Cushing’s Syndrome Revealing Carney Complex: A Case Report

 

Carney complex (CNC) is a rare multisystem disorder, inherited in an autosomal dominant manner and characterized by distinctive spotty skin pigmentation, myxomas and endocrine abnormalities.

We report a case of a 35-year-old patient diagnosed with Cushing’s syndrome complicated with an impaired glucose tolerance (IGT) and a severe psychiatric disturbance. The diagnosis of CNC was made by having two major criteria, namely a primary pigmented nodular adrenal disease (PPNAD) and thyroid carcinoma.

Read the entire report here: Cushing’s Syndrome Revealing Carney Complex: A Case
Report

A 12-year-old boy died from Addison’s disease after the chance of lifesaving treatment was ‘missed’

The death of a 12-year-old boy who was suffering from undiagnosed Addison’s disease was preventable, an inquest heard.

Ryan Lee Morse had been unwell from July 2012, with his parents noticing his skin darkening and him becoming lethargic and losing weight.

His condition worsened over the following months and he died during the early hours of December 8, 2012.

During the time he was unwell, Ryan’s mother, Carol Ann Morse, took him to Abernant Surgery in Abertillery several times.

She said: “Ryan was rarely ill as a child. In June 2012, which was towards the end of Ryan’s first comprehensive school year, I noticed his skin colour changing.

“His skin seemed to be getting darker.”

She said his joint areas, including elbows and knees, were getting darker. Under his eyes, it looked as if he had not slept for a month. I don’t suppose it worried me at the time because it was gradual.”

A post mortem was held on December 12 by Dr E. J. Lazda, a consultant pathologist at University Hospital of Wales in Cardiff who concluded that Ryan died as a result of Addison’s disease.

An inquest into Ryan’s death was held at Newport Coroner’s Court on Thursday.

Dr Yvette Cloette, a consultant paediatrician since 2004, was called during the early hours of December 8, 2012, by a registrar where she was told the details of Ryan’s death.

She said: “Ryan’s parents told me he had been unwell since July.

“It was thought Ryan had been particularly unwell since the Thursday before he passed away. He had to be collected from school that day. On (the) Friday morning, she said he hallucinated. His temperature did settle that afternoon but then he had diarrhoea.

“As his mum was cleaning him, she noticed his genitalia were black.

“I then examined Ryan. At this time I formed the opinion that Ryan may have had Addison’s disease. I didn’t share this with the family at the time because I didn’t have enough evidence.

“I believe that Ryan’s death was preventable. Addison’s is a disease which, once recognised, can be treated.”

She said it was easier to put things together retrospectively, as opposed to when treating an acute illness as a GP.

David Bowen, senior coroner for Gwent, paid tribute to Ryan’s family during the hearing.

“Before summing up, I think it’s right that I pay tribute to the dignity that has been shown by Mrs Morse and her family.

“It can’t have been easy for them to rehear events that took place over five years ago.

“Please accept my belated condolences.”

Mr Bowen told the inquest that Ryan had been fit and well up until July 2012.

“However at about that time, his parents began to notice a gradual change in his skin and a fluctuation in his general health.”

He had been diagnosed with a viral infection and prescribed Paracetamol, he said.

Over the next six to eight weeks, he did not improve.

Mr Bowen said: “Consequently, his mother took him back to the doctor. The GP was more concerned about the rash, it seems to me, than any of the other symptoms.

“He prescribed tablets and cream for that condition.”

Mr Bowen said that during October and November 2012, “Ryan’s health became much more of a concern for his parents.”

He suffered from headaches, pains in his legs, and occasional episodes of projectile vomiting.

On November 7, Mrs Morse took Ryan back to the GP surgery, where she described symptoms to Dr Rudling, who took samples of blood.

On November 21, they returned to receive the blood test results.

The results revealed a “slightly lower than normal” white blood cell count. The inquest heard Ryan was told he was still suffering from a viral infection that had been diagnosed some months earlier.

Mr Bowen said: “It appears that about this time, there was an outbreak of Norovirus or vomiting and sickness in the area that may have confused the diagnosis.”

Mrs Morse said: “I’d been told to bring Ryan back in January so I thought I would just get Christmas out of the way and take him back. I’d been a carer for 9-10 years but my job didn’t give me any insight into what Ryan had.”

On November 29, 2012, Ryan returned to school, but around a week later on December 6 he was so ill that his mum had to collect him early.

The following day, on December 7, Mrs Morse rang Abernant Surgery saying she needed to speak to a doctor.

