Carl D. Malchoff

A mutation of the glucocorticoid receptor in primary cortisol resistance

The precise molecular abnormalities that cause primary cortisol resistance have not been completely described. In a subject with primary cortisol resistance we have observed glucocorticoid receptors (hGR) with a decreased affinity for dexamethasone. We hypothesize that a mutation of the hGR glucocorticoid-binding domain is the cause of cortisol resistance. Total RNA isolated from the index subjects mononuclear leukocytes was used to produce first strand hGR cDNAs, and the entire hGR cDNA was amplified in segments and sequenced. At nucleotide 2,317 we identified a homozygous A for G point mutation that predicts an isoleucine (ATT) for valine (GTT) substitution at amino acid 729. When the wild-type hGR and hGR-Ile 729 were expressed in COS-1 cells and assayed for [3H]-Dexamethasone binding, the dissociation constants were 0.799 +/- 0.068 and 1.54 +/- 0.06 nM (mean +/- SEM) (P < 0.01), respectively. When the wild-type hGR and hGR-Ile 729 were expressed in CV-1 cells that were cotransfected with the mouse mammary tumor virus long terminal repeat fused to the chloramphenicol acetyl transferase (CAT) gene, the hGR-Ile 729 conferred a fourfold decrease in apparent potency on dexamethasone stimulation of CAT activity. The isoleucine for valine substitution at amino acid 729 impairs the function of the hGR and is the likely cause of primary cortisol resistance in this subject.

Somatostatin receptor scintigraphy: Its value in tumor localization in patients with cushing's syndrome caused by ectopic corticotropin or corticotropin-releasing hormone secretion

PURPOSE To assess the feasibility of somatostatin receptor scintigraphy for patients with Cushings syndrome caused by tumors secreting ectopic corticotropin or corticotropin-releasing hormone (CRH). PATIENTS AND METHODS Ten patients with Cushings syndrome, nine with ectopic corticotropin-secreting tumors and one with a CRH-secreting tumor, were consecutively studied. For comparison purposes, eight patients with corticotropin-secreting pituitary tumors and one patient with an autonomous adrenal adenoma were investigated. In vivo tumor localization was performed for all patients using a radionuclide-coupled somatostatin analog. The results obtained with this technique were compared with those obtained with conventional imaging techniques. For some patients, the clinical effects of octreotide therapy were evaluated. RESULTS Somatostatin analog scintigraphy successfully identified the primary ectopic corticotropin-secreting and CRH-secreting tumors or their metastases, or both, in 8 of 10 patients; in 2 patients with corticotropin-secreting bronchial carcinoids, the tumors could not be visualized. Normal scans were obtained for the 8 patients with corticotropin-secreting pituitary tumors and the one patient with an adrenal adenoma. CONCLUSION Somatostatin analog scintigraphy can be included as a diagnostic step in the workup of Cushings syndrome patients with a suspected ectopic corticotropin-secreting tumor or a CRH-secreting tumor.

A comparison of open vs laparoscopic adrenalectomy

AbstractBackground: To compare the outcome of patients who underwent laparoscopic transabdominal adrenalectomy (LA) with those who had open adrenalectomy (OA). Methods: A retrospective review of consecutive adrenalectomies performed by a single surgical team at a university hospital. Outcome measurements were operative time, operative blood loss, procedure-related complications, postoperative stay, and return to regular activity. Results: Twenty-nine adrenalectomies were done in 23 patients during a 54-month period. There were 12 OAs performed in nine patients and 17 LAs were done in 14 patients. Both groups were similar in their demographics and their indications for operation. All attempted LAs were successfully completed. The mean operative time was longer for LA than for OA (289 vs 201 min; p= 0.042). Resumption of oral intake (1.0 vs 3.0 days; p= 0.002), postoperative hospital stay (3.0 vs 7.9 days; p= 0.002), and return to regular activity (8.9 vs 14.6 days; p= 0.002) were significantly shorter after LA than after OA. There were no postoperative deaths and there was no difference in operative blood loss between the two groups. Procedure-related complications occurred in three patients having LA and in five patients having OA. Conclusions: Patients having LA had longer operative procedures but shorter hospital stays and faster return to normal activity than patients having OA. Procedure-related complications for LA were due to bleeding into the retroperitoneum or abdominal wall. Significant postoperative cardiac and respiratory complications occurred only in the OA group.

