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Open access

Sharmin Jahan, M A Hasanat, Tahseen Mahmood, Shahed Morshed, Raziul Haq and Md Fariduddin

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.
Open access

Mara Ventura, Leonor Gomes, Joana Rosmaninho-Salgado, Luísa Barros, Isabel Paiva, Miguel Melo, Diana Oliveira and Francisco Carrilho

Summary

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background.

Learning points:

  • Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism.
  • The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation.
  • Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology.
  • 16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders.
  • Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion.
  • Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.
Open access

Yew Wen Yap, Steve Ball and Zubair Qureshi

Summary

The coexistence of primary hypothyroidism and thyroid-stimulating hormone (TSH)-stimulating pituitary macroadenoma can be a rare occurrence and can make diagnosis very challenging. We describe a case of a 44-year-old female with a history of fatigue, poor concentration, weight gain and amenorrhoea together with biochemical evidence of primary autoimmune hypothyroidism. Her initial TSH levels were elevated with low normal free thyroxine (T4) levels. Levothyroxine treatment was initiated and the dose was gradually titrated to supraphysiologic doses. This led to the normalisation of her TSH levels but her free T4 and triiodothyronine (T3) levels remained persistently elevated. This prompted a serum prolactin check which returned elevated at 2495 µ/L, leading onto pituitary imaging. A MRI of the pituitary gland revealed a pituitary macroadenoma measuring 2.4 × 2 × 1.6 cm. Despite starting her on cabergoline therapy with a reduction in her prolactin levels, her TSH levels began to rise even further. Additional thyroid assays revealed that she had an abnormally elevated alpha subunit at 3.95 (age-related reference range <3.00). This corresponded to a thyroid-secreting hormone pituitary macroadenoma. She went on to have a transphenoidal hypophysectomy. Histology revealed tissues staining for TSH, confirming this to be a TSH-secreting pituitary macroadenoma. This case highlighted the importance of further investigations with thyroid assay interferences, heterophile antibodies, alpha subunit testing and anterior pituitary profile in cases of resistant and non-resolving primary hypothyroidism.

Learning points:

  • Levothyroxine treatment in primary hypothyroidism can potentially unmask the presence of a latent TSH-secreting pituitary macroadenoma, which can make diagnosis very challenging.
  • A high index of suspicion should prompt clinicians to further investigate cases of primary hypothyroidism which despite increasing doses of levothyroxine treatment with normalisation of TSH, the free T4 and T3 levels remain persistently elevated.
  • Clinicians should consider investigating for adherence to levothyroxine, thyroid assay interference, heterophile antibodies, TSH dilution studies, alpha subunit and anterior pituitary profile testing to further clarity the diagnosis in these patients.
  • Although coexistent cases of TSHoma with primary hypothyroidism are rare, it should always be in the list of differential diagnoses in cases of unresolving primary hypothyroidism.
Open access

Maria Mercedes Pineyro, Daiana Arrestia, Mariana Elhordoy, Ramiro Lima, Saul Wajskopf, Raul Pisabarro and Maria Pilar Serra

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.
Open access

B Cangiano, C Cacciatore, L Persani and M Bonomi

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic–pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion.

Learning points:

  • Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.
  • In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.
  • In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.
  • Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.
Open access

Regina Streuli, Ina Krull, Michael Brändle, Walter Kolb, Günter Stalla, Marily Theodoropoulou, Annette Enzler-Tschudy and Stefan Bilz

Summary

Ectopic ACTH/CRH co-secreting tumors are a very rare cause of Cushing’s syndrome and only a few cases have been reported in the literature. Differentiating between Cushing’s disease and ectopic Cushing’s syndrome may be particularly difficult if predominant ectopic CRH secretion leads to pituitary corticotroph hyperplasia that may mimic Cushing’s disease during dynamic testing with both dexamethasone and CRH as well as bilateral inferior petrosal sinus sampling (BIPSS). We present the case of a 24-year-old man diagnosed with ACTH-dependent Cushing’s syndrome caused by an ACTH/CRH co-secreting midgut NET. Both high-dose dexamethasone testing and BIPSS suggested Cushing’s disease. However, the clinical presentation with a rather rapid onset of cushingoid features, hyperpigmentation and hypokalemia led to the consideration of ectopic ACTH/CRH-secretion and prompted a further workup. Computed tomography (CT) of the abdomen revealed a cecal mass which was identified as a predominantly CRH-secreting neuroendocrine tumor. To the best of our knowledge, this is the first reported case of an ACTH/CRH co-secreting tumor of the cecum presenting with biochemical features suggestive of Cushing’s disease.

