Samuel A. Wells

Predictive DNA Testing and Prophylactic Thyroidectomy in Patients at Risk for Multiple Endocrine Neoplasia Type 2A

BackgroundMissense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. MethodsA polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. ResultsDirect DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. ConclusionThe PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Lethality of Multiple Endocrine Neoplasia Type I

Abstract. The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years,p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years,p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n= 12), ulcer disease (n= 6), hypercalcemia/uremia (n= 3), carcinoid tumor (n= 6), and nonendocrine malignancies (n= 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

Parathyroid autotransplantation during thyroidectomy. Results of long-term follow-up.

SUMMARY BACKGROUND DATA Permanent hypoparathyroidism is a recognized complication of thyroidectomy. Operative strategies to prevent this complication include preservation of parathyroid glands in situ and autotransplantation of parathyroid glands resected or devascularized during thyroidectomy. METHODS An analysis of 194 patients having thyroidectomy and simultaneous parathyroid autotransplantation at Barnes Hospital from 1990 to 1994 was performed. Data were collected regarding patient demographics, indication for thyroidectomy, operative procedure, pathologic diagnoses, and postoperative course, including biochemical assessment of parathyroid autograft function. RESULTS Of 194 patients having either total, subtotal, or completion thyroidectomy, 104 (54%) experienced a [Ca(+2)]nadir less than or equal to 8.0 mg/dL and had symptoms and signs of hypocalcemia. Parathyroid autotransplantation was successful in 103 (99%) of these 104 cases and resulted in a 1.0% incidence of hypoparathyroidism in this series. CONCLUSIONS Although preservation of parathyroid glands in situ is desirable, routine parathyroid autotransplantation during thyroidectomy virtually eliminates postoperative hypoparathyroidism. Normal parathyroid glands resected or devascularized during thyroidectomy for well-differentiated thyroid carcinoma or benign disease should be transplanted in the sternocleidomastoid muscle. Patients with Multiple Endocrine Neoplasia type 2A should have parathyroid glands resected at the time of thyroidectomy for medullary thyroid carcinoma and transplanted in the nondominant forearm. Postoperative management in most patients after thyroidectomy and parathyroid autotransplantation involves temporary calcium and vitamin D replacement and close biochemical evaluation. This precautionary measure of parathyroid autotransplantation markedly reduces the incidence of permanent postoperative hypoparathyroidism.

Provocative Agents and the Diagnosis of Medullary Carcinoma of the Thyroid Gland

Twenty-six patients with known or suspected medullary thyroid carcinoma (MTC) and 21 normal control subjects were tested intravenously on four separate days with calcium gluconate (CG), 2 mg Ca++/kg/l min.; pentagastrin (P), 0.5 ug/kg/ 5 sec; calcium chloride (CC), 3 mg Ca++/kg/10 min.; and a combination of calcium gluconate and pentagastrin (CG + P). Calcitonin (CT) levels were determined by radioimmunoassay on plasma collected before and immediately following each test infusion. In none of the 21 control subjects was there a clear increase in CT above 200 pg/ml following any of the four provocative tests. Conversely, in all 26 patients with known or suspected MTC, plasma CT levels were markedly increased (>300 pg/ml) following the combined infusion of CG + P. The peak CT response was greater with CG + P than with a) CG alone (22 of 24 patients, p < 0.002), b) P alone (25 of 26 patients, p < 0.002), or c) CC alone (17 of 17 patients, p < 0.002). Of 12 MTC patients with undetectable basal calcitonin levels, all had peak responses greater than 300 pg/ml following CG + P, whereas such responses occurred less often following CG alone (8 of 12) or P alone (8 of 12). The results demonstrate that the combined administration of pentagastrin and calcium gluconate constitutes a more effective and reliable stimulus for CT secretion from MTC cells than the use of either agent alone, and appears the most useful single screening test for the detection of occult MTC.

Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes

ObjectiveThe authors sought to determine the optimal surgical management of pheochromocytomas that develop in patients with multiple endocrine neoplasia (MEN) type 2 syndromes. Summary Background dataThe performance of empirical bilateral adrenalectomy in patients with MEN 2A or MEN 2B, whether or not they have bilateral pheochromocytomas, is controversial. MethodsThe results of unilateral or bilateral adrenalectomy were studied in 58 patients (49 with MEN 2A and 9 with MEN 2B). Recurrence of disease was evaluated by measuring 24-hour urinary excretion rates of catecholamines and metabolites and by computed tomography (CT) scanning. ResultsThe mean postoperative follow-up was 9.40 years. There was no operative mortality and malignant or extra-adrenal pheochromocytomas were not present. Twenty-three patients with a unilateral pheochromocytoma and a macroscopically normal contralateral gland underwent unilateral adrenalectomy. A pheochromocytoma developed in the remaining gland a mean of 11.87 years after the primary adrenalectomy in 12 (52%) patients. Conversely, 11 (48%) patients did not develop a pheochromocytoma during a mean interval of 5.18 years. In the interval after unlateral adrenalectomy, no patient experienced hypertensive crises or other complications related to an undiagnosed pheochromocytoma. Ten (23%) of 43 patients having both adrenal glands removed (either at a single operation or sequentially) experienced at least one episode of acute adrenal insufficiency or Addisonian crisis, including one patient who died during a bout of influenza. ConclusionsBased on these data, the treatment of choice for patients with MEN 2A or MEN 2B and a unilateral pheochromocytoma is resection of only the involved gland. Substantial morbidity and significant mortality are associated with the Addisonian state after bilateral adrenalectomy.

Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation.

Since 1973, we have performed total parathyroidectomy and forearm parathyroid autotransplantation in 36 patients with generalized (four gland) primary parathyroid hyperplasia. Twenty (56%) patients had nonfamilial parathyroid hyperplasia (NFPH) and 16 (44%) patients had familial parathyroid hyperplasia (FPH). Twenty-one patients (Group A) were undergoing operation for the first time and 15 (Group B) were having either second, third or fourth re-explorations for persistent hyperparathyroidism. All patients in Group A and nine patients in Group B had parathyroid resection and immediate autotransplantation as a single procedure. Six Group B patients had hyperfunctioning parathyroid tissue resected, cryopreserved, and subsequently grafted when it was evident that they had been rendered aparathyroid. A sustained differential elevation (13.7 fold ± 2.7) of parathyroid hormone was detected in the antecubital vein of the grafted compared to the nongrafted arm in 35 (97%) patients. Two (5.6%) of the 36 patients (both with FPH; one Group A and one Group B) required permanent oral calcium and vitamin D replacement therapy and one (3%) patient (NFPH: Group A) had persistent hypercalcemia postoperatively, presumably due to a supernumerary gland. The remaining 33 (92%) patients became normocalcemic after surgery and 23 (70%) of them remained so. Ten (30%) of the 33 patients developed recurrent graft dependent hyperparathyroidism. Eight patients were from the group with FPH (8/14, 57%) and two were from the group with NFPH (2/19, 11%) (FPH vs. NFPH, p < 0.005). Because of symptoms of hypercalcemia or a serum calcium concentration exceeding 11 mg/dl, partial graft resection was performed in five patients and four became normocalcemic. Patients with generalized primary parathyroid hyperplasia may be difficult to cure, especially if the disease is familial. The technique of total parathyroidectomy and heterotopic autotransplantation of fresh or cryopreserved parathyroid tissue offers distinct advantages over alternative techniques.

Sipple's syndrome: medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease. Studies in a large family. NIH conference.

Abstract Sipples syndrome is medullary carcinoma of the thyroid, pheochromocytoma, and parathyroid disease. It is transmitted as an autosomal dominant trait with a high degree of penetrance. Medul...

Aminoglutethimide as Treatment of Postmenopausal Women with Advanced Breast Carcinoma

Hormone-dependent breast carcinomas respond to deprivation of biologically active estrogens with objectively quantifiable tumor regression. Aminoglutethimide, a known inhibitor of steroid synthesis, is also a potent blocker of the aromatase enzyme and, thus, of estrogen production. We developed an effective regimen to inhibit estrogen production in postmenopausal women using aminoglutethimide and replacement glucocorticoid. One hundred forty-seven women initially received aminoglutethimide and replacement glucocorticoid as treatment of metastatic breast carcinoma. One hundred twenty-nine women are currently evaluable for assessment of clinical and hormonal responses. Thirty-seven percent of unselected women and 49% of estrogen receptor-positive patients experienced objective tumor regression. Responses occurred predominantly in soft tissue (47%) and bone (35%) and lasted 30 +/- 9.1 months for complete and 14 +/- 1.5 months for partial regressions. Plasma and urinary estrogen levels fell equally in responder versus nonresponder groups whereas androgen levels declined less in patients with progressive disease.

Parathyroid Autotransplantation in Primary Parathyroid Hyperplasia

Four patients with primary parathyroid hyperplasia were treated by total parathyroidectomy and autotransplantation of parathyroid tissue into the forearm muscle. All patients remained normocalcemic after vitamin D and oral calcium replacement therapy were stopped at 1 1/2, four, nine and 13 months, respectively. Graft function was documented further by detection of a higher concentration of parathyroid hormone in plasma from the basilic vein draining the graft bed than from the basilic vein in the contralateral arm. Intravenous calcium infusion suppressed parathyroid hormone secretion from the graft whereas hypocalcemia induced by ethylenediaminetetra-acetic acid markedly stimulated hormone release. In two patients histologic examination of a grafted fragment revealed hyperplastic parathyroid tissue. This method of treatment offers a suitable alternative to radical subtotal parathyroidectomy in selected patients with hyperparathyroidism.

Osteomalacia After Parathyroidectomy in Patients with Uremia

Five patients on maintenance dialysis had symptoms of osteomalacia, proven by biopsy, after parathyroidectomy. In all five patients clinical and radiographic manifestations of secondary hyperparathyroidism were present before surgery, and in two patients preoperative biopsy of bone confirmed the existence of osteitis fibrosa. Like previously described patients with osteomalacia all five had multiple fractures and normal or high serum calcium concentrations that rose to abnormally high values on treatment with vitamin D or dihydrotachysterol. Quantitative histomorphometry of biopsy after parathyroidectomy showed no residual parathyroid hormone effect and nearly complete cessation of mineralization. Four patients had forearm autografts of parathyroid tissue that appeared to be functioning at very low rates according to paired venous sampling, and all five patients had relatively low circulating concentrations of parathyroid hormone. This and earlier experiences reported by others suggest that secondary hyperparathyroidism may have an important facilitative role in the mineralization of bone in uremic patients.