Between 8.50am and 8.55am, she received a call from Dr Lyndsey Elizabeth Thomas.

Mrs Morse said: “She asked if he’d been given Paracetamol and I explained he wouldn’t take it. She asked what his temperature was like.

“I’d said Ryan was awake (that morning) and talking rubbish.”

The inquest heard Mrs Morse was asked to take Ryan to the surgery, but she said she was unable to.

“She then told me to give Ryan some dissolvable Paracetamol and see how it goes until dinner. She said fetch him up if you need to.”

Dr Lyndsey Elizabeth Thomas said her contact with Ryan was limited to a single telephone conversation with his mother on December 7.

She said: “I considered whether Ryan needed to be seen or admitted to hospital.

“I clearly recall explaining that if she had any concerns or if Ryan’s delirium or temperature didn’t improve in two hours, he would need to be seen, I would be able to go and visit him at the end of the morning surgery if necessary.”

Mrs Morse said she later noticed that her son’s genitals were black.

She rang the surgery and was put her through to Dr Rudling.

Mrs Morse said: “She said ‘it’s all to do with his hormones’. Phone Monday and we’ll fit him in. At this point I didn’t know what to think.

“I was thinking I’ll take him in on Monday and see what they say. There was no more temperature, no more sickness and no more diarrhoea.”

The inquest heard Dr Joanne Louise Rudling, who qualified in 1993, joined Abernant in August 2011.

She said her first contact with Ryan was in November 2012.

On December 7, Dr Rudling said the receptionist took a call from Ryan’s mother while she was in reception.

Dr Rudling said: “I decided to speak to Ryan’s mother in reception there and then.

“She also asked if this could be age related, I said it could be but I would have to examine him first.

“The impression I got was Ryan was improving. His mother was concerned about the darkening of his genitalia.”

Ryan’s father said goodnight around 10.15pm and went to bed. At around 11.10pm Mrs Morse could see Ryan had fallen asleep, and went to sleep herself at around 11.30pm.

She said: “I woke up and saw it was 4.10am and then I looked at Ryan and looking at his chest could see he wasn’t breathing.

“I started to do chest compressions, dialled 999, continued chest compressions until the paramedics arrived. They took over. They told me Ryan had died.”

Mr Bowen said: “This is a rare but natural disease, one which apparently GPs will not normally encounter.

“Unfortunately, neither doctor nor parents thought it necessary to refer Ryan to hospital, where the true nature of his illness may have been diagnosed.”

Recording a narrative conclusion, Mr Bowen said Ryan died of natural causes.

He said: “The opportunity to administer life-saving treatment was missed.”

Speaking after the inquest, Ryan’s sister Christina Morse said: “First of all I would like to thank everyone involved with Ryan and Ryan’s case.

“Today, after five long years, the coroner has come to the conclusion that Ryan’s death was due to natural causes and that Ryan’s death was preventable.”

From http://www.walesonline.co.uk/news/wales-news/boy-died-addisons-disease-after-13687355

Massachusetts Hospital Opens New Neurosurgery Program

Please let us know your experiences with this new program!

 

Hallmark Health and Tufts Medical Center have established a new neurosurgery program at Melrose-Wakefield Hospital to bring advanced care and services to the community. Fellowship-trained neurosurgeon Mina G. Safain, MD, has been jointly hired by Hallmark Health and Tufts Medical Center to lead the new program. He will provide care at both Melrose-Wakefield Hospital and Tufts Medical Center.

The neurosurgery program is an example of clinical integration of services between Hallmark Health and Tufts Medical Center since Hallmark Health joined Wellforce as a third founding member this past January. At that time, leaders from the organizations discussed finding ways to bring specialized care traditionally performed at academic medical centers into the community hospital setting for the benefit and convenience of patients.

“Offering neurosurgery provides a service for our patients that few community hospitals can offer,” said Steven Sbardella, MD, chief medical officer at Hallmark Health. “Our clinical relationship with Tufts Medical Center enables us to bring more highly specialized care options to our patients.”

“We are extremely excited to work with the physicians at Melrose-Wakefield Hospital and look forward to increasing the services available to care for patients with neurologic diseases,” said Carl Heilman, MD, neurosurgeon-in-chief at Tufts Medical Center. “Dr. Safain is an exceptionally talented and compassionate neurosurgeon and the perfect person to spearhead the launch of this new program.”

