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First Case of Myhre Syndrome Diagnosed in an Adult after Hereditary Cancer Gene Panel Testing

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First Case of Myhre Syndrome Diagnosed in an Adult after Hereditary Cancer Gene Panel Testing

Topic: Cancer Genetics

Presenting Author: Isha Kalia

Co-Authors: A. Alali, Montefiore Medical Center; E. Pereira, Montefiore Medical Center, Albert Einstein College of Medicine; T. Goldwaser, Montefiore Medical Center, Albert Einstein College of Medicine; S. Klugman, Montefiore Medical Center, Albert Einstein College of Medicine

Session Type: Poster Presentation only


Background:  Multi-gene hereditary cancer panels allow for the analysis of multiple hereditary cancer genes with a single sample of DNA. Cancer panels became commercially available in 2013 and are routinely offered in clinical practice for indications including a personal and/or family history of cancer. National Comprehensive Cancer Network encourages multi-gene cancer panels in instances where more than one gene can explain an inherited cancer syndrome and when an individual has tested negative for a single syndrome, especially when a personal and/or family history is strongly suggestive of an inherited predisposition. While panel testing can provide critical information in instances of imperfect family histories, one of the main challenges to this testing is the discovery of new genetic mutations.

Mutations in the SMAD4 gene are associated with cholangiocarcinoma, juveline polyposis syndrome, hereditary hemorrhagic telangiectasia and Myhre syndrome. Myhre syndrome is a rare autosomal dominant connective tissue disorder characterized by skeletal abnormalities, dysmorphic facial features, intellectual disability and hearing loss. To date, there are only 54 documented cases of Myhre syndrome in the literature. Most often Myhre syndrome is diagnosed in childhood due to medical history, symptoms and physical exam.

Case: A 47-year-old Puerto Rican woman was seen for genetic consultation due to a personal history of stage IA endometrial carcinoma. Patient reported a significant family history of cancer including 1 full brother who died of colon cancer at age 28, 1 maternal uncle who died of colon cancer in his 80s, 1 maternal first cousin with colon cancer diagnosed in his 50s, 2 maternal aunts with cancer (1 with endometrial and 1 with breast, ages of diagnosis unknown), and 1 maternal first cousin with breast cancer (age of diagnosis unknown).

The results from the 32 gene panel determined that the patient had a pathogenic mutation in the SMAD4 gene (p.R496C) and two variants of uncertain significance in the PMS2 (p.V717M) and POLE (c.6682_6684delAAG) genes. The documented mutation is consistent with a diagnosis of Myhre syndrome. The patient welcomed the diagnosis as it provided her with a name for her lifelong suspicions.

Workup: After results disclosure, the patient had a full genetic physical exam, revealing some signs and symptoms consistent with Myhre syndrome. Her skeletal abnormalities included short stature- 143 cm tall (<5th percentile) and arthritis in her right hand and both knees. Patient had bilateral brachydactyly of fingers and toes, mild prognathia, bilateral belpharophimosis, short philtrum, high arched palate and small head circumference- 51 cm (3rd percentile). She had bilateral mild sensorineural hearing loss by audiology, mild myopia and dry eye. Though our patient is employed, she has never lived independently. Patient reported menstrual issues including bleeding every day from 15 to 26 years old. However, our patient did not have any cardiac issues often associated with Myhre syndrome.

Conclusion: To our knowledge, this is the first case of Myhre syndrome diagnosed in an adult when testing for hereditary cancer predisposition syndromes. While this patient had multiple symptoms and had seen many medical providers over 47 years, she had never seen a geneticist. Genetics providers must be prepared for the incidental findings in multi-gene hereditary cancer panels.  While providers cannot discuss all possible syndromes with patients in the informed consent process for multi-gene cancer testing, they must inform patients of the potential for unexpected findings, such as the discovery of genetic mutations responsible for disorders other than cancer.

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