V804M RET mutation and familial medullary thyroid carcinoma: report of a large family with expression of the disease only in the homozygous gene carriers

BACKGROUND: Only 9 families with familial medullary thyroid carcinoma due to V804M mutation have been reported until now. We describe a large kindred with not only heterozygous but also homozygous members with the V804M mutation. This is, to our knowledge, the first report of a homozygous RET mutation. METHODS: Fifty-three members from 4 successive generations of a family with a high level of consanguinity underwent genetic analysis. The pentagastrin provocative test and biochemical screening to rule out either hyperparathyroidism or pheochromocytoma were performed only on gene carriers of the mutation. RESULTS: Twenty-six gene carriers for V804M mutation were identified (4 homozygous and 22 heterozygous). Three of 4 homozygous patients underwent total thyroidectomy. In 1 patient neither medullary thyroid carcinoma nor C-cell hyperplasia was detected, and in another patient only 3 small foci of C-cell hyperplasia were found on the histologic examination. The pentagastrin stimulation test result was within the normal range in all the heterozygous gene carriers and, consequently, thyroidectomy was not indicated. The screening for both hyperparathyroidism and pheochromocytoma was negative in all patients. CONCLUSIONS: In the family reported, the V804M mutation in heterozygous patients seems not to be enough to express the full disease. This finding strongly supports the concept of the indolent behavior of V804M RET proto-oncogene mutation. In addition, our results suggest that when counseling for preventive total thyroidectomy, the specific mutation of RET proto-oncogene and also the natural history of the disease within a particular family should be considered.     

Emergence of medullary thyroid carcinoma in a family with the Cys630Arg RET germline mutation

BACKGROUND: Individual germline mutations in the RET (REarranged during Transfection) proto-oncogene may set the time window for malignant progression from C-cell hyperplasia to familial medullary thyroid carcinoma. Owing to the close genotype-phenotype correlation, genetic information may lend to individual timing of prophylactic thyroidectomy according to RET genotype. Limited information exists on the Cys630 RET genotype. Most of the few published carriers of this genotype who developed medullary thyroid carcinomas (MTCs) were in their mid-30s. METHODS: This case series of a German RET family with the Cys630Arg genotype was assembled to study malignant progression of MTC in this rare RET genotype. RESULTS: There was considerable variability of malignant progression from C-cell hyperplasia to MTC in carriers of the Cys630Arg genotype. In these persons, MTCs had developed by the age of 32 years (index patient, pT2bN0M0), and 15 years and 1 year (non-index patients; pT1apN1bM0 and pT1bpN0M0, respectively). The Cys630Arg genotype always segregated with the familial medullary thyroid carcinoma phenotype. CONCLUSIONS: The Cys630 RET genotype may have a more vigorous transforming activity than currently thought and can cause MTC in RET gene carriers within the first year of life. Starting in early infancy, identified RET gene carriers should be scrutinized until stimulated serum calcitonin levels become positive or, when these remain normal, should undergo prophylactic thyroidectomy before they reach 5 years of age.     

99mTc(V)-dimercaptosuccinic acid scintigraphy for medullary thyroid carcinoma

Ten patients with medullary thyroid carcinoma (MTC) and 2 patients with papillary carcinoma of the thyroid were investigated by scintigraphy using^99mTc(V)-dimercaptosuccinic acid [^99mTc(V)-DMS], a new radiopharmaceutical agent for imaging MTC. At surgery, a tracer dose of the agent was administered intravenously, and the distribution of the agent was studied in the surgically removed tissues. Among the patients with MTC, 7 had clear scintigraphic images of tumors, 2 had faint images, and 1 patient with a recurrent tumor in a lymph node had no significant image. In 3 patients, mediastinal involvements were clearly demonstrated, and mediastinal dissection confirmed the scintigraphic findings. No significant images were obtained in the patients with papillary carcinoma. The tissue distribution studies of^99mTc(V)-DMS revealed specific accumulation of the agent in MTC tissue and low uptake in other tissues. This new scintigraphy for MTC is of great value in deciding the surgical approach and follow-up.

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Resumen Diez pacientes con carcinoma medular de tiroides (CMT) y 2 pacientes con carcinoma papilar fueron investigados mediante centelleografía utilizando^99mTc(V)-ácido dimercaptosuccínico, un nuevo agente radiofarmacéutico para imágenes de CMT. En el curso de la cirugía se administró una dosis trazadora del agente por vía intravenosa, y su distribución fue estudiada en los tejidos de la resección quirúrgica. Entre los pacientes con CMT, 7 presentaron imágenes claras de centelleografía del tumor, 2 presentaron imágenes débiles, y 1 paciente con tumor recurrente en un ganglio linfático no exhibió imagen de significación. En 3 pacientes la invasión mediastinal pudo ser claramente demostrada, y la disección mediastinal confirmó los hallazgos de la centelleografía. No se obtuvieron imágenes significativas en los pacientes con carcinoma papilar. Los estudios de distribución tisular del^99mTc(V)-ADMS revelaron acumulación específica del agente en tejido de CMT y baja captación por otros tejidos. Este nuevo método de centelleografía para CMT es de gran valor para decidir sobre el aproche quirúrgico y para el seguimiento.

