Figure Illustration organs affected by HDGC

Frequency

Among the hereditary types of gastric cancer, hereditary diffuse gastric cancer (HDGC) is the most extensively researched. It affects approximately 5-10 individuals per 100,000 births. This syndrome predisposes for gastric and breast cancer and for very specific histological types: the diffuse type of gastric cancer and the lobular type of breast cancer.

Genes

HDGC is primarily associated with mutations in the CDH1 gene. The CDH1 gene provides instructions for making a protein called E-cadherin, which plays a crucial role in cell adhesion and epithelial architecture. Cell adhesion is the process by which cells bind together to form tissues and organs. E-cadherin is specifically involved in maintaining the integrity and stability of tissues, and plays a critical role in the normal functioning of the stomach lining. The CDH1 gene mutations that cause HDGC are those that completely destroy the protein function or result in loss of E-cadherin (truncating mutations) in gastric and breast epithelial cells. These are typically inherited in an autosomal dominant manner and affect multiple generations. Recently, loss of function variants (truncating mutations) in the alpha-catenin-1 protein, encoded by the CTNNA1 gene were identified in families meeting clinical criteria for HDGC, however the involvement of CTNNA1 in HDGC is less consolidated than for CDH1.

Symptoms or Manifestations

HDGC is often asymptomatic until cancer presents at an advanced stage. Therefore, screening and surveillance play a crucial role in the early detection and management of diffuse gastric cancer in individuals at risk. The most common symptoms include indigestion or heartburn, abdominal pains, loss of appetite, weight loss, nausea, vomiting, bloating and feeling of fullness. It is important to emphasize that these symptoms are common to various gastrointestinal issues, and experiencing them does not necessarily indicate the presence of HDGC or gastric cancer.
Lobular breast cancer is a distinct subtype of invasive breast cancer, and, similar to diffuse gastric cancer, its early detection is challenging due to the subtle and asymptomatic nature in early stages. Common symptoms associated with more advanced stages of lobular breast cancer may include changes in breast texture, skin thickening, nipple changes, or breast asymmetry.

Surveillance and Treatment

Management and prevention strategies for HDGC patients bearing CDH1 or CTNNA1 truncating mutations often involve surveillance with regular (annual) endoscopic examinations of the stomach and prophylactic (risk-reduction) total gastrectomy (surgical removal of the stomach). Endoscopic surveillance should be performed after age 18, unless there is family history of very early onset diffuse gastric cancer. Prophylactic gastrectomy should be discussed with the clinical team and considered preferentially after age 18.

Breast surveillance for HDGC patients bearing CDH1, but not CTNNA1 truncating mutations, should start at age 30 years with annual bilateral MRI screenings alongside yearly mammography between MRI screens from age 40. In case MRI is inaccessible, it should be combined with ultrasonographic evaluation. Bilateral risk-reduction mastectomy or contralateral risk-reduction mastectomy should be discussed in multidisciplinary teams.

The goal of these interventions is to prevent development of advanced cancer and/or to detect and treat cancer at an early and treatable stage.

Treatment of advanced diffuse gastric cancer and advanced lobular breast cancer follows the surgical and medical approaches used in sporadic cancer counterparts

Patient Association

Czech Republic: http://arcus-oc.org/

France: http://geneticancer.org

Italy: https://mutagens.it/ and https://viveresenzastomaco.org/chi-siamo/

Portugal: http://www.evitacancro.org and http://www.europacolon.pt/

Spain: http://actitudfrentealcancer.org

Belgium: https://digestivecancers.eu/for-patients/

Find Your Support

Individuals affected by HDGC can find their support by connecting to the patient organisation(s) and patients’ advocacy groups to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialised in rare diseases, namely Expert Reference Centres from the ERN GENTURIS, which represent the access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Oliveira C, et al. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol. 2015. doi: 10.1016/S1470-2045(14)71016-2. PMID: 25638682.
2. Lobo S, Benusiglio PR, Coulet F, Boussemart L, Golmard L, Spier I, Hüneburg R, Aretz S, Colas C, Oliveira C. Cancer predisposition and germline CTNNA1 variants. Eur J Med Genet. 2021 Oct;64(10):104316. doi: 10.1016/j.ejmg.2021.104316. Epub 2021 Aug 21. PMID: 34425242.
3. Blair VR et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020. doi: 10.1016/S1470-2045(20)30219-9.
4. Garcia-Pelaez J et al. Genotype-first approach to identify associations between CDH1 germline variants and cancer phenotypes: a multicentre study by the European Reference Network on Genetic Tumour Risk Syndromes. Lancet Oncol. 2023 doi: 10.1016/S1470-2045(22)00643-X.
5. Guilford P. & Decourtye-Espiard L. Hereditary Diffuse Gastric Cancer. Gastroenterology. 2023. DOI: 10.1053/j.gastro.2023.01.038

More Information

1. Diffuse Gastric and Lobular Breast Cancer Syndrome (DGLBC) by ERN Genturis
2. Hereditary Diffuse Gastric Cancer by MedlinePlus
3. Hereditary Diffuse Gastric Cancer by GARD

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 Organs affected by LFS. LFS has also been associated with various other cancer types.

