Scientific Background


Li-Fraumeni syndrome (LFS) is a rare familial tumor disease characterized by the occurrence of multiple tumors (soft tissue sarcomas, osteosarcomas, brain tumors, breast cancer, leukemias, adrenocortical carcinomas). It is inherited in an autosomal dominant pattern, and the prevalence is estimated at 1:5,000 to 1:20,000. The risk of developing a tumor before the age of 31 is estimated to be about 40-50%, whilst from the age of 70 onward the risk is 70-100%.


Criteria for the diagnosis of LFS include:


  • index patient with sarcoma before the age of 45; and
  • first degree relative with carcinoma before the age of 45; and
  • other first or second degree relatives with carcinoma before the age of 45 or sarcoma regardless of age of manifestation.


LFS is caused by germline variants in the tumor suppressor gene TP53. After pathogenic TP53 variants were also identified in families that did not meet the LFS or LFL (Li-Fraumeni like) criteria due to a different tumor spectrum, age of manifestation or sporadic tumor incidence, the Chompret criteria were defined in 2001 and revised in 2017.


The revised Chompret criteria (National Comprehensive Cancer Network, NCCN Guidelines 2017) are:


  • index patient with a tumor from the LFS spectrum (soft tissue sarcoma, osteosarcoma, breast cancer, brain tumor, adrenal sarcoma, leukemia, bronchoalveolar lung carcinoma, adrenocortical carcinoma) before the age of 46; and
  • at least one first or second degree relative with an LFS tumor (excluding breast cancer if the index patient has breast cancer) before the age of 56; or
  • index patient with multiple tumors (except breast cancer), two of which are from the LFS spectrum, and the manifestation of the first occurred before the age of 46; or
  • index patient with an adrenal sarcoma or carcinoma of the choroid plexus, regardless of the family history; or
  • index patient with breast cancer before the age of 31.


Pathogenic germline variants can be detected in TP53 in up to 70-80% of families with classical LFS, but only in 40% of patients with LSF-L. In breast cancer patients who become ill before the age of 31, pathogenic germline variants can be detected in TP53 in 3-8% of cases.


In a high percentage of cases, heterozygous TP53 germline variants lead to a total loss of function of the gene product p53 after modification of the second, still intact allele (loss of heterozygosity, LOH). The cellular tumor antigen p53 has an important role as a "guardian of the genome", since it can convert the cell into the G0 phase at the control point between the G1 and S phases of the cell cycle. This initially stops cell division in order to repair possible damage in the cellular DNA or to initiate controlled cell death (apoptosis). In addition to germline variants in families with LFS, somatic variants in TP53 are the most common genetic modification in malignant tumors. In a few families with LFS or LFS-L, pathogenic variants in the CHEK2 gene have been detected.


Carriers with a proven pathogenic variant in the TP53 gene should make use of intensified preventive examinations at specialized centers with regard to LFS-associated tumor diseases. The benefits and risks of radiation diagnostics and therapy should be considered. Blood relatives and offspring of TP53 carriers have an increased risk of being carriers themselves, and they can be specifically tested for the variant detected in the family after a genetic consultation. Predictive testing should be performed early in infancy.



NCCN Guidelines®, Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 1, 2018 / Valdez et al. 2017, Br J Haematol 176:539 / Vogel et al. 2017, J Adv Pract Oncol 8(7):742-746 / Chen et al. 2016, Cold Spring Harb Perspect Med 6(3):a026104 / Bougeard et al. 2015, Indikation J Clin Oncol 33:2345 / Schneider et al 2013, Li-Fraumeni-Syndrome, GeneReviews®, / Villani et al. 2011, Lancet Oncol 12(6):559 / Tinat et al. 2009, J Clin Oncol 27:1 / Bougeard et al. 2009, J Clin Oncol 27:e108 / Ruijs et al. 2009, Hered Cancer Clin Pract 7:4 / Varley 2003, Hum Mutat 21:313 / Chompret 2002, Biochimie 84:75




Phenotypically, PTEN hamartoma tumor syndrome (PHTS) can be divided into Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS) and Proteus-like syndrome depending on the clinical manifestation.


Cowden syndrome (CS) is an autosomal dominant inherited disease with a prevalence of 1:200,000 that is characterized by the presence of gastrointestinal hamartoma, breast cancer, endometrial carcinoma, follicular thyroid carcinoma, mucocutaneous lesions and macrocephaly (main criteria). In addition, intestinal cancer, lipomas, loss of intelligence, renal cell carcinoma and/or vascular abnormalities (secondary criteria) may occur.