Laparoscopic resection of large adrenal tumors

BackgroundThe maximum size of adrenal tumors that should be removed with a laparoscopic approach is controversial. It has been suggested that laparoscopic adrenalectomy is appropriate only for adrenal tumors <6 cm in size. We report our experience with laparoscopic adrenalectomy in patients with adrenal tumors of ≥6 cm compared with patients with smaller tumors.MethodsWe retrospectively reviewed a consecutive series of patients who had a laparoscopic adrenalectomy. Patients were considered candidates for laparoscopic adrenalectomy if their computed tomography (CT) scan showed a well-encapsulated tumor confined to the adrenal gland.ResultsSixty laparoscopic adrenalectomies were performed in 53 patients. Twelve of the adrenalectomies (20%) were for tumors that were ≥6 cm (median, 8 cm; range, 6 to 12 cm). There have been no local or regional recurrences but one patient with adrenocortical carcinoma developed pulmonary metastases. When the 12 patients with large tumors were compared with the 36 patients with tumors <6 cm, the median operative time (190 vs. 180 minutes;P=.32), operative blood loss (100 vs. 50 mL;P=.53), and postoperative hospital stay (2 vs. 2 days;P=1.0) were similar.ConclusionsThe size of an adrenal tumor should not be the primary factor in determining whether a laparoscopic adrenalectomy should be performed. Large adrenal tumors that are confined to the adrenal gland on CT can be removed with a laparoscopic approach.

Familial nonmedullary thyroid carcinoma.

It is well-known that medullary thyroid carcinoma occurs in a familial form as part of the multiple endocrine neoplasia (MEN) 2 syndromes. However, it is less well-recognized that nonmedullary thyroid carcinoma (NMTC) sometimes is familial. Arising from the thyroid epithelial cell, the NMTCs include papillary, follicular, and anaplastic thyroid carcinoma. Although most NMTC are sporadic, there is increasing evidence for a familial form. When inherited, NMTC is autosomal dominant with partial penetrance, and it is not associated consistently with other malignancies. The average age of onset is about 38 years, and in some cases, it may be more aggressive than sporadic PTC; up to 5% of subjects with NMTC have a family history positive for the same disorder. The etiologic gene(s) have not been identified, although positional cloning of these genes may be possible. The evidence for and characteristics of familial NMTC will be reviewed, and the clinical and research implications will be discussed.

Performance of Elastography for the Evaluation of Thyroid Nodules: A Prospective Study

BACKGROUND In the ultrasound evaluation of masses, elastography measures stiffness, which may predict malignancy. Studies of small or selected subgroups suggest that elastography may be useful in the evaluation of thyroid nodules (TNs). We prospectively tested the hypothesis that TN stiffness, as measured by strain elastography (SE), is an independent predictor of thyroid cancer (TC) in unselected TNs. METHODS In 706 unselected patients with 912 TNs meeting the ATA criteria for a fine-needle aspiration biopsy (FNAB), we first performed conventional thyroid ultrasound and SE. Nodule stiffness was graded from least to most stiff by an elastography score (ES) of ES 0 to ES 3. Surgical resection was recommended for FNAB results that were not clearly benign. Bivariate and multivariate regression analyses identified the independent predictors of TC. RESULTS There were 86 malignant TNs. ES was a significant predictor of TC (p=0.0001). The prevalence of TC was 57 of the 158 TNs (36.1%) for the ES 3 group, 12 of the 158 TNs (7.7%) for the ES 2 group, 16 of the 565 TNs (2.8%) for the ES 1 group, and 1 of the 33 TNs (3%) for the ES 0 group. By multivariate regression analysis, the independent predictors of TC were ES, microcalcifications, hypoechogenicity, and isthmus location. The positive predictive value (PPV) of ES was 36.1%, which was similar to the PPV of microcalcifications (35.9%), but greater compared with hypoechogenicity (13.6%) and isthmus location (16.9%). The negative predictive value (NPV) of ES was 97.2%, which was better than any other predictor for malignancy. CONCLUSIONS We conclude that TN stiffness measured by elastography is an independent predictor of TC with a PPV that is equal to or greater than that of conventional ultrasonographic characteristics. NPV was greater than any other predictor of malignancy.

Pituitary Adenoma With Paraganglioma/Pheochromocytoma (3PAs) and Succinate Dehydrogenase Defects in Humans and Mice

CONTEXT Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported. DESIGN We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages. RESULTS No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex. CONCLUSION The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.