Figure 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

Association 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/

Find Your Support

Individuals affected by LFS can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you will gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

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

Peutz-Jeghers Syndrome (PJS)

Definition

Peutz-Jeghers syndrome (PJS) is a rare condition marked by the existence of multiple hamartomatous polyps with a specific histologic pattern (Peutz-Jeghers polyps) across the gastrointestinal tract, excluding the oesophagus, alongside distinctive mucocutaneous pigmentation. Certain individuals with PJS manifest gastrointestinal polyps during childhood, necessitating ongoing medical attention into adulthood and occasionally experiencing severe complications that substantially impact their quality of life. Adult patients with PJS have in particular an increased risk for colorectal cancer, pancreatic cancer, and breast cancer (females).

Frequency

The estimated incidence of this condition ranges from 1 in 50,000 to 1 in 200,000 live births.

Genes

This autosomal dominant condition arises from constitutional pathogenic variants (“mutations”) in the STK11 gene, a crucial regulator of cell growth that, when altered, increases the susceptibility to various cancers.

Symptoms or Manifestations

The hallmark of PJS includes the formation of non-cancerous gastrointestinal hamartomatous polyps, most with the specific histologic features of a Peutz-Jeghers polyp, with a predominance in the small intestine. These polyps can result in symptoms such as abdominal pain, gastrointestinal bleeding, and bowel obstruction. Concurrently, individuals with PJS often exhibit mucocutaneous pigmentation during early childhood, characterised by dark blue or brown spots found on the lips, inside the mouth, and on the hands and feet. In addition, individuals with PJS might suffers from cancers affecting the breast, colon, rectum, pancreas, stomach, testicles, ovaries, lung, and cervix.

Surveillance

PJS involves a lifelong commitment to regular intense surveillance measures. These include in particular colonoscopy, upper endoscopy, and small-bowel examination by  video capsule endoscopy (VCE) and/or magnetic resonance enterography (MRE).in women, an intensive breast cancer surveillance including clinical breast, mammogram and breast MRI or bilateral mastectomy is recommended. Annual pancreatic cancer surveillance with imaging techniques (endoscopic ultrasound or MRI/MRCP) can be offered, ideallöy in specilized centers within scientific studies . Genetic counselling serves as a cornerstone in supporting individuals and families affected by PJS, aiding in informed decision-making and optimising healthcare strategies for improved outcomes.. Recommended guidelines are listed the surveillance organs shown in Figure Surveillance organs for PJS.

Figure Surveillance organs for PJS

Patient Association

Lynch and polyposis

Belgium: https://belgianfapa.be/nl/

France: https://www.hnpcc-lynch.com/

Germany: Peutz-Jeghers-Syndrom Germany (www.peutz-jeghers.eu)

Netherlands: http://www.lynch-polyposis.nl/

Spain: Afectados por el Síndrome de Peutz-Jeghers (http://sindromedepeutzjeghers.blogspot.com)

Hereditary Breast and Ovarian Cancer

Europe: https://www.europadonna.org

Germany: https://www.brca-netzwerk.de

Italy: http://www.abrcadabra.it

Northern Ireland: http://brcani.co.uk

UK: http://brcaumbrella.ning.com

Find Your Support

Individuals affected by PJS can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you will gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Wagner et al. The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline. J Clin Med 2021; PMID: 33513864
2. Hodgdon S.V. et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010. DOI: 10.1136/gut.2009.198499
3. Nakayama Y. et al. Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults. Digestion. 2023. DOI: 10.1159/000529799
4. Carsote M. et al. Peutz-Jeghers syndrome: Skin manifestations and endocrine anomalies (Review). Experimental and Therapeutic Medicine. 2021. DOI: 10.3892/etm.2021.10823
5. Syngal S. et al. ACG Clinical Guidelines: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes. 2015. DOI: 10.1038/ajg.2014.435

More Information

1. Peutz-Jeghers syndrome by MedlinePlus
2. Peutz-Jeghers syndrome by Gard
3. Lynch syndrome and polyposis by ERN Genturis
4. Peutz-Jeghers syndrome by GeneReviews

PTEN Hamartoma Tumour Syndrome (PHTS)

Definition

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare genetic disorder characterized by the development of hamartomas—benign, non-cancerous growths—in various organs and an increased risk of certain types of cancer.

Frequency

The estimated prevalence of PHTS is around 1 in 200,000 to 250,000, but it’s likely that the condition is underdiagnosed.

Genes

PHTS is caused by pathogenic germline variants in the tumour suppressor gene PTEN. When loss of function occurs in PTEN, it can lead to the dysregulation of cell growth and division, increasing the likelihood of hamartoma formation and cancer development. PHTS is inherited in an autosomal dominant pattern and can also occur newly (de novo) in individuals.

