The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications.

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

Incomplete Carney triad--a review of two cases.

A curious association of three rare tumours was described by Carney in 1977. 'Carney's triad' characteristically includes multifocal pulmonary chondroma, gastric stromal sarcoma and extra-adrenal paraganglioma. Patients may exhibit complete or incomplete expression of the triad. Carney acknowledged that, of 79 patients, only 17 possessed all three tumours. We report here two patients with incomplete expression of Carney's triad.

A calcified lung tumour and microcytic anaemia in a young woman: partial expression of the Carney triad.

The Carney triad is the non-familial addociation of gastric stromal tumours (GISTs), pulmonar chondromas and extra-adrenal paragangliomas. Fewer than 100 cases of the disorder have been reported since its description in 1977. The condition has a predeliction for young women. Most patients exhibit only two of the three components. The tumours tend to be multifocal in the affected organ or system. Herein, we describe the case of a 27-year-old woman with multiple gastric GISTs and a pulmonary chondroma, partial expression of the Carney triad. It is important to be aware of the Carney triad when one of its constituent tumours is found, particularly if the patient is a young woman, so that a search can be made for and surveillance instituted for the other components. Treatment for the gastric tumours (sarcomas) and the paragangliomas (potentially malignant) is surgical. The lung chondromas are benign neoplasms and ordinarily not symptomatic. If a diagnosis of the tumour can be established by biopsy, surgical resection may not be necessary.

Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions.

A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (iMAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11A ( PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues.

A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions.

BACKGROUND: Inactivation of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours. METHODS AND RESULTS: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes. CONCLUSION: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIalpha as a candidate tumour suppressor gene.

Chromosome 2 (2p16) abnormalities in Carney complex tumours.

Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22-24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations. These changes are mostly amplifications of the 2p16 region, that overlap with a previously identified amplicon in sporadic thyroid cancer, and an area often deleted in sporadic adrenal tumours. Both thyroid and adrenal tumours constitute part of CNC indicating that the responsible gene(s) in this area may indeed be involved in both inherited and sporadic endocrine tumour pathogenesis and/or progression.

Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicatesthat pituitary tumors in patients with Carney complex may not exhibit the same phenotype.

Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation.

Carney complex is a multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous, and neural tumors, as well as a variety of pigmented lesions of the skin and mucosae. Carney complex is inherited as an autosomal dominant trait and may simultaneously involve multiple endocrine glands, as in the classic multiple endocrine neoplasia syndromes 1 and 2. Carney complex also has some similarities to McCuneAlbright syndrome, a sporadic condition that is also characterized by multiple endocrine and nonendocrine tumors. Carney complex shares skin abnormalities and some nonendocrine tumors with the lentiginoses and certain of the hamartomatoses, particularly Peutz-Jeghers syndrome, with which it shares mucosal lentiginosis and an unusual gonadal tumor, large-cell calcifying Sertoli cell tumor. Careful clinical analysis has enabled positional cloning efforts to identify two chromosomal loci harboring potential candidate genes for Carney complex. Most recently, at the 17q22-24 locus, the tumor suppressor gene PRKAR1A, coding for the type 1alpha regulatory subunit of PKA, was found to be mutated in approximately half of the known Carney complex kindreds. PRKAR1A acts a classic tumor suppressor gene as demonstrated by loss of heterozygosity at the 17q22-24 locus in tumors associated with the complex. The second locus, at chromosome 2p16, to which most (but not all) of the remaining kindreds map, is also involved in the molecular pathogenesis of Carney complex tumors, as demonstrated by multiple genetic changes at this locus, including loss of heterozygosity and copy number gain. Despite the known genetic heterogeneity in the disease, clinical analysis has not detected any corresponding phenotypic differences between patients with PRKAR1A mutations and those without. This article summarizes the clinical manifestations of Carney complex from a worldwide collection of affected patients and also presents revised diagnostic criteria for Carney complex. In light of the recent identification of mutations in the PRKAR1A gene, an estimate of penetrance and recommendations for genetic screening are provided.