Learning points:

  • The discrimination between a Cushing’s disease and ectopic Cushing’s syndrome is challenging and has many caveats.
  • Ectopic ACTH/CRH co-secreting tumors are very rare.
  • Dynamic tests as well as BIPSS may be compatible with Cushing’s disease in ectopic CRH-secretion.
  • High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.
  • Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing’s syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing’s syndrome and lead to further investigations.
Open access

Nikolaos Kyriakakis, Jacqueline Trouillas, Mary N Dang, Julie Lynch, Paul Belchetz, Márta Korbonits and Robert D Murray

Summary

A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH) and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient’s acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed.

Learning points:

  • Ectopic acromegaly is rare, accounting for less than 1% of all cases of acromegaly.
  • Ectopic acromegaly is almost always due to extra-pituitary GHRH secretion, mainly from neuroendocrine tumours of pancreatic or bronchial origin.
  • Differentiating between acromegaly of pituitary origin and ectopic acromegaly can cause diagnostic challenges due to similarities in clinical presentation and biochemistry.
  • Serum GHRH can be a useful diagnostic tool to diagnose ectopic acromegaly.
  • Pituitary imaging is crucial to differentiate between a pituitary adenoma and pituitary hyperplasia, which is a common finding in ectopic acromegaly.
  • Diagnosing ectopic acromegaly is pivotal to avoid unnecessary interventions to the pituitary and preserve normal pituitary function.
Open access

Kharis Burns, Darshika Christie-David and Jenny E Gunton

Summary

Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.

Learning points

  • Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.
  • Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.
  • Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.
  • Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.

Open access

Nicole Maison, Esther Korpershoek, Graeme Eisenhofer, Mercedes Robledo, Ronald de Krijger and Felix Beuschlein

Summary

Pheochromocytomas (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest. Mutations in the RET-proto-oncogene are associated with sporadic pheochromocytoma, familial or sporadic medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2. In the past, only few cases of pigmented PCCs, PGLs, and one case of pigmented MTC have been reported in the literature. Herein, we present the case of a 77-year old woman with a history of Tako-tsubo-cardiomyopathy and laboratory, as well as radiological, high suspicion of pheochromocytoma, who underwent left-sided adrenalectomy. The 3 cm tumor, which was located on the upper pole of the left adrenal, appeared highly pigmented with dark red to black color. Histologic examinations revealed highly pleomorphic cells with bizarre, huge hyperchromatic nuclei, that immunohistochemically were positive for chromogranin A and synaptophysin, focally positive for HMB45 and negative for melan A. These clinical and pathological features led to the diagnosis of the rare variant of a melanotic ‘black’ pheochromocytoma. In our case a somatic RET mutation in exon 16 (RET c.2753T>C, p.Met918Thy) was detected by targeted next generation sequencing. In summary, this case represents a rare variant of catecholamine-producing tumor with distinct histological features. A potential relationship between the phenotype, the cellular origin and the genetic alterations is discussed.

Learning points

  • Pheochromocytoma is a rare neuroendocrine tumor.
  • Pigmentation is seen in several types of tumors arising from the neural crest. The macroscopic black aspect can mislead to the diagnosis of a metastasis deriving from a malignant melanoma.
  • RET mutation are seen in catecholamine and non-catecholamine producing tumors of the same cellular origin.

Open access

W C Candy Sze, Joe McQuillan, P Nicholas Plowman, Niall MacDougall, Philip Blackburn, H Ian Sabin, Nadeem Ali and William M Drake

Summary

We report three patients who developed symptoms and signs of ocular neuromyotonia (ONM) 3–6 months after receiving gamma knife radiosurgery (GKS) for functioning pituitary tumours. All three patients were complex, requiring multi-modality therapy and all had received prior external irradiation to the sellar region. Although direct causality cannot be attributed, the timing of the development of the symptoms would suggest that the GKS played a contributory role in the development of this rare problem, which we suggest clinicians should be aware of as a potential complication.

Learning points

  • GKS can cause ONM, presenting as intermittent diplopia.
  • ONM can occur quite rapidly after treatment with GKS.
  • Treatment with carbamazepine is effective and improve patient's quality of life.