Frank-Raue K, Döhring J, Scheumann G, Rondot S, Lorenz A, Schulze E, Dralle H, Raue F, Leidig-Bruckner G
Endocrine Practice, Molecular Laboratory, Heidelberg, Germany.
Exp Clin Endocrinol Diabetes. 2010 Aug;118(8):550-3. doi: 10.1055/s-0029-1241851. Epub 2009 Dec 11.
Clinical studies are needed to classify rare and novel RET mutations associated with hereditary medullary thyroid carcinoma (MTC) into one of the clinical risk groups. Here we describe two new RET mutations/variants, R770Q and L881V, in patients with MTC and analyzed genotype-phenotype correlations associated with these RET mutations in the gene carriers. FAMILY 1: Calcitonin screening in a 42-year-old female patient with multinodular goiter showed elevated levels. RET mutation analysis revealed a new variant in exon 13 R770Q (CGA>CAA) in the patient. A thyroidectomy with central and lateral node dissection was done. Histology showed MTC in a mixed variance with follicular cancer of 2 cm diameter (T2N0M0). Postoperatively there was no increase of calcitonin after pentagastrin stimulation. The patient is biochemically cured concerning MTC and FTC after radioiodine therapy. In the sister of the index patient surprisingly another, previously not described amino-acid substitution Y791N (TAT><) in the RET protooncogene was found. In the parents the R770Q variant was detected in the mother, the Y791N mutation in the father. Another sister carries the R770Q variant. In all other gene carriers (aged 44-70 years), calcitonin levels were in the normal range, therefore, thyroidectomy had not yet been performed. FAMILY 2: In a 46-year-old female patient with nodular goiter thyroidectomy, central and left lateral lymph node dissection was done because of elevated calcitonin levels. Histology revealed a microcarcinoma with one lymph node metastasis (T1N1(1/8)Mx). RET analysis revealed a new mutation in exon 15 L881V (CTG>GTG). The L881V mutation was detected in five other family members. In the first generation stimulated calcitonin levels were in the normal range, therefore thyroidectomy had not yet been performed. In the sons of the index case thyroidectomy revealed CCH in the older one, no MTC in both. In a cousin thyroidectomy is intended because of elevated basal and stimulated calcitonin.
Our clinical findings indicate that the L881V mutation may be associated with late-onset nonaggressive disease. If the germline RET R770Q variant has a causative role in the pathogenesis of the mixed medullar/follicular derived histology of the thyroid tumour in the index patient of family 1 has to be proven. The recommendations for prophylactic thyroidectomy in these mutations should be individualized depending on basal and stimulated calcitonin levels until more data are available.
需要进行临床研究，以将与遗传性甲状腺髓样癌（MTC）相关的罕见和新型RET突变分类到临床风险组中。在此，我们描述了MTC患者中的两种新的RET突变/变体，即R770Q和L881V，并分析了基因携带者中与这些RET突变相关的基因型-表型相关性。家族1：对一名患有多结节性甲状腺肿的42岁女性患者进行降钙素筛查，结果显示其水平升高。RET突变分析显示该患者外显子13存在一个新的变体R770Q（CGA>CAA）。进行了甲状腺切除术及中央和侧方淋巴结清扫术。组织学检查显示为MTC合并直径2厘米的滤泡癌（T2N0M0）的混合变异型。术后五肽胃泌素刺激后降钙素没有升高。经放射性碘治疗后，该患者在生化方面治愈了MTC和FTC。在索引患者的姐姐中，令人惊讶地发现了RET原癌基因中另一个先前未描述的氨基酸取代Y791N（TAT><）。在父母中，母亲检测到R770Q变体，父亲检测到Y791N突变。另一个姐姐携带R770Q变体。在所有其他基因携带者（年龄44 - 70岁）中，降钙素水平在正常范围内，因此尚未进行甲状腺切除术。家族2：一名患有结节性甲状腺肿的46岁女性患者因降钙素水平升高接受了甲状腺切除术、中央和左侧淋巴结清扫术。组织学检查显示为微癌伴一处淋巴结转移（T1N1(1/8)Mx）。RET分析显示外显子15存在一个新的突变L881V（CTG>GTG）。在其他五名家庭成员中检测到L881V突变。在第一代中，刺激后的降钙素水平在正常范围内，因此尚未进行甲状腺切除术。在索引病例的儿子中，甲状腺切除术显示年龄较大的儿子患有CCH，两人均无MTC。在一个表亲中，由于基础和刺激后的降钙素升高，打算进行甲状腺切除术。
我们的临床研究结果表明，L881V突变可能与迟发性非侵袭性疾病相关。如果种系RET R770Q变体在家族1索引患者甲状腺肿瘤的混合髓样/滤泡样组织学发病机制中起致病作用，则必须得到证实。在获得更多数据之前，对于这些突变进行预防性甲状腺切除术的建议应根据基础和刺激后的降钙素水平进行个体化。