Osteochondromyxoma of bone: a congenital tumor associated with lentigines and other unusual disorders.

This article describes the clinical and pathologic features of four unusual bone tumors. Three were congenital or most likely so; the fourth, detected at age 1 year, was probably of considerable duration. The patients, three boys and one girl, each presented with a painless mass. Two had the Carney complex, a familial lentiginous and multiorgan tumorous syndrome; another probably had this disorder; the fourth did not show it, but his mother did. The tumors occurred in the nasal region (n = 2) and the diaphysis of the tibia and radius (n = 1 each). Roentgenographically, three had benign characteristics; the fourth, malignant features. Grossly, the tumors were gelatinous, cartilaginous. and bony. Microscopically, they featured benign-appearing polymorphic cells with few division figures arranged in sheets and lobules set in a myxomatous, cartilaginous, osseous, and hyaline fibrous matrix. Cellularity was low to moderate. The tumors eroded bone, one infiltrated between bony trabeculae, and three had soft tissue extension. Complete resection of one tumor was curative; incomplete excision of two tumors resulted in local recurrence (intracranial and fatal) in one and persistence in the other; the fourth tumor remains under observation after biopsy. No tumor metastasized.

Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex.

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome, which has been linked to loci on 2p16 and 17q22-24. We recently reported that PRKAR1A, which codes for the type 1A regulatory subunit of protein kinase A (PKA), is a tumor suppressor gene on chromosome 17 that is mutated in some CNC families. To evaluate the spectrum of PRKAR1A mutations, we identified its genomic structure and screened for mutations in 54 CNC kindreds (34 families and 20 patients with sporadic disease). Fourteen families were informative for linkage analysis: four of four families that mapped to 17q had PRKAR1A mutations, whereas there were no mutations found in seven families exhibiting at least one recombination with 17q. In six of the latter, CNC mapped to 2p16. PRKAR1A mutations were also found in 12 of 20 non-informative families and 7 of 20 sporadic cases. Altogether, 15 distinct PRKAR1A mutations were identified in 22 of 54 kindreds (40.7%). In 14 mutations, the sequence change was predicted to lead to a premature stop codon; one altered the initiator ATG codon. Mutant mRNAs containing a premature stop codon were unstable, as a result of nonsense-mediated mRNA decay. Accordingly, the predicted truncated PRKAR1A protein products were absent in these cells. We conclude that (i) genetic heterogeneity exists in CNC; and (ii) all of the CNC alleles on 17q are functionally null mutations of PRKAR1A. CNC is the first human disease recognized to be caused by mutations of the PKA holoenzyme, a critical component of cellular signaling.

Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy.

