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Open access

Yael Lefkovits and Amanda Adler

Summary

Necrobiosis lipoidica diabeticorum (NLD) is a chronic granulomatous dermatitis generally involving the anterior aspect of the shin, that arises in 0.3–1.2% of patients with diabetes mellitus (1). The lesions are often yellow or brown with telangiectatic plaque, a central area of atrophy and raised violaceous borders (2). Similar to other conditions with a high risk of scarring including burns, stasis ulcers and lupus vulgaris, NLD provides a favourable environment for squamous cell carcinoma (SCC) formation (3). A number of cases of SCC from NLD have been recorded (3, 4, 5); however, our search of the literature failed to identify any cases of either metastatic or fatal SCC which developed within an area of NLD. This article describes a patient with established type 1 diabetes mellitus who died from SCC which developed from an area of NLD present for over 10 years. Currently, there are a paucity of recommendations in the medical literature for screening people with NLD for the early diagnosis of SCC. We believe that clinicians should regard non-healing ulcers in the setting of NLD with a high index of clinical suspicion for SCC, and an early biopsy of such lesions should be recommended.

Learning points:

  • Non-healing, recalcitrant ulcers arising from necrobiosis lipoidica diabeticorum, which fail to heal by conservative measures, should be regarded with a high index of clinical suspicion for malignancy.

  • If squamous cell carcinoma is suspected, a biopsy should be performed as soon as possible to prevent metastatic spread, amputation or even death.

  • Our literature search failed to reveal specific recommendations for screening and follow-up of non-healing recalcitrant ulcers in the setting of necrobiosis lipoidica diabeticorum.

  • Further research is required in this field.

Open access

M A Shehab, Tahseen Mahmood, M A Hasanat, Md Fariduddin, Nazmul Ahsan, Mohammad Shahnoor Hossain, Md Shahdat Hossain and Sharmin Jahan

Summary

Congenital adrenal hyperplasia (CAH) due to the three-beta-hydroxysteroid-dehydrogenase (3β-HSD) enzyme deficiency is a rare autosomal recessive disorder presenting with sexual precocity in a phenotypic male. Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy presenting with hypergonadotropic hypogonadism in a male. However, only a handful of cases of mosaic KS have been described in the literature. The co-existence of mosaic KS with CAH due to 3β-HSD enzyme deficiency portrays a unique diagnostic paradox where features of gonadal androgen deficiency are masked by simultaneous adrenal androgen excess. Here, we report a 7-year-old phenotypic male boy who, at birth presented with ambiguous genitalia, probably a microphallus with penoscrotal hypospadias. Later on, he developed accelerated growth with advanced bone age, premature pubarche, phallic enlargement and hyperpigmentation. Biochemically, the patient was proven to have CAH due to 3β-HSD deficiency. However, the co-existence of bilateral cryptorchidism made us to consider the possibility of hypogonadism as well, and it was further explained by concurrent existence of mosaic KS (47,XXY/46,XX). He was started on glucocorticoid and mineralocorticoid replacement and underwent right-sided orchidopexy on a later date. He showed significant clinical and biochemical improvement on subsequent follow-up. However, the declining value of serum testosterone was accompanied by rising level of FSH thereby unmasking hypergonadotropic hypogonadism due to mosaic KS. In future, we are planning to place him on androgen replacement as well.

Learning points:

  • Ambiguous genitalia with subsequent development of sexual precocity in a phenotypic male points towards some unusual varieties of CAH.

  • High level of serum testosterone, adrenal androgen, plasma ACTH and low basal cortisol are proof of CAH, whereas elevated level of 17-OH pregnenolone is biochemical marker of 3β-HSD enzyme deficiency.

  • Final diagnosis can be obtained with sequencing of HSD3B2 gene showing various mutations.

  • Presence of bilateral cryptorchidism in such a patient may be due to underlying hypogonadism.

  • Karyotyping in such patient may rarely show mosaic KS (47,XXY/46,XX) and there might be unmasking of hypergonadotropic hypogonadism resulting from adrenal androgen suppression from glucocorticoid treatment.

Open access

Benedetta Zampetti, Giorgia Simonetti, Roberto Attanasio, Antonio Silvani and Renato Cozzi

Summary

We describe the 20-year course of a 63-year-old male with a macroprolactinoma that acquired resistance to treatment and aggressive behavior after a 4-year successful treatment with cabergoline. He was submitted to multiple surgical resections by a skilled surgeon, fractionated radiotherapy and was eventually treated with temozolomide. After a first 6-month standard cycle, a relapse occurred and he was treated again successfully.

Learning points:

  • Prolactinomas are the most frequent type of pituitary adenoma.

