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Open access

Lima Lawrence, Peng Zhang, Humberto Choi, Usman Ahmad, Valeria Arrossi, Andrei Purysko and Vinni Makin

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.

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

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

Tanja Miličević, Ivan Žaja, Deša Tešanović and Maja Radman

Summary

Laugier–Hunziker syndrome (LHS) is a rare, benign and acquired disorder characterized by hyperpigmentation of the oral cavity and lips along with longitudinal melanonychia. No underlying systemic abnormalities or malignant predisposition is associated with it. In everyday clinical practice, an endocrinologist encounters certain endocrine conditions (e.g. Addison’s disease, McCune–Albright syndrome) that present with, inter alia, mucocutaneous hyperpigmentation. Even though LHS is easily distinguished from endocrine entities mentioned earlier, diagnostic evaluation usually requires skilled and thorough practitioner. Since it is the diagnosis of exclusion, a number of systemic conditions must be ruled out prior to making the final diagnosis. However, its major differential diagnosis is primarily Peutz-Jeghers syndrome, which carries an increased risk of cancer. Here, we report a case of a young woman who was referred to the endocrinologist for diagnostic evaluation of dark-colored lesions of the oral cavity and nails. All performed laboratory tests were within reference range. Endoscopic gastrointestinal evaluation did not reveal neoplastic formations. Owing to an adult-onset, asymptomatic clinical course and negative diagnostic findings, we made a final diagnosis. In this case, target diagnostic evaluation notably reduced the need for additional expensive and invasive procedures and treatments.

Learning points:

  • Laugier–Hunziker syndrome is a rare, acquired cause of asymptomatic, benign mucocutaneous hyperpigmentation.

  • Prior to making a final diagnosis, certain medical entities with overlapping clinical features must be excluded.

  • Endocrine conditions that usually present with the hyperpigmentation of the skin and mucous membranes (e.g. Addison’s disease, McCune–Albright syndrome) can be easily ruled out based on clinical and laboratory findings.

  • Its major differential diagnosis, Peutz-Jeghers syndrome is characterized by melanotic macules of the face and mouth, intestinal polyposis and significantly increased risk of different types of cancer, especially gastrointestinal.

  • Anamnesis, physical examination and target diagnostic evaluation reduce the need for additional invasive and expensive procedures and treatment.

Open access

Su Ann Tee, Earn Hui Gan, Mohamad Zaher Kanaan, David Ashley Price, Tim Hoare and Simon H S Pearce

Summary

Primary adrenal insufficiency secondary to syphilis is extremely rare, with only five cases being reported in the literature. We report a case of adrenal insufficiency as a manifestation of Treponema pallidum infection (tertiary syphilis). A 69-year-old, previously fit and well Caucasian male was found to have adrenal insufficiency after being admitted with weight loss, anorexia and postural dizziness resulting in a fall. Biochemical testing showed hyponatraemia, hyperkalaemia, and an inadequate response to Synacthen testing, with a peak cortisol level of 302 nmol/L after administration of 250 µg Synacthen. Abdominal imaging revealed bilateral adrenal hyperplasia with inguinal and retroperitoneal lymphadenopathy. He was started on hydrocortisone replacement; however, it was not until he re-attended ophthalmology with a red eye and visual loss 1 month later, that further work-up revealed the diagnosis of tertiary syphilis. Following a course of penicillin, repeat imaging 5 months later showed resolution of the abnormal radiological appearances. However, adrenal function has not recovered and 3 years following initial presentation, the patient remains on both glucocorticoid and mineralocorticoid replacement. In conclusion, this case highlights the importance of considering syphilis as a potential differential diagnosis in patients presenting with adrenal insufficiency and bilateral adrenal masses, given the recent re-emergence of this condition. The relative ease of treating infectious causes of adrenal lesions makes accurate and timely diagnosis crucial.

Learning points:

  • Infectious causes, including syphilis, should be excluded before considering adrenalectomy or biopsy for any patient presenting with an adrenal mass.

  • It is important to perform a full infection screen including tests for human immunodeficiency virus, other blood-borne viruses and concurrent sexually transmitted diseases in patients presenting with bilateral adrenal hyperplasia with primary adrenal insufficiency.

