PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Abstract

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended.

Thyroid cancer in adolescents and young adults

“…The genetic basis of autosomal dominant inherited nonmedullary TC is not known. The risk for DTC is increased in familial adenomatous polyposis (Gardner syndrome), Cowden disease, DICER1 mutations, the full spectrum of PTEN hamartoma tumor syndrome, Werner Syndrome, and the Carney complex …”

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

“…Of note, maternal imprinting with silencing of the maternal allele occurs for SDHD and SDHAF2, and thus, only mutations inherited from the father will cause disease [10,11]. Some of the genetic syndromes associated with PPGL can be diagnosed based on clinical criteria [Multiple Endocrine Neoplasia type 2 (MEN2), Von Hippel Lindau syndrome (VHL), Neurofibromatosis type 1 (NF1), Multiple Endocrine Neoplasia type (MEN1) and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC)], see Table 1 [12][13][14][15][16][17][18], and recommendations for the surveillance of healthy carriers of pathogenic variants in these syndromes are already published [19][20][21][22][23][24][25][26][27][28][29][30][31], Table 2. Surveillance recommendations were lacking at the initiation of this work for genes discovered from year 2000 and onwards: SDHA, SDHB, SHDC, SDHD, SDHAF2 (together abbreviated SDHx), as well as TMEM127, and MAX [10,[32][33][34][35][36][37][38].…”

Next Generation Sequencing and Pediatric Brain Tumors: Detection of Cancer Predisposition Syndromes in Patients and Their Families

“…The benefit of such programs has been established for common CPS such as familial breast and ovarian cancer [4], hereditary colorectal cancer [5], neurofibromatosis [16,17], or multiple endocrine neoplasia [18,19]. Also, for very rare CPS such as DICER1 syndrome or hereditary paraganglioma/pheochromocytoma syndrome, surveillance recommendations exist [20][21][22] and recent data show advantages for patients with TP53 variants under screening protocols [23,24]. A benefit of screening for rare pediatric CPS is assumed but needs to be evaluated in ongoing studies [25].…”