J. Aidan Carney

Mutations of the gene encoding the protein kinase A type I-α 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-α (RIα), 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.

Prevalence of columnar-lined (Barrett's) esophagus: Comparison of population-based clinical and autopsy findings

In this study, two different methods were used to investigate the prevalence of columnar-lined (Barretts) esophagus. First, a population-based study of clinically diagnosed cases was performed in Olmsted County, Minnesota. Twenty-five residents of this county, who had undergone endoscopy and biopsy between 1969 and 1986, were diagnosed as having Barretts esophagus. On January 1, 1987, 17 of these patients were still living in the county, representing an age- and sex-adjusted prevalence rate of 22.6 cases per 100,000 population (95% confidence interval, 11.7-33.6 cases). A prospective search of Mayo Clinic autopsy material for Barretts esophagus was conducted using the same diagnostic criteria as in the clinical study. Over an 18-month period ending in September 1987, 7 cases of Barretts esophagus were found in 733 unselected autopsies. In 5 of the 7 cases, Barretts esophagus was first detected at the time of autopsy. Using the age- and sex-specific prevalence from the clinically diagnosed study, researchers expected to find 0.19 cases of Barretts esophagus at the 226 autopsies performed on Olmsted County residents, although 4 were actually observed (P less than 0.001). This approximately 21-fold increase (95% confidence interval, 5-54 cases) corresponds to an autopsy estimated prevalence of 376 cases per 100,000 population (95% confidence interval, 95-967 cases). In conclusion, a majority of cases of Barretts esophagus, a condition that predisposes to esophageal malignancy, remains unrecognized in the general population.

Gastric Stromal Sarcoma, Pulmonary Chondroma, and Extra-adrenal Paraganglioma (Carney Triad): Natural History, Adrenocortical Component, and Possible Familial Occurrence

OBJECTIVE To investigate the natural history of the triad of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma, a rare syndrome of unknown cause primarily affecting young women. METHODS Mayo Clinic records, the world literature, and the authors files were searched for patients with all or 2 of the 3 tumors. RESULTS Seventy-nine patients, 67 women and 12 men, were identified, 17 (22%) with the 3 tumors and 62 (78%) with 2 tumors. Forty-two (53%) had gastric and pulmonary tumors, the most common combination. The longest interval between detection of the first and second components was 26 years (mean, 8.4 years; median, 6 years). Follow-up ranged from 1 year to 49 years (mean, 20.6 years; median, 20 years). Sixty-four patients (81%) were alive, 19 (24%) apparently free of disease and 45 (57%) with residual or metastatic tumors. Thirty-two patients (41%) had had 1 or more local recurrences of the gastric sarcoma; the longest interval to first recurrence was 36 years. Twenty-one survivors (27%) had hepatic metastatic gastric sarcoma with follow-up of 1 year to 25 years (mean, 9.3 years; median, 7 years). Fifteen patients (19%) were dead, 10 (13%) of whom died of the disorder. Ten patients (13%) had nonfunctioning adrenocortical tumors. Two patients each had a sibling with 1 component of the triad. CONCLUSIONS The triad is a chronic, persistent, and indolent disease. Benign adrenocortical tumors are a component of the condition. The disorder may be familial.

Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-α (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of ‘paraganglioma and gastric stromal sarcoma’; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma

The association of three uncommon neoplasms — gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma — in two patients and the occurrence of two of these tumors in ...

Dominant Inheritance of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity

We describe a family in which lentigines were present in the index patient, in three of her seven siblings, in their mother, and in a niece (the daughter of an affected sister). Cutaneous myxomas were present in the index patient, in two of her brothers, and probably in their mother. In addition, the index patient had two cardiac myxomas. multiple myxoid mammary fibroadenomas, and the Cushing syndrome, and an affected brother had acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. Thus, at least one manifestation of the complex of myxomas, spotty pigmentation, and endocrine overactivity has occurred in three successive generations of this family. Both male and female family members were affected, and 5 of the 11 children of affected persons had the disorder. The karyotypes of two affected persons were normal. These observations are consistent with mendelian dominant inheritance of the syndrome.