According to the diagnostic recommendations of the National Comprehensive Cancer Network 2018, genetic diagnostics is indicated when in a patient:


  • three or more of the main criteria are fulfilled, whereby either macrocephaly, Lhermitte-Duclos disease or gastrointestinal hamartoma have been detected; or
  • two main criteria and three secondary criteria are met.


Bannayan-Riley-Ruvalcaba syndrome is characterized by macrocephaly, intestinal hamartomatous polyps, lipomas and genital maculae. The prevalence of BRRS is unknown. The most common manifestations of Proteus syndrome are macrodactyly and hemihypertrophy.


PHTS is caused by pathogenic germline variants in the tumor suppressor gene PTEN in about 60-80% of patients. The phosphatase PTEN is mainly involved in the regulation of the AKT/PKB signaling pathway and inhibits cell proliferation. Causal variants in PTEN can lead to the defective regulation of the cell cycle and to the uncontrolled division of the affected cell. In about 30% of the patients with Cowden-like symptoms and without evidence of a pathogenic PTEN variant, hypermethylations of the KLLN gene can be detected. Pathogenic germline variants in the SDHB, SDHC, SDHD, AKT1 and PIK3CA genes are detected less frequently. Differential diagnosis should also exclude suspicion of Peutz-Jeghers syndrome (PJS), Birt-Hogg-Dube syndrome (BHD) and neurofibromatosis type 1 (NF1).


If a pathogenic PTEN variant is detected, patients should undergo more intensive preventive examinations such as thyroid sonography and colonoscopy. In addition, female carriers should be offered intensive examinations with regards to breast and endometrial carcinomas. Furthermore, a prophylactic hysterectomy can be considered from the age of 40 (or 5 years before the earliest age of illness in the family). The current S3 guideline recommends regular monitoring of PHTS/CS patients in cooperation with specialized centers.



Valle et al. 2019, J Pathol 247:574 / Pilarski et al. 2019, Cancers 11:844 / Leitlinienprogramm Onkologie: Diagnostik, Therapie und Nachsorge der Patientinnen mit Endometriumkarzinom, Langversion 1.0, 2018 / Lorans et al. 2018, Clin Colorectal Cancer 17:e293 / Syngal et al. 2015, Am J Gastroenterol 110: 223 / Eng et al. 2016, PTEN Hamartoma Tumor Syndrome, GeneReviews®, / Jelsing et al. 2014, Orphanet Journal of Rare Disease 9:101




DICER1 syndrome is a rare, autosomal dominant hereditary predisposition disorder with (moderately) increased risk for the development of certain benign and malignant tumors. In the few cases reported so far, pleuropulmonary blastomas, multinodular goiter, cystic nephromas, thyroid tumors, rhabdomyosarcoma and Sertoli-Leydig cell tumors of the ovaries have been diagnosed. In addition, pineoblastomas, developmental disorders, lung cysts or macrocephaly can also occur. The tumors mostly occur in children and adolescents. The severity of the tumors is variable, even within a family. In addition, there are indications that the penetrance is not complete, so that it can sometimes be difficult to identify carriers. The prevalence is unknown.


It is caused by inactivating variants in the DICER1 gene which is located on chromosome 14q32.13 and consists of 27 exons. The gene encodes the 1922 amino acid long endoribonuclease DICER, which controls the formation of microRNAs and thus plays a role in the translational control of protein synthesis. It is possible that inactivating variants in DICER1 lead to loss of expression control of tumor suppressor or proto-oncogenes and thus to an increased risk of tumors. However, only after failure of the second intact DICER1 allele by spontaneous somatic variants, can the affected cell degenerate. It is estimated that 80% of carriers inherit the causative variants from one parent and 20% develop them de novo.


The therapy of affected persons depends on the type of manifestation. As soon as a pathogenic variant has been identified, blood relatives can be specifically tested. However, due to the rarity of the syndrome, there are currently no precautionary screening recommendations for carriers or persons at risk. Annual physical examinations and imaging procedures have been proposed depending on the age of the carrier.



Stewart et al. 2019, J Clin Oncol 10:37 / Robertson et al. 2018, Cancers (Basel) 10:143 / Schultz et al. 2018, Clin Cancer Res 15:2251 / Bueno et al. 2017, Pediatr Radiol 47:1292 / Doros et al. DICER1-Related Disorders. 2014 Apr 24. GeneReviews®, NBK196157/




Peutz-Jeghers syndrome (PJS, or hamartomatous intestinal polyposis) is a rare, autosomal dominant inherited disorder with an estimated prevalence of 1-9:1,000,000. Two symptom complexes are characteristic of PJS:

1. hamartomatous polyps in the GI tract (the jejunum has a predisposition to intussusception, obturation and intestinal bleeding, secondary anemia) and

2. pigment spots on lips, mucous membranes, fingers, toes and vulva, occurring mostly in infancy and early childhood.