  • Awareness of syphilis as a potential differential diagnosis is important, as it not only has a wide range of clinical presentations, but its prevalence has been increasing in recent times.

Open access

Diana Oliveira, Adriana Lages, Sandra Paiva and Francisco Carrilho

Summary

Addison’s disease, or primary adrenocortical insufficiency, is a long-term, potentially severe, rare endocrine disorder. In pregnancy, it is even rarer. We report the case of a 30-year-old pregnant patient with Addison’s disease, referred to Obstetrics-Endocrinology specialty consult at 14 weeks gestation. She had been to the emergency department of her local hospital various times during the first trimester presenting with a clinical scenario suggestive of glucocorticoid under-replacement (nausea, persistent vomiting and hypotension), but this was interpreted as normal pregnancy symptoms. Hydrocortisone dose was adjusted, and the patient maintained regular follow-up. No complications were reported for the remainder of gestation and delivery. Pregnant patients with Addison’s disease should be monitored during gestation and in the peripartum period by multidisciplinary teams. Adjustments in glucocorticoid and mineralocorticoid replacement therapy are often necessary, and monitoring should be based mainly on clinical findings, which becomes increasingly difficult during pregnancy. Patient education and specialized monitoring are key to avoiding complications from under- or over-replacement therapy in this period.

Learning points:

  • An increase in glucocorticoid replacement dose is expected to be necessary during pregnancy in a woman with Addison’s disease.

  • Patient education regarding steroid cover and symptoms of acute adrenal crisis are fundamental.

  • Monitoring in this period is challenging and remains mainly clinical.

  • The increase in hydrocortisone dose often obviates the need to increase fludrocortisone dose.

Open access

Lukas Burget, Laura Audí Parera, Monica Fernandez-Cancio, Rolf Gräni, Christoph Henzen and Christa E Flück

Summary

Steroidogenic acute regulatory protein (STAR) is a key protein for the intracellular transport of cholesterol to the mitochondrium in endocrine organs (e.g. adrenal gland, ovaries, testes) and essential for the synthesis of all steroid hormones. Several mutations have been described and the clinical phenotype varies strongly and may be grouped into classic lipoid congenital adrenal hyperplasia (LCAH), in which all steroidogenesis is disrupted, and non-classic LCAH, which resembles familial glucocorticoid deficiency (FGD), which affects predominantly adrenal functions. Classic LCAH is characterized by early and potentially life-threatening manifestation of primary adrenal insufficiency (PAI) with electrolyte disturbances and 46,XY disorder of sex development (DSD) in males as well as lack of pubertal development in both sexes. Non-classic LCAH manifests usually later in life with PAI. Nevertheless, life-long follow-up of gonadal function is warranted. We describe a 26-year-old female patient who was diagnosed with PAI early in life without detailed diagnostic work-up. At the age of 14 months, she presented with hyperpigmentation, elevated ACTH and low cortisol levels. As her older brother was diagnosed with PAI two years earlier, she was put on hydrocortisone and fludrocortisone replacement therapy before an Addisonian crisis occurred. Upon review of her case in adulthood, consanguinity was noted in the family. Genetic analysis for PAI revealed a homozygous mutation in the STAR gene (c.562C>T, p.Arg188Cys) in both siblings. This mutation has been previously described in non-classic LCAH. This case illustrates that early onset, familial PAI is likely due to autosomal recessive genetic mutations in known genes causing PAI.

Learning points:

  • In childhood-onset PAI, a genetic cause is most likely, especially in families with consanguinity.

  • Adult patients with an etiologically unsolved PAI should be reviewed repeatedly and genetic work-up should be considered.

  • Knowing the exact genetic diagnosis in PAI is essential for genetic counselling and may allow disease-specific treatment.

  • Young men and women with NCLAH due to homozygous STAR Arg188Cys mutation should be investigated for their gonadal function as hypogonadism and infertility might occur during puberty or in early adulthood.

