Primary Pigmented Nodular Adrenal Disease Research Articles

The molecular genetics of adrenal cushing.

Adrenal Cushing represents 20% of cases of endogenous hypercorticism. Unilateral cortisol-producing adenoma (CPA), a benign tumor, and adrenocortical carcinoma (ACC), a malignant tumor, are more frequent than bilateral adrenal nodular diseases (primary bilateral macronodular adrenal hyperplasia (PBMAH) and primary pigmented nodular adrenal disease (PPNAD)).In cortisol-producing adrenal tumors, the signaling pathways mainly altered are the protein kinase A and Wnt/β-catenin pathways. Studying components of these pathways and exploring syndromic and familial cases of these tumors has historically enabled identification of many of the predisposing genes. More recently, pangenomic sequencing revealed alterations in sporadic tumors.In ACC, mainly due to TP53 alterations causing Li-Fraumeni syndrome, germline predisposition is frequent in children, while it is rare in adults. Pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2, which cause Lynch syndrome or alterations of IGF2 and CDKN1C (11p15 locus) in Beckwith-Wiedemann syndrome, can also cause ACC. Rarely, ACC is described in other hereditary tumor syndromes due to germline pathogenic variants in MEN1 or APC and, in very rare cases, NF1, SDH, PRKAR1A, or BRCA2. Concerning ACC somatic alterations, TP53 and genetic or epigenetic alterations at the 11p15 locus are also frequently described, as well as CTNNB1 and ZNRF3 pathogenic variants.CPAs mainly harbor somatic pathogenic variants in PRKACA and CTNNB1 and, less frequently, PRKAR1A, PRKACB, or GNAS1 pathogenic variants. Isolated PBMAH is due to ARMC5 inactivating pathogenic variants in 20 to 25% of cases and to KDM1A pathogenic variants in food-dependent Cushing. Syndromic PBMAH may be due to germline pathogenic variants in MEN1, APC, or FH, causing type 1 multiple endocrine neoplasia, familial adenomatous polyposis, or hereditary leiomyomatosis-kidney cancer syndrome, respectively. PRKAR1A germline pathogenic variants are the main alteration causing PPNAD (isolated or part of Carney complex).

P-47 Rare case of acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome

Abstract Introduction The concurrence of acromegaly and Cushing syndrome is infrequent. Pituitary adenomas are responsible for acromegaly and for Cushing syndrome in about 95% and 80% of cases respectively. Except adrenal adenoma, the other causes of Cushing syndrome remain rare. We here describe a case of a Tunisian patient with acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome with bilateral macronodules. Clinical Case A 35-year-old male patient was diagnosed with acromegaly by acrofacial dysmorphia. He had a family history of type 2 diabetes mellitus and hypertension but no endocrine diseases. He has diabetes mellitus for 15 years, hypertension and obstructive sleep apnea. Physical examination showed multiple blue nevi in the trunk. IGF-1 was elevated (1680ng/mL) and GH levels were not suppressed after an oral glucose load (nadir 78ng/mL). He had hypogonadotropic hypogonadism with normal prolactin (9,66ng/mL). Basal cortisol, FT4 and TSH levels were in the normal ranges. Pituitary MRI showed pituitary macroadenoma of 25×20.7 mm, invading both cavernous sinuses and compression of optic chiasma. He underwent transsphenoidal resection with histology confirming a prolactin, GH and LH co-secretory pituitary adenoma. He received postoperatively somatostatin analogue and cabergoline, in addition to external radiotherapy. Ultrasonography found infracentimetric EU-TIRADS 2 left nodule and multiple colloid cysts of the thyroid, testicles microlithiasis and no cardiac myxomas. Nine years after the diagnosis of acromegaly, bilateral adrenal adenomas (left:14 mm, right: 9 mm) were incidentally discovered by CT-scan done for abdominal pain. Low dose dexamethasone suppression test was carried out showing no suppression of cortisol and the low ACTH level confirmed ACTH-independent Cushing syndrome. Conclusion In our patient, at least two endocrine syndromes deserve to be mentioned. The first syndrome is Multiple Endocrine Neoplasia Type 1 but calcium and PTH levels were normal and there was no sign for neuroendocrine tumors. The second one is Carney's complex since our patient has acromegaly and multiple blue nevi which are two major criteria confirming the diagnosis. Cushing syndrome in Carney's complex is related to primary pigmented nodular adrenal disease characterized by micronodular hyperplasia. However, bilateral macronodules could be found in up to 30% of cases.

