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PRKAR1A-negative familial Cushing's syndrome: two case reports.

Lim LL, Kitan N, Paramasivam SS, Ratnasingam J, Ibrahim L, Chan SP, Tan AT, Vethakkan SR - J Med Case Rep (2015)

Bottom Line: Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen.He was successfully treated with bilateral adrenalectomy.Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. leelinglimll@gmail.com.

ABSTRACT

Introduction: Determining the etiology of Cushing's syndrome is very challenging to endocrinologists, with most of the difficulty arising from subtype differentiation of adrenocorticotropic hormone-dependent Cushing's syndrome. We present the pitfalls of evaluating a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome in the transition period between adolescence and adulthood.

Case presentation: A sibling pair with familial isolated primary pigmented nodular adrenocortical disease is described. The index case, a 20-year-old Chinese woman, presented with premenopausal osteoporosis with T12 compression fracture and young hypertension. Biochemical analysis confirmed adrenocorticotropic hormone-independent Cushing's syndrome (elevated 0800 h plasma cortisol 808 nmol/L with suppressed adrenocorticotropic hormone level <5 pg/ml). Computed tomography of her adrenal glands revealed a 0.7-cm left adrenal hypodense nodule. After a left adrenalectomy, she had residual hypercortisolism (progressive weight gain, new T10 compression fracture, and not glucocorticoid-dependent postoperatively). Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen. Similarly, her younger brother developed adrenocorticotropic hormone-independent Cushing's syndrome at age 18 years, with typical cushingoid habitus, but no osteoporosis or hypertension. His adrenal computed tomographic scans showed micronodularities over bilateral adrenal glands. He was successfully treated with bilateral adrenalectomy. Screening for Carney's complex and PRKAR1A gene mutation was negative. Signs and symptoms of Cushing's syndrome resolved after bilateral adrenalectomy for both patients. They were placed on lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term surveillance for Carney's complex.

Conclusions: The cases of these two patients illustrate the difficulties involved in diagnosing primary pigmented nodular adrenocortical disease, a variant of adrenocorticotropic hormone-independent Cushing's syndrome that is managed with bilateral adrenalectomy. A high index of suspicion for this disease is needed, especially in adolescents with adrenocorticotropic hormone-independent Cushing's syndrome who have a significant family history, features of Carney's complex, and no resolution of Cushing's syndrome after unilateral adrenalectomy. Patients with primary pigmented nodular adrenocortical disease can either have bilateral/multiple adrenal nodules or normal adrenal glands visualized by computed tomography. Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.

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Adrenal histology [hematoxylin and eosin stain; original magnifications ×4 (a) and ×10 (b)]. Multiple nodules (2–5 mm in diameter) containing brown pigment can be seen in the adrenal cortex, composed of cells with round to ovoid nuclei with eosinophilic cytoplasm. Many cells with vacuolated, foamy cytoplasm were noted, also in addition to marked vascular congestion. Immunohistochemistry showed positivity for synaptophysin and vimentin, focal positivity for chromogranin A and S100, and a negative result for cytokeratin antibody MNF116
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Fig2: Adrenal histology [hematoxylin and eosin stain; original magnifications ×4 (a) and ×10 (b)]. Multiple nodules (2–5 mm in diameter) containing brown pigment can be seen in the adrenal cortex, composed of cells with round to ovoid nuclei with eosinophilic cytoplasm. Many cells with vacuolated, foamy cytoplasm were noted, also in addition to marked vascular congestion. Immunohistochemistry showed positivity for synaptophysin and vimentin, focal positivity for chromogranin A and S100, and a negative result for cytokeratin antibody MNF116

Mentions: Preoperatively, she was treated with spironolactone (for hypertension and edema), ketoconazole (to inhibit steroidogenesis), and teriparatide, cholecalciferol, and calcium supplements (for low BMD and vertebral fracture). A left retroperitoneoscopic adrenalectomy was performed 4 weeks later. Her hypertension and edema resolved after surgery. She was commenced on physiologic hydrocortisone replacement therapy in anticipation of transient hypocortisolism due to suppression of the contralateral adrenal gland. One month postoperatively, her 0800 h serum cortisol measured before the morning dose of hydrocortisone was 384 nmol/L. She continued to gain weight, had persistent oligomenorrhea, and developed a new T10 compression fracture with 2-cm height reduction. Reevaluation after cessation of hydrocortisone showed failed suppression of endogenous plasma cortisol with a 1-mg overnight LDDST (0800 h plasma cortisol 248 nmol/L). By then, histology of the excised left adrenal gland unexpectedly revealed pigmented nodular adrenocortical hyperplasia (Fig. 2). The patient’s preoperative CT was reviewed, confirming micronodularity with multiple nodules of the left adrenal gland, which had been missed initially. She had no dermatologic features (lentigines/blue nevi) or murmurs suggestive of cardiac myxoma characteristic of Carney’s complex (CNC). The results of ultrasound (US) of her breasts and pelvis, as well as of transthoracic echocardiography (TTE) and other tests performed to screen for features of CNC, were negative (Table 1).Fig. 2


PRKAR1A-negative familial Cushing's syndrome: two case reports.