Open access

Carlos Tavares Bello, Emma van der Poest Clement and Richard Feelders

Summary

Cushing’s syndrome is a rare disease that results from prolonged exposure to supraphysiological levels of glucocorticoids. Severe and rapidly progressive cases are often, but not exclusively, attributable to ectopic ACTH secretion. Extreme hypercortisolism usually has florid metabolic consequences and is associated with an increased infectious and thrombotic risk. The authors report on a case of a 51-year-old male that presented with severe Cushing’s syndrome secondary to an ACTH-secreting pituitary macroadenoma, whose diagnostic workup was affected by concurrent subclinical multifocal pulmonary infectious nodules. The case is noteworthy for the atypically severe presentation of Cushing’s disease, and it should remind the clinician of the possible infectious and thrombotic complications associated with Cushing’s syndrome.

Learning points:

  • Severe Cushing’s syndrome is not always caused by ectopic ACTH secretion.

  • Hypercortisolism is a state of immunosuppression, being associated with an increased risk for opportunistic infections.

  • Infectious pulmonary infiltrates may lead to imaging diagnostic dilemmas when investigating a suspected ectopic ACTH secretion.

  • Cushing’s syndrome carries an increased thromboembolic risk that may even persist after successful surgical management.

  • Antibiotic and venous thromboembolism prophylaxis should be considered in every patient with severe Cushing’s syndrome.

Open access

Xin Feng and Gregory Kline

Summary

In a 61-year-old Caucasian male with prostate cancer, leuprolide and bicalutamide failed to suppress the androgens. He presented to endocrinology with persistently normal testosterone and incidental massive (up to 18 cm) bilateral adrenal myelolipomas on CT scan. Blood test did not reveal metanephrine excess. The patient was noted to have short stature (151 cm) and primary infertility. Elementary school photographs demonstrated precocious puberty. Physical examination revealed palpable abdominal (adrenal) masses. Abiraterone and glucocorticoid treatment was commenced with excellent suppression of testosterone. Genetic testing revealed a mutation in CYP21A2 confirming 21-hydroxylase-deficient congenital adrenal hyperplasia (CAH). Association of large myelolipomas with CAH has been reported in the literature. Our case highlights the importance of considering CAH in patients with non-suppressed testosterone despite androgen deprivation therapy. Large myelolipomas should raise the suspicion of congenital adrenal hyperplasia.

Learning points:

  • Adrenal myelolipomas are rare benign lesions that are more common in patients with longstanding untreated congenital adrenal hyperplasia thought to be due to ACTH stimulation.

  • Consider undiagnosed congenital adrenal hyperplasia in patients with adrenal myelolipoma.

  • Glucocorticoid replacement may be an efficacious treatment for patients with prostate cancer and CAH. Abiraterone therapy has a risk of adrenal crisis if glucocorticoids are not replaced.

Open access

Andromachi Vryonidou, Stavroula A Paschou, Fotini Dimitropoulou, Panagiotis Anagnostis, Vasiliki Tzavara and Apostolos Katsivas

Summary

We describe a case of a 40-year-old woman who was admitted to the intensive care unit with a rapid onset of dyspnea and orthopnea. She presented progressive weakness, weight loss and secondary amenorrhea during last year, while intermittent fever was present for the last two months. Initial biochemical evaluation showed anemia, hyponatremia and increased C-reactive protein levels. Clinical and echocardiographic evaluation revealed cardiac tamponade, which was treated with pericardiocentesis. Pleural fluid samples were negative for malignancy, tuberculosis or bacterial infection. Hormonal and serologic evaluation led to the diagnosis of autoimmune polyglandular syndrome (APS) type 2 (including primary adrenal insufficiency and autoimmune thyroiditis), possibly coexisting with systemic lupus erythematosus. After symptomatic rheumatologic treatment followed by replacement therapy with hydrocortisone and fludrocortisone, the patient fully recovered. In patients with the combination of polyserositis, cardiac tamponade and persistent hyponatremia, possible coexistence of rheumatologic and autoimmune endocrine disease, mainly adrenal insufficiency, should be considered. Early diagnosis and non-invasive treatment can be life-saving.

Learning points:

  • In patients with the combination of polyserositis, cardiac tamponade and persistent hyponatremia, possible coexistence of rheumatologic and autoimmune endocrine disease, mainly adrenal insufficiency, should be considered.

  • Early diagnosis and non-invasive treatment can be life-saving for these patients.

  • Primary adrenal insufficiency requires lifelong replacement therapy with oral administration of 15–25 mg hydrocortisone in split doses and 50–200 µg fludrocortisone once daily.