Congenital adrenal hyperplasia with associated giant adrenal myelolipoma, testicular adrenal rest tumors and primary pigmented nodular adrenocortical disease: A case report and brief review of the literature.

Congenital adrenal hyperplasia is an autosomal recessive disease most commonly associated with 21-hydroxylase deficiency, an enzyme integral in the biosynthesis of mineralocorticoids and glucocorticoids. We present a case of a 49-year-old male with congenital adrenal hyperplasia and commonly associated findings of adrenal myelolipoma, testicular adrenal rest tumors, as well as primary pigmented nodular adrenocortical disease. Adrenal myelolipoma is a rare, benign disease process associated with exogenous steroid treatment noncompliance in the setting of congenital adrenal hyperplasia. Testicular adrenal rest tumors are benign testicular tumors associated with congenital adrenal hyperplasia. Primary pigmented nodular adrenocortical disease is an ACTH-independent cortisol producing lesion. Our case emphasizes the association of congenital adrenal hyperplasia with adrenal myelolipoma and testicular adrenal rest tumors as well as the importance of familiarity with these associations to guide patient management.

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.

Obstetric and Neonatal Outcome of Pregnancy in Carney Complex: A Case Report.

Background: Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome with autosomal dominant inheritance. Affected individuals present with mucocutaneous lentigines/blue nevi, cardiac and noncardiac myxomatous tumors, and multiple endocrine tumors. Mutations in PRKAR1A have been identified as genetic cause of the disease. Here, we report on pregnancy, delivery and puerperium in a woman with genetically confirmed CNC and her newborn. Case: The 31 year-old gravida 5 para 1 with CNC was referred at 26 weeks of gestation. Adrenocorticotropin-independent hypercortisolism, hyperglycemia, hypertension, low serum potassium, and osteoporotic fractures were present. Treatment with metyrapone, a reversible 11-beta-hydroxylase inhibitor, was initiated. The maternal condition improved, and a 5 weeks' pregnancy prolongation could be achieved. Elective repeat cesarean section was performed at 31 weeks of gestation for recurrent vaginal bleeding. The neonate developed transient hyponatremia necessitating hydrocortisone substitution for 2 weeks. Conclusion: In our case, treatment of CNC-associated hypercortisolism in pregnancy with metyrapone was effective. Maternal side effects did not occur. The newborn presented with transient hypocortisolism most likely due to transplacental drug effect. Our case illustrates that the treatment of rare diseases in pregnancy represents a challenge requiring interdisciplinary team work.

Corticotropinoma as the underlying cause of intermittent Cushing's syndrome in a patient previously diagnosed with primary pigmented nodular adrenocortical disease.

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Adrenalectomy for non-neuroblastic pathology in children.

BACKGROUND: Adrenalectomy for non-neuroblastic pathologies in children is rare with limited data on outcomes. We reviewed our experience of adrenalectomy in this unique population. METHODS: Retrospective study of children (age ≤ 18) who underwent adrenalectomy with non-neuroblastic pathology from 1988 to 2018. Clinical and operative details of patients were abstracted. Outcomes included length of stay and 30-day postoperative morbidity. RESULTS: Forty children underwent 50 adrenalectomies (12 right-sided, 18 left-sided, 10 bilateral). Six patients (15%) presented with an incidental adrenal mass while 4 (10%) had masses found on screening for genetic mutations or prior malignancy. The remaining 30 (75%) presented with symptoms of hormonal excess. Nineteen patients (48%) underwent genetic evaluation and 15 (38%) had genetic predispositions. Diagnoses included 9 patients (23%) with pheochromocytoma, 8 (20%) with adrenocortical adenoma, 8 (20%) with adrenocortical carcinoma, 7 (18%) with adrenal hyperplasia, 2 (5%) with metastasis, and 6 (14%) with additional benign pathologies. Of 50 adrenalectomies, twenty-five (50%) were laparoscopic. Median hospital length of stay was 3 days (range 0-11). Post-operative morbidity rate was 17% with the most severe complication being Clavien-Dindo grade II. CONCLUSION: Adrenalectomy for non-neuroblastic pathology can be done with low morbidity. Its frequent association with genetic mutations and syndromes requires surgeons to have knowledge of appropriate pre-operative testing and post-operative surveillance.

Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience.

Background Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome (CS) in childhood. We describe a case series of patients presenting at our centre along with a review of the literature. Methods A retrospective analysis of six index cases and one family were done for demographic features, hormonal profile, imaging findings, genetic mutation status, histopathologic findings and follow-up details. Diagnosis was based on biochemistry and confirmed with histopathology and or genetic mutation. All patients had suppressed 8 am adrenocorticotropic hormone (ACTH) (<10 pg/mL) despite evidence of hypercortisolism. Results The mean age in our cohort was 8.2 years (range 15 months to 20 years). All patients presented with overt CS, including one patient with cyclic Cushing's. Three patients had additional features of Carney complex (CNC). Imaging did not reveal any obvious mass lesions on computed tomography (CT), the classical beaded appearance was present in only two of the patients. Mutation analysis was positive in three patients. Five patients underwent bilateral adrenalectomy and had features of PPNAD on histopathology. Conclusions PPNAD is a rare cause of ACTH-independent CS in childhood and may signal underlying CNC. Patients with younger age of onset with overt CS may still have a mutation in the PRKAR1A gene and warrant genetic testing.

Unilateral Adrenalectomy Could Be a Valid Option for Primary Nodular Adrenal Disease: Evidence From Twins.

Primary pigmented nodular adrenal disease (PPNAD) accounts for <1% of ACTH-independent Cushing syndrome. We describe the case of twin female patients with PPNAD who both had sustainable disease control after unilateral adrenalectomy, which corroborates current evidence in favor of unilateral adrenalectomy for a subset of patients with PPNAD. Patient A presented with a 10-kg weight gain over the past year and facial plethora. Diagnostic evaluation revealed abolition of normal cortisol rhythm with suppressed ACTH levels, normal adrenal CT and MRI imaging and a slightly left-predominant adrenal uptake on 131I iodomethyl norcholesterol scintigraphy coupled with single-photon emission CT/CT. PPNAD was confirmed after genetic testing revealed a known pathogenic PRKA1A mutation (c.709 (-7-2) del6). At that time, her twin sister (patient B) was asymptomatic. Patient A underwent successful unilateral adrenalectomy and histology confirmed PPNAD. Two years after initial onset of symptoms in patient A, patient B was seen for the same subtle symptoms of progressive weight gain. Diagnostic test results were identical, revealing the same clinical features and mutational status as patient A. Patient B also underwent unilateral adrenalectomy with a favorable outcome. Follow-up 3 years after surgery for patient A and 18 months for patient B showed sustained disease control without recurrence and uncompromised quality of life, with no adrenal insufficiency having occurred. Unilateral adrenalectomy can be a successful therapeutic approach for patients with PPNAD with a mild phenotype without the risk and the inconvenience of subsequent adrenal insufficiency, which alters quality of life.

Cyclic Cushing's syndrome caused by neuroendocrine tumor: a case report.

Cushing's syndrome (CS) is a clinical syndrome characterized by hypercortisolemia. Cyclic Cushing's syndrome (CCS), which exhibits a periodic or irregular increasing pattern in cortisol, is a rare type of Cushing's syndrome. A 37-year-old man came to our hospital because of repeated dizzy spells, weakness and hypercortisolemia lasting two weeks. Endocrinological examinations indicated CCS with periodic and intermittent increases in cortisol. Enhanced computed tomography (CT) revealed space occupying lesions on the upper lobe of left lung, and biopsy eventually proved that these were pulmonary carcinoid tumors with ectopic ACTH secretion, which was subsequently manifested a Cushing's syndrome. PET-CT, ultrasound and biopsy of the thyroid gland indicated bilateral thyroid papillary carcinoma. CT scan showed bilateral nodular hyperplasia of the adrenal gland. Enhanced magnetic resonance imaging (MRI) confirmed that the high signal disappeared on the posterior lobe of the pituitary gland and that the pituitary stalk shifted left, which was suspected to be non-functional pituitary microadenoma. The patient underwent surgery involving resection of the left upper pulmonary lobe and the mediastinal lymph node around the hilus pulmonis, which resulted in complete remission of CCS. The patient then chose elective surgery for the thyroid papillary carcinoma. An analysis of the patient's genomic DNA identified a novel mutation in PDE11A: c.2032 (exon 12) G > A, which is associated with primary pigmented nodular adrenocortical disease (PPNAD). This is a novel mutation which has been no previous public clinical report on this mutation as it relates to this disease.