Abstract 15843: Biatrial and Recurrent Cardiac Myxoma in a Rare Case of Carney Complex

Primary cardiac tumors (CTs) are exceptionally rare, and are predominantly benign masses. Myxomas make up more than 60% of these lesions and most frequently develop in the left atrium (LA), followed by the right atrium (RA). Carney complex (CNC) is a rare, typically autosomal dominant, multiple endocrine neoplasia characterized by cutaneous findings, myxomas, endocrine and/or nonendocrine neoplasms. We report a rare case of CNC involving biatrial and recurrent myxomas. A 36-year-old female presented to Cardiology Clinic at our center for management of CNC. Three years prior, she was evaluated at a local hospital for acute stroke where TTE showed a myxoma (2 x 2 x 2.5cm) attached to the left atrial septum, prompting resection. On followup TTE 2 years later, she had a mass in the LA, prolapsing through the mitral valve into the left ventricle. She underwent resection of the myxoma (2.9 x 3.9 cm) and left atrial appendage, which was complicated by recurrent stroke. She was found to have a PRKAR1A gene mutation (c.97 deletion) suggestive of CNC and was referred to our center. At Cardiology Clinic, she denied chest pain, dyspnea, presyncope, and syncope. Her father and children did not have the gene mutation. Exam revealed lentigines on her lower lip and pigmentation of an inner canthus. She was diagnosed with primary pigmented nodular adrenal disease by Endocrinology. On TEE, she was found to have a recurrent LA mass (1 x 1 x 0.8 cm) attached to the interatrial septum, but no right-to-left atrial shunt. This prompted surgery consultation. Numerous intracardiac myxomas were removed during surgery; one in the LA attached to the septum, 3-4 smaller ones, and one 2 cm myxoma located in the RA. The interatrial septum was also resected given recurrent myxoma in this region. She underwent cryoablation to prevent recurrence and did well post-surgery. CTs, which includes primary CTs and secondary metastatic disease, are uncommon where the former has an incidence of 0.001-0.3%. We presented a case of recurrent and biatrial cardiac myxomas in the setting of CNC, which is seldomly reported in the literature. Taken together, given the rarity of primary CTs, genetic predispositions or syndromes should be considered especially in the setting of recurrence and/or multiple masses.

Primary pigmented nodular adrenal disease: a report of three cases

总结3例原发性色素沉着性结节性肾上腺皮质病（PPNAD）患者的临床特征及诊疗方案。PPNAD除符合促肾上腺皮质激素（ACTH）非依赖性库欣综合征特征外，有以下特点：（1）Liddle试验后尿游离皮质醇反常升高；（2）伴生长停滞或Carney综合征表现；（3）肾上腺为小结节改变；（4）基因检测分别为PRKACA、PRKAR1A突变；（5）病理均为肾上腺色素沉积的结节改变；（6）治疗最终需要行双侧肾上腺切除，并予终身激素替代。PPNAD是罕见的库欣综合征类型，临床不易识别，认识其特征并行基因检测对明确诊断和治疗具有重要意义。.

Cushing Syndrome in Carney Complex: Unilateral or Bilateral Adrenalectomy?

