Long-Term Follow-Up of Survivors of Pediatric Cushing Disease

Objective:

Cushing disease (CD) describes the state of hypercortisolemia secondary to cortisol producing pituitary adenomas. The rarity of the disease (2-5 new cases per million, 1 out of 10 in children) and the subtle initial findings result in prolonged undiagnosed hypercortisolemia, that increases the risk for significant complications, including obesity, height deceleration, hyperlipidemia, hyperglycemia, hypertension, osteoporosis, immunodeficiency, and others. Although hypercortisolemia usually resolves after successful resection of the pituitary adenoma, the reversal of the above-mentioned complications and the long-term effects of the previous prolonged exposure of the body to supraphysiologic levels of cortisol have not been clarified, especially when hypercortisolemia occurs during childhood.

Previous studies have addressed the possible complications after resolution of hypercortisolemia, but most of them refer to adult patients. Amongst the described complications, suppression of the pituitary hormones, such as the growth and thyroid hormone axes, and persistent increase of the body mass index (BMI) and abnormal fat distribution, have been described in limited number of pediatric patients followed for a few years after cure. Other complications, such as components of the metabolic syndrome or cardiovascular dysfunction, have not been extensively studied in children. Furthermore, equally important are the long-term effects of glucocorticoids on other aspects of health. For example, it has been previously described that the neurocognitive function of children with CD declines the first year after treatment. This can potentially result in impaired quality of life, lower education level, and lower job and life satisfaction in the future; however, the long-term neurocognitive sequelae of Cushing syndrome (CS) diagnosed in childhood have not been studied.

This study aims to provide novel insight on the long-term effects of hypercortisolemia on the developing child, their underlying pathogenetic mechanisms, their evolution over time, and the risk factors for developing them. This will assist in designing methods to closely monitor or prevent them in the future. Certain results of this study could potentially apply to children with iatrogenic CS, which is much more common due to the widespread use of pharmacologic doses of glucocorticoids in malignancies, autoimmune and atopic disorders.

Study population:

The study population will consist of patients that were previously successfully treated for CD before the age of 21 years. We aim to identify these patients through review of our current protocol 97-CH-0076 on "Clinical and genetic investigation of pituitary and hypothalamic tumors", which has been recruiting patients since 1997. We will also accept patients who have been diagnosed and successfully treated for pediatric CD at outside institutions after reviewing the medical records and confirming their diagnosis. The patients must not be hypercortisolemic at the time of their recruitment. Family members (any age) of patients with a family history of pituitary tumors may participate in the DNA/linkage analysis study.

Design:

We will evaluate patients at least 3 years after documented resolution of hypercortisolemia. Patients will be evaluated at least once, with optional follow-up visit(s) if indicated.

The study will include an online survey offered to all patients, as well as an on-site short visit for those willing to travel to NIH.

The online survey will include questionnaires on assessment of various aspects of health: Current medical diagnoses, Medication use, History of endocrine disorders, Fertility, Quality of life, Behavioral and emotional symptomology, and Socioeconomic and Demographic information. The survey will be developed and distributed with the help of CTDB and will be sent with secure email to all the patients and/or their parents (for patients who are <18yo at the time of evaluation) after consent and eligibility have been confirmed.

The short on-site visit at NIH will be offered to all the patients willing to travel. Blood tests, imaging studies (MRI pituitary/brain and DXA scan), and neurocognitive screening and patient reported outcome questionnaires will be performed.

Outcome measures:

The primary outcome measure of the study is the difference of the Body Mass Index (BMI) z-score of the patients previously treated for pediatric CD compared to the general population, as calculated by data derived from the NHANES study.

The secondary outcomes will be to describe the prevalence of other endocrine and non-endocrine abnormalities after successful treatment of CD in childhood, including growth hormone, thyroid, gonadal, adrenal function; bone mineral density; glucose metabolism; lipid profile; cardiovascular abnormalities; immunologic changes; coagulation function; psychiatric diseases, behavioral symptomology; neurocognitive function; and quality of life.