Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Abstract

Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the Multiple Endocrine Neoplasia (MEN) syndromes, including MEN1, MEN2A and B, MEN4, and Hyperparathyroid-Jaw Tumor (HPT-JT) Syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic MEN1 variants (11q13), MEN2A and B are due to pathogenic RET variants (10q11.21), MEN4 is due to pathogenic CDKN1B variants (12p13.1), and the HPT-JT Syndrome is due to pathogenic CDC73 variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome.

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

“…Depending on the affected gene, family members at risk can be included in prevention and surveillance programs, as illustrated for patient 3. 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].…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…As such, the penetrance estimates above are intended to be illustrative. References relevant to specific genes include AIP 19,42 ; CDC73 123,124 ; MEN1 26,125 ; SDH complex genes 11,12,120,121 ; PRKAR1A 28 ; RET 23,24,126 ; and VHL. 127 Penetrance estimates for MEN4 due to CDKN1B mutations are not available due to low numbers of reported cases.…”