Abstract Carney Complex (CNC) is a rare multiple endocrine syndrome dueto PRKR1A germline mutations. Primary pigmented nodular adrenal disease (PPNAD), the most frequent manifestation of the disease is responsible for non-ACTH dependent Cushing syndrome and bilateral adrenalectomy is the recommended treatment. We had followed up a CNC family with mainly Cushing syndrome disease secondary to PPNAD for more than 40 years over 2 generations. Six members carry the disease and present a germline mutation of PRKR1A, 4 women and 2 men. One patient accidently died one year after surgery and the others 5 patients were regularly followed up. The index case, a 25 years woman, was diagnosed with Cushing syndrome in 1972 with hyperandrogenism, short stature and mild manifestations of hypercortisolism. Unilateral adrenalectomy was performed on the side of a nodular adrenal and pathology described PPNAD. Her sister was subsequently diagnosed and treated the same way. The 2 sisters did well, with pregnancies for both of them but different post surgery hormonal results. The index case had partial cortisol deficiency with persistent low cortisol level at 108 nmol/L. Her sister presented a moderate increase in cortisol in the evening or after dexamethasone at 306 nmol/L at last evaluation. The only events possibly associated to hypercortisolism in this patient were central overweight and three episodes of spontaneous pulmonary embolism and veinous thrombosis. Their 2 brothers were evaluated at 17 and 39 years while they developed cushing syndrome signs (round face, HTA, amyotrophy and fatigability). As CNC have been recognized at this time by Dr Carney, bilateral adrenalectomy was performed in one patient who died accidentally a few months later. His brother chose unilateral adrenalectomy on the side of the macronodular gland, recovered hypercortisolism signs and still needs adrenal substitution. The daughter of the index case demonstrated at 21 years old a mild Cushing syndrome and chose unilateral adrenalectomy like her mother. Symptoms resumed without any recurrence during 20 years follow up. The daughter of the patient II.2 was diagnosed earlier at seven years of age because she developed hyperandrogenism, central weight gain and growth arrest due to Cushing syndrome. Bilateral adrenalectomy was successfully performed and adrenal substitution was prescribed. Surprisingly, adrenal function seemed to recover 5 to 6 years post surgery and treatment was decreased then stopped. Adrenal CT scan did not show any residual gland but noriodocholesterol scintigraphy confirmed bilateral adrenal uptake. She is now mother of 2 and present a near normal cortisol circadian rythm without any treatment. Finally, we showed in this long-term study that unilateral adrenalectomy in PPNAD could be an option for the treatment of mild Cushing syndrome in adults. Recovery after bilateral adrenalectomy occurred in one patient.

Frequency and incidence of Carney complex manifestations: A prospective multicenter study with a three-year follow-up

Introduction Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. Methods This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. Results The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. Conclusion This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes. Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n <9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n<50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted. Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n <9), post 1 mg DST cortisol - 470 nmol/l (n<50) and ACTH-concentration below detection <1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement. Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side. Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.

Cushing's syndrome due to primary pigmented nodular adrenal disease in two brothers with Carney complex.

Two brothers (19 and 18 years old, respectively) presented with weight gain and stunted growth since the age of 10 years. They had spotty skin pigmentation over the face along with florid features of Cushing's syndrome with low bone density, renal calculi, dyslipidaemia, hypertension, and dilated cardiomyopathy. They underwent evaluation of the hypothalamic-pituitary-adrenals axis, which suggested ACTH-independent Cushing's syndrome, and the abdominal CT imaging revealed normal adrenals. The diagnosis of Familial Cushing's syndrome with primary pigmented nodular adrenal disease and Carney complex was made. Bilateral adrenalectomy was carried out in both of them with resolution of the features of hypercortisolaemia post-operatively.

SUN-356 The Effects of Selective Serotonin Reuptake Inhibitors on Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease

PPNAD is a rare cause of ACTH-independent Cushing syndrome mainly associated with Carney complex (CNC). It is diagnosed by histologic examination or a 6-day Liddle test (LT) showing a paradoxical increase of >50% in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6 [D6]). PPNAD tissue has neuroendocrine features and can overexpress the serotonin (5-HT) synthesizing enzyme tryptophan hydroxylase type 2 and the 5-HT receptors types 4, 6, and 7, with formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production [1]. SSRIs inhibit the reuptake of 5-HT and are used as 1st-line antidepressants. This is a retrospective cohort study of patients with CNC and PPNAD that underwent a LT with the objective to evaluate the effect of SSRIs on UFCs in these patients. Of the 34 patients (4-65 y) with CNC and PPNAD that had a LT at our institution between 2004 and 2018, 4 patients took an SSRI during testing. No statistically significant differences were demonstrated between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and urine 17-hydroxycorticosteroids (17OHS) and the percent increase in UFC and 17OHS on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13-252) mcg/24h (nl 4-56) vs 35 (13-98) mcg/24h in the NS group (P=0.95). Baseline 17OHS were 11 (8-18) mg/mg creatinine (Cr) (nl ≤6) in the S group vs 8 (5-11) mg/mgCr in the NS group (P=0.27). The percent change in UFC was 208 (93-683)% in the S group and 185 (28-364)% in the NS group (P=0.89), while the percent change in 17OHS was 56 (40-87)% in the S group and 67 (16-92)% in the NS group (P=0.91). On D6, the S group appeared to have higher UFC [118 (63-635) mcg/24h vs 112 (58-201) mcg/24h; P=0.64] and 17OHS [16 (10-39) mg/mgCr vs 13 (7-17) mg/mgCr; P=0.25] than the NS group, but these were not statistically significant. Though these data do not confirm an effect of SSRIs on UFC and ultimately cortisol production in PPNAD, and the percent change in UFC during the LT was similar between both groups, the higher D6 UFC in the S group, when the baseline UFCs between the 2 groups were similar may suggest a degree of increased cortisol production in the S group. The data are limited by the small number of patients in the S group (n=4). In addition, 50% of patients in the S group vs 77% in the NS group underwent adrenalectomy, which is indicative of more severe disease in the NS group. More data are needed from this cohort to determine if SSRI use affects cortisol production in vivo, as this may have significant diagnostic and therapeutic implications for patients with CNC and PPNAD. Reference: 1. Bram, Z., et al., PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. JCI Insight, 2016. 1(15): p. e87958.