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome (OMIM 160980, http://www.ncbi.nlm.nih.gov/omim) with features overlapping those of other multiple endocrine neoplasias and hamartomatoses, Peutz-Jeghers syndrome (PJS) in particular. Although a number of patients with CNC and ovarian tumors have been described in individual patient reports, it is unclear whether ovarian lesions constitute a component of the syndrome or are coincidental events. We investigated 18 women with CNC [age at first evaluation, 31.3+/-12.1 yr (mean +/- SD)] prospectively for the development of ovarian tumors over a period of 35.7+/-30.6 months by physical examination and pelvic ultrasonography. They were compared with 11 women (age at first evaluation, 32.9+/-17 yr) who were enrolled under the same protocol (follow up, 32.3+/-25.1 months) and served as a control group. In addition, a registry of 178 women from among a total of 309 patients with CNC was searched retrospectively for any having ovarian tumors. Seven available histological specimens were rereviewed. None of the CNC patients had ovarian tumors analogous to those of PJS. Two patients with CNC in the prospective group developed ovarian tumors and were operated upon. One had bilateral oophorectomy for asynchronous serous cystadenomas. The second patient had a unilateral serous cystadenoma. Resected tumor tissue from both patients was tested for genetic abnormalities of the chromosomal regions to which CNC genetic loci have been mapped. Both showed genomic amplification of chromosomal region 2p16. An additional 10 patients had at least 1 sonogram positive for ovarian cysts. Only 1 of the patients in the control group was found to have a persistent, simple ovarian cyst by ultrasonography. The registry of 178 CNC patients included 4 who had undergone surgery for ovarian tumors. The diagnoses included endometrioid adenocarcinoma (1 patient) and metastatic mucinous adenocarcinoma (the primary site was probably ovarian; 1 patient). In addition, 7 of 12 patients (58%) with CNC, who died of other causes, had ovarian lesions at autopsy. In conclusion, although the same stromal tumor, large-cell calcifying Sertoli cell tumor, affects the testes in CNC and PJS, we did not find such tumors in a small population of CNC patients that was studied prospectively or a larger group of CNC patients that was studied retrospectively. The results of our study also suggested that women with CNC commonly develop ovarian cysts and may be at risk for ovarian carcinoma. The chromosome 2p16 CNC locus was involved in ovarian pathology with apparent copy number gain, suggesting that at least molecularly there is some involvement of the CNC gene(s) in these lesions. Although ovarian tumors do not seem to be a major manifestation of CNC, sonography of the ovaries may be part of the initial evaluation for this genetic syndrome in women with CNC; follow-up of any identified lesion is recommended because of the possible risk for malignancy.

Genetic and histologic studies of somatomammotropic pituitary tumors in patients with the "complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex).

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes, MEN type 1 (MEN 1), in particular. GH-producing pituitary tumors have been described in individual reports and in at least two large CNC patient series. It has been suggested that the evolution of acromegaly in CNC resembles that of the other endocrine manifestations of CNC in its chronic, often indolent, progressive nature. However, histologic and molecular evidence has not been presented in support of this hypothesis. In this investigation, the pituitary glands of eight patients with CNC and acromegaly [age, 22.9+/-11.6 yr (mean +/- SD)] were studied histologically. Tumor DNA was used for comparative genomic hybridization (CGH) (four tumors). All tumors stained for both GH and prolactin PRL (eight of eight), and some for other hormones, including alpha-subunit. Evidence for somatomammotroph hyperplasia was present in five of the eight patients in proximity to adenoma tissue; in the remaining three only adenoma tissue was available for study. CGH showed multiple changes involving losses of chromosomal regions 6q, 7q, 11p, and 11q, and gains of 1pter-p32, 2q35-qter, 9q33-qter, 12q24-qter, 16, 17, 19p, 20p, 20q, 22p and 22q in the most aggressive tumor, an invasive macroadenoma; no chromosomal changes were seen in the microadenomas diagnosed prospectively (3 tumors). We conclude that, in at least some patients with CNC, the pituitary gland is characterized by somatotroph hyperplasia, which precedes GH-producing tumor formation, in a pathway similar to that suggested for MAS-related pituitary tumors. Three GH-producing microadenomas showed no genetic changes by CGH, whereas a macroadenoma in a patient, whose advanced acromegaly was not cured by surgery, showed extensive CGH changes. We speculate that these changes represent secondary and tertiary genetic "hits" involved in pituitary oncogenesis. The data (1) underline the need for early investigation for acromegaly in patients with CNC; (2) provide a molecular hypothesis for its clinical progression; and (3) suggest a model for MAS- and, perhaps, MEN 1-related GH-producing tumor formation.

Association of Peutz-Jeghers-like mucocutaneous pigmentation with breast and gynecologic carcinomas in women.