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Résumé Dix malades présentant un cancer médullaire thyroïdien et 2 malades un cancer papillaire ont été soumis à une scintigraphie employant un nouveau radioisotope le^99mTc(V)-DMS. Au cours de l'intervention une dose traçante de ce nouvel agent fut injectée par voie intraveineuse pour permettre l'étude de sa répartition au niveau de la pièce opératiore. Parmi les malades atteints de cancer médullaire 7 sur 10 ont présenté des images scintigraphiques patentes, 2 des images estompées cependant qu'un malade qui était porteur d'une récidive au niveau d'un ganglion lymphatique ne présentait pas d'image significative. Chez 3 malades une diffusion médiastinale fut clairement démontrée et la dissection médiastinale vint confirmer les constatations scintigraphiques. En revanche aucune image ne fut observée chez les malades atteints de cancer papillaire. Les études de la distribution tissulaire du^99mTC(V)-DMS démontrent une imprégnation spécifique importante du néoplasme médullaire par rapport aux autres tissus. Ce nouvel agent scintigraphique de dépistage du cancer médullaire thyroïdien est d'une grande valeur pour déterminer la conduite opératoire et pour suivre le malade après l'intervention.

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Presented at the International Association of Endocrine Surgeons in Paris, September 1985.     

Various penetrance of familial medullary thyroid carcinoma in patients with RET protooncogene codon 790/791 germline mutations

OBJECTIVE: To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers. SUMMARY BACKGROUND DATA: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children. METHODS: Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy. RESULTS: Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology. CONCLUSIONS: Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.     

Surgical approach to early familial medullary carcinoma of the thyroid gland

The application of a radioimmunoassay for human calcitonin to a high risk family group has predicted the diagnosis of medullary carcinoma of the thyroid in twelve persons. With the calcium infusion test, elevated levels of calcitonin have been measured in the serum and urine in these patients with medullary carcinoma. In eleven, the tumors were clinically occult.     

Malignant progression from C-cell hyperplasia to medullary thyroid carcinoma in 167 carriers of RET germline mutations

BACKGROUND: Hereditary medullary thyroid carcinoma (MTC) is the most common and potentially life-shortening phenotypic manifestation of RET (rearranged during transfection) germline mutations. If a distinct time lag between the successive stages of malignant progression were identifiable, the information could be used to individualize prophylactic surgery. The study objective was to investigate the impact of RET genotype on disease progression from C-cell hyperplasia (CCH) to MTC. METHODS: An institutional series of 167 (67 index, 100 nonindex) consecutive carriers of RET gene point mutations in exons 10, 11, 13, 14, or 16 who underwent total thyroidectomy between November 1994 and November 2002. RESULTS: Regarding codons 618, 620, 634, 768, 790, and 804, patient age at diagnosis differed significantly depending on the type of pathology encountered (CCH, MTC without and with nodal metastasis). The variability in age, which may reflect the number of necessary somatic mutations, explained the pathological strata in 38% (codon 634) to 77% (codon 768) of patients. Conversely, 62% (codon 634) to 23% (codon 768) of variability in age at different pathological strata may have been determined by the RET genotype. CONCLUSIONS: The pace of malignant progression of the RET genotype should be taken into account when considering prophylactic thyroidectomy in RET gene carriers.     

散发型甲状腺髓样癌酪氨酸激酶受体基因第918位点基因突变及意义

目的研究不同人种散发型甲状腺髓样癌（sMTC）酪氨酸激酶受体基因（RET）第918位点基因突变及意义。方法提取17例中国人sMTC基因组DNA，聚合酶链反应（PCR）扩增RET基因第16外显子，PCR产物经纯化后直接测序，分析中国人sMTCRET基因第918位点处基因突变，并与文献报道的其他人种sMTC该位点处基因突变比较。结果中国人sMTC此位点处未发现基因突变；黄种人、白种人、棕种人此位点处基因突变率分别为：7．1％、33．5％、50．0％。基因突变形式均为ATG→ACG点突变。白种人与黄种人，棕种人与黄种人间比较均差异有统计学意义（P〈0．05）。结论中国人sMTC发病与RET基因第918位点处基因突变无关；不同人种sMTC此位点处基因突变率有差异；不同人种sMTC发病的基因基础可能不同。     