Genetics of tumors of the adrenal cortex.

This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genome-wide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers.

Dyslipidemia, weight gain, and decreased growth velocity in a 14-year-old male

A 14-year-old male was referred for dyslipidemia. His findings were consistent with metabolic syndrome. Although he lacked the typical physical appearance, his accelerated weight gain combined with a decreased linear growth velocity suggested Cushing syndrome. He was subsequently found to have adrenocorticotropic hormone–independent Cushing syndrome secondary to primary pigmented nodular adrenal disease without Carney Complex. After bilateral adrenalectomy, his lipid profile returned to normal. In this article, we discuss the role of glucocorticoids on lipid and lipoprotein metabolism.

PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.

Spontaneous resolution of avascular necrosis of femoral heads following cure of Cushing's syndrome.

SummaryAvascular necrosis (AVN) is a rare presenting feature of endogenous hypercortisolism. If left untreated, complete collapse of the femoral head may ensue, necessitating hip replacement in up to 70% of patients. The majority of the described patients with AVN due to endogenous hypercortisolaemia required surgical intervention. A 36-year-old female, investigated for right leg pain, reported rapid weight gain, bruising and secondary amenorrhoea. She had abdominal adiposity with violaceous striae, facial plethora and hirsutism, atrophic skin, ecchymosis and proximal myopathy. Investigations confirmed cortisol excess (cortisol following low-dose 48h dexamethasone suppression test 807nmol/L; 24h urinary free cortisol 1443nmol (normal<290nmol)). Adrenocorticotrophic hormone (ACTH) was <5.0pg/mL. CT demonstrated subtle left adrenal gland hypertrophy. Hypercortisolaemia persisted after left adrenalectomy. Histology revealed primary pigmented micronodular adrenal disease. Post-operatively, right leg pain worsened and left leg pain developed, affecting mobility. MRI showed bilateral femoral head AVN. She underwent right adrenalectomy and steroid replacement was commenced. Four months after surgery, leg pain had resolved and mobility was normal. Repeat MRI showed marked improvement of radiological abnormalities in both femoral heads, consistent with spontaneous healing of AVN. We report a case of Cushing’s syndrome due to primary pigmented nodular adrenocortical disease, presenting with symptomatic AVN of both hips. This was managed conservatively from an orthopaedic perspective. Following cure of hypercortisolaemia, the patient experienced excellent recovery and remains symptom free 4 years after adrenalectomy. This is the first report of a favourable outcome over long-term follow-up of a patient with bilateral AVN of the hip, which reversed with treatment of endogenous hypercortisolaemia.Learning pointsAVN of femoral head can be a presenting feature of hypercortisolism, both endogenous and exogenous.Rarely, treatment of hypercortisolaemia can reverse AVN without the need for orthopaedic intervention.Primary pigmented nodular adrenal disease is a rare cause of ACTH-independent Cushing’s syndrome.

