CARNEY COMPLEX (NAME SYNDROME, LAMB SYNDROME, CARNEY SYNDROME)
Carney complex (CNC) is a rare autosomal dominant heritable multiple neoplasia syndrome characterized by cardiac, endocrine, cutaneous, and neural Tumours and a variety of mucocutaneous pigmented lesions. CNC is linked to at least two different loci. Germline mutations in PRKAR1A, on 17q22–q24, have been shown to cause a subset of CNC (Kirschner et al. 2000a, b). The gene on 2p15–p16, which may account for 20 % of all CNC families, has yet to be identified. Some believe that a third minor locus might also be involved.
This rare condition is characterized by cardiac, breast, and cutaneous myxomas, pigmented skin lesions, and micronodular pigmented adrenal hyperplasia (Koopman and Happle 1991). The Tumours are commonly multicentric or bilateral, and the mean age at diagnosis of the first manifestation is 18 years. Most patients have two or more manifestations of the condition. Pituitary adenomas and testicular Tumours (Sertoli or Leydig cell in about 50 % of affected males) are associated, and the hormones secreted by these Tumours cause characteristic phenotypic effects (Carney et al. 1986). Skin lesions include lentigines, blue nevi, dermal fibromas, and myxoid neurofibromas. The pigmentation is spotty, particularly on the face (in 70 % of cases), hands, and feet, and is similar to that seen in Peutz–Jeghers syndrome (PJS), although in the latter the lesions are seen more in the buccal region and palate, and the visceral lesions appear to be quite distinct in these two syndromes (Carney et al. 1985; Lodish and Stratakis 2011). Further, inner canthal pigmentation is virtually only seen in CNC. Eyelid myxomas are found in 16 % of affected patients. The Tumours are usually benign, but liposarcomas and other malignant Tumours may develop. The cardiac Tumours are life-threatening via embolism or by a direct mass effect. Recently pancreatic cancer has been found in 9 of 354 cases of Carney complex (1 adenocarcinoma, 2 acinar cell carcinomas, and 3 intraductal mucinous neoplasms where histology was available), and loss of heterozygosity for PRKAR1A was suggested, with a lack of expression of the protein in 5/6 Tumours studies (Gaujoux et al. 2011).
CNC was found to be linked to 17q22–q24 and 2p15–p16. Germline loss-of-function mutations in PRKR1A, encoding the type 1A subunit of the protein kinase A receptor on 17q22–q24, have been found in a subset of CNC (Kirschner et al. 2000a, b). Nonsense-mediated decay of mutant transcript appears to be the mechanism leading to loss of function (Kirschner et al. 2000a). Over 380 CNC patients with >20 years of follow-up in a bi-institutional series were analyzed for genotype-phenotype associations (Bertherat et al. 2009). There were 80 different germline PRKR1A mutations. Mutations in this gene were more commonly found in individuals with a combination of myxomas (affecting multiple organs), psammomatous melanotic schwannomas (PMS), thyroid Tumours, and large cell calcifying Sertoli cell Tumours (LCCSCT) than in individuals with CNC without this combination of clinical features. The “hot spot” mutation, c.491_492delTG, was more commonly associated with lentigines, cardiac myxoma, and thyroid Tumours than all other PRKAR1A mutations combined (Bertherat et al. 2009). Individuals with isolated PPNAD tended to carry either the c.709-7 to c.709- 2delATTTTT or c.1 A>G, and these are the only two mutations that have incomplete penetrance. In general, splice site mutations tended to occur with milder disease. Nonetheless, penetrance of PRKAR1A mutation is >95 % by age 50 years. Germline PDE11A variation seems to modify germline PRKAR1A mutations, conferring 4–5-fold increased prevalences of PPNAD and LCCSCT compared to those without PDE11A variants (Libe et al. 2011).
As with other inherited Tumours syndromes, mutation analysis by bidirectional Sanger sequencing should begin with a clinically affected individual. Once a family-specific mutation in PRKR1A is found, then predictive testing may be offered. Clinical and biochemical screening for CNC and medical surveillance for affected patients remain the gold standard for the care of patients with CNC. In brief, for postpubertal pediatric and for adult patients of both sexes with established CNC, the following annual studies are recommended: echocardiogram, measurement of urinary free cortisol levels (which may be supplemented by diurnal cortisol or the overnight 1 mg dexamethasone testing), and serum IGF1 levels (Stratakis et al. 1999). Male patients should also have testicular ultrasonography at the initial evaluation; microscopic LCCSCT (large cell calcifying Sertoli cell Tumours) may be followed by annual ultrasound thereafter (Stratakis et al. 2001). Thyroid ultrasonography should be obtained at the initial evaluation, and may be repeated, as needed (Stratakis et al. 2001). Transabdominal ultrasonography in female patients is recommended during the first evaluation but need not be repeated, unless there is a detectable abnormality, because of the relatively low risk of ovarian malignancy (Stratakis et al. 2001). Because cardiac myxoma is responsible for a significant amount of morbidity and mortality, pediatric patients with CNC should have echocardiography during their first 6 months of life and annually thereafter; biannual echocardiographic evaluation may be necessary for patients with history of an excised myxoma.