Most reports describe an increased risk of malignancy in Peutz-Jeghers syndrome (PJS). We identified individuals with PJS-like pigmentation but no polyposis, designated as isolated mucocutaneous melanotic pigmentation (IMMP), and 1) characterized their clinical features, 2) assessed them for cancer events, and 3) screened a sample of these subjects for mutations in LKB1, a gene responsible for a portion of PJS cases. Review of Mayo Clinic records from 1945 to 1996 identified 26 patients with IMMP. All were then interviewed or their medical records reviewed to determine if cancer had developed. Conformation-sensitive gel electrophoresis (CSGE) screening for LKB1 mutations was followed by direct sequencing. Ten of these 26 individuals (38%) developed 12 malignancies that arose in the cervix (n = 3), endometrium (n = 3), breast (n = 1), kidney (n = 1), lung (n = 2), colon (n = 1), and lymphatic tissue (n = 1). In females with IMMP, the relative risk for cancer was 3.2 (95% CI, 1.2-6.9), while that for males was not increased. The relative risk for breast and gynecologic cancers was 7.8 (95% CI, 2.5-18.1) in affected females. Of 9 individuals tested, no LKB1 mutations were detected. Classical PJS is associated with an increased cancer risk. Our results indicate that IMMP is another lentiginosis with cancer predisposition. In particular, the relative risk for cancer in females with IMMP was significantly increased, as is true in females with PJS. However, LKB1 mutations did not contribute to the development of IMMP in the patients tested.

Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.

Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas. CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6, 7). Because of its similarities to the McCune-Albright syndrome and other features, such as paradoxical responses to endocrine signals, genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours. We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.

Salivary heterotopia, cysts, and the parathyroid gland: branchial pouch derivatives and remnants.

Five cases of periparathyroid salivary heterotopia associated with cysts were studied. The specimens were obtained from three men and two women age 36 to 62 years who underwent surgery for primary hyperparathyroidism (four patients) and thyroid nodule (one patient). The heterotopia-cyst combination occurred with normal and abnormal parathyroid glands (four inferior and one of unknown location). Review of histologic slides of all parathyroid glands excised from 258 patients during a 1-year period at the Mayo Clinic revealed two similar salivary gland-cyst units. Seven more cases featured one or more periparathyroid cysts, five with other nonsalivary-type epithelial accompaniments. One of the latter additionally had a focus of parathyroid cells in the cyst wall, and associated thyroid parenchyma with C cells, and cartilage.

Hyalinizing trabecular adenoma and papillary carcinoma of the thyroid gland express different cytokeratin patterns.

It has recently been suggested that hyalinizing trabecular adenoma of the thyroid is an encapsulated variant of papillary carcinoma because of certain similarities of their histology, the occasional occurrence of both tumors in the same gland, and their similar pattern of expression of cytokeratins, including staining for cytokeratin 19. To investigate this notion further, we examined immunocytochemically the expression of a series of cytokeratins in 12 hyalinizing trabecular adenomas and six papillary carcinomas. Hyalinizing trabecular adenoma showed no or minimal reactivity for cytokeratin 19, whereas papillary carcinoma was almost always strongly reactive. Also, hyalinizing trabecular adenoma showed no staining for high-molecular-weight (HMW) cytokeratin, whereas papillary carcinoma was strongly positive. Thus, there are different patterns of cytokeratin 19 and HMW cytokeratin expression in hyalinizing trabecular adenoma and papillary carcinoma. The findings do not support the suggestion that hyalinizing trabecular adenoma is an encapsulated variant of papillary carcinoma.

Prolactin secretion abnormalities in patients with the "syndrome of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas" (Carney complex).

