Diagnosis and Treatment > Signs and Symptoms
Search for other papers by Sharmin Jahan in
Google Scholar
PubMed
Search for other papers by M A Hasanat in
Google Scholar
PubMed
Search for other papers by Tahseen Mahmood in
Google Scholar
PubMed
Search for other papers by Shahed Morshed in
Google Scholar
PubMed
Search for other papers by Raziul Haq in
Google Scholar
PubMed
Search for other papers by Md Fariduddin in
Google Scholar
PubMed
Summary
Silent corticotroph adenoma (SCA) is an unusual type of nonfunctioning pituitary adenoma (NFA) that is silent both clinically and biochemically and can only be recognized by positive immunostaining for ACTH. Under rare circumstances, it can transform into hormonally active disease presenting with severe Cushing syndrome. It might often produce diagnostic dilemma with difficult management issue if not thoroughly investigated and subtyped accordingly following surgery. Here, we present a 21-year-old male who initially underwent pituitary adenomectomy for presumed NFA with compressive symptoms. However, he developed recurrent and invasive macroadenoma with severe clinical as well as biochemical hypercortisolism during post-surgical follow-up. Repeat pituitary surgery was carried out urgently as there was significant optic chiasmal compression. Immunohistochemical analysis of the tumor tissue obtained on repeat surgery proved it to be an aggressive corticotroph adenoma. Though not cured, he showed marked clinical and biochemical improvement in the immediate postoperative period. Anticipating recurrence from the residual tumor, we referred him for cyber knife radio surgery.
Learning points:
-
Pituitary NFA commonly present with compressive symptoms such as headache and blurred vision.
-
Post-surgical development of Cushing syndrome in such a case could be either drug induced or endogenous.
-
In the presence of recurrent pituitary tumor, ACTH-dependent Cushing syndrome indicates CD.
-
Rarely a SCA presenting initially as NFA can transform into an active corticotroph adenoma.
-
Immunohistochemical marker for ACTH in the resected tumor confirms the diagnosis.
Search for other papers by Catherine D Zhang in
Google Scholar
PubMed
Search for other papers by Pavel N Pichurin in
Google Scholar
PubMed
Search for other papers by Aleh Bobr in
Google Scholar
PubMed
Search for other papers by Melanie L Lyden in
Google Scholar
PubMed
Search for other papers by William F Young Jr in
Google Scholar
PubMed
Search for other papers by Irina Bancos in
Google Scholar
PubMed
Summary
Carney complex (CNC) is a rare multiple neoplasia syndrome characterized by spotty pigmentation of the skin and mucosa in association with various non-endocrine and endocrine tumors, including primary pigmented nodular adrenocortical disease (PPNAD). A 20-year-old woman was referred for suspected Cushing syndrome. She had signs of cortisol excess as well as skin lentigines on physical examination. Biochemical investigation was suggestive of corticotropin (ACTH)-independent Cushing syndrome. Unenhanced computed tomography scan of the abdomen did not reveal an obvious adrenal mass. She subsequently underwent bilateral laparoscopic adrenalectomy, and histopathology was consistent with PPNAD. Genetic testing revealed a novel frameshift pathogenic variant c.488delC/p.Thr163MetfsX2 (ClinVar Variation ID: 424516) in the PRKAR1A gene, consistent with clinical suspicion for CNC. Evaluation for other clinical features of the complex was unrevealing. We present a case of PPNAD-associated Cushing syndrome leading to the diagnosis of CNC due to a novel PRKAR1A pathogenic variant.
Learning points:
-
PPNAD should be considered in the differential for ACTH-independent Cushing syndrome, especially when adrenal imaging appears normal.
-
The diagnosis of PPNAD should prompt screening for CNC.
-
CNC is a rare multiple neoplasia syndrome caused by inactivating pathogenic variants in the PRKAR1A gene.
-
Timely diagnosis of CNC and careful surveillance can help prevent potentially fatal complications of the disease.
Search for other papers by Lima Lawrence in
Google Scholar
PubMed
Search for other papers by Peng Zhang in
Google Scholar
PubMed
Search for other papers by Humberto Choi in
Google Scholar
PubMed
Search for other papers by Usman Ahmad in
Google Scholar
PubMed
Search for other papers by Valeria Arrossi in
Google Scholar
PubMed
Search for other papers by Andrei Purysko in
Google Scholar
PubMed
Search for other papers by Vinni Makin in
Google Scholar
PubMed
Summary
Ectopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing’s syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment.
Learning points:
-
Functional thymic neuroendocrine tumors are exceedingly rare.
-
Ectopic Cushing’s syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections.
-
The ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high.
-
A high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.