Detection of new potentially pathogenic mutations in two patients with primary pigmented nodular adrenocortical disease (PPNAD) - case reports with literature review.

INTRODUCTION: Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of ACTH-independent Cushing's syndrome (CS). Half of patients with PPNAD are sporadic cases and the other half familial. MATERIAL AND METHODS: We present two patients with PPNAD confirmed by genetic analysis. RESULTS: In both patients there were no abnormal findings on diagnostic imaging of both adrenals and heart. Patients underwent bilateral two-stage adrenalectomy. Histopathological examination confirmed PPNAD. Genetic testing showed the following mutations in the PRKAR1A gene coding for the regulatory subunit type 1A of the protein kinase A enzyme: c.125dupG (patient 1) and c.15dupT (patient 2). Both these defects lead to inactivation of the PRKAR1A protein and are consequently causative of PPNAD in these patients. CONCLUSIONS: The novel mutations presented in this article are considered to be pathogenic for PPNAD.

Primary pigmented nodular adrenocortical disease: literature review and case report of a 6-year-old boy.

Cushing's syndrome is rare in childhood and is usually caused by a pituitary adenoma. Primary hyperfunction of adrenal glands is less frequent, particularly primary pigmented nodular adrenocortical disease (PPNAD). It occurs usually in children and adolescents, with female preponderance, while Cushing's disease has increased frequency in prepubertal males. A case of a 6-year-old boy is presented with isolated non-familiar PPNAD. The clinical pattern involved Cushingoid appearance, hypertension, virilization and depressive mood. Laboratory analyses showed loss of circadian rhythm of cortisol, undetectable adrenocorticotropic hormone (ACTH) level, impaired fasting glucose, polycythemia and elevated white blood count (WBC). Radiology investigation revealed a slightly enlarged medial branch of the left adrenal gland and a normal right one, so a unilateral adrenalectomy was performed. Pathohistology described multiple dark brownish pigmented nodules of various sizes confined to the cortex. Contralateral adrenalectomy was done 3 months later. Follow-up of 3 years was uneventful, except for one adrenal crisis during an intercurrent respiratory illness.

Surgical treatment of primary pigmented nodular adrenocortical disease / 中华泌尿外科杂志

Objective To discuss the surgical treatment of primary pigmented nodular adrenocortical disease(PPNAD).Methods twenty-four cases of PPNAD were treated in our hospital from January 2005 to December 2017.Clinical data of these patients were reviewed.It included 8 males and 16 females with a mean age of 23 years old (range 14 to 58).23 cases presented with typical symptoms of Cushing syndrome, 1 case presented with hypertension.Eight cases could be diagnosed with Carney complex.All cases were confirmed as ACTH-independent Cushing syndrome.Adrenal imaging showed bilateral multiple nodules in 11 cases, unilateral multiple nodules in 4 cases, unilateral single mass or nodule in 3 cases, normal adrenals in 6 cases.Results All of the 24 cases received laparoscope unilateral adrenalectomy or laparoscope unilateral mass resection.After the operation, 8 cases underwent secondary operation because of symptom recurrence and the elevated 24-hour urinary free cortisol.Among them, 5 cases received contralateral subtotal adrenalectomy, 3 cases received contralateral total adrenalectomy.Seven cases with a slightly elevated 24-hour urinary free cortisol but a good recovery of Cushing symptoms were followed-up.Nine cases recovered well after the first operation and they didn't undergo secondary surgical treatment, but 1 of the 9 cases needed glucocorticoid replacement.Conclusions Bilateral adrenalectomy followed with long-term glucocorticoid replacement is the standard treatment of PPNAD.Unilateral adrenalectomy or subtotal adrenalectomy may be suitable for elected patients, but appropriate criteria need to be explored.

Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia.

Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels.

Residual manifestations of hypercortisolemia following surgical treatment in a patient with Cushing syndrome.

CONTEXT: Cushing Syndrome is difficult to diagnose, and the comorbidities and persistent late effects of hypercortisolemia after treatment of the primary disease are challenging for the patient and the endocrinologist. OBJECTIVE: To report the case of a girl with obesity and hypertension, ultimately diagnosed with Cushing syndrome due to primary pigmented nodular adrenocortical disease. In this case, the complications of hypercortisolism persisted short term despite surgical intervention. PATIENT: A 4 year old morbidly obese African-American girl with developmental delay presented with hypertensive emergency in the ER and 18-month history of progressive weight gain. Her previous history included premature adrenarche, hypertension, seizures and a random high cortisol with suppressed ACTH. She was subsequently stabilized, and a diagnostic work-up persistently demonstrated elevated cortisol and suppressed ACTH. An abdominal MRI showed bilateral adrenal multinodular disease, consistent with multinodular hyperplasia of the adrenal glands. Based on these findings the patient underwent a bilateral adrenalectomy, which confirmed primary pigmented nodular adrenocortical disease. The patient had a complicated, protracted post-operative course requiring adjustment of therapy for persistent hypertension. Two months after surgery, she was readmitted to the Emergency Department with hyperpyrexia and hypertension and succumbed to the complications of sepsis. CONCLUSIONS AND OUTCOME: This case highlights the significant diagnostic and therapeutic challenges in treating children with Cushing syndrome. Resolution of the source of hypercortisolemia does not imply regression of hypertension or recovery of the immune system. Although the child underwent bilateral adrenalectomy, persistent consequences of prolonged severe hypercortisolism contributed to her death two months later.

Absence of PRKAR1A loss of heterozygosity in laser-captured microdissected pigmented nodular adrenocortical tissue from a patient with Carney complex caused by the novel nonsense mutation p. Y21X / Ausência da perda de heterozigose do PRKAR1A em células capturadas por microdissecção a laser de tecido de nódulo pigmentoso adrenocortical de um paciente com complexo de Carney causado por uma nova mutação nonsense

OBJECTIVE: Primary pigmented nodular adrenocortical disease (PPNAD) is the main endocrine manifestation of Carney complex, a multiple neoplasia syndrome caused by PRKAR1A gene mutations. The presence of PRKAR1A loss of heterozygosity (LOH) in adrenocortical tumorigenesis remains controversial. The aim of the present study is to investigate the presence of PRKAR1A LOH in adrenocortical cells in a patient with Carney complex. METHODS: The LOH was investigated using a PRKAR1A informative intragenic marker by GeneScan software analysis in DNA obtained from laser-captured microdissected cells of several adrenal nodules. Patients: A young adult male patient with Carney complex and his family were studied. RESULTS: A novel heterozygous mutation (p. Y21X) was identified at PRKAR1A in blood DNA of the male proband and his relatives. No PRKAR1A LOH was evidenced in the laser-captured microdissected cells from PPNAD tissue by different methodologies. CONCLUSION: We identified a new PRKAR1A nonsense mutation and in addition we did not evidence PRKAR1A LOH in laser-captured nodules cells, suggesting that adrenocortical tumorigenesis in PPNAD may occurs apart from the second hit.