Dr. Safain’s clinical interests include all diseases affecting the brain, spine and peripheral nervous system.  He has specific interests in minimal access procedures for degenerative, infectious and oncologic spine disorders, as well as minimally invasive treatments for brain tumors, including neuro-endoscopy.

“The opportunity to practice in the community is very important to me,” said Dr. Safain. “I look forward to working with the esteemed staff and providers at Melrose-Wakefield Hospital and Lawrence Memorial Hospital and treating the patients in the surrounding communities.”

“Welcoming such a highly-respected neurosurgeon as Mina Safain to our team is a tremendous benefit for our communities and patients across our system including Lawrence Memorial Hospital in Medford and Melrose-Wakefield Hospital,” said Dr. Sbardella.

Dr. Safain, together with Ran Ku, PA, a neurosurgery physician assistant with more than 12 years of experience, will provide neurosurgery coverage and expertise five days a week.

Dr. Safain received his medical degree from Yale University School of Medicine.  He completed his neurosurgery residency at Tufts Medical Center serving as chief resident during his final year.  Dr. Safain also completed fellowship training in pituitary and neuro-endoscopic surgery at Brigham and Women’s Hospital.

Dr. Safain has published and presented nationally on a range of topics related to neurosurgical diseases and minimally invasive treatments for brain tumors.

From https://www.hallmarkhealth.org/Neurosurgery-program-established-at-Melrose-Wakefield-Hospital.html

Crinetics Pharmaceuticals Awarded Two SBIR Grants to Develop New Therapeutics for Congenital Hyperinsulinism and Cushing’s Disease

SAN DIEGO, Sept. 06, 2017 (GLOBE NEWSWIRE) — Crinetics Pharmaceuticals, Inc., a rare disease therapeutics company focused on endocrine disorders and endocrine-related cancers, announced today that it was awarded two new grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) that could total $2.4 million. Both are Small Business Innovation Research (SBIR) grants and include a Fast Track grant for up to $2.1 million and a Phase I grant of $0.3 million, which will be used for the development of Crinetics’ nonpeptide, oral somatostatin agonists for congenital hyperinsulinemia, and the discovery of novel small molecule drugs for Cushing’s disease, respectively.

“We are delighted with the NIH’s continuing support of our programs to develop new drugs for patients with rare endocrine disorders,” said Stephen Betz, Ph. D., Founder and Vice President of Biology of Crinetics. “These awards will enable us to advance our efforts in both hyperinsulinemia and Cushing’s disease, expanding our pipeline to include these diseases with significant unmet medical needs, and bring these treatments to the patients who need them.”

Presently, there are no medical therapies that were specifically developed to treat the life-threatening chronic hypoglycemia precipitated by congenital hyperinsulinism (CHI). The current options for patients are limited to drugs developed for other purposes in the hope that they might help. Despite their poor profiles, these drugs are prescribed because the next line of treatment is typically a partial or full pancreatectomy. Even when successful, patients who undergo the surgery often become diabetic and must actively manage glucose with multiple daily insulin injections for the rest of their lives.

Similarly, first line treatments for Cushing’s disease are surgical and involve removal of either the ACTH-secreting tumor in the pituitary or the adrenal glands themselves. As this is often unsuccessful, contraindicated or delayed, medical therapy for these patients becomes necessary. Current treatment options include inhibitors of steroid synthesis enzymes that can prevent the production of cortisol and improve symptoms, but these treatments also induce a host of unwanted side effects due to the accumulation of other steroid products.

About Congenital Hyperinsulinism (CHI)

Hyperinsulinemic hypoglycemia (HH) is one of the most frequent causes of persistent hypoglycemia in infants and can result in seizures, developmental delays, learning disabilities, and even death. The most severe form of HH is inherited and referred to as CHI. CHI largely results from mutations in key genes in the insulin secretion pathway in the islets of Langerhans in the pancreas.

About Cushing’s Disease

Clinical signs of Cushing’s syndrome include growth of fat pads (collarbone, back of neck, face and trunk), excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disturbances resulting in high morbidity. If inadequately controlled in its severe forms, Cushing’s syndrome is associated with high mortality. The most common form of Cushing’s syndrome is Cushing’s disease which is caused by microadenomas of pituitary corticotropic cells that secrete excess adrenocorticotropic hormone (ACTH).

About the NIDDK

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. For more information about the NIDDK and its programs, visit www.niddk.nih.gov.

