Clinical and genetic diagnosis of Cowden syndrome: A case report of a rare PTEN germline variant and diverse clinical presentation

Abstract

Introduction: Cowden syndrome is a rare autosomal dominant disease characterized by the development of hamartomas and increased risks of other tumors, including breast, thyroid, and uterine cancers. Most patients with Cowden syndrome show mutations of the phosphatase and tensin homolog (PTEN) gene on chromosome 10; however, some patients with mutations do not show clinical symptoms, while patients with clinical symptoms may not have detectable PTEN mutations.Case presentation: A 39-year-old woman with macrocephaly had previously been diagnosed with Cowden syndrome at another hospital, when she presented with the onset of breast cancer. A wide variety of complications were detected, including cerebellar tumors treated by resection, hydrocephalus, and multiple polyps in the stomach and large intestine. She was further diagnosed with adult-onset Lhermitte-Duclos disease as a complication of Cowden syndrome. She subsequently developed a dural arteriovenous fistula treated by transvenous embolization. After transfer to our hospital, she developed adenomatous goiter treated by resection, recurrent breast cancer treated with hormonal therapy, and multifocal oral mucosal papillomatosis. Her older sister had previously been diagnosed with Cowden syndrome and her father was undiagnosed but had macrocephaly, hydrocephalus, and multifocal oral mucosal papillomatosis, suggestive of Cowden syndrome. After consultation with a genetic specialist, analysis of the PTEN gene showed a rare but likely pathogenic germline c.801 + 2T>A variant located at the splice donor site of intron 7. The patient's clinical diagnosis of Cowden syndrome was accordingly confirmed by the genetic findings. Appropriate surveillance procedures were put in place to detect any further tumors. Conclusions:The clinical symptoms of Cowden syndrome do not always correlate with the genetic results. However, recent improvements in genetic testing suggest the importance of diagnosing this disease using both clinical and genetic approaches, in collaboration with genetic experts, to ensure an accurate diagnosis and appropriate surveillance for malignant tumors.Abbreviations: AKT = protein kinase B, mRNA = messenger RNA, mTOR = mammalian target of rapamycin, NCCN = National Comprehensive Cancer Network, PHTS = PTEN hypomethyloma syndrome, PI3K = phosphoinositide 3-kinase, PTEN = phosphatase and tensin homolog, RNA = ribonucleic acid.

mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development

“…Routine molecular testing and integration of genetic results into the classification and diagnosis of FMCDs will be key to enhancing the characterization of FMCD cohorts, improving our understanding of underlying pathophysiology and allowing development of novel targeted treatment options and personalized medicine. 53 …”

Insights into Clinical Disorders in Cowden Syndrome: A Comprehensive Review

“…PHTS is an autosomal dominant genetic predisposition caused by heterozygous germline variants in the PTEN tumour suppressor gene, localised on 10q23.31 [3,4]. The PTEN gene is endowed with a double activity: lipid phosphatase and protein phosphatase at the cytoplasmic level.…”

“…Kidney complications have a recognized association with CS [3,47]. The literature reports both benign manifestations, such as renal cysts [22], and malignant ones, notably renal cell carcinoma (RCC) [15,29].…”

“…The literature reports both benign manifestations, such as renal cysts [22], and malignant ones, notably renal cell carcinoma (RCC) [15,29]. RCC is considered a minor diagnostic criterion for CS [3,29], and in the general population, the risk of developing RCC is approximately 1.6% [2,23,42]. However, in CS patients, the lifetime risk is significantly elevated, with estimates ranging from 34% to 35% [4,24,29].…”

“…1 Moderate evidence for the age of commencement of surveillance 2. Consider further surveillance as required 3. Consider surveillance as part of clinical trials.…”