Cushing Syndrome in Children: Growth after Surgical Cure

Posted on October 22, 2014 by MaryO

Cushing syndrome (CS) occurs only rarely in children, but when it does, it causes weight gain and stunting. In young children, adrenal tumors are usually the cause while in adolescents, pituitary tumors are more likely.

The September 2014 issue of Endocrine-Related Cancer examines growth patterns in 19 pediatric patients with ACTH-dependent CS (CD) and 18 patients with a form of ACTH-independent CS, micronodular adrenal hyperplasia (MAH). The researchers gathered data at the time of surgery and also followed up one year later.

Patients in the CD and the MAH groups had similar demographic characteristics, baseline heights and BMI scores before surgery. All patients experienced significant improvements in height and BMI after surgery. Patients with MAH, however, fared significantly better than those with CD and had better post-operative growth.

The researchers propose several reasons:

  • When ACTH-secreting pituitary adenoma requires extensive surgical exploration, remaining pituitary cells often lose some of their function.
  • CD patients tend to be older and have consistent and increased glucocorticoid exposure; they develop vertebral fractures more often leading to compromised skeletal and overall growth potential. MAH patients often have cyclical CS, with intermittent hypercortisolism and an overall milder CS.
  • CD patients often need a longer-than-expected course of therapy with steroids after surgery, which alters metabolism and growth.
  • CD patients have been shown to have advance bone age because of ACTH-induced metabolic changes.

The authors indicate that CS patients are often considered for growth hormone therapy once the underlying problem is corrected. They remind clinicians that MAH patients are less likely to need growth hormone. They recommend close monitoring for CD patients, and early intervention with growth hormone if growth does not meet expectation. –

See more at: http://www.hcplive.com/articles/Cushing-Syndrome-in-Children-Growth-after-Surgical-Cure

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Mutation of ARMC5 gene characterized as the cause of meningeal tumour growth

Posted on October 13, 2014 by MaryO

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have published their findings that mutations in a gene known as “ARMC5” promote the growth of benign tumours in the adrenal glands and on the meninges: ARMC5 appears to belong to the group of so-called tumour suppressor genes. It is the first time in years that scientists have characterized such a gene.

The ARMC5 gene was discovered by independent workgroups studying – so-called adrenal adenomas – in connection with Cushing’s syndrome. In this disease, the body produces too much of the . Now, for the first time, a mutation of ARMC5 has been characterized as the cause behind the growth of meningeal tumours. The results on this tumour syndrome, obtained by the group of Dr. Patrick May and PD. Dr. Jochen Schneider together with colleagues from Charité Berlin (Dr. Ulf Elbelt) and the Universities of Würzburg (Prof. Dr. Bruno Allolio) and Cologne (Dr. Michael Kloth), have been published recently in the Journal of Clinical Endocrinology Metabolism.

Cortisol is an important hormone. It influences many metabolic pathways in the body and has a suppressing effect on the immune system. Accordingly, it is commonly employed as an anti-inflammatory medication. Prolonged, elevated levels of cortisol in the body can lead to obesity, muscular dystrophy, depression and other symptoms. To maintain the correct concentration in the blood, the body has a refined regulation system: Certain areas of the brain produce the hormone corticotropin as a stimulator of cortisol release; the actual formation of cortisol takes place in the . As the concentration of cortisol in the blood rises, the brain reduces the production of corticotropin.

In search of the causes of Cushing’s syndrome, scientists recently encountered certain genetic causes of benign tumours of the adrenal cortex. Growth of these adrenal cortex adenomas is based on a combination of hereditary and spontaneous mutations: It affects people in whom one of two “alternative copies” – one of the so-called alleles – of the ARMC5 gene is mutated from birth. If the second allele of ARMC5 later also undergoes a spontaneous mutation in the adrenal cortex, then the gene no longer functions. “What is interesting is that the failure of ARMC5 has no direct influence on cortisol production. However, because the tumour cells multiply faster than other body cells, and the number of cells in the tumour increases, the blood cortisol level rises in the course of the disease”, says Dr Schneider. Then, the level in the body rises and ultimately results in the onset of Cushing’s syndrome.

When other scientific workgroups discovered that further benign tumours – in this case meningeal tumours – occur more often in ARMC5-Cushing families, the group of Patrick May and Jochen Schneider sequenced the ARMC5 gene and studied it using bioinformatic techniques. “We demonstrated for the first time, in a patient with an adrenal cortex tumour and simultaneously a meningeal tumour, that somatic, that is non-hereditary, ARMC5 mutations are present in both tumours. This observation suggests that ARMC5 is a true tumour-suppressor gene.”

