Protein kinase A and carney complex

Details Protein kinase A and carney complex Protein kinase A and carney complex

2001-08-23

2004-07-06

Fredman, Jeffrey (Department: 1634)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S022100, C536S024300, C536S024310, C536S024330, C435S006120, C435S091200

Reexamination Certificate

active

06759525

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods useful in the diagnosis and prognosis of Carney complex (CNC), as well as methods and compositions for the identification of compounds useful in the treatment and/or prevention of CNC. In addition, the present invention provides compositions and methods useful in the diagnosis and treatment of conditions associated with skin pigmentation defects, including but not limited to freckling, as well as endocrine tumors including, but not limited to adrenal and pituitary tumors. In addition, the present invention provides methods and compositions for the diagnosis and treatment of various types of cancers associated with abnormal activity of protein kinase A. In particular, the present invention provides genetic and other sequence information, as well as assay systems that will find use in these and related areas.
BACKGROUND OF THE INVENTION
Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome that affects the adrenal cortex, pituitary gland, thyroid gland, and the gonads. It is also associated with skin and mucosa pigmentation abnormalities, as well as myxoid and other neoplasms of mesenchymal and neural crest origin. The syndrome is characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas (Carney and Young, Endocrinologist 2:6-21 [1992]; Carney, Semin. Dermatol., 14:90-98 [1995]; Stratakis et al., Am. J. Med. Genet., 80:183-185 [1998]; Carney et al., Mayo Clin. Proc., 61:165-172 [1985]; and Stratakis, Front. Biosci., 5:D353-366 [2000]). The syndrome also belongs to another group of genetic disorders, referred to as the “lentiginoses” (lentigenoses), which also includes Peutz-Jeghers, LEOPARD, arterial dissections and lentiginosis, Laugier-Hunziker syndrome, Cowden disease, and Ruvalcaba-Myhre-Smith (Bannayan-Zonana) syndrome, and the centrofacial, benign patterned and segmental lentiginoses, all of which have been associated with a variety of developmental defects. The components of the complex have previously been described by the acronyms NAME (nevi, atrial myxomas and ephelides) or LAMB (lentigines, atrial myxomas, and blue nevi) (See e.g., Atherton et al., Br. J. Dermatol., 103:421-429 [1980]; and Rhodes et al., J. Am. Acad. Dermatol., 10,72-82 [1984]). However, it is presently accepted that most, if not all, of these patients had Carney complex (Stratakis, Pediatr. Pathol. Mol. Med., 19:41-68 [2000]).
Although it is relatively rare, the impact of the syndrome on affected patients is significant. As with other multiple neoplasias and lentigenosis syndromes, Carney complex affects many organs and systems. Typically, patients simultaneously have at least two endocrine tumors (e.g., primary pigmented nodular adrenocortical disease [PPNAD], growth hormone and/or prolactin-producing pituitary adenomas, thyroid nodules or carcinomas, testicular neoplasms [primarily large cell calcifying Sertoli cell tumor (LCCSCT)], and ovarian cysts), as well as psammomatous melanotic schwannoma (PMS), epithelioid blue nevus, breast ductal adenoma, and osteochondromyxoma (i.e., a rare bone tumor). The lesions are multicentric, often bilateral in paired organs, and originate in cells of mesenchymal (myxomas) or neural crest origin (spotty skin pigmentation and endocrine tumors). Thus, it is contemplated that the genetic defects associated with Carney complex are involved in the early development, growth, and proliferation of affected cells.
