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Other Rare Childhood Cancers

    Table 7. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated with Susceptibility Genesa

    Germline MutationSyndromeProportion of all PGL/PCC (%)Mean Age at Presentation (y)Penetrance of PGL/PCC (%)
    MEN1 = multiple endocrine neoplasia type 1; MEN2 = multiple endocrine neoplasia type 2; NF1 = neurofibromatosis type 1; VHL = von Hippel-Lindau.
    a Adapted from Welander et al.[42]
    RET MEN25.335.650
    VHLVHL9.028.610–26
    NF1NF12.941.60.1–5.7
    SDHDPGL17.135.086
    SDHFA2PGL2<132.2100
    SDHCPGL3<142.7Unknown
    SDHBPGL45.532.777
    SDHA-<340.0Unknown
    KIF1B-beta-<146.0Unknown
    EGLN1-<143.0Unknown
    TMEM127-<242.8Unknown
    MAX[45]-<234Unknown
    UnknownCarney triad<127.5-
    SDHB, C, DCarney-Stratakis<133Unknown
    MEN1MEN1<130.5Unknown
    No mutationSporadic disease7048.3-
    1. Von Hippel-Lindau (VHL) syndrome—Pheochromocytoma and paraganglioma occur in 10% to 20% of patients with VHL.
    2. Multiple Endocrine Neoplasia (MEN) Syndrome Type 2—Codon-specific mutations of the RET gene are associated with a 50% risk of development of pheochromocytoma in MEN 2A and MEN 2B. Somatic RET mutations are also found in sporadic pheochromocytoma and paraganglioma.
    3. Neurofibromatosis type 1 (NF1)—Pheochromocytoma and paraganglioma are a rare occurrence in patients with NF1, and typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and rarity in pediatrics.
    4. Familial pheochromocytoma/paraganglioma syndromes, associated with germline mutations of mitochondrial succinate dehydrogenase (SDH) complex genes (see Table 7). They are all inherited in an autosomal dominant manner but with varying penetrance.
      • PGL1—Associated with SDHD mutations, manifests more commonly with head and neck paragangliomas, and has a very high penetrance, with more than 80% of carriers developing disease by age 50 years.
      • PGL2—Associated with SDHAF2 mutations, is very rare, and generally manifests as parasympathetic paraganglioma.
      • PGL3—Associated with SDHC mutations, is very rare, and usually presents with parasympathetic paraganglioma, often unifocal, benign, and in the head and neck location.
      • PGL4—Associated with SDHB mutations and usually manifests with intra-abdominal sympathetic paraganglioma. The neoplasms associated with this mutation have a much higher risk of malignant behavior, with more than 50% of patients developing metastatic disease. There is also an increased risk of renal cell carcinoma and gastrointestinal stromal tumor (GIST).
    5. Other susceptibility genes recently discovered include KIF1B-beta, EGLN1/PHD2, TMEM127, SDHA, and MAX.[45]
    6. Other syndromes:
      • Carney triad syndrome is a condition that includes three tumors: paraganglioma, GIST, and pulmonary chondromas. Pheochromocytomas and other lesions such as esophageal leiomyomas and adrenocortical adenomas have also been described. The syndrome primarily affects young women, with a mean age of 21 years at time of presentation. Approximately one-half of the patients present with paraganglioma or pheochromocytoma, although multiple lesions occur in approximately only 20% of the cases. About 20% of the patients have all three tumor types; the remainder have two of the three, most commonly GIST and pulmonary chondromas. This triad doesn't appear to run in families and no responsible gene has been discovered.[46]
      • Carney-Stratakis syndrome (Carney dyad syndrome) is a condition that includes paraganglioma and GIST, but no pulmonary chondromas. It is inherited in an autosomal dominant manner with incomplete penetrance. It is equally common in men and women, with an average age of 23 years at presentation. The majority of patients with this syndrome have been found to carry germline mutations in the SDHB, SDHC, or SDHD genes.[46]
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