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 ( PDE11A ) in individuals with adrenocortical hyperplasia

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31–2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31–2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

PARATHYROID CARCINOMA : CLINICAL AND PATHOLOGIC FEATURES IN 43 PATIENTS

Parathyroid carcinoma accounts for 0.5 to 5% of all cases of hyperparathyroidism. We reviewed the clinical, surgical, and pathologic features observed in all patients with parathyroid carcinoma evaluated at the Mayo Clinic from 1920 through 1991. Forty-three patients (22 women, 21 men; mean age, 54 yrs, range 29-72) were identified, including 2 with familial hyperparathyroidism. Information on initial presentation was available in 40 patients: 15 (38%) presented with polydipsia or polyuria, 11 (27%) with myalgias or arthralgias, 7 (17%) with weight loss, and 4 (10%) with nephrolithiasis; 3 patients (7%) were asymptomatic at presentation. Of 31 patients in whom the initial neck examination was recorded, 14 (45%) had a palpable neck mass. The mean serum calcium and serum phosphorus levels were 14.6 mg/dl and 2.3 mg/dl, respectively. Parathyroid hormone levels were elevated in 21 of 21 patients (mean elevation, 10.2 times upper limit of normal). Complications included nephrolithiasis in 14 of 25 patients (56%), bone disease in 20 of 22 patients (91%) and both in 8 of 15 patients (53%). All patients underwent primary surgical resection of parathyroid carcinoma. Twenty-six of 43 patients (60%) required a second operation with 18 patients requiring multiple re-explorations. At the second operation, residual tumor was found in the neck (68%), mediastinum (16%), or both (12%). Six patients received radiation therapy to the neck (5 patients) or bones (1 patient) for recurrent or metastatic disease. Of these, 1 patient appeared cured of parathyroid carcinoma by radiation therapy 11 years after documented tumor invasion of his trachea. Repeated excision of tumor recurrences was an effective means of controlling hypercalcemia in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution and quantitation of gut neuropeptides in normal intestine and inflammatory bowel diseases.

To study hyperplasia of peptidergic nerves purported to be diagnostic of Crohns disease, we determined the distribution and concentrations of gut neuropeptides in specimens of normal intestine, ulcerative colitis, and Crohns disease. Tissue specimens obtained at surgery were dissected into the mucosal-submucosal and muscularis externa layers, and immunoreactive gut neuropeptides were acid-extracted for measurement by radioimmunoassay. The immunoreactive species were characterized by column chromatography. Mucosal-submucosal layer concentrations of vasoactive intestinal peptide were significantly decreased in Crohns colitis and ulcerative colitis, while mucosal-submucosal layer concentrations of substance P were significantly increased in left-sided ulcerative colitis. Muscularis externa layer concentrations of vasoactive intestinal peptide and met5-enkephalin were decreased in left-sided Crohns colitis. These neuropeptide concentration abnormalities did not clearly differentiate between Crohns colitis and ulcerative colitis, and no increase in concentration of a neuropeptide diagnostic of Crohns disease was identified.

Pigmented epithelioid melanocytoma: A low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus

In the course of a study of borderline melanocytic tumors, we observed a distinctive group of lesions characterized by features very similar to those previously described in the literature as “animal-type melanoma” and epithelioid blue nevus of Carney complex. We have designated these lesions as pigmented epithelioid melanocytoma (PEM). Herein, we present a clinical-pathologic analysis of 41 consecutive PEM from 40 patients and compare them with 11 epithelioid blue nevi from patients with Carney complex. PEM occurred in both sexes of different ethnic backgrounds, including white, Hispanic, black, Asian, and Persian. The median age of occurrence was 27 years (range 0.6–78 years). Tumors had wide distribution with extremities being the most common site. The tumors were formed by deep dermal (mean Breslows thickness 3.3 mm) proliferation of heavily pigmented epithelioid and/or spindled melanocytes. Five lesions were part of combined nevus. Ulceration was present in 7 cases. Tumor necrosis was present in 1 case. Regional lymph nodes were sampled in 24 cases (59%). In 11 cases, lymph nodes contained metastases (46%). Liver metastases occurred in 1 case. None of the patients died of disease. Clinical follow-up of more than a year (mean 32 months, range up to 67 months) was available in 27 cases (67%). We found no histologic criteria separating metastasizing and nonmetastasizing PEM. Ulceration was the only feature more common in PEM than epithelioid blue nevi of Carney complex. Otherwise, they were histologically indistinguishable. Our data show that PEM is a unique low-grade variant of melanoma with frequent lymph node metastases but indolent clinical course. We suggest that PEM be considered as a provisional histologic entity encompassing both animal-type melanoma and epithelioid blue nevus.