Symptoms or Manifestations

The phenotype of PHTS is diverse and includes hamartomas manifesting in tissues such as the skin, mucous membranes, gastrointestinal tract, and central nervous system. Additionally, individuals with PHTS have increased risks of certain cancer types, particularly female breast, thyroid, endometrial, colorectal and renal cancer, and melanoma (illustrated in Figure Organs Affected by PHTS).  Some individuals may also present with neurodevelopmental delay, autism spectrum disorder, arteriovenous malformations, and macrocephaly (enlarged head).

Figure Organs affected by PHTS

Treatment and Surveillance

PHTS requires a multidisciplinary approach involving various medical specialities. Regular surveillance for cancer risk and proactive management of symptomatic hamartomas are key components of care. Cancer surveillance is recommended for breast (female), thyroid, kidneys, and colon. Genetic counselling serves as a cornerstone in guiding individuals and families affected by PHTS, offering support and facilitating informed decision-making about their health and well-being.

Patient Association

Belgium and The Netherlands: https://www.ptenbelgienederland.nl

Germany: http://shg-cobald.de/

Italy: http://www.ptenitalia.org/

UK & Ireland: http://ptenuki.org/

International: https://ptenfoundation.org/family-council/

Find Your Support

Individuals affected by PHTS can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you will gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Hoogerbrugge N. et al. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. European Journal of Human Genetics. 2020. DOI: 10.1038/s41431-020-0651-7
2. Pilarski R. PTEN hamartoma tumor syndrome: a clinical overview. Cancers (Basel). 2019. DOI: 10.3390/cancers11060844
3. Hendricks L.A.J. et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. Journal of the National Cancer Institute. 2023. DOI: 10.1093/jnci/djac188
4. Elsayes K. PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy. Cancers. 2021. DOI: 10.3390/cancers13133120
5. Hendricks L.A.J. et al. Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review. European Journal of Medical Genetics. 2022. DOI: 1016/j.ejmg.2022.104533
6. Hendricks L.A.J. et al. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. European Journal of Medical Genetics. 2022. DOI: 10.1016/j.ejmg.2022.104632

More Information

1. PTEN Hamartoma Tumour Syndrome (PHTS) by ERN Genturis
2. PTEN hamartoma tumor syndrome by GARD

 

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)

Definition

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is a rare genetic syndrome that is characterised by the development of leiomyomas (benign smooth muscle tumours) in the skin and uterus, as well as an increased risk of type 2 pappilary renal cell cancer (RCC), a type of kidney cancer.

Frequency

The prevalence is not known precisely, but earlier estimates indicate that it might be around 1 in 200,000 individuals.

Genes

HLRCC is caused by mutations in the FH gene, which encodes the enzyme fumarate hydratase. This enzyme is involved in the Krebs cycle, a key cellular process for energy production. Mutations in the FH gene lead to the accumulation of fumarate, which can contribute to the development of tumours.

Symptoms or Manifestations

HLRCC often experience the development of multiple painful skin leiomyomas, which are non-cancerous smooth muscle tumours. Additionally, they may present with uterine fibroids, leading to complications such as early-onset uterine cancer in some cases. The increased risk of renal cell carcinoma, a type of kidney cancer known for its aggressiveness, is a significant concern for those with HLRCC. The organs affected by this cancer are illustrated by Figure Organ affected by HLRCC.

Figure Organ affected by HLRCC

Treatment and Surveillance

Given the hereditary nature of HLRCC, genetic counselling and testing are essential for individuals with a family history of the condition. Management and treatment strategies may vary depending on the specific symptoms and manifestations in each individual. Regular monitoring and early intervention for renal cell cancer are crucial for improving outcomes in individuals with HLRCC.

Patient Association

UK: https://ikcc.org/about-ikcc/

Find Your Support

Individuals affected by HLRCC can find their support by connecting to the patient organisation(s) to receive invaluable comfort, guidance, and encouragement and should engage with healthcare professionals specialising in rare diseases, you wll gain access to a wealth of knowledge and resources.

Additionally, stay informed about RTRS through our social media channels and European Reference Network Genetic Tumour Risk Syndromes (ERN Genturis) to ensure that you are up-to-date with the latest information about RTRS.

References

1. Ooi A. Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research. Seminars in Cancer Biology. 2020: DOI:10.1016/j.semcancer.2019.10.016.
2. Zeng C. et al. Hereditary Leiomyomatosis and Renal Cell Cancer: Recent Insights Into Mechanisms and Systemic Treatment. Frontiers in Oncology. 2021. DOI: 10.3389/fonc.2021.686556.
3. Iliopoilos O. Diseases of Hereditary Renal Cell Cancers. Urologic Clinics of North America. 2023. DOI: 10.1016/j.ucl.2023.01.01.

More Information

1. Hereditary leiomyomatosis and renal cell cancer by MedlinePlus
2. Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) by ERN Genturis
3. Hereditary leiomyomatosis and renal cell cancer by Gard