Cushing's conundrum: an unusual case of primary pigmented nodular adrenal disease in a 60-year-old woman

A 60-year-old woman with resistant hypertension, poorly controlled type 2 diabetes, and chronic obstructive pulmonary disease requiring inhaled corticosteroids was referred for investigation of Cushing’s syndrome. She had a BMI of 31 kg/m2, abdominal obesity, and proximal muscle wasting. Investigations showed a normal aldosterone-to-renin ratio, plasma metanephrines, and renal artery Doppler ultrasound fi ndings, but increased 24 h urine free cortisol concentration (454 nmol/L [normal range <350 nmol/L]). Adrenocorticotropic hormone remained undetectable on several occasions for 12 months, during the diagnostic workup (<5 pg/mL). Because of diffi culty in ceasing use of inhaled corticosteroids, an overnight 1 mg dexa methasone suppression test was done while the patient was taking fl uticasone, showing an 8 am cortisol concentration of 278 nmol/L (compared with a normal range of <120 nmol/L). Persistent hypercortisolism was then confi rmed with intravenous dexamethasone suppression testing done after inhaled fl uticasone was withheld for several days. An adrenal CT scan showed an enlarged left adrenal gland, with an 8 mm nodule at the inferior pole (fi gure A), insuffi cient to account for the patient’s hypercortisolism. Functional imaging with iodo cholesterol under dexamethasone suppression showed bilateral uptake of labelled cholesterol (fi gure B). Adrenal vein sampling under dexamethasone supp ression was consistent with bilateral autonomous cortisol secretion (appendix). The patient underwent a bilateral adrenalectomy. The macroscopic and histological appearance was consistent with primary pigmented nodular adrenal hyperplasia (also known as primary pigmented nodular adrenal disease [PPNAD]; fi gure C, D). PPNAD is associated with Carney’s complex in 90% of white patients. Carney’s complex is an autosomal dominant multiple neoplasia syndrome, typically presenting with the classic triad of myxomas, spotty skin pigmentation, and endocrine overactivity. 60% of Carney’s complex in the white population is associated with germline-inactivating mutations in regulatory subunit 1α of protein kinase A (PRKAR1A). To our knowledge, this patient is the oldest reported person to be diagnosed with PPNAD—most patients are diagnosed before age 40 years. She has no other manifestations of Carney’s complex and is currently undergoing genetic testing for mutations in the PRKAR1A gene. This case shows that PPNAD can be latent for many years and should be considered in diff erential diagnosis of adrenocorticotropic hormoneindependent Cushing’s syndrome in elderly individuals.

Cushing Syndrome Due to Primary Pigmented Nodular Adrenal Disease in Three Related Adolescent Girls With Carney Complex

Cushing Syndrome Due to Primary Pigmented Nodular Adrenal Disease in Three Related Adolescent Girls With Carney Complex

Etiology and clinical profile of patients with Cushing′s syndrome: A single center experience

Background:There is little published literature on the profile of patients with Cushing's syndrome (CS) from India. The aim of this study was to compile data of CS patients treated at this hospital.Materials and Methods:Patients referred to the endocrine services of this hospital for diagnosis/treatment of CS from January 1985 to July 2012 were the subjects for this study. All patients had detailed medical history, physical examination and biochemical and hormonal assays (which changed with availability of tests and changing views). Assays for plasma adrenocorticotropic hormone (ACTH) (late 90s), salivary cortisol estimation, IJV sampling for ACTH and corticotrophin releasing hormone stimulation tests were added on later. Imaging included computed tomography (CT), magnetic resonance imaging (since the late 80's) and 68Ga DOTA-TOC/FDG PET-CT (2008).Results:Three hundred sixty-four patients (250 females, 114 males, age 6 months to 65 years, mean 28 years + 12 years) were diagnosed to have CS during this period. Two hundred and ninety-three patients (80.5%) were ACTH dependent (CD 215, ectopic ACTH syndrome 22, occult ACTH source 56) while 71 (19.5%) were ACTH independent (adrenal carcinoma 36, adenoma 30, primary pigmented nodular adrenal disease 4, AIMAH 1). Pituitary macro adenoma was seen in 14% of the CD cases. The most common presenting complaints were hypertension and diabetes mellitus. A total of 63% patients complained of weight gain while 15% had lost weight. Myopathy, infections, skeletal fractures and psychiatric problems were the other common observations in our patients.Conclusion:The clinical spectrum was broad. CD was the most common cause for CS.