  • They usually have a benign course.

  • In most cases dopamine-agonist drugs, mainly cabergoline, are first-line (and usually only) treatment.

  • Occasionally prolactinomas can have or acquire resistance to treatment and/or aggressive behavior.

  • Temozolomide (TMZ), an oral alkylating drug, can be effective in such aggressive tumors.

  • Multimodal treatment (surgery, radiation, cabergoline and TMZ) is warranted in aggressive pituitary tumors.

  • We describe here successful rechallenge with TMZ after relapse occurring 18 months after a first TMZ cycle.

Open access

Philip D Oddie, Benjamin B Albert, Paul L Hofman, Craig Jefferies, Stephen Laughton and Philippa J Carter

Summary

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.

Learning points:

  • Adrenocortical carcinoma is an important differential diagnosis for virilization in young children

  • Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis

  • Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.

  • Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed

  • In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

Open access

Nikolaos Asonitis, Eva Kassi, Michalis Kokkinos, Ilias Giovanopoulos, Foteini Petychaki and Helen Gogas

Summary

Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range.

Learning points:

  • Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.

  • Breast cancer has the highest prevalence of hypercalcemia.

  • The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).

  • In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option.

Open access

Gueorgui Dubrocq, Andrea Estrada, Shannon Kelly and Natella Rakhmanina

Summary

An 11-year-old male with perinatally acquired human immune deficiency virus (HIV) infection on antiretroviral regimen, which included abacavir plus lamivudine (Epzicom), didanosine, ritonavir and atazanavir presented with bilateral axillary striae, increased appetite, fatigue, facial swelling and acute weight gain. Two months prior to presentation, the patient had received a diagnostic and therapeutic intra-articular triamcinolone injection in the knee for pain relief and subsequently became progressively swollen in the face, developed striae bilaterally at the axillae, experienced increased appetite, fatigue and an 8 pound weight gain. During the endocrine workup, suspicion for adrenal insufficiency prompted 24-h urine collection for free cortisol, which was found to be undetectable (below LLQ of 1.0 µg/L). This prompted further evaluation of the hypothalamic–pituitary axis (HPA) by standard dose adrenocorticotropic hormone (ACTH) stimulation test. A 250 µg cosyntropin stimulation test was performed and confirmed HPA axis suppression. Baseline cortisol level was <1 µg/dL and stimulated cortisol level at 30 min was 3.8 µg/dL. The patient was diagnosed with iatrogenic Cushing syndrome and suppression of HPA axis secondary to the drug interaction between ritonavir (RTV) and intra-articular triamcinolone injection. Following endocrine evaluation and workup, the patient was admitted for planned orthopaedic procedure including elective left hamstring lengthening, distal femoral osteotomy and patellar tendon advancement. Taking into consideration the diagnosis of iatrogenic Cushing syndrome, at the start of the surgical procedure, 100 mg IV stress dose of hydrocortisone followed by 50 mg hydrocortisone every 8 h for 24 h was administered. Stress dosing was discontinued 24 h after the procedure. Throughout the hospitalization and upon discharge, the patient continued his ART. From initial presentation, patient has remained clinically stable throughout surgery and postoperative period.

Learning points:

  • Drug–drug interaction between ritonavir and triamcinolone can cause Cushing syndrome.

  • Although triamcinolone has a half-life of 3 h, an intra-articular injection may be systematically absorbed for 3 weeks after injection, and adrenal suppression may last as long as 30 days.

  • Co-administration of ritonavir and corticosteroids may result in an increase of plasma levels of corticosteroids levels, as they are both eliminated by CYP3A metabolism, and this interaction has the potential to prolong the half-life of triamcinolone several fold.

  • No specific guidelines are available for the management of iatrogenic Cushing syndrome secondary to ritonavir and corticosteroids.

  • One treatment option includes replacing ritonavir with a non-protease inhibitor-based regimen.

  • Initiating hydrocortisone replacement therapy to prevent an adrenal crisis is also an alternate option.

Open access

Maryam Heidarpour, Mehdi Karami, Pegah Hedayat and Ashraf Aminorroaya

Summary

Primary hyperparathyroidism revealed by thoracic spine brown tumor and peptic ulcer bleeding is rare. We presented a case of 33-year-old male patient who was admitted with paraplegia. Thoracic spine magnetic resonance imaging (MRI) showed extradural lesion at T4 level. He underwent surgical decompression in T4. According to histopathologic finding and elevated serum parathormone (PTH) and hypercalcemia (total serum calcium 12.1 mg/dL), the diagnosis of brown tumor was down. Ultrasonography of his neck showed a well-defined lesion of 26 × 14 × 6 mm. The day after surgery, he experienced 2 episodes of melena. Bedside upper gastrointestinal endoscopy showed gastric peptic ulcer with visible vessel. Treatment with intragastric local instillation of epinephrine and argon plasma coagulation was done to stop bleeding. After stabilization of the patient, parathyroidectomy was performed. Histologic study showed the parathyroid adenoma without any manifestation of malignancy. At discharge, serum calcium was normal (8.6 mg/dL). On 40th day of discharge, standing and walking status was normal.

