When to Consider Referral to a Genetic Counselor for Lesser Known Cancer Syndromes

Carmelina E. Heydrich, MS, Katherine A. Schneider, MPH, and Huma Q. Rana, MD
Published: Sunday, Apr 05, 2015

This article reviews two newly described cancer syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four uncommon syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease which can be under-recognized in an oncology practice. Clinical features and indications for testing are reviewed to help oncologists identify patients appropriate for genetic evaluation. Medical management recommendations and notable counseling points, such as potential for pediatric risk are detailed to highlight the importance of testing for patients and families.


Over 200 hereditary cancer syndromes have been described, with the majority being rare or uncommon. These syndromes are almost certainly under-reported given the broad range and variable expressivity of the associated features. The advent of next generation sequencing has enabled greater access to testing and has led to the discovery that at least some of these syndromes are more common than previously thought.

The major benefit of cancer genetic testing is that it can lead to personalized treatment, screening, and risk reducing strategies for patients and their families. Oncologists are often the first-line providers in helping to recognize patients with inherited cancer syndromes and are increasingly integrating genetic test results in the care of their patients. While referrals to cancer genetics are diverse in nature, some indications include: patients with rare tumor types, patients diagnosed with cancer at younger than typical ages, patients diagnosed with multiple primary cancers, patients who do not have cancer, but do have at least one relative with a rare tumor or at least two relatives with related cancers or multiple primaries, and/or patients who have a known gene mutation in the family.

In this review, we discuss the clinical features, gene function, and medical management recommendations for six hereditary cancer syndromes. This includes two newly described syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four under-recognized syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease.

DICER1 Syndrome

DICER1 syndrome is an autosomal dominant hereditary cancer syndrome.1 The most common features of DICER1 syndrome are pleuropulmonary blastomas (PPB), cystic nephromas, and ovarian sex-cord stromal tumors, especially Sertoli Leydig2-4. Other associated tumors include embryonal rhabdomyosarcomas of the uterine cervix and other sites, nasal chondromesenchymal hamartomas, cerebral and ciliary body medulloepitheliomas, pituitary blastoma, Wilms’ tumor, bladder cancer, and thyroid cancer.4-9 Juvenile hamartomatous intestinal polyps, multinodular goiter, and thyroid, lung, and kidney cysts are also seen.9

The cancer risk is highest in early childhood, in large part due to the PPB risk with the majority of DICER1-associated tumors occurring before age 40.1 DICER1 syndrome is newly described and information about associated cancer risks is still emerging. The DICER1-related lifetime tumor risk seems to be 50% for females and 20% for males.1,10 Individuals who have personal and/or family histories of PPB, cystic nephroma, ovarian sex-cord stromal tumor, nasal chondromesenchymal hamartoma, medulloepitheliomas, pituitary blastoma, and/or embryonal rhabdomyosarcoma of the uterine cervix should be offered DICER1 genetic testing.1,4,9

DICER1 is a ribonuclease responsible for producing short-interfering RNA and microRNA (miRNA) that regulate post-translational gene expression.2,4,10 Aberrant DICER1 function results in oncogenic miRNA, which does not require loss of the wild-type allele or a second-hit for disease development.9

Management for infants and children with DICER1 syndrome includes complete physical exams, chest CT scans, chest x-rays, and renal ultrasound exams. Older children and adults with DICER1 syndrome should have clinical thyroid exams and possibly thyroid ultrasound scans.1,3

BAP1 Tumor Predisposition Syndrome

BAP1 (BRCA1 associated protein-1) tumor predisposition syndrome is an autosomal dominant inherited cancer syndrome. Germline BAP1 mutations are associated with an increased risk for atypical melanocytic tumors, cutaneous and uveal melanoma, mesothelioma, and renal cell carcinomas,11, 12. The atypical melanocytic lesions resemble Spitz nevi and have been characterized as “atypical Spitz tumors” (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.13, 14

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