Carney complex is a multiple neoplasia and lentiginosis syndrome. Acromegaly due to growth hormone (GH)-producing adenomas has been considered the only pituitary-related manifestation of the complex. In the present study, seven patients with Carney complex, who belonged to three unrelated kindreds and had relatives with acromegaly, were investigated for the presence of GH and prolactin (PRL) secretion abnormalities (familial cases). In addition, four patients with the complex and no family history of the complex were studied (sporadic cases). Seven of the patients were female and four were male; their mean age was 24.27 +/- 4.34 years. Sampling every 20 min for one hour in the morning and under fasting and unstimulated conditions was performed in all patients, for determination of serum PRL levels. Insulin-like growth factor-I (IGF-I) levels and magnetic resonance imaging (MRI) of the pituitary were also obtained. Patients who had elevated IGF-I levels underwent investigation for acromegaly by oral glucose tolerance test and thyrotropin-releasing hormone. Seven of the 11 patients (63.6%) had moderately high PRL levels (mean Z score value 2.12 +/- 0.66); three of these patients also had elevated IGF-I levels but a negative investigation for acromegaly. All patients had negative pituitary MRI. The patient with the highest PRL levels underwent 24-hour sampling every 20 min, which demonstrated a higher baseline secretion of this hormone with preservation of its circadian pulsatility. Hyperprolactinemia was present in two siblings and a parent-child pair. We conclude that prolactin hypersecretion, albeit mild, appears to be frequent in patients with Carney complex, is inherited in an autosomal dominant manner in kindreds with the syndrome, and may be associated with elevated IGF-I levels in some, but not all, patients.

Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thyroid gland.

The monoclonal MIB-1 antibody reacts with the nuclei of cells in the late G1, S, G2, and M phases of the cell cycle. Previously, we found two cases of hyalinizing trabecular adenoma that showed cell membrane and cytoplasmic immunopositivity for the antibody. The purpose of this investigation was to confirm this exceptional reactive pattern of MIB-1 in hyalinizing trabecular adenoma. For the study, we collected 13 additional hyalinizing trabecular adenomas and stained a total of 15 tumors using MIB-1 antibody. Ten cases of papillary thyroid carcinoma were studied similarly. All hyalinizing trabecular adenomas showed strong positivity for the antibody in 90% or more of the tumor cells, localized especially to the cell membrane and also to the cytoplasm. There was no cell membrane or cytoplasmic MIB-1 positivity among the 10 papillary carcinomas. Luminal border of normal extratumoral thyroid follicles rarely showed faint immunopositivity. Our findings indicate that strong cell membrane and cytoplasmic immunoreactivity for MIB-1 is a characteristic of the hyalinizing trabecular adenoma. Staining for MIB-1 will be useful in differentiating hyalinizing trabecular adenoma from papillary carcinoma, which shares a number of cytologic and histologic findings with hyalinizing trabecular adenoma.

Neurosurgical implications of Carney complex.

OBJECT: The authors present their neurosurgical experience with Carney complex. Carney complex, characterized by spotty skin pigmentation, cardiac myxomas, primary pigmented nodular adrenocortical disease, pituitary tumors, and nerve sheath tumors (NSTs), is a recently described, rare, autosomal-dominant familial syndrome that is relatively unknown to neurosurgeons. Neurosurgery is required to treat pituitary adenomas and a rare NST, the psammomatous melanotic schwannoma (PMS), in patients with Carney complex. Cushing's syndrome, a common component of the complex, is caused by primary pigmented nodular adrenocortical disease and is not secondary to an adrenocorticotropic hormone-secreting pituitary adenoma. METHODS: The authors reviewed 14 cases of Carney complex, five from the literature and nine from their own experience. Of the 14 pituitary adenomas recognized in association with Carney complex, 12 developed growth hormone (GH) hypersecretion (producing gigantism in two patients and acromegaly in 10), and results of immunohistochemical studies in one of the other two were positive for GH. The association of PMSs with Carney complex was established in 1990. Of the reported tumors, 28% were associated with spinal nerve sheaths. The spinal tumors occurred in adults (mean age 32 years, range 18-49 years) who presented with pain and radiculopathy. These NSTs may be malignant (10%) and, as with the cardiac myxomas, are associated with significant rates of morbidity and mortality. CONCLUSIONS: Because of the surgical comorbidity associated with cardiac myxoma and/or Cushing's syndrome, recognition of Carney complex has important implications for perisurgical patient management and family screening. Study of the genetics of Carney complex and of the biological abnormalities associated with the tumors may provide insight into the general pathobiological abnormalities associated with the tumors may provide insight into the general pathobiological features of pituitary adenomas and NSTs.