OBJETIVO: A doença adrenocortical nodular pigmentosa primária (PPNAD) é uma das manifestações do complexo de Carney, uma neoplasia endócrina múltipla causada por mutações no PRKAR1A. A perda de heterozigose (LOH) do PRKAR1A na tumorigenese adrenal permanece controversa dada à possibilidade de contaminação com o tecido normal. Nosso objetivo foi investigar a presença de LOH no PRKAR1A a partir de células do nódulo adrenal de um paciente com complexo de Carney. MÉTODOS: A pesquisa da LOH do PRKAR1A foi realizada através do estudo de um marcador intragênico em DNA de células do nódulo adrenal microdissecadas a laser, evitando contaminação com o tecido normal. Pacientes: Um paciente com PPNAD e cinco familiares foram estudados. RESULTADOS: A nova mutação (p. Y21X) foi identificada no PRKAR1A sem evidência de LOH no tecido adrenal. CONCLUSÃO: Identificamos uma nova mutação no PRKAR1A e não evidenciamos LOH nas células dos nódulos adrenocorticais, sugerindo que a PPNAD possa ocorrer na ausência de um segundo evento molecular.

Primary pigmented nodular adrenocortical disease and Cushing's syndrome

Primary pigmented nodular adrenocortical disease (PPNAD) is a form of bilateral adrenocortical hyperplasia that is often associated with corticotrophin (ACTH)-independent Cushing's syndrome (CS) and is characterized by small to normal-sized adrenal glands containing multiple small cortical pigmented nodules (1,2). PPNAD may occur in an isolated form or associated with a multiple neoplasia syndrome, the complex of spotty skin pigmentation, myxomas, and endocrine overactivity, or Carney complex, in which Cushing's syndrome is the most common endocrine manifestation (3). Molecular studies have led to the identification of several genes, defects in which may predispose PPNAD formation; all of these molecules play important role for the cAMP signaling pathway. This review intends to present the most recent knowledge of the pathology and molecular genetics of the benign bilateral adrenocortical lesions, as well as to discuss the modern tools for diagnostics and treatment of this condition.

A doença adrenocortical nodular pigmentada primária (PPNAD) é uma forma de hiperplasia adrenocortical bilateral que está freqüentemente associada com a síndrome de Cushing (SC) ACTH-independente, sendo caracterizada por glândulas adrenais de tamanho pequeno ou normal contendo múltiplos nódulos corticais pigmentados pequenos. PPNAD pode ocorrer de forma isolada ou associada com uma síndrome de neoplasia múltipla, o complexo de manchas pigmentadas na pele (lentigíneas), mixomas e hiperatividade endócrina, ou complexo de Carney, no qual a SC é a manifestação endócrina mais comum. Estudos moleculares levaram à identificação de vários genes que, quando mutados, podem predispor à formação da PPNAD; todas essas moléculas têm um papel importante na via de sinalização do AMPc. Esta revisão pretende apresentar os conhecimentos mais recentes sobre a patologia e a genética molecular das lesões adrenocorticais benignas bilaterais e discutir os modernos instrumentos para diagnóstico e tratamento dessa condição.

A Case of Cushing's syndrome due to Primary Pimary Pigmented Nodular Adrenal Dysplasia ( PPNAD ): A Case of Carney's Complex / 대한내분비학회지

Primary Pigmented Nodular Adrenal Dysplasia (PPNAD) is a rare cause of Cushing's syndrome in infants and young adults. The familial occurrence, it may be variably associated with a complex of other pathologic characteristics that manifests extraadrenal disorders (includes cardiac myxomas, lentigines, mammary myxoid lesions, testicular tumors, pituitary adenomas, and neuroectodermal tumors) was considered indicative of Carneys complex. This was based on the failure of cortisol suppression by high-dose dexamethasone, either normal or suppressed basal adrenocorticotropic hormone (ACTH) levels, and normal radiographic studies of the sellar turcica, and adrenals glands is almost normal or slightlg eulaged.. Bilateral adrenalectomy has thus the only effective means of cure. The disease may be a component of a rare, but potentially dangerous complex of abnormalities that follow an autosomal-dominant mode of inheritance. Recently we experienced a case of Carney's complex composed by Cushings syndrome due to PPNAD with familial purple colored lentigines on their lips and report it with reviews of the literatures.