About Crinetics Pharmaceuticals

Crinetics Pharmaceuticals discovers and develops novel therapeutics targeting peptide hormone receptors for the treatment of rare endocrine disorders and endocrine-related cancers. Crinetics was founded by a team of scientists with a proven track record of endocrine drug discovery and development to create important new therapeutic options for endocrinologists and their patients. The company is backed by top life sciences investors, 5AM Ventures, Versant Ventures, and Vivo Capital and is headquartered in San Diego. For more information, please visit www.crinetics.com.

More: http://www.pharmiweb.com/pressreleases/pressrel.asp?ROW_ID=241628#.WbFJGNN97-Y

The burden of Cushing’s disease: clinical and health-related quality of life aspects


Thanks to Robin Ess for the easy to read chart!

Abstract

Objective Cushing’s disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD.

Design Studies published in English were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, health-related quality of life (HRQoL), treatment outcomes, mortality, prevalence of comorbidities at diagnosis, and reversibility of comorbidities following the treatment.

Methods A two-stage literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD: i) articles published from 2000 to 2012 were identified and ii) an additional hand search (all years) was conducted on the basis of bibliography of identified articles.

Results At the time of diagnosis, 58–85% of patients have hypertension, 32–41% are obese, 20–47% have diabetes mellitus, 50–81% have major depression, 31–50% have osteoporosis, and 38–71% have dyslipidemia. Remission rates following transsphenoidal surgery (TSS) are high when performed by expert pituitary surgeons (rates of 65–90%), but the potential for relapse remains (rates of 5–36%). Although some complications can be partially reversed, time to reversal can take years. The HRQoL of patients with CD also remains severely compromised after remission.

Conclusions These findings highlight the significant burden associated with CD. As current treatment options may not fully reverse the burden of chronic hypercortisolism, there is a need for both improved diagnostic tools to reduce the time to diagnosis and effective therapy, particularly a targeted medical therapy.

Introduction

Cushing’s disease (CD) is a rare condition caused by a pituitary adenoma that secretes excess ACTH (1), which promotes excess cortisol production from the adrenal glands. Excess cortisol induces a clinical phenotype that harbors all components of the metabolic syndrome, such as central obesity, diabetes mellitus, dyslipidemia, and hypertension, as well as muscle weakness, hirsutism, increased bruisability, psychological dysfunction, and osteoporosis (1234567891011).

Patients with CD experience a significant clinical burden due to comorbidities, increased mortality, and impaired health-related quality of life (HRQoL) due to prolonged exposure to elevated cortisol levels (3511121314151617181920). In particular, patients with CD often experience severe fatigue and weakness, physical changes, emotional instability, depression, and cognitive impairments, which have a profound impact on daily life (1321).

Although there have been several consensus statements published recently on the definition of remission, diagnosis, and the management of CD, the severity and diversity of the clinical scenario and associated morbidities continue to present a management challenge (12223). Additionally, there is recent evidence of persistent deleterious effects after remission, most notably persistent elevated cardiovascular risk (322). The main objective of the current literature review is to describe the current burden of the disease and to summarize data on specific aspects of this burden, which underscores the need for improved diagnostic and therapeutic approaches.

Materials and methods

Available literature were evaluated to address questions regarding the epidemiology of CD, time to diagnosis, mortality, prevalence of comorbidities at diagnosis, reversibility of comorbidities after treatment (in particular, after disease remission), outcomes and complications of current treatment options, and HRQoL associated with CD and interventions.

The literature search was performed in Medline, EMBASE, and Science Citation Index, using keywords related to the epidemiology, treatment, and outcomes of CD. It was conducted in two stages: i) articles published between 2000 and 2012 were identified through a PubMed search using the following keywords: CD, incidence, prevalence, mortality, treatment, remission, cure, excess cortisol, outcomes, cost, QoL, morbidities, transsphenoidal surgery (TSS), adrenalectomy, radiotherapy, steroidogenesis inhibitors, ketoconazole, mitotane, aminoglutethimide, etomidate, metyrapone, pasireotide, and cortisol receptor antagonists; and ii) an additional hand search was conducted on the basis of the bibliographies of identified articles. All studies that provided data (regardless of publication year) related to these research questions were retained.