Search for other papers by Maria Mercedes Pineyro in
Google Scholar
PubMed
Search for other papers by Daiana Arrestia in
Google Scholar
PubMed
Search for other papers by Mariana Elhordoy in
Google Scholar
PubMed
Search for other papers by Ramiro Lima in
Google Scholar
PubMed
Search for other papers by Saul Wajskopf in
Google Scholar
PubMed
Search for other papers by Raul Pisabarro in
Google Scholar
PubMed
Search for other papers by Maria Pilar Serra in
Google Scholar
PubMed
Summary
Spontaneous reossification of the sellar floor after transsphenoidal surgery has been rarely reported. Strontium ranelate, a divalent strontium salt, has been shown to increase bone formation, increasing osteoblast activity. We describe an unusual case of a young patient with Cushing’s disease who was treated with strontium ranelate for low bone mass who experienced spontaneous sellar reossification after transsphenoidal surgery. A 21-year-old male presented with Cushing’s features. His past medical history included delayed puberty diagnosed at 16 years, treated with testosterone for 3 years without further work-up. He was diagnosed with Cushing’s disease initially treated with transsphenoidal surgery, which was not curative. The patient did not come to follow-up visits for more than 1 year. He was prescribed strontium ranelate 2 g orally once daily for low bone mass by an outside endocrinologist, which he received for more than 1 year. Two years after first surgery he was reevaluated and persisted with active Cushing’s disease. Magnetic resonance image revealed a left 4 mm hypointense mass, with sphenoid sinus occupation by a hyperintense material. At repeated transsphenoidal surgery, sellar bone had a very hard consistency; surgery was complicated and the patient died. Sellar reossification negatively impacted surgery outcomes in this patient. While this entity is possible after transsphenoidal surgery, it remains unclear whether strontium ranelate could have affected sellar ossification.
Learning points:
-
Delayed puberty can be a manifestation of Cushing’s syndrome. A complete history, physical examination and appropriate work-up should be performed before initiating any treatment.
-
Sellar reossification should always be taken into account when considering repeated transsphenoidal surgery. Detailed preoperative evaluation of bony structures by computed tomography ought to be performed in all cases of reoperation.
-
We speculate if strontium ranelate may have affected bone mineralization at the sellar floor. We strongly recommend that indications for prescribing this drug should be carefully followed.
Search for other papers by Ayanthi A Wijewardene in
Google Scholar
PubMed
Kolling Institute of Medical Research
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Sarah J Glastras in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Diana L Learoyd in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Bruce G Robinson in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Venessa H M Tsang in
Google Scholar
PubMed
Summary
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing’s syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing’s syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing’s syndrome in metastatic MTC.
Learning points:
-
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour.
-
Cushing’s syndrome is a rare complication of MTC that has a significant impact on patients’ morbidity and mortality.
-
Tyrosine kinase inhibitors (TKI) provide an important therapeutic option for the management of ectopic ACTH in metastatic MTC.
Search for other papers by M J Trott in
Google Scholar
PubMed
Search for other papers by G Farah in
Google Scholar
PubMed
Search for other papers by V J Stokes in
Google Scholar
PubMed
Search for other papers by L M Wang in
Google Scholar
PubMed
Search for other papers by A B Grossman in
Google Scholar
PubMed
Summary
We present a case of a young female patient with a rare cause of relapsing and remitting Cushing’s syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing’s syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms ‘relapsing and remitting’ in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing’s syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking.
Learning points
-
Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing’s syndrome
-
There is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs)
-
The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohort
-
An exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populations
-
The relapsing and remitting course of our patient’s symptoms is noteworthy, given the paucity of this finding among other published cases
Department of Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan
Search for other papers by Ya-Wun Guo in
Google Scholar
PubMed
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
Search for other papers by Chii-Min Hwu in
Google Scholar
PubMed
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
Search for other papers by Justin Ging-Shing Won in
Google Scholar
PubMed
Department of Otorhinolaryngology-Head and Neck Surgery, Division of Otology, Taipei Veterans General Hospital, Taipei, Taiwan
Search for other papers by Chia-Huei Chu in
Google Scholar
PubMed
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
Search for other papers by Liang-Yu Lin in
Google Scholar
PubMed
Summary
A functional lesion in corticotrophin (ACTH)-independent Cushing’s syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and 131I-6β-iodomethyl-19-norcholesterol (131I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and 131I-NP-59 scintigraphy are good diagnostic methods for Cushing’s syndrome presenting with bilateral adrenal masses.
Learning points
-
The clinical presentation of Cushing’ syndrome includes symptoms and signs of fat redistribution and protein-wasting features.
-
The diagnosis of patients with ACTH-independent Cushing’s syndrome with bilateral adrenal masses is challenging for localisation of the lesion.
-
Both adrenal venous sampling and 131I-NP-59 scintigraphy are good methods to use in these patients with Cushing’s syndrome presenting with bilateral adrenal masses.
Search for other papers by A Pazderska in
Google Scholar
PubMed
Search for other papers by S Crowther in
Google Scholar
PubMed
Search for other papers by P Govender in
Google Scholar
PubMed
Departments of Surgery, Trinity College, Dublin, Ireland
Search for other papers by K C Conlon in
Google Scholar
PubMed
Departments of Endocrinology, Trinity College, Dublin, Ireland
Search for other papers by M Sherlock in
Google Scholar
PubMed
Departments of Endocrinology, Trinity College, Dublin, Ireland
Search for other papers by J Gibney in
Google Scholar
PubMed
Summary
Avascular 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 points
-
AVN 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.
