Accardo Marie-Louise, Osborne Jenae, Else Tobias
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
tumor predisposition (-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional solid tumors and hematologic neoplasms (e.g., thyroid cancer) have been reported in individuals with -TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of -associated cancers are diagnosed in adulthood.
DIAGNOSIS/TESTING: The diagnosis of -TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in identified by molecular genetic testing.
The treatments for -TPD tumors are those used in standard practice. Full skin examination by a dermatologist beginning at age 18 years at least every six months with excision of any lesions suspicious for melanoma; consider exams every three months in individuals with multiple atypical nevi, history of melanoma, and/or family history of melanoma; in addition, monthly self-examination should be encouraged. Annual whole-body MRI beginning at age 18 years, or earlier depending on personal and family history of non-cutaneous, non-brain malignancies. Annual complete blood count with differential beginning at age 18 years to screen for CLL. Annual comprehensive physical examination including examination of lymph nodes. Consider brain MRI every one to two years beginning at age 18 years depending on family history of glioma. Tanning bed use and unprotected sun exposure; radiation in diagnostic procedures. Molecular genetic testing for the familial pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for -TPD is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18 years.
-TPD is inherited in an autosomal dominant manner. To date, most individuals diagnosed with -TPD have an affected parent; the proportion of individuals with -TPD caused by a pathogenic variant is unknown. Each child of an individual with -TPD has a 50% chance of inheriting the pathogenic variant. Clinical manifestations of -TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of -TPD are unknown. Once the germline pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
肿瘤易感性（-TPD）的特点是患多发性皮肤黑色素瘤、肉瘤（尤其是心脏血管肉瘤）、慢性淋巴细胞白血病（CLL）和神经胶质瘤的终生风险增加。据报道，患有-TPD的个体还存在其他实体瘤和血液系统肿瘤（如甲状腺癌）。首例原发性皮肤黑色素瘤的发病年龄在15至80岁之间。大多数与-TPD相关的癌症在成年期被诊断出来。
诊断/检测：在先证者中，若有提示性发现且通过分子遗传学检测鉴定出杂合的种系致病性变异，则可确立-TPD的诊断。
-TPD肿瘤的治疗采用标准治疗方法。皮肤科医生应从18岁开始至少每六个月进行一次全面皮肤检查，切除任何可疑为黑色素瘤的病变；对于有多发性非典型痣、黑色素瘤病史和/或黑色素瘤家族史的个体，考虑每三个月进行一次检查；此外，应鼓励每月进行自我检查。从18岁开始每年进行一次全身MRI检查，或根据非皮肤、非脑恶性肿瘤的个人和家族史更早进行检查。从18岁开始每年进行一次全血细胞计数及分类检查以筛查CLL。每年进行包括淋巴结检查在内的全面体格检查。根据神经胶质瘤家族史，从18岁开始每1至2年考虑进行一次脑部MRI检查。避免使用晒黑床和无防护的阳光照射；避免诊断性程序中的辐射。应向一级亲属提供针对家族性致病性变异的分子遗传学检测，以确定那些将从早期监测和干预中受益的人。虽然一般不建议对18岁以下的高危个体进行-TPD的分子遗传学检测，但家族中有早期癌症病史可能需要在18岁之前进行预测性检测。
-TPD以常染色体显性方式遗传。迄今为止，大多数被诊断为-TPD的个体都有患病的父母；由致病性变异导致的-TPD个体比例尚不清楚。患有-TPD的个体的每个孩子都有50%的机会继承致病性变异。由于-TPD的完整表型谱和外显率尚不清楚，因此无法预测杂合家庭成员中-TPD的临床表现。一旦在受影响的家庭成员中鉴定出种系致病性变异，就可以进行产前和植入前基因检测。