Lateral transperitoneal laparoscopic adrenalectomy

Abstract Several laparoscopic approaches to the adrenal gland have been described. The lateral transperitoneal approach has several distinct advantages when contrasted with other techniques for laparoscopic adrenalectomy (LA). We present our technique and results obtained in 50 consecutive transperitoneal LAs. We review 50 consecutive laparoscopic adrenalectomies (28 female, 19 male) performed from 1993 to 1998. S.J. Shichman or R.E. Sosa was either the primary surgeon or the first assistant for all cases. The lateral transperitoneal approach described below was used in all cases. Indications for adrenalectomy included Cushings syndrome (13), aldosteronoma (15), pheochromocytoma (7), nonfunctioning adenoma (11), hyperplasia (2), and 1 case each of Carneys syndrome and metastasis to the adrenal gland. We performed 5 bilateral, 22 left, and 18 right laparoscopic adrenalectomies. The average time needed for bilateral adrenalectomy was 503 min (range 298–690 min); for left adrenalectomy, 227 min (range 121–337 min); and for right LA, 210 min (range 135–355 min). We demonstrated a yearly trend in lower operative times. The largest adrenal gland removed measured 13.8 × 6.7 × 3.5 cm. Intraoperative blood loss was low. Only one patient received a blood transfusion. Conversion to open adrenalectomy was not required. Postoperative analgesic requirements were low. The average length of stay was 3.8 days for bilateral LA and 3 days for unilateral LA. Complications occurred in 5 patients (2 wound infections, 2 hematomas, and 1 pleural effusion). There was no mortality. Lateral transperitoneal adrenalectomy is a safe and efficient technique for the removal of functional and nonfunctional adrenal masses. This technique is associated with low morbidity, a minimal postoperative analgesic requirement, and a short hospital stay and, in our opinion, is more versatile than the retroperitoneal approach.

Unilateral adrenal hyperplasia causing primary aldosteronism: limitations of I-131 norcholesterol scanning

Primary aldosteronism is a disorder that is commonly considered in patients referred to the hypertension clinic. The ease of measuring the random aldosterone-to-renin ratio in conjunction with an elevated serum aldosterone level has led to an increased screening for this disorder. Typically, patients undergo a confirmatory test after a positive screening test. However, once primary aldosteronism is confirmed, subtype delineation is critical to decide on the optimal treatment. We report a patient with resistant hypertension and primary aldosteronism with a normal computed tomographic scan of the adrenal glands, a left-sided uptake on adrenal scintigraphy, and a right-sided lateralization of aldosterone after adrenal vein sampling. A repeat adrenal vein sampling confirmed the aldosterone lateralization to the right adrenal gland, which was then removed laparoscopically. The patient had a good clinical and biochemical response, and unilateral adrenal hyperplasia was discovered at histology. Excessive reliance on adrenal scintigraphy without adrenal vein sampling may lead to serious errors in patient management.

Familial Nonmedullary Thyroid Carcinoma

BACKGROUND Nonmedullary thyroid carcinomas (NMTCs) originate from the thyroid epithelial cells and, until recently, were thought to arise sporadically without an inherited genetic predisposition. However, evidence of a familial predisposition to NMTC is accumulating. METHODS This review addresses the strengths, weaknesses, and clinical implications of the observations indicating an inherited genetic predisposition to NMTC. These observations include epidemiologic studies, descriptions of large kindreds, and genetic analyses. RESULTS Familial NMTC (FNMTC) may be caused by an inherited genetic predisposition and can be divided into two groups. The first group has an increased prevalence of NMTC within a familial cancer syndrome with a preponderance of nonthyroidal tumors. In the second group the predominant neoplasm is NMTC, although other neoplasms may occur with increased frequency. These disorders are the focus of this review. CONCLUSIONS A family history in NMTC patients should be directed at detecting those familial tumor syndromes with a preponderance of NMTC as well as those familial tumor syndromes enriched in NMTC but with a preponderance of nonthyroidal tumors. Since the recurrence rates may be greater in FNMTC than in sporadic NMTC, careful monitoring is indicated for affected individuals. The advantages and disadvantages of screening asymptomatic members of FNMTC kindreds with thyroid ultrasound are discussed, and the final decision is deferred to the treating physicians and their patients. It is hoped that positional cloning research will identify the FNMTC susceptibility genes.