Early reports suggested that Carney complex was an inherited disease of immunological origin (Young et al., N. Eng. J. Med., 321:1659-1664 [1989]; and Berkhout et al., Clin. Endocrinol., 31:185-191 [1989]). Later reports indicated no association with autoimmune disease or immune dysfunction in affected patients (See e.g., Stratakis et al., J. Clin. Invest. 97:699-705). More recently, CNC has been reported to be inherited as an autosomal dominant trait and the responsible genes have been mapped to 2p16 and 17q22-24 (Stratakis et al., J. Clin. Invest., 97:699-705 [1996]; and Casey et al., Circul., 98:2560-2566 [1998]). Nonetheless, the genetic defects responsible for the complex remained unknown, making diagnosis and treatment of Carney complex problematic.
Currently, to make a diagnosis of Carney complex, a patient must either exhibit two of the manifestations listed in Table 1 below, or exhibit one of these manifestations and meet one of the supplemental criteria (i.e., an affected first-degree relative or an inactivating mutation of the PRKAR1A gene).
TABLE 1
Manifestations of Carney Complex Used in Diagnosis
Spotty skin pigmentation with a typical distribution (lips,
conjunctiva, and inner or outer canthi,
vaginal and penile mucosa)
Myxoma (cutaneous and mucosal), (with histologic confirmation)
Cardia myxoma
Breast myxomatosis or fat-suppressed magnetic resonance imaging
findings suggestive of this diagnosis
(with histologic confirmation)
PPNAD (with histologic confirmation) or paradoxical positive
response of urinary glucocorticosteroids to dexamethasone
administration during Liddle's test
Acromegaly due to growth hormone-producing adenoma
LCCSCT (with histologic confirmation) or characteristic
calcification on testicular ultrasonography
Thyroid carcinoma (with histologic confirmation) or multiple,
hypoechoic nodules on thyroid ultrasonography
Psammomatous melanotic schwannoma (with histologic confirmation)
Blue nevus, epithelioid blue nevus (multiple) (with histologic
confirmation)
Breast ductal adenoma (multiple)
Osteochondromyxoma (with histologic confirmation)
Additional findings that are suggestive or possibly associated with Carney complex, but are not diagnostic for the disease include: (1) intense freckling (without darkly pigmented spots or typical distribution); (2) blue nevus, usual type (if multiple); (3) café-au-lait spots or other “birthmarks”; (4) elevated IGF-1 levels, abnormal oGTT, or paradoxical growth hormone responses to TRH testing, in the absence of clinical acromegaly; (5) cardiomyopathy; (6) pilonidal sinus; (7) history of Cushing syndrome, acromegaly, or sudden death in extended family; (8) multiple skin tags and other skin lesions; lipomas; (9) colonic polyps (usually in association with acromegaly); (10) hyperprolactinemia (usually mild and almost always in association with clinical or subclinical acromegaly); (11) single, benign thyroid nodule in a young patient or multiple thyroid nodules in an older patient (detected by ultrasonography); and (12) family history of carcinoma, in particular of the thyroid, colon, pancreas, and the ovary, or other multiple benign or malignant tumors.
Once the above diagnostic criteria have been applied, and a diagnosis has been confirmed, for post-pubertal pediatric and adult patients, the recommended clinical surveillance of patients with Carney complex involves: echocardiograms (annually or biannually for adolescent patients with a history of excised myxoma), testicular ultrasound (annually), thyroid ultrasound (baseline examination; it may be repeated, as needed), transabdominal ultrasound of the ovaries (baseline examination; it may be repeated, as needed); urinary free cortisol levels (annually); and serum IGF-1 levels (annually). For pre-pubertal pediatric Carney complex patients, the recommended clinical surveillance typically involves echocardiograms (annually; biannually for patients with a history of excised myxoma), testicular ultrasound for boys, and close monitoring of growth rate and pubertal staging (annually). In addition to monitoring of urinary free cortisol levels, further evaluation of patients with primary pigmented nodular adrenocortical disease (all age groups) includes monitoring of diurnal cortisol levels (11:30 PM, 12:00 MN, 7:30 AM, and 8:00 AM sampling), dexamethasone-stimulation test (modified Liddle's test; See, Stratakis et al., Ann. Intern. Med., 131:585-591

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