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Abstract：
PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples.
Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome.
This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.
Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome.
This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.
摘要：
背景：PTEN错构瘤综合征（PHTS）是一种常染色体显性疾病，其特征是肿瘤抑制基因磷酸酶和张力蛋白同源物（PTEN）的致病变异。它与粘膜皮肤特征的风险增加有关，错构瘤,和癌症。在少数从头PHTS患者中发现了镶嵌现象，从血液样本中鉴定出来。我们报告了一名从血液样本中没有发现变异的PHTS患者。通过对来自不同肿瘤和非肿瘤样品的DNA进行测序来检测宪法性PTEN镶嵌性。
方法：我们的患者在56岁时出现临床Cowden综合征，有三个主要标准(大头畸形，LhermitteDuclos病,口腔乳头状瘤病)，和两个次要标准(结构性甲状腺病变，食管糖原性棘皮病）。血液白细胞PTEN的深度测序没有发现任何致病变异。探索肿瘤（结肠神经节神经瘤，食管乳头状瘤,神经麻痹性肌瘤）和非肿瘤胃组织发现相同的PTEN致病变体（NM_000314.4c.389G>A；p。（Arg130Gln）），等位基因频率为12-59%，证实了Cowden综合征的基因组镶嵌。
结论：此病例报告，和文献综述，提示系统的肿瘤分析对于出现PTEN错构瘤综合征的患者在血液白细胞中没有发现任何因果变异的情况下是必不可少的。尽管深度测序。在65％至70％的临床Cowden综合征病例中，在血液样本中没有观察到PTEN中的致病变异:镶嵌现象可以解释这些患者中的大量患者.肿瘤分析将提高我们对该综合征从头变化频率的认识。最后,患有PTEN镶嵌症的患者可能没有轻度表型;应提供与杂合携带者相同的医疗服务.
方法：我们的患者在56岁时出现临床Cowden综合征，有三个主要标准(大头畸形，LhermitteDuclos病,口腔乳头状瘤病)，和两个次要标准(结构性甲状腺病变，食管糖原性棘皮病）。血液白细胞PTEN的深度测序没有发现任何致病变异。探索肿瘤（结肠神经节神经瘤，食管乳头状瘤,神经麻痹性肌瘤）和非肿瘤胃组织发现相同的PTEN致病变体（NM_000314.4c.389G>A；p。（Arg130Gln）），等位基因频率为12-59%，证实了Cowden综合征的基因组镶嵌。
结论：此病例报告，和文献综述，提示系统的肿瘤分析对于出现PTEN错构瘤综合征的患者在血液白细胞中没有发现任何因果变异的情况下是必不可少的。尽管深度测序。在65％至70％的临床Cowden综合征病例中，在血液样本中没有观察到PTEN中的致病变异:镶嵌现象可以解释这些患者中的大量患者.肿瘤分析将提高我们对该综合征从头变化频率的认识。最后,患有PTEN镶嵌症的患者可能没有轻度表型;应提供与杂合携带者相同的医疗服务.