Definitions

Different criteria for defining the remission of hypercortisolism have been proposed, ranging from the occurrence of definitive or transient postoperative hypocortisolemia to the adequate suppression of cortisol after dexamethasone administration. According to a recent consensus statement (23), persistent postoperative morning serum cortisol levels of <2 μg/dl (∼50 nmol/l) are associated with remission and a low recurrence rate of ∼10% at 10 years. Persistent serum cortisol levels above 5 μg/dl (∼140 nmol/l) for up to 6 weeks following surgery require further evaluation. When serum cortisol levels are between 2 and 5 μg/dl, the patient can be considered in remission and can be observed without additional treatment for CD. A subset of patients can even develop complete adrenal insufficiency (serum cortisol levels below 2 μg/dl (∼50 nmol/l)) up to 12 weeks postsurgery (2425). Therefore, repeated evaluation in the early postoperative period is recommended. However, long-term follow-up is necessary for all patients because no single cortisol cutoff value excludes those who later experience disease recurrence, and up to 25% of patients develop a recurrent adenoma within 10 years after surgery (262728).

Results

Incidence and prevalence of CD

Although epidemiologic data on CD are limited, several population-based studies indicate an incidence of 1.2–2.4 per million (1419) and the prevalence of diagnosed cases to be ∼39 per million population (14). Lindholm et al(19) used the case definition as either the presence of a corticotroph adenoma or remission after neurosurgery, which yielded an estimated incidence rate of 1.2–1.7 per million per year. Etxabe & Vazquez (14) reported an incidence of 2.4 per million in Vizcaya, Spain. A large-scale retrospective survey carried out in New Zealand by Bolland et al(29) found the approximate prevalence of all forms of Cushing’s syndrome (CS) (the majority of these cases were of pituitary origin) to be 79 per million and the incidence to be 1.8 per million per year. Differences in epidemiologic estimates may be attributable to varying case definitions (for instance, the study by Lindholm excluded cases in which the adenoma could not be localized or those that could not achieve remission from surgery), geographical differences, and temporal effects. The prevalence of CD may be underestimated due to unrecognized patients with mild symptoms and patients with a cyclic form of CD (30).

Time to diagnosis

Data on the time from onset of symptoms to diagnosis are also limited. In a prospective study by Flitsch et al(31) of 48 patients with pituitary adenomas, including 19 who had ACTH-secreting adenomas causing CD, the reported time from onset of symptoms to diagnosis was 4.3 years. A study by Martinez Ruiz et al(32), which was based on only four pediatric CD patients, reported the time between onset of symptoms and diagnosis as ranging from 2.5 to 5 years. Etxabe & Vazquez (14) estimated that the average time from onset of clinical symptoms to diagnosis in 49 CD patients was 45.8±2.7 months (6–144 months), thus 3.8 years. This is corroborated by the findings from a Belgian cross-sectional study on pituitary adenomas including CD, which estimated that patients experienced symptoms for an average of 45 months before diagnosis (33). However, the reliability and generalizability of these data are limited by small sample sizes and the retrospective nature of the studies. Indeed, the New Zealand data from Bolland et al(29) report that on presentation, patients experienced symptoms for a median of 2.0 years (but ranging up to 20 years) before diagnosis. On the basis of data from the prospective European Registry on Cushing’s syndrome (ERCUSYN) (total number of patients=481, of whom 66% of patients had CD), median delay in diagnosis was 2 years (34).

Mortality in patients with CD

Mortality in patients with CD has been analyzed in several small studies, with overall rates reported as standardized mortality ratio (SMR) ranging from 1.7 to 4.8 (Table 1) (14151719). In studies in which mortality was assessed among those in remission and those with persistent disease separately, patients with persistent hypercortisolemia consistently had the highest mortality risk (15193536). In addition, TSS as a first-line treatment has been an important advance as high remission rates after initial surgery have been accompanied by mortality rates that mirror those observed in the general population (173537). In a case series from the UK, it was found that the majority of deaths occurred before 1985, which was before TSS was employed as the routine first-line treatment at the center (36). In a recent retrospective study, 80 patients undergoing TSS for CD between 1988 and 2009 were evaluated, and long-term cure (defined as ongoing absence of hypercortisolism at last follow-up) was reported in 72% of patients. However, overall elevated mortality persisted in patients (SMR 3.17 (95% CI: 1.70–5.43)), including those who achieved ‘cure’ (SMR 2.47 (95% CI: 0.80–5.77)), although even higher mortality was seen in those with postoperative recurrence/persistent disease (SMR 4.12 (95% CI: 1.12–10.54) (38). Additionally, a nationwide, retrospective study in New Zealand reported significant persistently increased mortality both in macro- and microadenomas (SMR 3.5 (1.3–7.8) and 3.2 (2.0–4.8) respectively), despite long-term biochemical remission rates of 93 and 91% of patients, respectively (29).

Read more at http://m.eje-online.org/content/167/3/311.full

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