Learning points:

  • Thoracic spine involvement is a very rare presentation of primary hyperparathyroidism.

  • The issue of whether primary hyperparathyroidism increases the risk of peptic ulcer disease remains controversial. However, gastrointestinal involvement has been reported in association with classic severe primary hyperparathyroidism.

  • The treatment of brown tumor varies from case to case.

Open access

Run Yu, Danielle Sharaga, Christopher Donner, M Fernando Palma Diaz, Masha J Livhits and Michael W Yeh

Summary

Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case.

Learning points:

  • Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.

  • Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.

  • Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.

  • Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.

  • Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma.

Open access

Gulay Simsek Bagir, Soner Civi, Ozgur Kardes, Fazilet Kayaselcuk and Melek Eda Ertorer

Summary

Pituitary apoplexy (PA) may very rarely present with hiccups. A 32-year-old man with classical acromegaloid features was admitted with headache, nausea, vomiting and stubborn hiccups. Pituitary magnetic resonance imaging (MRI) demonstrated apoplexy of a macroadenoma with suprasellar extension abutting the optic chiasm. Plasma growth hormone (GH) levels exhibited suppression (below <1 ng/mL) at all time points during GH suppression test with 75 g oral glucose. After treatment with corticosteroid agents, he underwent transsphenoidal pituitary surgery and hiccups disappeared postoperatively. The GH secretion potential of the tumor was clearly demonstrated immunohistochemically. We conclude that stubborn hiccups in a patient with a pituitary macroadenoma may be a sign of massive apoplexy that may result in hormonal remission.

Learning points:

  • Patients with pituitary apoplexy may rarely present with hiccups.

  • Stubborn hiccupping may be a sign of generalized infarction of a large tumor irritating the midbrain.

  • Infarction can be so massive that it may cause cessation of hormonal overproduction and result in remission.

Open access

Roberto Attanasio, Liana Cortesi, Daniela Gianola, Claudia Vettori, Fulvio Sileo and Roberto Trevisan

Summary

Cushing’s syndrome is associated with increased morbidity and mortality. Although surgery is the first-line treatment, drugs can still play a role as an ancillary treatment to be employed while waiting for surgery, after unsuccessful operation or in patients unsuitable for surgery. We were asked to evaluate a 32-year-old male waiting for cardiac transplantation. Idiopathic hypokinetic cardiomyopathy had been diagnosed since 6 years. He was on treatment with multiple drugs, had a pacemaker, an implantable cardioverter and an external device for the support of systolic function. Physical examination showed severely impaired general status, signs of hypercortisolism and multiple vertebral compression fractures. We administered teriparatide, and the few evaluable parameters supported the diagnosis of ACTH-dependent hypercortisolism: serum cortisol was 24.2 µg/dL in the morning and 20.3 µg/dL after overnight 1 mg dexamethasone, urinary free cortisol (UFC) was 258 µg/24 h and ACTH 125 pg/mL. Pituitary CT was negative. Pasireotide 300 µg bid was administered and uptitrated to 600 µg bid. Treatment was well tolerated, achieving dramatic improvement of clinical picture with progressive normalization of serum cortisol and ACTH levels as well as UFC. After 4 months, the patient underwent successful heart transplantation. Many complications ensued and were overcome. Pituitary MRI was negative. On pasireotide 300 µg bid and prednisone 2.5 mg/day (as part of immunosuppressive therapy), morning serum cortisol and ACTH were 15.6 µg/dL and 54 pg/mL respectively, UFC was 37 µg/24 h, fasting glucose: 107 mg/dL and HbA1c: 6.5%. In conclusion, primary treatment with pasireotide achieved remission of hypercortisolism, thus allowing the patient to undergo heart transplantation.

Learning points:

  • Untreated Cushing’s syndrome is associated with ominous prognosis.

  • First-line treatment is surgery (at pituitary or adrenal, according to disease localization).

  • A few drugs are available to treat hypercortisolism.

  • Pasireotide is a multi-ligand somatostatin analog approved for treatment of hypercortisolism.

  • Primary treatment with pasireotide was effective in a patient with severe Cushing’s syndrome, allowing him to undergo heart transplantation.