Familial micronodular adrenocortical disease, Cushing syndrome, and mutations of the gene encoding phosphodiesterase 11A4 (PDE11A)

Abstract

We present the pathologic findings in the adrenal glands of 4 patients, aged 10 to 38 years, with Cushing syndrome and germline inactivating mutations of the gene PDE11A4 that encodes phosphodiesterase11A4. The gene is expressed in the adrenal cortex and catalyses the hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate. Two of the patients were mother and daughter; the third had no affected relative; the fourth patient inherited the mutation from her father. Three of the group, including the mother and daughter, had the same pathology, primary pigmented nodular adrenocortical disease, a disorder known to be caused by inactivating mutations of the PRKAR1A gene. In these cases, the adrenal glands were small and the pathologic change was deep in the cortex in which numerous pigmented micronodules developed. In the remaining patient, the glands were slightly enlarged primarily owing to a diffuse hyperplasia of the superficial cortex that extended into the epi-adrenal fat.

FIGURE 1

(Case 3). Primary pigmented nodular adrenocortical disease. A, The cut surface of the fresh gland displayed pigmented nodules, ranging in size from less than 1mm (arrows) to 3mm in greatest dimension. B, Panoramic view of a microscopic transverse section of the adrenal gland showed a normal shape with sharply defined outline. Many cortical nodules, several confluent, and 3 small excrescences (arrows) were present. C, Diagrammatic representation of the findings in B. Cortical micronodules are enclosed in circles. Cortical excrescences in the periadrenal fat are shown in red. The medulla is depicted in green. D, The area in rectangle in B showed that the cortex was completely replaced by a series of juxtaposed nodules. A small cortical excrescence was present (arrow). This corresponds to the lesion indicated by the upper arrow in B and C.

FIGURE 2

(Case 4). Primary adrenocortical hyperplasia with extraadrenal cortical extension. A, Panoramic view of a microscopic transverse section of the left adrenal gland showed general preservation of the shape of the gland but loss of the normal sharp peripheral outline because of the presence of poorly circumscribed masses of cortical cells applied to the external aspect of the capsule. B, Diagrammatic representation of the findings in A. The adrenal capsule is indicated by a solid line, capsular attenuation by a broken line, and capsular breaks by an absent line. Cortical micronodules are enclosed in circles and permeating cortical excrescences indicated in red. The medulla is shown in green. The hyperplastic cortex and extracapsular cortical parenchyma occupied approximately equal areas.

FIGURE 3

(Case 4). A, An irregularly shaped nodule with fatty metaplasia composed of large eosinophilic and some vacuolated clear cells was present in the deep cortex abutting the medulla (left). A very attenuated capsule separated the cortex proper from extracapsular cortical tissue (upper right). B, A capsular break (upper portion of illustration) resulted in continuity of the hyperplastic cortex proper (left) and a solid excrescence (right) that contained 2 nodules, 1 with eosinophilic and the second with vacuolated clear cells (bottom left). C, Cortical nodule was composed of large cells with eosinophilic (top right) and amphophilic cytoplasm peripherally and centrally, respectively. D, The hyperplastic cortex (right) was separated from a solid cortical excrescence (left) by the adrenal capsule whose collagen bundles were separated by cortical cells.

FIGURE 4

Immunocytochemical results (case 3, A, C, E, and G; case 4, B, D, F, and H). Synaptophysin. A, Many cortical nodules were stained, often strongly; the extranodular cortex was unstained. The medulla was heavily stained. B, A vague cortical nodule (arrow) was less heavily stained than those in case 3; there was patchy staining throughout the extranodular cortex. Inhibin. C, Cortical nodules were strongly stained. Irregular clumps of enlarged cells between the nodules were lightly stained (arrows). D, A cortical nodule was strongly stained (arrow). There was patchy staining of the internodular cortex. Melan A. E, Juxtaposed nodules were moderately stained. A subcapsular rim of cortical cells was heavily stained. F, The outer cortex and extraadrenal cortical cells were stained. A nodule (arrow) was stained. Vimentin. G, The extranodular cortex, particularly the superficial aspect, was stained. Nodules were weakly stained or unstained. H, The intraadrenal and extraadrenal cortex were stained, but not as strongly as in case 3. A cortical nodule was not stained (arrow).