Medullary carcinoma of the thyroid gland (sporadic, familial)

Medullary thyroid cancer (MTC) is uncommon thyroid tumor with specific characteristics which undoubtedly divide this tumor from other thyroid malignancies. Patients with sporadic or hereditary form of MTC differ in clinical presentation, recurrence of the disease and outcome. The aim of study was to establish surgical characteristics of MTC as well as clinical factors that influence surgical treatment. The study group consisted of 68 patients with MTC managed at the Center for Endocrine Surgery between 1987 and 1999. Retrospective analysis included clinical form of the disease, general data, histological and other tumor characteristics. Mean age of the patients were 47.3 years (female/male ratio: 1.5:1). Mean size of tumor was 80.5 cm3, 72.1% patients had tumor greater than 4 cm. in diameter or extrathyroid spread. The majority of patients were in II and III stadium of the disease. Primary operation (at least total thyroidectomy) was performed in 57 (84%) patients. 2(3%) had postoperatively temporally nerve palsy and 7(10.29%) temporally hypoparathyroidism. The overall survival was 46.8 +/- 9.9% after 9 years and 63.6 +/- 7.2% at 5 years. Postoperative calcitonin value is significant predictor of survival/Spearman's coefficient (R = 0.7048)/, worse prognosis is in correlation with high postoperative calcitonin values. The treatment of choice is at least total thyroidectomy and central lymph nodes resection if enlarged lymph nodes are found. Precise operative technique lowers the risk of postoperative complications. Complex approach to the patient with MTC includes all available methods in pre and postoperative evaluation as well as surgeon's knowledge and skill.     

Orthopedic aspects of familial insensitivity to pain due to a novel nerve growth factor beta mutation

Background Congenital insensitivity to pain is a rare hereditary sensory neuropathy

Patients We present 6 patients from a family with a mutation in the nerve growth factor beta gene (NGFB)

Results 3 patients were homozygous with a mutilating arthropathy starting early in life, and 3 patients were presumably heterozygous with a milder course starting in adulthood. All patients had normal mental abilities. In addition to absence of deep pain, the patients had impaired temperature sensation, but no autonomic deficiency. Sural nerve biopsies showed a moderate loss of A-δfibres and a severe reduction in C fibers. Clinically, the disorder most often affected the lower extremities, with an insidious progressive joint swelling or a painless fracture, but the spine could also be involved with gross and unstable spondylolisthesis. Fracture healing was uneventful, but the arthropathy was progressive, eventually resulting in gross deformity and instability. When treating patients with congenital disorders such as this one, it is important to consider the slowly progressive nature of the disorder, and the orthopedic operations should therefore be planned from a long-term standpoint. Arthrodesis, limb lengthening and spinal decompression or fusion are the only elective procedures that seem reasonable. Fitting of orthosis for joint protection is also demanding. To delay the development of neuropathic arthropathy, patient education is essential but difficult in the very young

Interpretation The different expression between homo- and heterozygous subjects and the central role of nerve growth factor make this disease an interesting model system for studies of disease mechanisms and the molecular background to pain.     

Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease

Purpose

Prophylactic total thyroidectomy is now recommended after having confirmed RET mutations in children of parents with multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. We reviewed our experience to determine the incidence of medullary thyroid carcinoma with respect to age at surgery, the location of the mutation, and its association with Hirschsprung's disease (HD).

Methods

A retrospective review from 1996 to 2005 revealed 20 children with genetic screening for multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma who underwent a prophylactic total thyroidectomy with parathyroid gland preservation.

Results

The median age of the 20 patients (9 boys and 11 girls) included in this study was 8.2 years (range, 3.7-16.9 years) at the time of their surgery. Final pathology revealed normal thyroid tissue (n = 3; median age, 5.9 years), C-cell hyperplasia (n = 13; median age, 10 years), or medullary thyroid carcinoma (n = 4; median age, 8 years). Four children, all with mutations in C620, had a previous diagnosis of HD. At a median follow-up of 3.7 years (range, 1 month to 8.4 years), all patients were well and cancer free.

Conclusions

There is no correlation between histologic findings and median age at surgery. Hirschsprung's disease was found in 50% of the patients with the RET mutation in C620. In children of C620 parents, symptoms of HD should be actively sought, and if such are found, rectal biopsies should be performed even if mutation results are not yet available. Based on the age of the earliest cancer and the safety of total thyroidectomy, children should promptly undergo surgery after genetic screening and before their fifth year of life.