It must now be explored, Schneider continues, to what extent patients with adrenal cortex tumours ought to be screened for simultaneous presence of meningioma, and in which other types of tumour ARMC5 mutations are responsible for tumour growth: “Building upon that, we can learn whether the gene and the metabolic pathways it influences offer new approaches for treating the tumour syndrome.”

Explore further: Are you carrying adrenal Cushing’s syndrome without knowing it?

More information: “Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations are Associated with both Primary Macronodular Adrenal Hyperplasia and Meningioma.” Journal of Clinical Endocrinology Metabolism, October 2014. DOI: 10.1210/jc.2014-2648

Journal reference: Journal of Clinical Endocrinology & Metabolism search and more info website

Provided by University of Luxembourg search and more info

From http://medicalxpress.com/news/2014-10-mutation-armc5-gene-characterized-meningeal.html

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Brains in jars at the Cushing Center in the Yale Medical Library

Posted on October 7, 2014 by MaryO

harvey-cushing-memorial

Sitting quietly in jars in a custom-built room at Yale’s medical library are 550 human brains. The collection once belonged to pioneering neurosurgeon Harvey Cushing, who preserved the brains from 1903 to 1932 as part of his tumor registry. When Cushing died in 1939, his undergraduate alma mater Yale inherited the brains.

Cushing was among a handful of doctors operating on the brain during the early 20th century. At the time, about a third of patients who underwent brain tumor surgery did not survive the operation. Cushing introduced practices that dramatically lowered the mortality rate, such as monitoring blood pressure during surgery and operating with a local anesthesic instead of ether. He was also the first to use x-rays to diagnose brain tumors.

 

Read the entire article here: Brains in jars at the Cushing Center in the Yale Medical Library.

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EU Looks to Okay Ketoconazole for Use in Cushing’s Syndrome

Posted on September 27, 2014 by MaryO

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting a marketing authorization for ketoconazole (Ketoconazole HRA; Laboratoire HRA Pharma) for the treatment of Cushing’s syndrome, a rare hormonal disorder sometimes called hypercortisolism.

Cushing’s syndrome is characterized by an excess of the hormone cortisol in the blood, which may be caused by a tumor. Treatment options currently available in the European Union include surgery to remove the tumor responsible for the high cortisol levels and radiotherapy, as well as several medicines that reduce the production of cortisol.

But pharmacological options remain very limited, and there is an unmet medical need for additional treatments, especially when surgery fails or for patients who cannot undergo surgery or take other medications. For this reason, the EMA’s CHMP evaluated the medicine under expedited review.

The opinion adopted by the CHMP at its September 2014 meeting is an intermediary step on Ketoconazole HRA’s path to patient access.

The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once a marketing authorization has been granted, decisions about price and reimbursement will then take place at the level of each member state considering the potential role/use of this medicine in the context of the national health system of that country.

The recommendation is that Ketoconazole HRA is to be prescribed only by physicians specialized in treating Cushing’s syndrome, as the dosing needs to be individualized for each patient.

This is because oral ketoconazole was previously suspended in the European Union for the indication it was first approved for, fungal infections, due to risk for liver injury. The US Food and Drug Administration (FDA) also decreed, at the same time, that doctors should no longer prescribe ketoconazole tablets as a first-line therapy for any fungal infection, for the same reason.

Information will be sent to healthcare professionals to allow them to advise patients and prescribe the medicine safely and effectively.

A Medicine Used Off-Label for More than 30 Years

Doctors have used ketoconazole to treat Cushing’s syndrome for more than 30 years, although it has never been authorized for this indication in the European Union. The drug is also frequently used off-label in the United States and elsewhere for this purpose.

The CHMP’s recommendation builds on information from published literature and documented off-label use in clinical practice.

At the time of the suspension of ketoconazole for fungal infections, healthcare professionals and patients were concerned that ketoconazole would no longer be available for patients with Cushing’s syndrome.

The CHMP therefore reviewed Ketoconazole HRA through accelerated assessment to facilitate patients’ access to a fully authorized medicine as soon as possible with evidence-based information for patients and doctors.

When assessing Ketoconazole HRA for the treatment of Cushing’s syndrome, the CHMP considered that “in this rare and potentially life-threatening condition, the medicine’s benefits are greater than its risks, which can be manageable in clinical practice by specific measures mitigating the risk of liver toxicity, including close monitoring of the patients’ liver function.”

In 2012, it was estimated that the disease affected approximately 46,000 people in the European Union. Cushing’s syndrome is a long-lasting condition that can be life-threatening because of its complications, including diabetes, high blood pressure, and depression.

From http://www.medscape.com/viewarticle/832399?src=rss

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