Adrenal tumors and Cushing`s syndrome - our surgical expirience

Cushing's syndrome is a clinical condition of excess cortisol production secondary to disorders of the pituitary, adrenal glands, or ectopic production of adrenocorticotrophic hormone (ACTH). The syndrome is manifested by obesity, hypertension, diabetes, amenorrhea, and other symptoms and with out recognition and proper treatment can result in substantial morbidity and mortality. For patients who do not respond to treatment directed at pituitary adenomas, have occult ectopic ACTH secreting tumors, or have primary bilateral adrenal disorders such as primary pigmented nodular adrenal disease or macronodular adrenal hyperplasia, bilateral adrenalectomy is effective in curing or controlling hypercortisolism and reversing the signs and symptoms of excess cortisol production (1,2). The morbidity associated with bilateral adrenalectomy is not inconsequential, and reported mortality rates range from 2% to 5% (3-6). In general, patients with Cushing's syndrome are predisposed to infectious or hemorraghic complications as well as to impaired wound healing. The open operative approache, used in our clinic for adrenalectomy is the transabdominal approach through either a midline or bilateral subcostal incision (7). The anterior approach allows a complete abdominal and retroperitoneal exploration and may be most appropriate in patients in whom a coincidental abdominal procedure is contemplated (9,10). In particular, because many of these patients are relatively young at the time of treatment and return to fully productive lives after surgery. Scripta Scientifica Medica 2010;42(1):41-43

Expression of progesterone and estradiol receptors in normal adrenal cortex, adrenocortical tumors, and primary pigmented nodular adrenocortical disease

Adrenal tumors occur more frequently in women and are the leading cause of Cushing's syndrome during pregnancy. We aimed to evaluate the potential role of sex steroids in the susceptibility of women to adrenocortical tumors. We evaluated the presence of the progesterone receptor (PR), estradiol receptors (ERs), and aromatase in 5 patients with primary pigmented nodular adrenal disease (PPNAD), 15 adrenocortical adenomas (ACAs) and adjacent normal tissues, 12 adrenocortical carcinomas (ACCs), and 3 normal adrenal glands (NA). The expression of PR and ERalpha was evaluated by enzyme immunoassays, real-time RT-PCR, immunohistochemistry, and cytosol-based ligand-binding assays. ERbeta and aromatase levels were evaluated by real-time RT-PCR. ERalpha concentrations were low in NA, in adrenal tissues adjacent to ACA (51+/-33), in ACC (53+/-78), and lower in ACA (11+/-11 fmol/mg DNA). Conversely, PR concentrations were high in NA and adrenal tissues adjacent to ACA, at 307+/-216 fmol/mg DNA, and were even higher in tumors - 726+/-706 fmol/mg DNA in ACA and 1154+/-1586 fmol/mg DNA in ACC - and in isolated PPNAD nodules. Binding study results in four tumors were compatible with binding to a steroid receptor. In patients with PPNAD, a strong positive immunohistochemical signal was associated with the sole isolated nodular regions. ERbeta transcript levels were very high in all samples except those for two ACCs, whereas aromatase levels were low. PR and ERbeta are clearly present in normal adrenal glands and adrenal tumors. Further studies may shed light on the possible pathogenic role of these receptors in adrenal proliferation.

Primary pigmented nodular adrenocortical disease associated with Carney complex: case report and literature review

Carney complex (CNC), a familial multiple neoplasm syndrome with dominant autosomal transmission, is characterized by tumors of the heart, skin, endocrine and peripheral nervous system, and also cutaneous lentiginosis. This is a rare syndrome and its main endocrine manifestation, primary pigmented nodular adrenal disease (PPNAD), is an uncommon cause of adrenocorticotropic hormone-independent Cushing's syndrome. We report the case of a 20-year-old patient with a history of weight gain, hirsutism, acne, secondary amenorrhea and facial lentiginosis. Following the diagnosing of CNC and PPNAD, the patient underwent laparoscopic bilateral adrenalectomy, and she evolved with decreasing hypercortisolism. Screening was also performed for other tumors related to this syndrome. The diagnostic criteria, screening and follow-up for patients and affected family members are discussed.