Patients also have a disposition to gastrointestinal tumors and an increased risk of ovarian, cervical, pancreatic, lung, testicular and breast cancer. Carriers have a cumulative risk of up to 90% of developing an intestinal or extraintestinal tumor during their life.


Clinically, PJS is considered confirmed if one of the following criteria is met:

  • patient with two or more histologically confirmed hamartomatous polyps;
  • patient with any number of hamartomatous polyps and positive family history;
  • patient with characteristic mucocutaneous pigmentation and positive family history;
  • patient with any number of hamartomatous polyps and mucocutaneous pigmentation.


PJS is caused by pathogenic variants in the STK11 (LKB1) gene, which codes for a serine-threonine kinase with tumor suppressor activity. The inactivation of STK11 leads to the dysregulation of the mTOR signal transduction pathway, which plays a central role in the development of hamartomatous syndromes. In patients with clinically confirmed diagnosis and positive family history, the detection rate for point mutations in the STK11 gene is up to 70%. In patients without a conspicuous family history, causative variants are detected in STK11 in 20‑60% of cases. Since 15-30% of all pathogenic variants in the STK11 gene are deletions of single or multiple exons, the sensitivity of the examination can be increased to more than 90% by combining several methods (e.g., CNV diagnosis). The current S3 guideline recommends regular monitoring of PJS patients in cooperation with specialized centers.



Daniell et al. 2018, Fam Cancer 17:421 / McGarrity et al. 2016, Peutz-Jeghers syndrome, GeneReviews®, NBK1266/ / Yang et al. 2010, Dig Dis Sci 55:3458 / Aretz 2010, Dtsch Arztbl Int 107:163 / Beggs et al. 2010, Gut 59:975 / Restaetal. 2010, Hum Genet 128:373




Basal cell nevus syndrome (BCNS), also known as nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome, is an autosomal dominantly inherited disorder with variable clinical expression. The prevalence ranges from 1 in 57,000 in England to 1 in 256,000 in Italy. A predisposition for various carcinomas is characteristic. The most frequent clinical manifestations are multiple basal cell carcinomas (BCC), odontogenic keratocysts of the jaws, hyperkeratosis of the palms of the hands and soles of the feet, skeletal anomalies, ectopic intracranial calcifications and facial dysmorphia. To make a diagnosis, a distinction is made between main and secondary criteria. The clinical diagnosis of BCNS can be confirmed by the presence of two primary criteria and one secondary criterion, or one primary criterion in conjunction with three secondary criteria (Evans et al. 1993, J Med Genet. 30: 460; Kimonis et al. 1997, Am J Med Genet. 69:299).


Main criteria:


  • multiple basal cell carcinoma (BCCs >5) or one before the age of 30;
  • odontogenic keratocysts of the jaw;
  • palmar/plantar pits (≥2);
  • calcification of the falx cerebri;
  • first degree relative with BCNS.


Secondary criteria:


  • medulloblastoma in childhood;
  • macrocephaly (≥97th percentile);
  • cleft lip and palate;
  • anomalies of the vertebrae, rib anomalies;
  • preaxial or postaxial syndactyly;
  • ovarian/cardiac fibroids;
  • eye abnormalities;
  • lymphomesenteric/pleural cysts.


The molecular causes of BCNS are pathogenic variants in the PTCH1 gene, which is responsible for the patched receptor, a negative regulator within the Sonic Hedgehog signal transmission. Sequencing of all coding exons of the PTCH1 gene can detect a pathogenic change in 50-85% of patients; in 6-21% of patients, a genomic deletion or duplication in the PTCH1 gene is present. In 6% of BCNS patients a pathogenic variant in the SUFU gene can be identified by sequencing or deletion/duplication analysis. Patients with a pathogenic alteration in the SUFU gene have a higher risk of developing medulloblastoma compared to patients with PTCH1 variants. In individual cases, pathogenic variants in the PTCH2 gene have also been described in patients with BCNS.



Evans and Farndon In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® (Updated March 29, 2018) / Akbari et al. 2018, Pathophysiology 25:77 / Thomas et al. 2016, Ann Maxillofac Surg. 6:120 / John and Schwartz 2016, Br J Dermatol. 174:68


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