Considerations on Diagnosis and Surveillance Measures of PTEN Hamartoma Tumor Syndrome: Clinical and Genetic Study in a Series of Spanish Patients.

Background: The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease.Results: We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES).Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research.Conclusions: This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.

PTEN Hamartoma Tumor Syndrome/Cowden Syndrome: Genomics, Oncogenesis, and Imaging Review for Associated Lesions and Malignancy

PTEN hamartoma tumor syndrome/Cowden syndrome (CS) is a rare autosomal dominant syndrome containing a germline PTEN mutation that leads to the development of multisystem hamartomas and oncogenesis. Benign tumors such as Lhermitte–Duclos disease and malignant tumors involving the breast, thyroid, kidneys, and uterus are seen in CS. Radiologists have an integral role in the comanagement of CS patients. We present the associated imaging findings and imaging screening recommendations. Knowledge of the types of cancers commonly seen in CS and their imaging findings can aid in early tumor recognition during cancer screening to help ensure near-normal life spans in CS patients.

The Clinical Spectrum of PTEN Hamartoma Tumor Syndrome: Exploring the Value of Thyroid Surveillance

<b><i>Introduction:</i></b> Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) comprises a collection of clinical features characterized by constitutional variants in <i>PTEN</i>. Several guidelines recommend thyroid screening, beginning at the pediatric age at the time of PHTS diagnosis; however, the benefits of early surveillance has not been well defined. <b><i>Methods:</i></b> We conducted a retrospective investigation of patients followed up at the Children’s Hospital of Philadelphia with a diagnosis of PHTS between January 2003 and June 2019. In total, 81 patients younger than 19 years were identified. <b><i>Results:</i></b> The most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%). A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (51.7%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 7.4% (6/81) diagnosed with thyroid cancer. All thyroid cancer patients were older than 10 years at diagnosis, and all displayed low-invasive behavior. Of the patients younger than 10 years at the time of thyroid ultrasound (US) surveillance, 71.4% (15/21) had a normal US. The remaining 6 patients had thyroid nodules, including 4 undergoing thyroid surgery with benign histology. <b><i>Discussion/Conclusion:</i></b> Patients with macrocephaly, impaired cognitive development and thyroid nodules, and/or early-onset gastrointestinal polyps should undergo constitutional testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance before 10 years of age. In PHTS patients with a normal physical examination, thyroid US surveillance can be delayed until 10 years of age.

Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome

Context Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear. Objective Determine the prevalence and natural history of thyroid disease in children with PHTS. Design Retrospective cohort study (1998-2019). Setting Academic pediatric hospital. Patients Individuals with genetically confirmed PHTS diagnosed before age 19 years. Interventions Description of clinical, thyroid ultrasound, and laboratory characteristics. Main Outcome Measures Prevalence of thyroid nodules ≥10mm diameter, and time course and risk factors for nodule development, assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease. Results Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males [10.8 (7.0-17.9) vs. 14.2 (9.9-22.9) years, p=0.009]. In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (HR 2.90, 95% CI 1.16-7.27, p=0.02) and inversely associated with the presence of neurological findings of PHTS (HR 0.27, 95% CI 0.10-0.69, p=0.007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed. Conclusion Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.