Adult rhabdomyoma presenting as thyroid nodule on fine-needle aspiration in patient with Birt-Hogg-Dubé syndrome: Case report and literature review.

Extracardiac rhabdomyoma is an uncommon benign striated muscle tumor with a predilection for the head and neck region. However, it is extremely rare for extracardiac rhabdomyoma to present as a thyroid nodule. We report a case of rhabdomyoma diagnosed by thyroid fine-needle aspiration (FNA) in a patient with Birt-Hogg-Dubé (BHD) syndrome. A 60-year-old man with BHD syndrome presented for recurrent pneumothorax. Chest CT incidentally identified a thyroid nodule. Subsequent sonography confirmed a 4.44 × 2.28 × 2.82 cm solid, hypoechoic nodule with smooth margins in the right upper pole. Ultrasound-guided FNA revealed many clusters and scattered isolated large polygonal cells with abundant granular cytoplasm and small peripherally located nuclei. Vague striations in the cytoplasm were focally identified. No follicular cells or colloid was present. Immunocytochemistry on one direct smear slide demonstrated diffuse positivity for desmin, supporting muscular differentiation. Subsequent surgery identified an adult rhabdomyoma originating from the inferior constrictor muscle of the neck and anteriorly displacing the thyroid. Because the mass was intimately associated with the thyroid gland, it was initially mistaken for a thyroid nodule on ultrasound. Diagnosis of rhabdomyoma on FNA is challenging, especially when rhabdomyoma mimics a thyroid nodule on imaging. The differential diagnosis includes Hurthle cell neoplasm, granular cell tumor, colloid nodule, and normal striated skeletal muscle. Adequate radiologic data and familiarity with the cytologic features of rhabdomyoma are critical for an accurate diagnosis.

The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome.

CONTEXT: McCune-Albright syndrome (MAS) is caused by mutations in GNAS (most often R201C or R201H) leading to constitutive cAMP signaling and multiple endocrine dysfunctions, including morphological and functional thyroid involvement. OBJECTIVE: The objective of the study was to characterize the clinical and molecular features of the MAS-associated thyroid disease in a large cohort of patients. DESIGN: This was a retrospective analysis. SETTING: The study was conducted at the National Institutes of Health Clinical Center. PATIENTS: The study included 100 consecutive MAS patients. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Functional and morphological evaluation of the thyroid was measured. Ex vivo experiments were performed on MAS thyroid samples to study the effects of the GNAS mutations on the 5'-deiodinases. Reconstitution experiments in HEK-293 cells were performed to study the effects of GNAS mutations on the type-2 5'-deiodinase. RESULTS: Fifty-four patients had abnormal thyroid ultrasound findings. This group, compared with patients without abnormal findings, had higher T(3) to T(4) ratio, indicating an elevated 5'-deiodinase activity. Thyroid samples from MAS subjects, compared with normal tissue, showed a significant increase in both type 1 (D1) and type 2 (D2) 5'-deiodinase activity (D1 control 5.9 +/- 4.5 vs. MAS 41.7 +/- 26.8 fmol/min.mg, P < 0.001; D2 control 28.3 +/- 13.8 vs. MAS 153.1 +/- 43.7 fmol/min.mg, P < 0.001). Compared with cells transfected with the wild-type R201 allele, the basal transcriptional activity of the D2 promoter was significantly increased in both mutants (C and H) (R 10733 +/- 2855, vs. C 18548 +/- 4514, vs. H 19032 +/- 4410 RLU +/- SD, P < 0.001). CONCLUSION: Thyroid pathology is a common occurrence in MAS. Consistent with the molecular etiology of the disease, the shift in T(3) to T(4) ratio is at least in part secondary to a cAMP-mediated intrathyroidal activation of D2 and to elevated D1 activity.

Functional characterization of the 258 A/G (D2-ORFa-Gly3Asp) human type-2 deiodinase polymorphism: a naturally occurring variant increases the enzymatic activity by removing a putative repressor site in the 5' UTR of the gene.