Lim LL, Kitan N, Paramasivam SS, Ratnasingam J, Ibrahim L, Chan SP, Tan AT, Vethakkan SR - J Med Case Rep (2015)

Adrenal histology [hematoxylin and eosin stain; original magnifications ×4 (a) and ×10 (b)]. Multiple nodules (2–5 mm in diameter) containing brown pigment can be seen in the adrenal cortex, composed of cells with round to ovoid nuclei with eosinophilic cytoplasm. Many cells with vacuolated, foamy cytoplasm were noted, also in addition to marked vascular congestion. Immunohistochemistry showed positivity for synaptophysin and vimentin, focal positivity for chromogranin A and S100, and a negative result for cytokeratin antibody MNF116
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4666013&req=5

Fig2: Adrenal histology [hematoxylin and eosin stain; original magnifications ×4 (a) and ×10 (b)]. Multiple nodules (2–5 mm in diameter) containing brown pigment can be seen in the adrenal cortex, composed of cells with round to ovoid nuclei with eosinophilic cytoplasm. Many cells with vacuolated, foamy cytoplasm were noted, also in addition to marked vascular congestion. Immunohistochemistry showed positivity for synaptophysin and vimentin, focal positivity for chromogranin A and S100, and a negative result for cytokeratin antibody MNF116
Mentions: Preoperatively, she was treated with spironolactone (for hypertension and edema), ketoconazole (to inhibit steroidogenesis), and teriparatide, cholecalciferol, and calcium supplements (for low BMD and vertebral fracture). A left retroperitoneoscopic adrenalectomy was performed 4 weeks later. Her hypertension and edema resolved after surgery. She was commenced on physiologic hydrocortisone replacement therapy in anticipation of transient hypocortisolism due to suppression of the contralateral adrenal gland. One month postoperatively, her 0800 h serum cortisol measured before the morning dose of hydrocortisone was 384 nmol/L. She continued to gain weight, had persistent oligomenorrhea, and developed a new T10 compression fracture with 2-cm height reduction. Reevaluation after cessation of hydrocortisone showed failed suppression of endogenous plasma cortisol with a 1-mg overnight LDDST (0800 h plasma cortisol 248 nmol/L). By then, histology of the excised left adrenal gland unexpectedly revealed pigmented nodular adrenocortical hyperplasia (Fig. 2). The patient’s preoperative CT was reviewed, confirming micronodularity with multiple nodules of the left adrenal gland, which had been missed initially. She had no dermatologic features (lentigines/blue nevi) or murmurs suggestive of cardiac myxoma characteristic of Carney’s complex (CNC). The results of ultrasound (US) of her breasts and pelvis, as well as of transthoracic echocardiography (TTE) and other tests performed to screen for features of CNC, were negative (Table 1).Fig. 2

Bottom Line: Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen.He was successfully treated with bilateral adrenalectomy.Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. leelinglimll@gmail.com.

ABSTRACT

Introduction: Determining the etiology of Cushing's syndrome is very challenging to endocrinologists, with most of the difficulty arising from subtype differentiation of adrenocorticotropic hormone-dependent Cushing's syndrome. We present the pitfalls of evaluating a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome in the transition period between adolescence and adulthood.

Case presentation: A sibling pair with familial isolated primary pigmented nodular adrenocortical disease is described. The index case, a 20-year-old Chinese woman, presented with premenopausal osteoporosis with T12 compression fracture and young hypertension. Biochemical analysis confirmed adrenocorticotropic hormone-independent Cushing's syndrome (elevated 0800 h plasma cortisol 808 nmol/L with suppressed adrenocorticotropic hormone level <5 pg/ml). Computed tomography of her adrenal glands revealed a 0.7-cm left adrenal hypodense nodule. After a left adrenalectomy, she had residual hypercortisolism (progressive weight gain, new T10 compression fracture, and not glucocorticoid-dependent postoperatively). Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen. Similarly, her younger brother developed adrenocorticotropic hormone-independent Cushing's syndrome at age 18 years, with typical cushingoid habitus, but no osteoporosis or hypertension. His adrenal computed tomographic scans showed micronodularities over bilateral adrenal glands. He was successfully treated with bilateral adrenalectomy. Screening for Carney's complex and PRKAR1A gene mutation was negative. Signs and symptoms of Cushing's syndrome resolved after bilateral adrenalectomy for both patients. They were placed on lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term surveillance for Carney's complex.

Conclusions: The cases of these two patients illustrate the difficulties involved in diagnosing primary pigmented nodular adrenocortical disease, a variant of adrenocorticotropic hormone-independent Cushing's syndrome that is managed with bilateral adrenalectomy. A high index of suspicion for this disease is needed, especially in adolescents with adrenocorticotropic hormone-independent Cushing's syndrome who have a significant family history, features of Carney's complex, and no resolution of Cushing's syndrome after unilateral adrenalectomy. Patients with primary pigmented nodular adrenocortical disease can either have bilateral/multiple adrenal nodules or normal adrenal glands visualized by computed tomography. Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.

Show MeSH
Related in: MedlinePlus