A 32 year-old Caucasian female with history of asthma, hypothyroidism, and renal cell carcinoma (RCC) status-post right nephrectomy, presented with a progressively enlarging goiter causing solid food dysphagia. She had been diagnosed with goiter two years previously, but was lost to follow-up. A CT of the neck prior to hospital evaluation demonstrated a significantly enlarged thyroid. Medicine was consulted for symptomatic hypocalcemia following total thyroidectomy. Surgical pathology returned as papillary thyroid carcinoma with follicular-variants.
The patient also had prominent macrocephaly and disclosed a history of a resected hamartoma and acral tumors. Therefore, we hypothesized there might be a connection between her young age and multiple malignancies, as well as her macrocephaly and benign tumors. There was no familial history of thyroid or renal cancer, but majority of family history was unknown. Given these findings, phosphatase and tensin homolog protein encoding gene (PTEN) hamartoma tumor syndrome was thought to be the most likely diagnosis. Genetic testing was therefore performed, which confirmed a heterozygous mutation in the PTEN gene, a pathologic gene mutation consistent with the PTEN hamartoma tumor syndrome, a variant of which is Cowden syndrome.
The tumor suppressor gene PTEN is instrumental in controlling malignancy. When a mutation of the PTEN gene occurs, both benign and malignant cells can divide uncontrollably. The umbrella of PTEN mutations is known as PTEN hamartoma tumor syndrome, which encompasses three autosomal dominant genetic disorders: Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and Proteus and Proteus-like syndrome. CS is characterized by macrocephaly (in 80-100% of patients), the development of hamartomas, and a significant risk for numerous malignancies at much higher rates than the general population. Associated malignancies include breast, thyroid, endometrial, renal cell carcinoma and colorectal cancer. CS presents a 77% lifetime risk of breast cancer, a 38% lifetime risk of thyroid cancers and an 85% lifetime risk of all associated cancers. Although CS is considered a rare disorder (1 in 200,000), many patients are likely undiagnosed given lack of familiarity with the syndrome. Clinical diagnosis of CS involves a scoring system based on major and minor criteria. Once appropriate criteria are met, confirmatory genetic testing is recommended. Given the significantly elevated risk of developing numerous malignancies associated with CS, cancer screening in this group of individuals varies markedly from those utilized in the general population.
In the hospital setting, we treat patients with malignancy often, some of which are young adults. This vignette demonstrates the importance of considering a genetic syndrome in the differential for such patients, especially young adults with a history of multiple malignancies and also those with macrocephaly.
To cite this abstract:Garber A, Derby P. Big Heads, Bigger Problems; from Goiter to Genetic Disorder. Abstract published at Hospital Medicine 2015, March 29-April 1, National Harbor, Md. Abstract 525. Journal of Hospital Medicine. 2015; 10 (suppl 2). https://www.shmabstracts.com/abstract/big-heads-bigger-problems-from-goiter-to-genetic-disorder/. Accessed April 6, 2020.