OBJECTIVE: 5' deiodination of thyroid hormone represents an important step in the modulation of the hormonal message. Previous studies indicate that the naturally occurring polymorphism located in 5'-untranslated region of the gene, 258 A/G, is associated with a decrease in circulating T4/T3 ratio, suggesting an increased gene expression. The aim of this study was to characterize the gene variant in vitro. DESIGN: This was designed as an in vitro study. MAIN OUTCOME: The wild-type and mutant promoters were cloned into a reporter vector and transfected into HEK-293, GH3, and H3B cells. Compared to the 258G wild-type allele, the 258A variant had an increased basal activity in all the cell lines (HEK-293 258A 13998 +/- 371.9 RLU vs. 258G 5593 +/- 124.2 RLU, p < 0.0001). Electrophoresis mobility shift assay (EMSA) experiments were performed with nuclear extracts obtained from HEK-293 cells and from human thyroid, muscle, and liver. The EMSA experiments showed that the 258A variant decreased the binding ability of a nuclear protein in HEK-293 cells, thyroid, and muscle. No specific binding was observed in liver nuclei. CONCLUSION: These data suggest that the increase in gene transcription induced by the 258A polymorphism could be mediated by reduction in the binding ability of a putative nuclear repressor.

Obesity and Hypogonadism.

The relationship between obesity and hypogonadism is complicated. The relationship is bidirectional and there are numerous causative and correlative factors on both sides of the equation. Obesity is increasing in prevalence in epidemic proportions. Likewise, we are beginning to see the rapid increase in the incidence of male hypogonadism. It is only recently that we are learning the ways in which these 2 conditions exacerbate each other, and we are only beginning to understand how by treating one of these conditions, we can help to treat the other as well.

Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by mutations in the fumarate hydratase (FH) gene on chromosome 1q42.3-43. Massive macronodular adrenocortical disease (MMAD) is a heterogeneous condition associated with Cushing syndrome (CS) and bilateral hyperplasia of the adrenal glands. In MMAD, cortisol secretion is often mediated by ectopic, adrenocortical expression of receptors for a variety of substances; however, to date, no consistent genetic defects have been identified. In a patient with HLRCC caused by a germline-inactivating FH mutation, we diagnosed atypical (subclinical) CS due to bilateral, ACTH-independent adrenocortical hyperplasia. A clinical protocol for the detection of ectopic expression of various hormone receptors was employed. Histology was consistent with MMAD. The tumor tissue harbored the germline FH mutation and demonstrated allelic losses of the 1q42.3-43 FH locus. We then searched the National Institutes of Health (NIH) databases of patients with MMAD or HLRCC and found at least three other cases with MMAD that had a history of tumors that could be part of HLRCC; among patients with HLRCC, there were several with some adrenal nodularity noted on computed tomography but none with imaging findings consistent with MMAD. From two of the three MMAD patients, adrenocortical tumor DNA was available and sequenced for coding FH mutations; there were none. We conclude that in a patient with HLRCC, adrenal hyperplasia and CS were due to MMAD. The latter was likely due to the FH germline mutation because in tumor cells, only the mutant allele was retained. However, other patients with MMAD and HLRCC, or HLRCC patients with adrenal imaging findings consistent with MMAD, or MMAD patients with somatic FH mutations were not found among the NIH series. Although a fortuitous association cannot be excluded, HLRCC may be added to the short list of monogenic disorders that have been reported to be associated with the development of adrenal tumors; FH may be considered a candidate gene for MMAD.

Utility of plasma free metanephrines in diagnosis of factitious pheochromocytoma.

OBJECTIVE: To report a case of epinephrine-induced factitious pheochromocytoma in a young woman with a past medical history of Conn's syndrome. METHODS: We present a case report with clinical and laboratory details, review related reports in the literature, and demonstrate the usefulness of plasma free metanephrine levels in facilitating the diagnosis of factitious pheochromocytoma. RESULTS: A 34-year-old woman was admitted to our hospital for confirmation and localization of an occult pheochromocytoma. After thorough investigation, we discovered that the patient was surreptitiously injecting epinephrine in order to induce symptoms and signs consistent with a pheochromocytoma. Analysis of the patient's biochemical profile during and between her catecholaminergic crises revealed plasma epinephrine and free metanephrine levels that would be highly unusual for a patient with a pheochromocytoma. CONCLUSION: This case illustrates the utility of implementing the ratio of plasma epinephrine to free metanephrine levels in distinguishing factitious from organic pheochromocytoma.